Inhibitors of glycogen synthase kinase 3 for therapeutic use

Abstract

Novel compounds of Formula I and compositions thereof that are inhibitors of glycogen synthase kinase 3 beta (GSK3β). Some aspects of the invention relate to novel compounds and compositions having a better pharmacokinetic profile than previous GSK3β inhibitors, and a pharmacokinetic profile more suitable to therapeutic use. (I)

Description

INHIBITORS OF GLYCOGEN SYNTHASE KINASE 3 FOR THERAPEUTIC USECROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 512,825, filed July 10, 2023. The foregoing application is incorporated by reference herein in its entirety.FIELD OF THE INVENTION

[0002] Aspects of this invention are related to novel compositions for treating neurological disease or psychiatric disorders, including Alzheimer's disease, bipolar disorder, or depression, or neuroinflammation, or other conditions where modulation of GSK-30 signaling is clinically useful.BACKGROUND OF THE INVENTION

[0003] GSK-3 inhibitors have been proposed as a treatment of subjects having a neurological disease and / or psychiatric disorder, including Alzheimer's disease, bipolar disorder, depression, schizophrenia, Parkinsons' disease, traumatic brain injury, or for neuroinflammation. Inhibitors of GSK-3 are known to increase the expression of WNT proteins, enhancing a pathway in regenerative medicine that has been broadly proposed to treat neurological and psychiatric disorders. GSK-3 inhibition or enhancing of WNT signaling has been linked to potential treatments of type 2 diabetes, diabetic nephropathy, chronic kidney disease, atherosclerosis, alopecia, osteoarthritis, osteoporosis, alcoholic hepatitis, inflammatory bowel disease, wet age-related macular degeneration, dry age-related macular degeneration, diabetic macular edema, Fuch's dystrophy, limbal cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, Sjogren's syndrome, sensorineural hearing loss, conductive hearing loss, polycystic kidney disease, focal segmental glomerulosclerosis, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, short bowel syndrome, melanoma, pancreatic cancer, prostate cancer, colon cancer, leukemia, septic shock, and atherosclerosis. GSK-3 inhibitors have been proposed as monotherapy, in combination with lithium, and in combination with other treatments for bipolar disorder.

[0004] Highly potent and selective radioactive inhibitors of GSK30 have been developed for use in positron emission tomography (PET) as a diagnostic tool for Alzheimer's disease. PET imaging of GSK30 is also of interest as a diagnostic tool identifying cancers that express GSK3. PET imaging of GSK30 can also aid in the development of therapeutic agents. PET imaging of GSK30 in the brain could ensure adequate dosing of a GSK30 inhibitor for the treatment of a neurological or psychiatric disorder. PET imaging of GSK3P in the brain or elsewhere could ensure adequate dosing of a GSK3 inhibitor for the treatment ofcancer. The imaging could be used in animal studies as part of drug discovery, in clinical trials to establish therapeutic dose ranges, or in clinical practice to ensure optimal dosing of a therapeutic.

[0005] However, the development of highly potent and selective inhibitors of GSK30 as therapeutics has not been successful to date. One of the challenges has been safety, and development of some GSK30 inhibitors has been abandoned for safety reasons. The obstacle of developing safe GSK30 inhibitors has been described as "insurmountable." Safety issues are lower for PET imaging applications than for therapeutic use because PET studies are done only once or twice. Short-term safety data are sufficient for development of a PET ligand, and a short half-life of a compound is attractive for PET imaging because there is less of a safety issue if the imaging agent is rapidly metabolized and cleared.

[0006] PF-04802367 (also known as PF-367), an oxazole-4-carboxamide, was reported to have binding kinetics in brain tissue too fast for an effective therapeutic agent but ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. Subsequent efforts further explored optimization of oxazole carboxamides (OCMs) beyond PF-367, resulting in the greatest potency and selectivity in a compound referenced herein as OCM-51, or compound 1:

[0007] However, because of its rapid clearance, compound 1 is not suitable to serve as an inhibitor of GSK-30 for therapeutic use.BRIEF SUMMARY OF THE INVENTION

[0008] Compounds and compositions of the present invention are provided that surprisingly and unexpectedly have been found to have good potency and selectivity against GSK-30 while providing improved in vivo stability (slower clearance) that is necessary for therapeutic use. In some embodiments, the invention is directed to an inhibitor of GSK-30 for therapeutic use, having the structure of Formula I:IWherein,R1is L1-R5;R2is L2-R6; R3is H or C1-C6alkyl; R4is H or C1-C6alkyl; R5is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring or an 8- 12 membered fused bicyclic aryl or heteroaryl ring system, wherein R5is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and -(CH2)s-R11; R6is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2; R7is H, OR8or N(R8)2; each R8is independently H or -(C=O)p-(C1-C6alkyl); each R9is independently H, -(C=O)r-(C1-C6alkyl), or -(C=O)r-(CH2)x-(C3-C6cycloalkyl); each R10is independently H or C1-C6alkyl; each R11is independently H, OR12or N(R12)2; each R12is independently H or -(C=O)t-(C1-C6alkyl); each R13is independently H, -(C=O)v-(C1-C6alkyl), or S(O)2R14; each R14is independently H or C1-C6alkyl; L1is a direct link, -(CH2)n-, a 3-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring, wherein any carbon atom of L1is optionally substituted with one or two -(CH2)o-R7; L2is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2is optionally substituted with 1-2 C1-C6alkyl groups; X is O or N-R3; Y is O or N-R4; n is an integer from 1-5; o is 0 or an integer from 1-4; each p is independently 0 or 1; each q is independently 0 or 1; each r is independently 0 or 1; each s is independently 0 or an integer from 1-3;each t is independently 0 or 1; each u is independently 0 or 1; each v is independently 0 or 1; each w is independently 0 or 1; x is 0 or an integer from 1-3; and each stereogenic center is independently R, S or racemic.

[0009] The compounds in the present disclosure can also be administered in combination with lithium. The present disclosure also provides a method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful, a method of establishing an appropriate therapeutic dose of a compound of Formula I in a subject.

[0010] The present disclosure also provides a method of treating a subject with Alzheimer's disease, bipolar disorder, or depression who shows evidence of elevated GSK-3. In some embodiments, the present disclosure provides a method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful. In some embodiments, the disclosure provides a method for establishing an appropriate therapeutic dose of a compound of Formula I in a subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows a diagram of the therapeutic window for a drug on a graph of % maximum effect versus drug concentration.

[0012] FIG. 2 shows the radioactivity time curves of a related C11compound in rhesus monkey.

[0013] FIG. 3 shows the concentrations in plasma, brain and CSF hourly after injection of 50 mg / kg of a related compound in mice.

[0014] FIG. 4 shows the Intensity plotted as pCRMP2 levels remaining, normalized to b-iii-tubulin and relative to DMSO. N=4 per concentration. Cortical glutamatergic neurons were derived from induced- pluripotent stem cells and treated for 24 hours with DMSO or different molar concentrations of test compounds. Immunocytochemistry was used to measure CRMP2 and phosphorylated CRMP2 (phosphorylated at the T514 site) and b-iii-tubulin, a neuronal marker.

[0015] FIG. 5. Shows the positive appetitive ultrasonic vocalizations in the range of 50-60 kHz emitted by rats in the presence of food, upon seeing a friendly rat, or when being tickled by a familiar human, and are considered a reflection of positive affective state. N=5 rats per group. Adult male Wistar rats were treated with either saline, dextroamphetamine (AMP), Lithium 100 mg / kg followed by AMP (Li - AMP), or Compound 56 followed by AMP (Compound 56 - AMP). Compound 56 was administered at 10 mg / kgadministered via intraperitoneal injection, and the AMP was administered one hour later. The time 0-120 minutes reflects the timing of administration of AMP.DETAILED DESCRIPTION OF THE INVENTION

[0016] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0017] As disclosed herein, a number of ranges of values are provided. It is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges can independently be included or excluded in the range, and each range where either, neither, or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. The term "about" generally includes up to plus or minus 10% of the indicated number. For example, "about 10%" can indicate a range of 9% to 11%, and "about 20" can mean from 18 to 22. Preferably "about" includes up to plus or minus 6% of the indicated value. Alternatively, "about" includes up to plus or minus 5% of the indicated value. Other meanings of "about" may be apparent from the context, such as rounding off, so, for example "about 1" can also mean from 0.5 to 1.4.

[0018] The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Such salts include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'- methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiarybutylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

[0019] One problem with a short half-life in a therapeutic agent is that it may require dosing several times a day. If a compound with a short half-life is administered only once or twice a day, then the peak concentration may be many times higher than the trough concentration at the end of the dosing interval.

[0020] For example, a drug with a half-life of 24 hours can be given once a day with a peak drug concentration that is about 2 to 3 times the trough concentration. In contrast, a drug with a half-life of 6 hours, if given once a day, will have a peak concentration approximately 16 times the trough concentration.

[0021] A smaller ratio of peak to trough concentration is generally desirable as a principle of drug development because it keeps drug concentrations within the therapeutic window (see FIG. 1). The window is described by the dose response for efficacy and a dose response for toxicity. A lower peak / trough ratio helps keep a drug concentration at levels that provide efficacy throughout the dosing interval without being so high as to cause toxicity.

[0022] During the medicinal chemistry effort, there was evidence that the oxazole carboxamides that were developed have a short half-life. A compound in the program was evaluated in rhesus monkeys, where a rapid decline in radioactivity was seen, a decline more rapid than expected from the half-life of C11(see FIG. 2). Injection of 50 mg / kg of the same compound in mice also showed rapid declines in plasma and brain concentrations on an hourly basis (see FIG. 3).

[0023] While levels remained above the IC5o for the full seven hours measured, this was due to the large dose injected. Results were consistent with a peak / trough ratio of about 100 in mice for administration every 6 hours. Compounds that are potent and selective inhibitors of GSK30 will be more appropriate for therapeutic use if they have greater stability, providing a better pharmacokinetic profile that includes a lower peak / trough ratio.

[0024] For this reason, one aspect of the invention includes administration of the following compounds 2 through 38 (compound 1 is OCM-51) at a total daily dose of about 0.1 to about 4 mg / kg by injection, or about 0.125 to about 10 mg / kg administered orally.

[0025] As part of the medicinal chemistry exploration of the OCM-51 lead, compound 1, the phenyl group substitution is explored in compounds 2-10, the distal heterocycle is explored in compounds 11-17, the central carboxamide is explored in compounds 18-20, the linker is explored in compounds 21-24, andthe core heterocycle is explored in compounds 25-38. Compounds of the present invention have surprisingly and unexpectedly have been found to have good potency and selectivity against GSK-3β while providing the improved stability (slower clearance) that is necessary for therapeutic use.

[0026] Without wishing to be bound by any particular theory, one skilled in the art will recognize that ATP competitive kinase inhibitors generally interact with the “hinge region” of a given kinase. The kinase hinge region is a region critical to binding of ATP – the natural kinase substrate. Typically, the hinge region provides a hydrogen bond donor and a hydrogen bond acceptor – both being generally presented as part of the kinase protein backbone. In order to capitalize on this feature, a common strategy for the design of kinase inhibitors is to include a combination of a hydrogen bond donor and a hydrogen bond acceptor that is complementary to that of the kinase hinge region. Specifically, the hydrogen bond donor of the inhibitor will form a hydrogen bond with the hydrogen bond acceptor of the kinase hinge region. Simultaneously, the hydrogen bond acceptor of the inhibitor will form a hydrogen bond with the hydrogen bond donor of the kinase hinge region. For kinases, the hinge region is defined as the amino acid sequence connecting C-terminal lobe to the N-terminal lobe.

[0027] Hinge region binding alone is generally insufficient for development of a suitable kinase inhibiting therapeutic as all kinases possess hinge regions. In order to impart druggable characteristics of a given inhibitor, substituents on either side of the hinge binder are optimized to the structure of a specific kinase. In this way, selective inhibition can be achieved between different kinases and also between isoforms of specific kinases.

[0028] The compounds of the present invention utilize amides, amidines, acylated heteroaromatic groups, aminopyridines, aminopyrimidines and related structures as hinge region binders. One skilled in the art will recognize that additional useful functional groups and structures exist that are useful for kinase inhibitor hinge region binding.

[0029] The compounds of the present invention are generally represented by a structure of Formula I or a pharmaceutically acceptable salt thereof wherein,R1is L1-R5; R2is L2-R6; R3is H or C1-C6alkyl;R4is H or C1-C6alkyl; R5is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring or an 8- 12 membered fused bicyclic aryl or heteroaryl ring system, wherein R5is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and -(CH2)s-R11; R6is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2; R7is H, OR8, or N(R8)2; each R8is independently H or -(C=O)p-(C1-C6alkyl); each R9is independently H, -(C=O)r-(C1-C6alkyl), or -(C=O)r-(CH2)x-(C3-C6cycloalkyl); each R10is independently H or C1-C6alkyl; each R11is independently H, OR12or N(R12)2; each R12is independently H or -(C=O)t-(C1-C6alkyl); each R13is independently H, -(C=O)v-(C1-C6alkyl), or S(O)2R14; each R14is independently H or C1-C6alkyl; L1is a direct link, -(CH2)n-, a 3-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring, wherein any carbon atom of L1is optionally substituted with one or two -(CH2)o-R7; L2is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2is optionally substituted with 1-2 C1-C6alkyl groups; X is O or N-R3; Y is O or N-R4; n is an integer from 1-5; o is 0 or an integer from 1-4; each p is independently 0 or 1; each q is independently 0 or 1; each r is independently 0 or 1; each s is independently 0 or an integer from 1-3; each t is independently 0 or 1; each u is independently 0 or 1;each v is independently 0 or 1; each w is independently 0 or 1; x is 0 or an integer from 1-3; and each stereogenic center is independently R, S or racemic.

[0030] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. In at least some embodiments, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0031] An "alkyl" group refers, in one embodiment, to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. The alkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

[0032] In one embodiment, the term "halogen" refers, in one embodiment to F, in another embodiment to Cl, in another embodiment to Br, and in another embodiment to I.

[0033] A "cycloalkyl" group refers, in one embodiment, to a saturated or non-saturated hydrocarbon ring. In one embodiment, the cycloalkyl group has 3-12 carbons. In some embodiments, the cycloalkyl group has 3- 8 carbons. In some embodiments, the cycloalkyl group has 4-8 carbons. In another embodiment, the cycloalkyl group comprise of 2-3 fused rings. The cycloalkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl. The carbocyclic ring may be substituted by one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

[0034] A "heterocyclic" group refers, in one embodiment, to a ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. In another embodiment, the heterocyclic group is a 3-12 membered ring. In another embodiment the heterocyclic group is a 6 membered ring. In another embodiment, the heterocyclic group is a 5-7 membered ring. In anotherembodiment, the heterocyclic group is a 4-8 membered ring. In another embodiment, the heterocyclic group may be unsubstituted or substituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl. In another embodiment, the heterocyclic group may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In another embodiment, the heterocyclic group is a saturated ring. In another embodiment, the heterocyclic ring is an unsaturated ring.

[0035] An "aryl" group refers, in one embodiment, to an aromatic ring structure comprising 6-14 carbon atoms. In one embodiment, the aryl group has 6 carbons. In another embodiment, the aryl group has 12 carbons. In another embodiment, the aryl group has 14 carbon atoms. The aryl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl. The carbocyclic ring may be substituted by one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

[0036] A "heteroaryl" group refers, in one embodiment, to an aromatic ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. In another embodiment, the heteroaryl group is a 5-14 membered ring. In another embodiment, the heteroaryl group is a 5 membered ring. In another embodiment, the heteroaryl group is a 6 membered ring. In another embodiment, the heteroaryl group is a bicyclic ring structure containing 9 atoms. In another embodiment, the heteroaryl group is a bicyclic ring structure containing 10 atoms. In another embodiment, the heteroaryl group is a bicyclic ring structure containing 14 atoms. The heteroaryl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl. The carbocyclic ring may be substituted by one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

[0037] A "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like.

[0038] Reference to disorders comprising "aberrant signaling" of GSK-3 or GSK-3 beta means that the disorder type is one associated with abnormal regulation and expression of the GSK-3 or GSK-3 beta enzyme by the corresponding gene encoding the enzyme, or where the disorder is associated with a biomarker (such as a blood test, tumor biopsy result, or PET imaging study) indicating increased GSK-3 or GSK-3 beta activity.

[0039] The term "subject" as used herein is intended to include human and non-human animals. Nonhuman animals include all vertebrates, e.g. mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non- human primates, sheep, dogs, cats, cows and horses.

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds thatdiffer only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0042] At least one embodiment of the present invention provides a structure of Formula I or a pharmaceutically acceptable salt thereof wherein, 11R is L -R5; R2is L2-R6; R3is H or C1-C6alkyl; R4is H or C1-C6alkyl; R5is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring or an 8- 12 membered fused bicyclic aryl or heteroaryl ring system, wherein R5is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and -(CH2)s-R11; R6is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2; R7is H, OR8or, N(R8)2; each R8is independently H or -(C=O)p-(C1-C6alkyl); each R9is independently H, -(C=O)r-(C1-C6alkyl), or -(C=O)r-(CH2)x-(C3-C6cycloalkyl); each R10is independently H or C1-C6alkyl; each R11is independently H, OR12or N(R12)2; each R12is independently H or -(C=O)t-(C1-C6alkyl); each R13is independently H, -(C=O)v-(C1-C6alkyl), or S(O)2R14; each R14is independently H or C1-C6 alkyl;L1is a direct link, -(CH2)n-, a 3-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring, wherein any carbon atom of L1is optionally substituted with one or two -(CH2)o-R7; L2is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2is optionally substituted with 1-2 C1-C6alkyl groups; X is O or N-R3; Y is O or N-R4; n is an integer from 1-5; o is 0 or an integer from 1-4; each p is independently 0 or 1; each q is independently 0 or 1; each r is independently 0 or 1; each s is independently 0 or an integer from 1-3; each t is independently 0 or 1; each u is independently 0 or 1; each v is independently 0 or 1; each w is independently 0 or 1; x is 0 or an integer from 1-3; and each stereogenic center is independently R, S or racemic.

[0043] At least some embodiments of the present invention further provide a method for preparing a structure of Formula I, pharmaceutical compositions comprising a structure of Formula I and methods of using a structure of Formula I to treat various disorders characterized by aberrant signaling of GSK-3.

[0044] As defined generally above, R1is L1-R5.

[0045] As defined generally above, R2is L2-R6.

[0046] As defined generally above, R3is H or C1-C6alkyl. In some embodiments, R3is H. In some embodiments, R3is C1-C6alkyl.

[0047] As defined generally above, R4is H or C1-C6alkyl. In some embodiments, R4is H. In some embodiments, R4is C1-C6alkyl.

[0048] As defined generally above, R5is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6- membered heteroaryl ring or an 8-12 membered fused bicyclic aryl or heteroaryl ring system, wherein R5is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and -(CH2)s-R11. In someembodiments, R5is a 5-membered heteroaryl ring. In some embodiments, R5is a 6-membered aryl ring, a 6-membered heteroaryl ring. In some embodiments, R5is a 6-membered heteroaryl ring. In some embodiments, R5is an 8-12 membered fused bicyclic aryl or heteroaryl ring system. In some embodiments, R5is unsubstituted. In some embodiments, R5is substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and -(CH2)s-R11.

[0049] As defined generally above, R6is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6- membered heteroaryl ring, wherein R6is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2. In some embodiments, R6is a 5-6 membered heteroaryl ring. In some embodiments, R6is a 6-membered aryl ring. In some embodiments, R6is a 6-membered heteroaryl ring. In some embodiments, R6is unsubstituted. In some embodiments, R6substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2.

[0050] As defined generally above, R7is H, OR8or N(R8)2. In some embodiments, R7is H. In some embodiments, R7is OR8. In some embodiments, R7is N(R8)2.

[0051] As defined generally above, each R8is independently H or -(C=O)p-(C1-C6alkyl). In some embodiments, at least one of R8is H. In some embodiments, at least one of R8is -(C=O)p-(C1-C6alkyl). In some embodiments, each R8is the same. In some embodiments, each R8is different.

[0052] As defined generally above, each R9is independently H, -(C=O)r-(C1-C6alkyl), or -(C=O)r-(CH2)x- (C3-C6cycloalkyl). In some embodiments, at least one of R9is H. In some embodiments, at least one of R9is -(C=O)r-(C1-C6alkyl). In some embodiments, at least one of R9is -(C=O)r-(CH2)x-(C3-C6cycloalkyl). In some embodiments, at least two of R9are H. In some embodiments, at least two of R9are -(C=O)r-(C1-C6alkyl). In some embodiments, at least two of R9is -(C=O)r-(CH2)x-(C3-C6cycloalkyl). In some embodiments, each R9is the same. In some embodiments, each R9is different.

[0053] As defined generally above, each R10is independently H or C1-C6alkyl. In some embodiments, at least one of R10is H. In some embodiments, at least one of R10is C1-C6alkyl. In some embodiments, at least two of R10are H. In some embodiments, at least two of R10are C1-C6alkyl. In some embodiments, each R10is the same. In some embodiments, each R10is different.

[0054] As defined generally above, each R11is independently H, OR12or N(R12)2. In some embodiments, at least one of R11is H. In some embodiments, at least one of R11is OR12. In some embodiments, at least one of R11is N(R12)2. In some embodiments, at least two of R11are H. In someembodiments, at least two of R11are OR12. In some embodiments, at least two of R11are N(R12)2. In some embodiments, each R11is the same. In some embodiments, each R11is different.

[0055] As defined generally above, each R12is independently H or -(C=O)t-(C1-C6alkyl). In some embodiments, at least one of R12is H. In some embodiments, at least one of R12is -(C=O)t-(C1-C6alkyl). In some embodiments, each R12is the same. In some embodiments, each R12is different.

[0056] As defined generally above, each R13is independently H, -(C=O)v-(C1-C6alkyl), or S(O)2R14. In some embodiments, at least one of R13is H. In some embodiments, at least one of R13is -(C=O)v-(C1-C6alkyl). In some embodiments, at least one of R13is S(O)2R14. In some embodiments, at least two of R13are H. In some embodiments, at least two of R13are -(C=O)v-(C1-C6alkyl). In some embodiments, at least two of R13are S(O)2R14. In some embodiments, each R13is the same. In some embodiments, each R13is different.

[0057] As defined generally above, each R14is independently H or C1-C6alkyl. In some embodiments, at least one of R14is H. In some embodiments, at least one of R14is C1-C6alkyl. In some embodiments, at least two of R14are H. In some embodiments, at least two of R14are C1-C6alkyl. In some embodiments, each R14is the same. In some embodiments, each R14is different.

[0058] As defined generally above, L1is a direct link, -(CH2)n-, a 3-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring, wherein any carbon atom of L1is optionally substituted with -(CH2)o-R7. In some embodiments, L1is a direct link. In some embodiments, L1is -(CH2)n-. In some embodiments, L1is a 3-7 membered cycloalkyl ring. In some embodiments, L1is a 4-7 membered heterocyclic ring. In some embodiments, L1is a 6 membered aryl ring. In some embodiments, L1is unsubstituted. In some embodiments, any carbon atom of L1is may be substituted with one or two -(CH2)o-R7.

[0059] As defined generally above, L2is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2is optionally substituted with 1-2 C1-C6alkyl groups. In some embodiments, L2is a 5-6 membered heteroaryl ring. In some embodiments, L2is a 6-membered aryl ring. In some embodiments, L2is a 6-membered heteroaryl ring. In some embodiments, L2is unsubstituted. In some embodiments, L2is substituted with 1-2 C1-C6alkyl groups.

[0060] As defined generally above, X is O or N-R3. In some embodiments, X is O. In some embodiments, X is N-R3.

[0061] As defined generally above, Y is O or N-R4. In some embodiments, Y is O. In some embodiments, Y is N-R4.

[0062] As defined generally above, n is an integer from 1-5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0063] As defined generally above, o is 0 or an integer from 1-4. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

[0064] As defined generally above, each p is independently 0 or 1. In some embodiments, at least one of p is 0. In some embodiments, at least one of p is 1. In some embodiments, each p is the same. In some embodiments, each p is different.

[0065] As defined generally above, each q is independently 0 or 1. In some embodiments, at least one of q is 0. In some embodiments, at least one of q is 1. In some embodiments, at least two of q are 0. In some embodiments, at least two of q are 1. In some embodiments, each q is the same. In some embodiments, each q is different.

[0066] As defined generally above, each r is independently 0 or 1. In some embodiments, at least one of r is O. In some embodiments, at least one of r is 1. In some embodiments, at least two of r are 0. In some embodiments, at least two of r are 1. In some embodiments, each r is the same. In some embodiments, each r is different.

[0067] As defined generally above, each s is independently 0 or an integer from 1-3. In some embodiments, at least one of s is 0. In some embodiments, at least one of s is 1. In some embodiments, at least one of s is 2. In some embodiments, at least one of s is 3. In some embodiments, each 3 is the same. In some embodiments, each 3 is different.

[0068] As defined generally above, each t is independently 0 or 1. In some embodiments, at least one of t is O. In some embodiments, at least one of t is 1. In some embodiments, at least two of t are 0. In some embodiments, at least two of t are 1. In some embodiments, each t is the same. In some embodiments, each t is different.

[0069] As defined generally above, each u is independently 0 or 1. In some embodiments, at least one of u is 0. In some embodiments, at least one of u is 1. In some embodiments, at least two of u are 0. In some embodiments, at least two of u are 1. In some embodiments, each u is the same. In some embodiments, each u is different.

[0070] As defined generally above, each v is independently 0 or 1. In some embodiments, at least one of v is O. In some embodiments, at least one of v is 1. In some embodiments, at least two of v are 0. Insome embodiments, at least two of v are 1. In some embodiments, each v is the same. In some embodiments, each v is different.

[0071] As defined generally above, each w is independently 0 or 1. In some embodiments, at least one of w is 0. In some embodiments, at least one of w is 1. In some embodiments, at least two of w are 0. In some embodiments, at least two of w are 1. In some embodiments, each w is the same. In some embodiments, each w is different.

[0072] As defined generally above, each x is independently 0 or and integer from 1-3. In some embodiments, at least one of x is 0. In some embodiments, at least one of x is 1. In some embodiments, at least one of x is 2. In some embodiments, at least one of x is 3. In some embodiments, at least two of x are 0. In some embodiments, at least two of x are 1. In some embodiments, at least two of x are 2. In some embodiments, at least two of x are 3. In some embodiments, each x is the same. In some embodiments, each x is different.

[0073] As defined generally above, each stereogenic center is independently either R or S. In some embodiments, at least one stereogenic center is R and at least one stereogenic center is S. In some embodiments, at least two stereogenic centers are R and the other stereogenic centers are S. In some embodiments, at least two stereogenic centers are S and the other stereogenic centers are R.

[0074] Another aspect of this invention relates to a method of preparing a compound of Formula I or a pharmaceutically acceptable salt thereofwherein, R1is L1-R5; R2is L2-R6; R3is H or C1-C6alkyl; R4is H or C1-C6alkyl; R5is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring or an 8- 12 membered fused bicyclic aryl or heteroaryl ring system, wherein R5is optionally substituted with 1-3 groups independently selected from –(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and –(CH2)s-R11;R6is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6is optionally substituted with 1-3 groups independently selected from –(C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2; R7is H, OR8,or N(R8)2; each R8is independently H or –(C=O)p-(C1-C6alkyl); each R9is independently H, -(C=O)r-(C1-C6alkyl), or –(C=O)r-(CH2)x-(C3-C6cycloalkyl); each R10is independently H or C1-C6alkyl; each R11is independently H, OR12or N(R12)2; each R12is independently H or –(C=O)t-(C1-C6alkyl); each R13is independently H, -(C=O)v-(C1-C6alkyl), or S(O)2R14; each R14is independently H or C1-C6alkyl; L1is a direct link, -(CH2)n-, a 3-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring, wherein any carbon atom of L1is optionally substituted with – (CH2)o-R7; L2is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2is optionally substituted with 1-2 C1-C6alkyl groups; X is O or N-R3; Y is O or N-R4; n is an integer from 1-5; o is 0 or an integer from 1-4; each p is independently 0 or 1; each q is independently 0 or 1; each r is independently 0 or 1; each s is independently 0 or an integer from 1-3; each t is independently 0 or 1; each u is independently 0 or 1; each v is independently 0 or 1; each w is independently 0 or 1 x is 0 or an integer from 1-3; and each stereogenic center is independently R, S or racemic; Comprising the steps of:(1) Reacting a compound of Formula II with a compound of Formula IV, wherein; a. A compound of Formula II is used without modification, or b. A compound of Formula II is converted to a carboxylic acid; and (2) Removing a protecting group from a compound of Formula IV if a protecting group is present; or Comprising the steps of: (1) Reacting a compound of Formula III with a compound of Formula IV; and (2) Removing a protecting group from a compound of Formula IV if a protecting group is present; or wherein, all substitutions are defined according to a structure of Formula I, and wherein, R15is H, C1-C6alkyl or -(CH2)w-R16; R16is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R16is optionally substituted with 1-5 groups independently selected from F, NO2and OCH3; R17is a protecting group selected from the list comprising but not limited to acetyl, benzoyl, 4- nitrobenzoyl, benzyl, p-methoxybenzyl, tolyl, trityl, methoxymethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl dimethylsilyl, tert-butyl diphenylsilyl, tert-butyl carbamoyl (Boc), fluorenylmethylcarbamoyl (Fmoc) and benzylcarbamoyl (Cbz). w is 0 or 1.

[0075] As defined generally above, R15is H, C1-C6alkyl or -(CH2)w-R16. In some embodiments, R15is H. In some embodiments, R15is C1-C6alkyl. In some embodiments, R15is -(CH2)w-R16.

[0076] As defined generally above, R16is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R16is optionally substituted with 1-5 groups independently selected from F, NO2 and OCH3. In some embodiments, R16is a 5-membered heteroaryl group. In some embodiments, R16is a 6-membered aryl group optionally substituted with 1-5 groups independently selected from F, NO2and OCH3. In some embodiments, R16is a 6-membered heteroaryl group, wherein, R16is optionally substituted with 1-5 groups independently selected from F, NO2and OCH3.

[0077] As defined generally above, R17is a protecting group selected from the list comprising but not limited to acetyl, benzoyl, 4-nitrobenzoyl, benzyl, p-methoxybenzyl, tolyl, trityl, methoxymethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl dimethylsilyl, tert-butyl diphenylsilyl, tert-butyl carbamoyl (Boc), fluorenylmethylcarbamoyl (Fmoc) and benzylcarbamoyl (Cbz). In some embodiments,R17is acetyl. In some embodiments, R17is benzoyl. In some embodiments, R17is 4-nitrobenzoyl. In some embodiments, R17is benzyl. In some embodiments, R17is p-methoxybenzyl. In some embodiments, R17is tolyl. In some embodiments, R17is trityl. In some embodiments, R17is methoxymethyl. In some embodiments, R17is trimethylsilyl. In some embodiments, R17is triethylsilyl. In some embodiments, R17is triisopropylsilyl. In some embodiments, R17is tert-butyl dimethylsilyl. In some embodiments, R17is tertbutyl diphenylsilyl. In some embodiments, R17is tert-butyl carbamoyl (Boc). In some embodiments, R17is fluorenylmethylcarbamoyl (Fmoc). In some embodiments, R17is benzylcarbamoyl (Cbz). In some embodiments, In some embodiments, R17is a suitable protecting group for a hydroxyl functional group. In some embodiments, R17is a suitable protecting group for an amine functional group. One of ordinary skill in the art will recognize that there are multiple options for suitable protecting groups for hydroxyl groups and amines. Such options are generally available in the relevant literature and represented in books such as "Protective Groups in Organic Synthesis" (Wiley, Greene and Wuts).

[0078] As defined generally above, w is 0 or 1. In some embodiments, w is 0. In some embodiments, w is 1.

[0079] One of ordinary skill in the art will recognize that the combination of a structure of Formula II with a structure of Formula IV will form an ester or an amide linkage. One of ordinary skill in the art will recognize that esters and amides are formed by combining carboxylic acids with alcohols or amines using various coupling reagents including, but not limited to, isobutylchloroformate, DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU, T3P and DSC. One of ordinary skill in the art will further recognize that such coupling reactions are often facilitated by amine bases including, but not limited to, triethylamine, diisopropyl ethylamine, N-methylmorpholine and pyridine. One of ordinary skill in the art will also further recognize that such coupling reactions are often catalyzed by compounds including, but not limited to, HOBt and DMAP. Furthermore, one of ordinary skill in the art understands that the collection of suitable reagents and reaction conditions for formation of esters and amides are generally available in the relevant scientific literature and represented in books such as "Comprehensive Organic Transformation" (VCH, Larock).

[0080] One of ordinary skill in the art will recognize that the combination of a structure of Formula II with a structure of Formula IV will form an ester or an amide linkage. One of ordinary skill in the art will recognize that esters and amides are formed by combining activated esters of carboxylic acids with alcohols or amines. One of ordinary skill in the art will further recognize that such activated esters include, but are not limited to, acylimidazoles, nitrophenyl esters, pentafluorophenyl esters, succinimidyl esters and the like. One of ordinary skill in the art will further recognize that such coupling reactions are often facilitated by amine bases including, but not limited to, triethylamine, diisopropyl ethylamine, N-methylmorpholine and pyridine. One of ordinary skill in the art will also further recognize that such coupling reactions are often catalyzed by compounds including, but not limited to DMAP. Furthermore, one of ordinary skill in the art understands that the collection of suitable reagents and reaction conditions for formation of esters and amides from activated esters of carboxylic acids are generally available in the relevant scientific literature and represented in books such as "Comprehensive Organic Transformation"(VCH, Larock).

[0081] One of ordinary skill in the art will recognize that the combination of a structure of Formula III with a structure of Formula IV will form an amidine. One of ordinary skill in the art will recognize that amidines are formed by combining nitriles with amines. One of ordinary skill in the art understands that the collection of suitable reagents and reaction conditions for formation of amidines from activated nitriles and amines are generally available in the relevant scientific literature and represented in books such as "Comprehensive Organic Transformation" (VCH, Larock).

[0082] In at least some embodiments, exemplary compounds of Formula I include compounds 2-101:

[0083] In the spirit of the present invention, compounds 2-101 progressively address key issues associated with the parent compound 1. Such issues include, but are not limited to, metabolic stability and pharmacological properties in general. Compounds 2-101 are not intended to be inclusive of the compounds of the present invention and they should be viewed as examples only.

[0084] The compounds of the present invention and pharmaceutical compositions thereof are useful for the treatment of bipolar disorder, depression, Alzheimer's disease, autism spectrum disorder, Fragile X syndrome, Pitt Hopkins syndrome, Rett syndrome, traumatic brain injury, stroke, acute spinal cord injury, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), neurofibromatosis type 1, neuronal ceroid lipofuscinosis, chronic pain, neuropathic pain, chemotherapy- induced neuropathy, and chemotherapy-induced cognitive impairment. They are also useful for treating conditions where GSK-30 inhibition and or enhancement of WNT signaling have been identified or proposed, including alopecia, osteoarthritis, osteoporosis, alcoholic hepatitis, inflammatory bowel disease, wet age-related macular degeneration, dry age-related macular degeneration, diabetic macular edema, Fuch's dystrophy, limbal cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy(FEVR), Norrie disease, Coats disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, Sjogren's syndrome, sensorineural hearing loss, conductive hearing loss, schizophrenia, Parkinson's disease, polycystic kidney disease, focal segmental glomerulosclerosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, short bowel syndrome, melanoma, pancreatic cancer, prostate cancer, colon cancer, leukemia, septic shock, and ischemia / reperfusion injury.

[0085] In some embodiments, a compound of Formula I are administered to a subject in an amount of about 32 mg to about 320 mg once daily (QD). In some embodiments, a compound of Formula I are administered to a subject in an amount of about 16 mg to about 160 mg twice daily (BID).

[0086] The compounds in the present disclosure can also be administered in combination with lithium. In some embodiments, the subject is non-responsive to lithium. In some embodiments, the subject is lithium responsive. Lithium can be administered at a sub-effective dose based on monotherapy, wherein a compound of Formula I is administered at a sub-effective dose based on monotherapy. In some embodiments, the sub-effective dose of lithium is about 60 mg to about 600 mg QD, or about 30 mg to about 300 mg BID. In some embodiments, the sub-effective dose of a compound of Formula I is administered in about 8 mg to about 32 mg QD, or about 4 to about 16 mg BID.

[0087] The present disclosure also provides a method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful, comprising administering to a subject to be evaluated a therapeutically effective dose of a compound of Formula I and evaluating the subject's clinical response. Further, in some embodiments, the present disclosure provides a method of establishing an appropriate therapeutic dose of a compound of Formula I in a subject, which comprises administering increasing doses of compound and assessing response using GSK-3 imaging or GSK-3 serology.

[0088] In some embodiments, the present disclosure provides a method of treating a subject with Alzheimer's disease, bipolar disorder, or depression who shows evidence of elevated GSK-3, comprising administering to the subject a therapeutically effective dose of a compound of Formula I and evaluating and monitoring the subject using positron emission tomography (PET) or serology. In some embodiments, the present disclosure provides a method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful, comprising administering to a subject to be evaluated a therapeutically effective dose of a compound of Formula I with a therapeutically effective dose of lithium, and evaluating the subject's clinical response. In some embodiments, the dose of both a compound of Formula I and lithium are sub-effective based on monotherapy.

[0089] In some embodiments, the disclosure provides a method for treating a subject with Alzheimer's disease who has evidence of elevated GSK-3 beta activity, comprising administering to thesubject a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a therapeutically effective dose of lithium, and monitoring the subject using positron emission topography (PET). In some embodiments, the dose of both a compound of Formula I and lithium are sub-effective based on monotherapy.

[0090] In some embodiments, the disclosure provides a method for establishing an appropriate therapeutic dose of a compound of Formula I in a subject, comprising administering increasing doses of a compound of Formula I and lithium to the subject and assessing response using positron emission topography (PET).EXAMPLES

[0091] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

[0092] While certain reactions are represented in the claims below, it is to be understood that variations in final results are to be expected as the following examples are based on laboratory-scale reactions and not on manufacturing processes. Additionally, it is to be understood that in many cases the isolated product quantities are quantities isolated from multiple repeat-batches of said reactions and not from single reactions.Example 1 - Preparation of Compound 1 (OCM-51)

[0093] Compound 1 was prepared according to the following Scheme and through the numbered intermediate structures illustrated therein:

[0094] Intermediate 2: To a stirred suspension of Compound-1 (1) (10 g, 0.034 mol) in dichloromethane (100 mL) was added oxalyl chloride (4.6 mL, 0.050 mol) and 3 drops of DMF at 0°C, the resulting reaction mixture was warmed to rt and stirred for 2 h. After completion of reaction by TLC, the reaction mixture was evaporated under reduced pressure in presence of nitrogen atmosphere to affordcrude residue. The obtained crude Compound-2 (10.6 grams) was used for next step without further purification.

[0095] Intermediate 4: To a stirred solution of Compound-3 (4.2 mL, 0.033 mmol) in dry THF (100 mL) was added potassium tert-butoxide (12 g, 0.10 mol) portion-wise at 0 °C and stirred for15 minutes. Thereafter Compound-2 (10.6 g, 1.79 mmol) was dissolved in dry THF (100 mL) added drop wise at same temperature. The resulting reaction mixture was allowed to stir at RT for 2 h. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (2*100 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was further purified by silica-gel (100-200 mesh) column chromatography using ethyl acetate / hexane (30:70) an eluent to afford Compound-4 (3.6 grams) as a pale-yellow solid.1H NMR (400 MHz, CDCl3): δ 8.51(d, J=2.0 Hz, 1H), 8.16(dd, J=8.8 Hz, J=2 Hz, 1H),7.87(s, 1H), 6.9(d, J=8.8 Hz, 1H), 4.42(q, J=7.2 Hz, 2H), 3.95(s,3H), 1.43(t, J=7.2 Hz, 3H),

[0096] Intermediate 5: To a stirred solution of Compound-4 (7 g, 0.018 mol) in THF (15 mL) was added 1M NaOH solution (6 mL, 0.028 mmol) at 0 °C. The resulting reaction mass was warmed to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was taken into water and extracted with diethyl ether, the aqueous layer was acidified with 1 N H Cl and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was triturated with n-pentane, filtered and dried under high vacuum to afford Compound-5 (4.8 grams) as an off-white solid.1H NMR (400 MHz, DMSO6): δ 13.13(br, s, 1H), 8.49(s, 1H), 8.46(d, J=2.0 Hz, 1H), 8.03 (dd, J=8.8 Hz, J=2.4 Hz, 1H),7.15(d, J=8.8 Hz 1H), 3.91(s,3H).

[0097] Intermediate 8: To a stirred solution of 3-bromo-5-fluoropyridine (7) (15 g, 0.08 mmol), in triethylamine (150 mL) was added prop-2-yn-1-ol (9.5 g, 0.17 mmol), the reaction mixture was degassed for 25 min under nitrogen atmosphere at RT. Then Pd(PPh3)2Cl2(2.9 g, 0.004 mol) and CuI (1.6 g, 0.008 mmol) were added at RT and resulting reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a celite pad. The filter cake was thoroughly washed with dichloromethane, the filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was further purified by silica-gel (100-200 mesh) column chromatography using ethyl acetate / hexane (50:50) an eluent to afford Compound-8 (10.4 grams) as a pale-yellow solid.1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.41 (d, J=2.8 Hz, 1H), 7.46-7.42 (m, 1H), 4.52 (d, J=6.0 Hz, 1H), 1.96 (t, J=6.4 Hz, 1H).

[0098] Intermediate 9: To a stirred suspension of palladium on carbon (10% wet) (2.0 g) in methanol (180 mL) was added Compound-8 (10.2 g, 0.067 mmol) and the resulting reaction mixture was stirred under hydrogen (60 Psi) atmosphere at RT for 16 h. After completion of reaction by TLC, the mixture was filtered through a celite pad. The filter cake was thoroughly washed with MeOH (5 mL) and filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using (50:50) ethyl acetate in hexane as eluent to afford Compound-9 (8.4 grams) as pale-yellow liquid.1H NMR (400 MHz, CDCl3): δ 8.32-8.29 (m, 2H), 7.28-7.24 (m, 1H), 3.69 (t, J=6.0 Hz, 2H), 2.77 (t, J=7.6 Hz, 2H), 2.04-1.86 (m, 2H).

[0099] Intermediate 10: To a stirred solution of Compound-9 (8.2 g, 0.052 mol) in THF (100 mL) was added PPh3(27.8 g, 0.105 mol) and phthalimide (7.75 g, 0.052 mol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (20.8 mL, 0.105 mol) was added dropwise at 0°C. The resulting reaction mass was warmed to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using (50:50) ethyl acetate in hexane as eluent to afford Compound-10 (17.1 grams) as a pale-yellow solid.

[0100] Intermediate 6: To a stirred solution of Compound-10 (12.0 g, 0.042 mol) in MeOH (36 mL) was added N2H4.H2O (5.5 g, 0.109 mol) at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was washed with EtOAc and filtered. The filtrate was evaporated under reduced pressure to get crude residue and the obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using (5:10:85) (Aq. NH3: MeOH: DCM) as an eluent to afford Int-6 (1.2 grams) as a colorless liquid.1H NMR (400 MHz, CDCl3): δ 8.31-8.28 (m, 2H), 7.28-7.23 (m, 1H), 2.76 (t, J=7.2 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 1.82-1.74 (m, 2H).

[0101] Compound 1: To a stirred solution of Compound-5 (3.8 g, 0.011 mol) and Int-6 (2 g, 0.013 mol) in DMF (40 mL) was added HATU (4.95 g, 0.013 mol) and triethylamine (7.7 mL, 0.055 mol) at 0°C and the resulting reaction mixture warmed to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with water and aqueous layer was extracted with EtOAc (2*50 mL). The combined organic phases were dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using (50:50) EtOAc in hexane as an eluent to afford Compound-1 (3.2 grams) as an off-white solid.1H NMR (400 MHz, CDCl3): δ 8.64 (d, J=2.4 Hz 1H), 8.49 (dd, J=8.4 Hz, 8.8 Hz, 1H), 8.32-8.30 (m, 2H), 7.80(s, 1H), 7.38-7.32 (m, 1H), 7.28-7.26 (m, 1H), 6.89 (d, J=8.8 Hz 1H), 3.94 (s, 3H), 3.5 (q, J=6.8 Hz, 2H), 2.75 (t, J=6.8 Hz, 2H), 1.99-1.96 (m, 2H). Example 2 – General Scheme for the Preparation of Compounds 2-10

[0102] Compounds 2-10 were prepared according to the following Scheme and through the numbered intermediate structures illustrated therein:

[0103] Compound 2 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0104] Intermediate 2: To a stirred suspension of substituted benzoic acid (1) (1.79 mmol) in DCM (5 mL) was added oxalyl chloride (2.69 mmol), a few drops of DMF at 0 °C. The resulting reaction mixture was warmed to rt and stirred for 2 to 4 h. After completion of reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure in the presence of nitrogen atmosphere to get crude residue. The obtained crude residue of Compound-2 (1.2 grams) was used in the next step, as such, without any further purification.

[0105] Intermediate 4: To a stirred solution of Compound-3 (1.79 mmol) in dry THF (5 mL) was added potassium tert-butoxide (5.37 mmol) portion-wise at 0 °C and stirred for 15 minutes. Thereafter Compound-2 (1.79 mmol) dissolved in dry THF (5 mL) was added drop wise at same temperature into the reaction. The resulting reaction mixture was allowed to stir at RT for 2 to 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with sat. ammonium chloride (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with ethyl acetate in hexaneto afford Compound-4 (0.8 gram).1H NMR (400 MHz, CDCl3): δ 8.09-8.06 (m, 2H), 7.92 (s, 1H), 7.51-7.45 (m, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

[0106] Intermediate 5: To a stirred solution of Compound-4 (0.34 mmol) in THF (5 mL) was added 1M NaOH solution (0.5 mL, 0.52 mmol) at 0 °C. The resulting reaction mass was allowed to stir at RT for 12 to 16 h. After completion of the reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was taken into water (5 mL) and extracted with ethyl acetate (10 mL), separated the organic layer, acidified the aqueous layer using 1 N HCl (pH 1-2), filtered the precipitated solid and washed with water (5 mL), dried the product under vacuum at 45-50°C to afford Compound-5 (0.5 gram).1H NMR (400 MHz, DMSO-d6): δ 13.18 (br s, 1H), 8.54 (s, 1H), 8.00-7.98 (m, 2H), 7.55-7.50 (m, 3H)

[0107] Compound 2: To a stirred solution of Compound-5 (0.58 mmol) and Int-6 (0.69 mmol) in DMF (5 mL) was added HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL), separated the organic layer and washed with brine (5 mL) and the organic layer was dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with ethyl acetate in hexane to afford Compound-2 (130 mg).1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.51 (t, J=6.0 Hz 1H), 8.39 (d, J=2.8 Hz, 1H), 8.35 (t, J=1.6 Hz, 1H), 8.21-8.20 (m, 1H), 8.18 (d, J=1.2 Hz, 1H), 7.67-7.64 (m, 1H), 7.52-7.46 (m, 3H), 3.29 (q, J=6.8 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 1.90-1.83 (m, 2H). Example 4 – Preparation of Compound 3

[0108] Compound 3 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0109] Intermediate 2 of Compound 3 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 4-methylbenzoic acid and yielding 1.2 grams of desired product.

[0110] Intermediate 4 of Compound 3 was prepared according to the protocol described in Example 3 and utilizing Intermediate 2 of the present example. 0.7 gram of desired product isolated.1H NMR (400 MHz, CDCl3): δ 7.98 (dd, J=6.4, 1.6 Hz, 2H), 7.89 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

[0111] Intermediate 5 of Compound 3 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 180 mg of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 13.13 (br s, 1H), 8.50 (s, 1H), 7.89 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H).

[0112] Compound 3 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 0.4 gram of desired product isolated.1H NMR (400 MHz, DMSO- d6): δ 8.55 (s, 1H), 8.47 (t, J=6.0 Hz 1H), 8.39 (d, J=2.8 Hz, 1H), 8.35 (t, J=1.6 Hz, 1H), 8.10 (d, J= 8.4 Hz, 2H), 7.67-7.63 (m, 1H), 7.30 (d, J= 8.0 Hz, 2H), 3.28 (q, J=6.8 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.36 (s, 3H), 1.90- 1.82 (m, 2H). Example 5 – Preparation of Compound 4

[0113] Compound 4 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0114] Intermediate 2 of Compound 4 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 4-methoxybenzoic acid and yielding 1.25 grams of desired product.

[0115] Intermediate 4 of Compound 4 was prepared according to the protocol described in Example 3 and utilizing Intermediate 2 of the present example. 0.7 gram of desired product isolated.1H NMR (400 MHz, CDCl3): δ 8.07 (dd, J=6.8, 2.0 Hz, 2H), 7.86 (s, 1H), 6.99 (dd, J=6.8, 2.0 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

[0116] Intermediate 5 of Compound 4 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 0.4 gram of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 13.10 (br s, 1H), 8.47 (s, 1H), 7.98 (dd, J= 7.2, 2.0 Hz, 2H), 7.07 (dd, J= 7.2, 2.0 Hz, 2H).

[0117] Compound 4 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 180 mg of desired product isolated.1H NMR (400 MHz, DMSO- d6): δ 8.42 (s, 1H), 8.40-8.36 (m, 2H), 8.20 (d, J=10.0 Hz, 2H), 7.67-7.63 (m, 1H), 7.06 (d, J=10.0 Hz, 2H), 3.83 (s, 3H), 3.30 (t, J=6.8 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 1.90-1.83 (m, 2H). Example 6 – Preparation of Compound 5

[0118] Compound 5 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0119] Intermediate 2 of Compound 5 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 4-chlorobenzoic acid and yielding 1.3 grams of desired product.

[0120] Intermediate 4 of Compound 5 was prepared according to the protocol described in Example 3 utilizing Intermediate 2 of the present example.0.5 gram of desired product isolated.1H NMR (400 MHz, CDCl3): δ 8.08-8.05 (m, 2H), 7.92 (s, 1H), 7.47-7.44 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

[0121] Intermediate 5 of Compound 5 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 0.2 gram of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 13.26 (br s, 1H), 8.57 (s, 1H), 8.03 (d, J= 8.0 Hz, 2H), 7.61 (d, J= 8.0 Hz, 2H).

[0122] Compound 5 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 120 mg desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.57 (t, J= 5.6 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (t, J= 1.6 Hz, 1H), 8.27 (d, J= 9.6 Hz, 2H), 7.67-7.63 (m, 1H), 7.58 (d, J= 9.6 Hz, 2H), 3.30 (q, J=6.8 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 1.89-1.86 (m, 2H). Example 7 – Preparation of Compound 6

[0123] Compound 6 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0124] Intermediate 2 of Compound 6 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 3,4-dichlorobenzoic acid and yielding 1.3 grams of desired product.

[0125] Intermediate 4 of Compound 6 was prepared according to the protocol described in Example 3 and utilizing Intermediate 2 of the present example. 0.5 gram of desired product isolated.

[0126] Intermediate 5 of Compound 6 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 0.2 gram of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.61 (s, 1H), 8.34 (d, J= 2.0 Hz, 1H), 7.97 (dd, J= 8.4, 2.0 Hz, 1H), 7.82 (d, J= 8.8 Hz, 1H).

[0127] Compound 6 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 120 mg of desired product isolated.1H NMR (400 MHz, DMSO- d6): δ 8.70 (d, J= 2.0 Hz, 1H), 8.66 (s, 1H), 8.61 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.35 (s, 1H), 8.14 (dd, J= 8.8, 2.0 Hz, 2H), 7.78 (d, J= 8.4 Hz, 1H), 7.66-7.63 (m, 1H), 7.58 (d, J= 9.6 Hz, 2H), 3.30-3.28 (m, 2H), 2.68 (t, J=7.6 Hz, 2H), 1.91-1.84 (m, 2H). Example 8 – Preparation of Compound 7

[0128] Compound 7 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0129] Intermediate 2 of Compound 7 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 3-iodo-4-isopropxybenzoic acid and yielding 1.2 grams of desired product.

[0130] Intermediate 4 of Compound 7 was prepared according to the protocol described in Example 3 and utilizing Intermediate 2 of the present example. 0.6 gram of desired product isolated.

[0131] Intermediate 5 of Compound 7 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 0.2 gram of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 8.48 (s, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.00 (dd, J= 8.8, 2.4 Hz, 1H), 7.17 (d, J= 8.8 Hz, 1H), 4.81-4.75 (m, 1H), 1.33 (d, J= 6.0 Hz, 6H).

[0132] Compound 7 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 170 mg of desired product isolated.1H NMR (400 MHz, DMSO- d6): δ 8.77 (d, J= 2.4 Hz, 1H), 8.53 (s, 1H), 8.46 (t, J= 6.4 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (t, J= 2.0 Hz, 1H), 8.16 (dd, J= 8.8, 2.0 Hz, 1H), 7.67-7.63 (m, 1H), 7.14 (d, J= 8.8 Hz, 2H), 4.79-4.75 (m, 1H), 3.30-3.27 (m, 2H), 2.70-2.66 (m, 2H), 1.88-1.84 (m, 2H). Example 9 – Preparation of Compound 8

[0133] Compound 8 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0134] Intermediate 2 of Compound 8 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 3-iodo-4-cyclopropylmethoxybenzoic acid (preparation described in Example 12) and yielding 1 gram of desired product.

[0135] Intermediate 4 of Compound 8 was prepared according to the protocol described in Example 3 and utilizing Intermediate 2 of the present example. 0.7 gram of desired product isolated.

[0136] Intermediate 5 of Compound 8 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 0.2 gram of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 13.12 (br s, 1H), 8.47 (s, 1H), 8.45 (d, J= 2.0 Hz, 1H), 7.99 (dd, J= 8.8, 2.0 Hz, 1H), 7.12 (d, J= 8.8 Hz, 1H), 4.00 (d, J= 6.8 Hz, 2H), 1.30-1.25 (m, 1H), 0.62-0.57 (m, 2H), 0.43-0.38 (m, 2H).

[0137] Compound 8 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 115 mg of desired product isolated.1H NMR (400 MHz, DMSO- d6): δ 8.78 (d, J= 2.0 Hz, 1H), 8.52 (s, 1H), 8.46 (t, J=6.0 Hz 1H), 8.38 (d, J=2.8 Hz, 1H), 8.35 (s, 1H), 8.16 (dd, J= 8.8, 2.0 Hz, 1H), 7.67-7.63 (m, 1H), 7.09 (d, J= 8.8 Hz, 1H), m, 3H), 3.99 (d, J= 6.4 Hz, 2H), 3.29-3.27 (m, 2H), 2.68 (t, J=7.6 Hz, 2H), 1.90-1.83 (m, 2H), 1.29-1.23 (m, 1H), 0.62-0.57 (m, 2H), 0.41-0.40 (m, 2H). Example 10 – Preparation of Compound 9

[0138] Compound 9 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0139] Intermediate 2 of Compound 9 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 3-isopropyl-4-methoxybenzoic acid and yielding 1.2 grams of desired product.

[0140] Intermediate 4 of Compound 9 was prepared according to the protocol described in Example 3 and utilizing Intermediate 2 of the present example. 0.6 gram of desired product isolated.

[0141] Intermediate 5 of Compound 9 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 0.3 gram of desired product isolated.1H NMR (400MHz, DMSO-d6): δ 13.01 (s, 1H), 8.44 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.85 (dd, J= 8.4, 2.0 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 3.86 (s, 3H), 3.32-3.29 (m, 1H), 1.18 (d, J= 6.8 Hz, 6H).

[0142] Compound 9 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 140 mg of desired product isolated.1H NMR (400 MHz, DMSO- d6): δ 8.48 (s, 1H), 8.39 (d, J= 6.4 Hz, 2H), 8.35 (s, 1H), 8.15 (d, J= 2.0 Hz, 1H), 8.05 (dd, J= 8.8, 2.0 Hz, 1H), 7.68-7.65 (m, 1H), 7.06 (d, J= 8.8 Hz, 1H), 3.85 (s, 3H), 3.30-3.23 (m, 3H), 2.68 (t, J= 7.6 Hz, 2H), 1.90-1.83 (m, 2H), 1.19 (d, J= 7.2 Hz, 6H). Example 11 – Preparation of Compound 10

[0143] Compound 10 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.

[0144] Intermediate 2 of Compound 10 was prepared according to the protocol described in Example 3 by replacing benzoic acid with 3-(tert-butyl)-4-methoxybenzoic acid and yielding 1.2 grams of desired product.

[0145] Intermediate 4 of Compound 10 was prepared according to the protocol described in Example 3 and utilizing Intermediate 2 of the present example. 0.6 gram of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 8.04-7.98 (m, 2H), 7.85 (s, 1H), 6.95 (d, J= 8.8 Hz, 1H), 4.42 (q, J= 7.2 Hz, 1H), 3.90 (s, 3H), 1.40 (s, 9H).

[0146] Intermediate 5 of Compound 10 was prepared according to the protocol described in Example 3 and utilizing Intermediate 4 of the present example. 210 mg of desired product isolated.1H NMR (400 MHz, DMSO-d6): δ 12.96 (br s, 1H), 8.44 (s, 1H), 8.02 (d, J= 2.4 Hz, 1H), 7.86 (dd, J= 8.8, 2.4 Hz, 1H), 7.12 (d, J= 8.8 Hz, 1H), 3.88 (s, 3H), 1.36 (s, 9H).

[0147] Compound 10 was prepared according to the protocol described in Example 3 and utilizing Intermediate 5 of the present example. 142 mg of desired product isolated.1H NMR (400 MHz, DMSO- d6): δ 8.48 (s, 1H), 8.39 (d, J= 2.8 Hz, 2H), 8.35 (s, 1H), 8.24 (d, J= 2.4 Hz, 1H), 8.03 (dd, J= 8.8, 2.4 Hz, 1H), 7.68-7.63 (m, 1H), 7.09 (d, J= 8.8 Hz, 1H), 3.87 (s, 3H), 3.29-3.28 (m, 2H), 2.69-2.66 (m, 2H), 1.88-1.84 (m, 2H), 1.35 (s, 9H).Example 12 – Preparation of 3-Iodo-4-Cyclopropylmethoxybenzoic Acid (Example 9 Starting Material)

[0148] 3-Iodo-4-cyclopropylmethoxybenzoi acid was prepared according to following Scheme: HO K2CO3LiOH.HO O2DMF THF OmL), was added potassium carbonate (2.1 g, 15.15 mmol) and (bromomethyl)cyclopropane (1.53 g, 11.36 mmol) in a sealed tube. The resulting reaction contents were heated to 60°C and stirred for 16 h. After completion of reaction (monitored by TLC), the reaction was cooled to RT and partitioned between ethyl acetate (30 mL) and water (15 mL). Separated the organic layer and washed with brine (15 mL), separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to afford compound- 1b as brown liquid (1.6 grams isolated product).1H NMR (400 MHz, CDCl3): δ 8.47 (d, J= 2.0 Hz, 1H), 8.01 (d, J= 2.0 Hz, 1H), 7.98 (d, J= 2.0 Hz, 1H), 6.78 (d, J= 8.8 Hz, 1H), 4.12 (d, J= 7.2 Hz, 2H), 3.96 (d, J= 6.4 Hz, 2H), 2.96 (s, 2H), 2.88 (s, 2H), 1.34-1.22 (m, 2H), 0.69-0.66 (m, 2H), 0.64-0.59 (m, 2H), 0.46-0.42 (m, 2H), 0.37-0.33 (m, 2H). Intermediate 1: To a stirred solution of Compound-1b (1.6 g, 6.06 mmol) in THF: MeOH: H2O (3:1:1) (10 mL), was added lithium hydroxide monohydrate (0.54 g, 18.18 mmol) and stirred for 16 h at RT. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was taken into water (5 mL) and extracted with ethyl acetate (10 mL), separated the organic layer, acidified the aqueous layer with 1 N HCl (pH 1-2) and the precipitated solid was filtered, washed with water (10 mL), dried the compound under vacuum at 45- 50°C to afford Compound-1, as a white solid (0.85 gram isolated product).1H NMR (400 MHz, DMSO-d6): δ 12.86 (s, 1H), 8.26 (d, J= 2.0 Hz, 1H), 7.91 (dd, J=8.8, 2.0 Hz, 1H), 7.05, J= 8.8 Hz, 1H), 4.00 (d, J= 6.8 Hz, 2H), 1.28-1.24 (m, 1H), 0.62-0.57 (m, 2H), 0.42-0.37 (m, 2H).Example 13 – Preparation of Compound 11

[0150] Compound 11 was prepared according to the following Scheme:

[0151] Interme -ol 1 (1.415 ml, 10.93mmol, 1.0 eq), phthalimide 2 (1.931 g, 13.12 mmol, 1.2 eq) and triphenylphosphine (3.58 g, 13.67 mmol, 1.25 eq) in THF (20.0 mL) was added DIAD (4.29 mL, 21.87 mmol, 2 eq) at 0 °C . The reaction mixture was warmed to room temperature and then stirred overnight under nitrogen atmosphere. Upon completion of reaction (as confirmed by TLC, 100% ethyl acetate Rf ~ 0.3), the reaction mixture was acidified with 1.5 N HCl (50 mL) and diluted with MTBE (2 × 20 mL). The obtained organic layer was basified with saturated sodium bicarbonate (50.0 mL) until pH 9-10. The precipitated solid was filtered and dried under vacuum for 45 min to afford 2-(3-(pyridin-4-yl)propyl)isoindoline-1,3-dione 3 (2.01 g, 7.51 mmol, 68.7 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.43-8.41 (m, 1H), 7.87-7.82 (m, 2H), 7.25 (d, J = 6.00 Hz, 1H), 3.61 (t, J = 6.80 Hz, 1H), 2.65 (t, J = 7.60 Hz, 1H), 1.97-1.90 (m, 1H).

[0152] Intermediate 4: To a stirred solution of 2-(3-(pyridin-4-yl)propyl)isoindoline-1,3-dione 3 (2.0 g, 7.51 mmol, 1.0 eq) in ethanol (40.0 mL) was added hydrazine hydrate (50-60% sol in H2O, 3.42 g, 37.6 mmol, 5.0 eq) at room temperature and the resulting solution was stirred at 80 °C for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure, triturated with DCM (2 x 15 mL) and filtered. The filtrate was concentrated under reduced pressure to afford crude 3-(pyridin-4-yl)propan-1-amine 4 (0.850 g, 5.48 mmol, 73.0 % yield) as pale yellow oil.1H-NMR (400 MHz, DMSO-d6): δ 8.45-8.43 (m, 2H), 7.24-7.22 (m, 2H), 2.64-2.53 (m, 2H), 2.52-2.50 (m, 2H), 1.68-1.44 (m, 2H).Compound 11: To a stirred solution of an 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4 (Intermediate 5 of Example 1, 0.300 g, 0.869 mmol, 1.0 eq) and 3-(pyridin-4-yl)propan-1-amine (0.178 g, 1.304 mmol, 1.5 eq) in DMF (8.0 mL) was added DIPEA (0.562 g, 4.35 mmol, 5.0 eq) followed by HATU (0.397 g, 1.043 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was diluted with ice cold water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (2 x 10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude . The obtained crude was purified by reverse-phase column chromatography (Grace column: C1840 µm, 0.330 g; flow rate: 30 mL / min; 0.1% aqueous TFA / MeCN mobile phase) to afford 5-(3-iodo-4-methoxyphenyl)-N-(3-(pyridin-4- yl)propyl)oxazole-4-carboxamide 11 (0.248 g, 0.535 mmol, 61.5 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): 8.82 (d, J = 2.00 Hz, 1H), 8.75-8.73 (m, 2H), 8.54-8.50 (m, 2H), 8.18 (dd, J = 2.00, 8.80 Hz, 1H), 7.83 (dd, J = 6.40, Hz, 2H), 7.14 (dd, J = 8.80, Hz, 1H), 3.90 (s, 3H), 3.35-3.31 (m, 2H), 2.87 (t, J = 7.60 Hz, 2H), 1.97-1.90 (m, 2H). Example 14 – Preparation of Compound 12

[0153] Compound 12 was prepared according to the following Scheme: NHBoc Cl N2NHBocM [0, , mmol) and tert-butyl prop-2-yn-1-ylcarbamate 2 (0.411 g, 2.65 mmol, 2.0 eq) in anhydrous DMF (5.0 ml) and triethylamine (1.846 ml, 13.25 mmol, 10.0 eq) were added copper(I) iodide (0.050 g, 0.265 mmol, 0.2 eq) followed by PdCl2(PPh3)2(0.093 g, 0.132 mmol, 0.1 eq). The resulting suspension was degassed with nitrogen for 10 min and the reaction mixture was stirred at RT for overnight under nitrogen atmosphere.Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite, the bed was washed with EtOAc (1 x 10 mL) and the filtrate was concentrated under reduced pressure to afford the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous TFA / MeCN mobile phase). The fractions were combined, volatiles were removed under reduced pressure. Ice cold saturated aqueous NaHCO3solution (75 mL) was added to the residue, followed by DCM (70 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl (3-(pyrimidin-4-yl)prop-2-yn-1-yl)carbamate 3 (0.200 g, 0.857 mmol, 64.6 % yield) as pale brown gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.82 (d, J = 4.80 Hz, 1H), 7.59-7.57 (m, 1H), 7.48 (m, 1H), 4.06 (d, J = 5.60 Hz, 2H), 1.41 (s, 9H).

[0155] Intermediate 4: A stirred solution of tert-butyl (3-(pyrimidin-4-yl)prop-2-yn-1-yl)carbamate 3 (0.200 g, 0.857 mmol, 1.0 eq) in methanol (10 mL) was degassed and purged with nitrogen. Pd / C (10% w / w) (0.912 g, 0.857 mmol, 0.1 eq) was added to the solution and the mixture was stirred at RT under hydrogen atmosphere for 2h. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure to afford crude tert-butyl (3-(pyrimidin-4-yl)propyl)carbamate 4 (0.130 g, 0.456 mmol, 53.2 % yield) as brown gummy liquid. The crude product was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 9.07 (d, J = 1.20 Hz, 1H), 8.67 (d, J = 5.20 Hz, 1H), 7.43-7.41 (m, 1H), 6.89-6.87 (m, 1H), 2.99-2.94 (m, 2H), 2.73-2.68 (m, 2H), 1.78 (quintet, J = 7.20 Hz, 2H), 1.38 (s, 9H).

[0156] Intermediate 5: To a stirred solution of tert-butyl (3-(pyrimidin-4-yl)propyl)carbamate 4 (0.132 g, 0.556 mmol, 1.0 eq) in DCM (3 mL) was added HCl (4M sol in 1,4-dioxane, 2.78 ml, 11.13 mmol, 20.0 eq) at 0oC. The resulting solution was stirred for 2h at RT under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC, 70% Ethyl acetate in Pet-ether, product Rf ~ 0.0), the reaction mixture was concentrated under reduced pressure and titrated with MTBE (2 x 3 ml), dried under reduced pressure to afford crude 3-(pyrimidin-4-yl)propan-1-amine, HCl 5 (0.095 g, 0.141 mmol, 25.4 % yield) as brown sticky solid. The crude product was taken as such for next step without further purification.

[0157] Compound 12: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 5 (Intermediate 5 of Example 1, 0.2 g, 0.580 mmol, 1.0 eq) and 3-(pyrimidin-4-yl)propan-1-amine (0.095 g, 0.695 mmol, 1.2 eq) in DMF (8 ml) was added DIPEA (0.516 ml, 2.90 mmol, 5.0 eq) followed by HATU (0.331 g, 0.869 mmol, 1.5 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirredat room temperature for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-HPLC (Column: XBRIDGE C18-150, 500 ul, Mobile phase: A: 100 mm ammonium bicarbonatein water, B: MeCN, Flow rate: 15 mL / min, Retention time: 11.0 min) to afford the final compound 12 [5-(3-iodo-4-methoxyphenyl)-N-(3- (pyrimidin-4-yl)propyl)oxazole-4-carboxamide (0.018 g, 0.037 mmol, 6.3 % yield)] as beige solid.1H-NMR (400 MHz, DMSO-d6): δ 9.07 (d, J = 1.20 Hz, 1H), 8.81 (d, J = 2.40 Hz, 1H), 8.66 (d, J = 5.20 Hz, 1H), 8.53 (s, 1H), 8.51-8.47 (m, 1H), 8.20 (dd, J = 2.40, 8.60 Hz, 1H), 7.45 (m, 1H), 7.14 (d, J = 9.20 Hz, 1H), 3.90 (s, 3H), 3.33 (m, 2H), 2.77 (t, J = 8.00 Hz, 2H), 1.88-1.97 (m, 2H). Example 15 – Preparation of Compound 13

[0158] Compound 13 was prepared according to the following Scheme:

[0159] mmol, 1.0 eq) and tert-butyl prop-2-yn-1-ylcarbamate 2 (1.074 g, 6.92 mmol, 1.1 eq) in anhydrous acetonitrile (20.0 mL), diisopropylamine (1.343 mL, 9.43 mmol, 1.5 eq), CuI (0.120 g, 0.629 mmol, 0.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.727 g, 0.629 mmol, 0.1 eq) were added. The resulting suspension was degassed with nitrogen for 10 minutes and heated at 65 °C for overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 60% EtOAc in pet ether, Rfof the product ~ 0.1 & LCMS analysis), the reaction mixture was diluted with ethyl acetate (10 mL), filtered through Celite bed and washed with ethyl acetate (1 x 10 mL). The filtrate was concentrated under reduced pressure to afford the crude as pale brown gummy solid. The obtained crude was purified bycolumn chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 25% ethylacetate in pet ether to afford tert-butyl (3-(pyrimidin-5-yl)prop-2-yn-1-yl)carbamate 3 (1.1 g, 4.56 mmol, 72.5 % yield) as brown gummy liquid.

[0160] Intermediate 4: A solution of tert-butyl (3-(pyrimidin-5-yl)prop-2-yn-1-yl)carbamate 3 (1.1 g, 4.72 mmol, 1.0 eq) in methanol (30 mL) was degassed and purged with argon and then PdOH2 (20% w / w) (0.331 g, 0.472 mmol, 0.1 eq) was added. The reaction was stirred at RT under hydrogen atmosphere for 16h. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through celite bed, the bed was washed with methanol (2 x 20 mL) and filtrate was concentrated under reduced pressure to afford the crude product tert-butyl (3-(pyrimidin-5-yl)propyl)carbamate 4 (0.750 g, 2.279 mmol, 48.3 % yield) as pale brown gummy liquid. The obtained crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.69 (s, 2H), 6.89 (s, 1H), 4.11-4.07 (m, 1H), 3.18 (d, J = 5.20 Hz, 1H), 2.97-2.92 (m, 2H), 2.59 (t, J = 7.60 Hz, 2H), 1.71 (t, J = 7.20 Hz, 2H), 1.39 (d, J = 9.60 Hz, 12H).

[0161] Intermediate 5: To a stirred solution of tert-butyl (3-(pyrimidin-5-yl)propyl)carbamate 4 (0.300 g, 1.264 mmol, 1.0 eq) in DCM (6 ml) was added HCl (4 M soln. in dioxane, 6.32 ml, 25.3 mmol, 20.0 eq) at 0oC. The resulting solution was stirred for overnight at RT under nitrogen atmosphere. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture was concentrated under reduced pressure to get crude compound as brown semi solid. The crude compound was triturated with MTBE (2 x 5 mL), decanted the solvent and dried the solid under reduced pressure to afford the crude product 3- (pyrimidin-5-yl)propan-1-amine, HCl 5 (0.205 g, 1.171 mmol, 93 % yield) as pale brown semi solid.1H- NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.76 (s, 2H), 8.14 (d, J = 12.80 Hz, 4H), 3.57 (s, 1H), 2.81-2.70 (m, 5H), 1.95-1.88 (m, 2H).

[0162] Compound 13: To a stirred solution of an 5-(3-iodo-4-methoxyphenyl)oxazole-4- carboxylic acid 4a (Intermediate 5 of Example 1, 0.200 g, 0.580 mmol, 1.0 eq) and 3-(pyrimidin-5- yl)propan-1-amine 5 (0.080 g, 0.580 mmol, 1.0 eq) in DMF (3.0 mL) was added DIPEA (0.506 ml, 2.90 mmol, 5.0 eq) followed by HATU (0.264 g, 0.695 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extract was washed with brine (1 x 10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude product as yellow liquid. The crude product was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous TFA / MeCN mobile phase) to afford [5-(3-iodo-4-methoxyphenyl)-N-(3-(pyrimidin-5-yl)propyl)oxazole-4-carboxamide 13 (0.11 g, 0.234 mmol, 40.34 % yield)] as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.81 (d, J = 2.40 Hz, 1H), 8.72 (s, 2H), 8.54-8.48 (m, 2H), 8.22-8.19 (m, 1H), 7.14 (d, J = 8.80 Hz, 1H), (s, 1H), 3.33-3.28 (m, 2H), 2.68-2.63 (m, 2H), 1.91-1.87 (m, 2H). Example 16 – Preparation of Compound 14

[0163] Compound 14 was prepared according to the following Scheme: [0g, 5.23 mmol, 1.0 eq) in THF (12.0 ml) was added BH3.THF (1.0 M sol in THF, 15.69 ml, 15.69 mmol, 3.0 eq) at 0oC under nitrogen atmosphere and stirred for 10 min. Then the reaction mixture was warmed to RT and stirred for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was quenched with 1N HCl solution (10 mL) at 0oC and stirred for 10 min. Then saturated aqueous NaHCO3solution (35 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / MeCN mobile phase). Product containing fractions were combined and concentrated under reduced pressure to afford (3-fluoroquinolin-5-yl)methanol 2 (0.605 g, 3.37 mmol, 64.4 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.96 (d, J = 2.80 Hz, 1H), 8.34-8.31 (m, 1H), 7.98 (d, J = 8.00 Hz, 1H), 7.74-7.67 (m, 2H), 5.44 (t, J = 5.60 Hz, 1H), 4.94 (d, J = 5.60 Hz, 2H).

[0165] Intermediate 3: To a stirred solution of (3-fluoroquinolin-5-yl)methanol 2 (0.6 g, 3.39 mmol, 1.0 eq) in Dichloromethane (6.0 mL) was added triethylamine (1.028 g, 10.16 mmol, 3.0 eq)followed by mesyl chloride (0.465 g, 4.06 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The resulting reaction mixture was stirred for 2 h at room temperature. Upon completion of reaction (as confirmed by TLC, 50% ethylacetate in pet ether, Rf of desired product 0.6), ice cold saturated NaHCO3solution (15 mL) was added to the reaction mixture, diluted with DCM (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layer was washed with brine (1 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the 5- (chloromethyl)-3-fluoroquinoline 3 (0.71 g, 3.62 mmol, 107.2 % yield) as pale brown solid. The crude compound was used for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 9.03 (d, J = 3.60 Hz, 1H), 8.48-8.44 (m, 1H), 8.10 (d, J = 11.20 Hz, 1H), 7.83 (d, J = 9.20 Hz, 1H), 7.78-7.72 (m, 1H), 5.31 (s, 2H).

[0166] Intermediate 4: To a stirred solution of 5-(chloromethyl)-3-fluoroquinoline 3 (0.7 g, 3.57 mmol, 1.0 eq) in DMSO (5.0 mL) was added sodium cyanide (0.269 g, 5.48 mmol, 2.0 eq) at RT under nitrogen atmosphere and solution was stirred for overnight at room temperature. Upon completion of reaction (as confirmed by TLC, 30% ethylacetate in pet ether, Rf of desired product 0.2), ice cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as yellow gummy liquid. The crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 17-19% ethylacetate in pet ether to afford 2-(3-fluoroquinolin-5-yl)acetonitrile 4 (0.4 g, 2.140 mmol, 59.9 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.04 (d, J = 2.80 Hz, 1H), 8.41-8.38 (m, 1H), 8.09 (d, J = 8.40 Hz, 1H), 7.81-7.75 (m, 2H), 4.54 (s, 2H).

[0167] Intermediate 5: To a stirred solution of 2-(3-fluoroquinolin-5-yl)acetonitrile 4 (0.23 g, 1.235 mmol) in a mixture of methanol (6.0 ml) and ammonia (7 N soln in MeOH, 6.0 mL) was added Raney Nickel (10.58 mg, 0.124 mmol, 0.1 eq) at room temperature slowly under nitrogen atmosphere. The mixture was stirred at room temperature for 4 h under hydrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite bed, and washed with methanol (2 x 5 mL). The filtrate was concentrated under reduced pressure to afford the crude 2-(3-fluoroquinolin-5-yl)ethan-1-amine 5 (0.22 g, 1.054 mmol, 85 % yield) as pale yellow gummy solid. The crude product was used for next step without further purification.1H-NMR (400 MHz, DMSO- d6): δ 8.94 (d, J = 2.80 Hz, 1H), 8.42 (dd, J = 2.40, 10.80 Hz, 1H), 7.93 (d, J = 8.40 Hz, 1H), 7.67 (t, J = 8.40 Hz, 1H), 7.52 (d, J = 6.80 Hz, 1H), 3.10 (t, J = 7.20 Hz, 2H), 2.82 (t, J = 7.20 Hz, 2H), 1.44 (br s, H).

[0168] Compound 14: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (Intermediate 5 of Example 1, 0.35 g, 1.014 mmol, 1.0 eq) and 2-(3-fluoroquinolin-5-yl)ethan-1- amine 5 (0.232 g, 1.217 mmol, 1.2 eq) in N,N-Dimethylformamide (8.0 mL) was added N,N- diisopropylethylamine (0.903 mL, 5.07 mmol) followed by HATU (0.578 g, 1.521 mmol) at 0oC under nitrogen atmosphere. The mixture was warmed to RT and stirred for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-HPLC (Column: XSelect C18 150, 500 ul, Mobile phase: A: 10 Mm ammonium bicarbonate in water, B: MeCN, Flow rate: 15 mL / min, Retention time: 14.0 min) to afford [N-(2-(3- fluoroquinolin-5-yl)ethyl)-5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxamide 14 (0.204 g, 0.393 mmol, 38.7 % yield)] as pale beige solid.1H-NMR (400 MHz, DMSO-d6): δ 8.95 (d, J = 2.40 Hz, 1H), 8.80 (d, J = 2.40 Hz, 1H), 8.67 (t, J = 6.00 Hz, 1H), 8.61 (dd, J = 2.40, 10.80 Hz, 1H), 8.55 (s, 1H), 8.21-8.18 (m, 1H), 7.96 (d, J = 8.40 Hz, 1H), 7.68 (t, J = 8.40 Hz, 1H), 7.57 (d, J = 7.20 Hz, 1H), 7.14 (d, J = 8.80 Hz, 1H), 3.91 (s, 3H), 3.59-3.54 (m, 2H), 3.29-3.28 (m, 2H). Example 17 – Preparation of Compound 15

[0169] Compound 15 was prepared according to the following Scheme:

[0170] Intermediate 2: A solution of 7-amino-4-fluoroisoquinolin-1(2H)-one 1 (0.510 g, 2.86 mmol, 1.0 eq) in toluene (3.0 mL) was added POCl3(2.67 ml, 28.6 mmol, 10.0 eq) as dropwise and the reaction mixture was heated at 110oC for overnight under nitrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to dryness. Ice cold saturated NaHCO3solution (55 mL) was added to the reaction mixture and diluted with DCM (40 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layer was washed with brine (1 X 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 20-25 % ethylacetate in pet ether to afford 1-chloro-4-fluoroisoquinolin-7-amine 2 (0.098 g, 0.496 mmol, 17.33 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 7.90-7.85 (m, 2H), 7.34 (dd, J = 2.00, 9.00 Hz, 1H), 7.15-7.14 (m, 1H), 6.33 (br s, 2H).

[0171] Intermediate 3: To a stirred solution of 1-chloro-4-fluoroisoquinolin-7-amine 2 (0.095 g, 0.483 mmol, 1.0 eq) in a mixture of ethanol (1.5 ml) and ammonia (7N sol in methanol, 0.209 ml, 9.66 mmol, 20.0 eq) was added Pd / C (0.051 g, 0.048 mmol, 0.1 eq) at RT under nitrogen atmosphere and solution was stirred for under hydrogen atmosphere for overnight at room temperature. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite, and washed with MeOH (1 x 5 mL). The filtrate was concentrated under reduced pressure to afford the crude 4- fluoroisoquinolin-7-amine 3 (0.080 g, 0.478 mmol, 99 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.04 (d, J = 2.40 Hz, 1H), 7.79 (d, J = 8.80 Hz, 1H), 7.28 (d, J = 2.00 Hz, 1H), 7.26 (br s, 4H), 7.00 (t, J = 2.00 Hz, 1H), 5.97 (br s, 2H).

[0172] Intermediate 4: To a stirred solution of 4-fluoroisoquinolin-7-amine 3 (0.230 g, 1.418 mmol, 1.0 eq) in water (1.0 mL) and Conc.HCl (1.0 mL) was added a solution of sodium nitrite (0.117 g, 1.702 mmol, 1.2 eq) in water (1.0 mL) at 0 °C as dropwise and allowed to stirred for 30 minutes. Then a solution of potassium iodide (0.330 g, 1.986 mmol, 1.4 eq) in water (1.0 mL) was added to the reaction mixture at 0 °C and allowed to stirred for 4 h at RT. Upon completion of reaction (as confirmed by TLC, 15% ethylacetate in pet ether, Rf of desired product 0.7), ice cold saturated NaHCO3solution (25 mL) was added to the reaction mixture and diluted with DCM (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 7% ethylacetate in pet ether to afford 4-fluoro-7-iodoisoquinoline 4 (0.170 g, 0.620 mmol, 43.7 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO- d6): δ 9.18 (s, 1H), 8.75 (t, J = 1.60 Hz, 1H), 8.56 (d, J = 2.40 Hz, 1H), 8.18 (dd, J = 1.60, 8.80 Hz, 1H), 7.90 (d, J = 8.80 Hz, 1H).

[0173] Intermediate 5: To a stirred solution of 4-fluoro-7-iodoisoquinoline 4 (0.21 g, 0.769 mmol, 1.0 eq), zinc(II) cyanide (0.135 g, 1.154 mmol, 1.5 eq) and dppf (0.021 g, 0.038 mmol, 0.05 eq) in DMF (5.00 mL). The resulting solution was degassed with nitrogen for 10 minutes. Then Pd2(dba)3(0.070 g, 0.077 mmol, 0.1 eq) was added to the mixture under nitrogen atmosphere and the resulting solution was degassed again with nitrogen for 10 minutes. The resulting solution was heated to 130 °C for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (25 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude compound. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 23-25 % ethylacetate in pet ether to afford 4- fluoroisoquinoline-7-carbonitrile 5 (0.11 g, 0.638 mmol, 83 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.35 (s, 1H), 8.95 (s, 1H), 8.73 (d, J = 2.40 Hz, 1H), 8.29 (d, J = 8.40 Hz, 1H), 8.22-8.20 (m, 1H).

[0174] Intermediate 6: To a stirred solution of 4-fluoroisoquinoline-7-carbonitrile 5 (0.110 g, 0.639 mmol, 1.0 eq) in ammonia (7N in methanol, 4.0 mL) was added Raney Nickel (5.47 mg, 0.064 mmol, 0.1 eq) at room temperature slowly under nitrogen atmosphere. The mixture was stirred at room temperature for overnight under hydrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite, washed with methanol (2 x 5 mL) and the filtrate was concentrated under reduced pressure to afford the crude (4-fluoroisoquinolin-7- yl)methanamine 6 (0.115 g, 0.599 mmol, 94 % yield) as pale brown gummy solid. The crude compound used for next step without further purification.

[0175] Compound 15: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (Intermediate 5 of Example 1, 0.150 g, 0.435 mmol, 1.0 eq) and (4-fluoroisoquinolin-7- yl)methanamine 6 (0.092 g, 0.522 mmol, 1.2 eq) in DMF (5.0 mL) was added N,N-diisopropylethylamine (0.228 ml, 1.304 mmol, 3.0 eq) followed by HATU (0.248 g, 0.652 mmol, 1.5 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 h. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried overNa2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-HPLC (Column: XBRIDGE C18-150, 500 ul, Mobile phase: A: 10 Mm ammonium bicarbonate in water, B: MeCN, Flow rate: 15 mL / min, Retention time: 10.1 min) to afford 15 [N-((4- fluoroisoquinolin-7-yl)methyl)-5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxamide (0.059 g, 0.116 mmol, 26.6 % yield)] as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.20 (m, 2H), 8.80 (d, J = 2.40 Hz, 1H), 8.59 (s, 1H), 8.47 (d, J = 2.40 Hz, 1H), 8.21 (dd, J = 2.40, 8.60 Hz, 1H), 8.12-8.09 (m, 2H), 7.92 (dd, J = 1.20, 8.60 Hz, 1H), 7.13 (d, J = 8.80 Hz, 1H), 4.71 (d, J = 6.40 Hz, 2H), 3.90 (s, 3H). Example 18 – Preparation of Compound 16

[0176] Compound 16 was prepared according to the following Scheme:

[0177] 4.0 g, 17.85 mmol, 1.0 eq) in methanol (25.00 mL) and CH3CN (25.00 mL) was added selectfluor (7.59 g, 21.42 mmol, 1.2 eq) at RT and allowed to stirred at 50 °C for 1 h under nitrogen atmosphere. The reaction mixture was concentrated and dissolved in DCE (20 mL) under nitrogen atmosphere. To the resulting solution was added POCl3(3.33 ml, 35.7 mmol, 2.0 eq), then allowed to stirred at 50 °C for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (30 mL) was added to the reaction mixture, diluted with ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35mL / min) to afford 8-bromo-4-fluoroisoquinolin-3(2H)-one 2 (4.2 g, 11.87 mmol, 66 % yield) as pale brown solid.1H-NMR (400 MHz, DMSO-d6): δ 8.83 (br s, 1H), 7.89 (d, J = 8.80 Hz, 1H), 7.72 (d, J = 7.20 Hz, 1H), 7.59-7.54 (m, 2H).

[0178] Intermediate 3: To a stirred solution of 8-bromo-4-fluoroisoquinolin-3(2H)-one 2 (4.02 g, 16.61 mmol, 1.0 eq) in a mixture of methanol (20 mL) and DMF (20 mL) was added triethylamine (4.63 ml, 33.2 mmol, 2.0 eq) and purged with nitrogen. PdCl2(dppf).CH2Cl2(1.356 g, 1.661 mmol, 0.1 eq) was added and the mixture was heated at 100 °C under carbon monoxide atmosphere at 4 kg / cm2overnight. Upon completion of reaction (as confirmed by TLC, 60% ethylacetate in pet ether, Rfof desired product 0.2), the reaction mixture was filtered through Celite bed and the filtrate was concentrated under reduced pressure to dryness. Ice cold water (70 mL) was added to the residue, diluted with ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (1 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 60 % ethylacetate in pet ether) to afford desired product methyl 4-fluoro-3-oxo-2,3-dihydroisoquinoline-8-carboxylate 3 (1.1 g, 4.34 mmol, 26.1 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 12.02 (br s, 1H), 9.39 (s, 1H), 8.10 (d, J = 8.80 Hz, 1H), 7.97 (t, J = 5.20 Hz, 1H), 7.77-7.73 (m, 1H), 3.96 (s, 3H).

[0179] Intermediate 4: To a stirred solution of methyl 4-fluoro-3-oxo-2,3-dihydroisoquinoline-8- carboxylate 3 (1.1 g, 4.97 mmol, 1.0 eq) in DCM (20.00 mL) was added trifluoromethanesulfonic anhydride (2.088 ml, 12.43 mmol, 2.5 eq) and triethylamine (2.080 ml, 14.92 mmol, 3.0 eq) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred for overnight at 25 °C under nitrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (25 mL) was added to the reaction mixture, diluted with DCM (15 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was washed sodium bicarbonate solution (1 x 10 mL) followed by brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product methyl 4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydroisoquinoline-8- carboxylate 4 (2.5 g, 5.59 mmol, 112 % yield) as brown gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 9.79 (d, J = 0.80 Hz, 1H), 8.56 (d, J = 8.40 Hz, 1H), 8.47 (t, J = 0.80 Hz, 1H), 8.17-8.13 (m, 1H), 4.02 (s, 3H).

[0180] Intermediate 5: To a stirred solution of methyl-4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)-2,3- dihydroisoquinoline-8-carboxylate 4 (2.5 g, 7.04 mmol, 1.0 eq), formic acid (0.972 g, 21.11 mmol, 3.0 eq) and DIPEA (3.69 ml, 21.11 mmol, 3.0 eq) in NMP (12.0 mL) was degassed with nitrogen for 10 min. Then added tetrakis(triphenylphosphine)palladium(0) (0.813 g, 0.704 mmol, 0.1 eq) to reaction mixture,degassed with nitrogen for additional 5 min and heated to 80 °C under nitrogen atmosphere for 4h. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (40 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (1 x 150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted with) 7-8 % ethylacetate in pet ether to afford methyl 4-fluoroisoquinoline-8-carboxylate 5 (0.425 g, 1.921 mmol, 27.3 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 8.65 (d, J = 2.00 Hz, 1H), 8.41-8.36 (m, 1H), 8.04-8.01 (m, 1H), 4.01 (s, 3H).

[0181] Intermediate 6: To a solution of methyl 4-fluoroisoquinoline-8-carboxylate 5 (0.44 g, 2.144 mmol, 1.0 eq) in anhydrous dichloromethane (6.0 mL) at -78 °C in a round-bottomed flask, under inert atmosphere (N2) was added DIBAL-H (1.2 M sol in Toluene, 5.36 ml, 6.43 mmol, 3.0 eq) at -78°C as drop wise. The reaction mixture was stirred at -20 °C for 2h under nitrogen atmosphere. Upon completion of reaction (as confirmed by TLC, 30% ethylacetate in pet ether, Rfof desired product 0.1), the reaction mixture was quenched with sat. aq. sodium potassium tartrate solution (3 mL) very carefully at -10oC and stirred for 15 min. The reaction mixture was diluted with DCM (3 mL), organic layer separated, aqueous layer was extracted with DCM (2 × 4 mL). The combined org. layers are washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 4 % MeOH in DCM to afford (4-fluoroisoquinolin-8-yl)methanol 6 (0.185 g, 0.975 mmol, 45.5 % yield) as pale yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.54 (d, J = 2.40 Hz, 1H), 8.03 (d, J = 8.40 Hz, 1H), 7.88 (t, J = 8.40 Hz, 1H), 7.80 (d, J = 6.80 Hz, 1H), 5.58 (t, J = 5.60 Hz, 1H), 5.10 (d, J = 5.60 Hz, 2H).

[0182] Intermediate 7: To a stirred solution of (4-fluoroisoquinolin-8-yl)methanol 6 (0.180 g, 1.016 mmol, 1.0 eq) in Dichloromethane (3.0 mL) was added triethylamine (0.425 ml, 3.05 mmol, 3.0 eq) followed by mesyl-Cl (0.158 ml, 2.032 mmol, 2.0 eq) at 0oC and stirred for 10 min. The reaction mixture was allowed warm to RT and stirred for 2h. Upon completion of reaction (as confirmed by TLC, 50% ethylacetate in pet ether, Rfof desired product 0.5 & LCMS analysis), ice cold saturated aq. NaHCO3solution (5 mL) was added to the reaction mixture, diluted with DCM (5 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layer was washed with brine (1 x 10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure toafford the crude (4-fluoroisoquinolin-8-yl)methyl methanesulfonate 7 (0.345 g, 0.840 mmol, 83 % yield) as yellow gummy liquid. The crude compound used for next step without further purification.

[0183] Intermediate 8: To a stirred solution of (4-fluoroisoquinolin-8-yl)methyl methanesulfonate 7 (0.32 g, 1.254 mmol, 1.0 eq) in DMSO (2.00 mL) was added sodium cyanide (0.123 g, 2.507 mmol, 2.0 eq) at 25 °C and allowed to stirred for overnight under nitrogen atmosphere at 25 °C. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 25 mL / min, eluted using 18-20% ethylacetate in pet ether) to afford 2-(4-fluoroisoquinolin-8-yl)acetonitrile 8 (0.06 g, 0.319 mmol, 25.5 % yield) as pale brown solid.

[0184] Intermediate 9: To a stirred solution of 2-(4-fluoroisoquinolin-8-yl)acetonitrile 8 (0.060 g, 0.322 mmol, 1.0 eq) in a mixture of ammonia (7N soln. in methanol, 2.0 mL) and ethanol (2.0 mL) was added Raney Nickel (0.014 g, 0.161 mmol, 0.5 eq) at room temperature slowly under nitrogen atmosphere. The mixture was stirred at room temperature for overnight under hydrogen atmosphere. Upon completion of reaction (as confirmed by TLC, 50% ethylacetate in pet ether, Rfof desired product 0.1), the reaction mixture was filtered through celite, bed was washed with Methanol (2 x 5 mL) and the filtrate was concentrated under reduced pressure to afford the crude 2-(4-fluoroisoquinolin-8-yl)ethan-1- amine 9 (0.053 g, 0.261 mmol, 81% yield) as pale yellow gummy liquid. The crude compound used for next step without further purification.

[0185] Compound 16: To a stirred solution of 2-(4-fluoroisoquinolin-8-yl)ethan-1-amine 9 (0.05 g, 0.263 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (Intermediate 5 of Example 1, 0.091 g, 0.263 mmol, 1.0 eq) in DMF (1.5 mL) was added DIPEA (0.138 ml, 0.789 mmol, 3.0 eq) followed by HATU (0.150 g, 0.394 mmol, 1.5 eq) at 0oC under nitrogen atmosphere and stirred for 10 min. Then the reaction mixture was allowed to RT and stirred for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (5 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic layer was washed with brine (1 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted with 30-32 % ethylacetate in pet ether) to afford final compound 16 [N-(2-(4-fluoroisoquinolin-8-yl)ethyl)-5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxamide (0.065 g, 0.122 mmol, 46.2 % yield)] as off-white solid.1H- NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 8.73 (d, J = 2.00 Hz, 1H), 8.68 (t, J = 6.00 Hz, 1H), 8.54-8.51 (m, 2H), 8.19 (dd, J = 2.40, 8.60 Hz, 1H), 8.00 (d, J = 8.40 Hz, 1H), 7.83 (t, J = 8.40 Hz, 1H), 7.66 (d, J = 7.20 Hz, 1H), 7.14 (d, J = 8.80 Hz, 1H), 3.91 (s, 3H), 3.67-3.62 (m, 2H), 3.47-3.43 (m, 2H). Example 19 – Preparation of Compound 17

[0186] Compound 17 was prepared according to the following Scheme: [0187added to 6-bromoquinolin-3-amine 1 (0.6 g, 2.69 mmol, 1.0 eq) at RT and then the resultant solution was cooled to 0oC. Then a solution of sodium nitrite (0.278 g, 4.03 mmol, 1.5 eq) in water (1.5 mL) was added slowly to the reaction mixture over a period of 5 min., and the resultant mixture was allowed to stir for 30 min at 0 °C. Then tetrafluoroboric acid (48% sol in water, 9.84 g, 53.8 mmol, 20.0 eq) was added to the reaction mixture slowly, stirred for 1h and then heated at 50 °C for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the RM was cooled to 0 °C and basified with saturated NaHCO3solution until pH~10. The obtained solid was filtered, rinse with water (2 x 20 mL) and dried under vacuum for one hour to afford the crude product. The crude was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / MeCN mobile phase). to afford 6-bromo-3-fluoroquinoline 2 (0.130 g, 0.404 mmol, 15 % yield) as pale beige solid.1H-NMR (400 MHz, DMSO-d6): δ 9.00 (d, J = 4.00 Hz, 1H), 8.31-8.30 (m, 1H), 8.25 (dd, J = 4.00, 12.40 Hz, 1H), 8.04-8.00 (m, 1H), 7.92-7.87 (m, 1H).

[0188] Intermediate 3: To a stirred solution of 6-bromo-3-fluoroquinoline 2 (0.15 g, 0.664 mmol, 1.0 eq), zinc(II) cyanide (0.117 g, 0.995 mmol, 1.5 eq) and dppf (0.018 g, 0.033 mmol, 0.05 eq) in DMF (5.0 mL). The resulting solution was degassed with nitrogen bubbling for 10 minutes. Then Pd2(dba)3(0.061 g,0.066 mmol, 0.1 eq) was added to the mixture under nitrogen atmosphere and the resulting solution was degassed again with nitrogen bubbling for 10 minutes. The resulting solution was heated to 130 °C for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (25 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min., eluted using 15-17 % ethylacetate in pet ether) to afford 3-fluoroquinoline-6-carbo- nitrile 3 (0.07 g, 0.407 mmol, 61.3 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.16 (d, J = 2.80 Hz, 1H), 8.66 (d, J = 2.00 Hz, 1H), 8.41-8.38 (m, 1H), 8.24 (d, J = 8.80 Hz, 1H), 8.08-8.05 (m, 1H).

[0189] Intermediate 4: To a stirred solution of 3-fluoroquinoline-6-carbonitrile 3 (0.07 g, 0.407 mmol, 1.0 eq) in ammonia (7N soln. in MeOH, 6.0 mL) was added Raney Nickel (3.48 mg, 0.041 mmol, 0.1 eq) at room temperature slowly under nitrogen atmosphere. The mixture was stirred at room temperature for 4 h under hydrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite bed, bed was washed with methanol (2 x 5 mL) and the filtrate was concentrated under reduced pressure to afford the crude (3-fluoroquinolin-6- yl)methanamine 4 (0.055 g, 0.256 mmol, 63.0 % yield) as pale brown gummy solid. The crude compound was taken for next step without further purification.

[0190] Compound 17: To a stirred solution of (3-fluoroquinolin-6-yl)methanamine 4 (0.05 g, 0.284 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (Intermediate 5 of Example 1, 0.098 g, 0.284 mmol, 1.0 eq) in DMF (2.0 mL) was added DIPEA (0.149 ml, 0.851 mmol, 3.0 eq) followed by HATU (0.162 g, 0.426 mmol, 1.5 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4h. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by prep-HPLC (Column: Atlantis T3250, 500 ul, Mobile phase: A: 0.1% TFA in water, B: MeCN, Flow rate: 15 mL / min, Retention time: 10.1 min) to afford the final compound 17 [N-((3-fluoroquinolin-6-yl)methyl)-5-(3-iodo-4- methoxyphenyl)oxazole-4-carboxamide, TFA (0.038 g, 0.062 mmol, 21.8 % yield)] as off-white solid.1H- NMR (400 MHz, DMSO-d6): δ 9.14-9.18 (m, 1H), 8.90 (d, J = 3.60 Hz, 1H), 8.81 (d, J = 3.20 Hz, 1H), 8.59 (s,1H), 8.30-8.20 (m, 2H), 8.04 (d, J = 11.60 Hz, 1H), 7.87 (m, 1H), 7.76-7.73 (m, 1H), 7.13 (d, J = 12.00 Hz, 1H), 4.67 (d, J = 8.40 Hz, 2H), 3.90 (s, 3H). Example 20 – Preparation of Compound 18

[0191] Compound 18 was prepared according to the following Scheme: wasadded triethyl amine (0.47 mL, 3.40 mmol) and cooled to 0°C, followed by the addition of Boc2O (0.41 mL, 1.78 mmol). The resulting reaction mixture was allowed to stir at RT for 16 h. After completion of the reaction (monitored by TLC), added water (5 mL) into the reaction and extracted with DCM (2 x 10 mL), combined the organic layers were dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Compound-6a, as a pale-yellow liquid (400 mg isolated product).1H NMR (400 MHz, CDCl3): δ 8.31 (d, J= 2.4 Hz, 1H), 8.27 (s, 1H), 7.26-7.23 (m, 2H), 4.60 (br s, 1H), 3.193.17 (m, 2H), 2.68 (t, J= 7.6 Hz, 1H), 1.86-1.81 (m, 2H).1.45 (s, 9H).

[0193] Intermediate 6b: To a stirred solution of Compound-6a (100 mg, 0.39 mmol) in dry THF (5 mL) was added KHMDS (1M in THF) (1.56 mL, 1.56 mmol) at 0°C, under nitrogen atmosphere and stirred for 1 h. After addition of methyl iodide (0.05 mL, 0.63 mmol) at 0°C, the resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), quenched with sat. NH4Cl (3 mL) and extracted with ethyl acetate (2 x 10 mL), combined the organic layers and dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Compound-6b, as a pale-yellow liquid (100 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J= 2.8 Hz, 1H), 8.34 (t, J= 1.6 Hz, 1H), 7.66-7.63 (m, 1H), 7.28-7.24 (m, 2H), 7.18-7.14 (m, 2H), 3.16 (br s, 2H), 2.76 (s, 3H), 2.61-2.59 (m, 2H), 1.79 (br s, 2H).

[0194] Intermediate E18: A solution of Compound-6b (100 mg, 0.37 mmol) in dioxane (1 mL) was added 4M HCl in dioxane (2 mL) at 0°C. The resulting reaction mixture was gradually warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under vacuum at 45-50°C and the obtained residue was triturated with diethyl ether (5 mL), decanted thesolvent and dried the residue under vacuum at 45-50°C to afford crude Int-E18 as a brown colored semi- solid (90 mg isolated product).

[0195] Compound 18: To a stirred solution of Int-5 (Intermediate 5 of Example 1, 170 mg, 0.49 mmol) in DMF (3 mL) was added triethylamine (0.35 mL, 2.46 mmol) at 0°C, followed by the addition of Int-E18 (120 mg, 0.59 mmol), stirred for 15 min at 0°C, then was added HATU (230 mg, 0.59 mmol). The resulting reaction mixture was allowed to stir at RT for 16 h. After completion of the reaction by TLC, the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with 2-4% methanol in DCM to obtain Compound-18 as a light yellow semi-solid (120 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.33 (s, 2H), 8.15-8.11 (m, 2H), 7.72 (d, J= 7.6 Hz, 1H), 7.55-7.35 (m, 1H), 7.10 (d, J= 8.8 Hz, 1H), 3.87 (s, 3H), 3.49-3.34 (m, 2H), 3.00 (s, 3H), 2.82-2.79 (m, 2H), 1.88 (br s, 2H). Example 21 – Preparation of Compound 19

[0196] Compound 19 was prepared according to the following Scheme: N Fmg, 1.34 mmol) in methanol (10 mL) was added 7M NH3in methanol (15 mL, 30 vol) at 0°C, in a sealed tube. The resulting reaction contents were heated to 50°C for 16 h. After completion of the reaction (monitored by TLC), cooled to RT and filtered the precipitated solid, then washed the solid with methanol (1 mL) and dried under vacuum at 40-45°C to afford Compound-11 as an off-white solid (180 mg isolated product).

[0198] Intermediate 12: To a solution of triethyl amine (1.25 mL, 8.72 mmol) in dichloromethane (12 mL) was added trifluoro acetic anhydride (1.14 g, 5.45 mmol) at 0°C, stirred for 10 min, then Compound-11 (750 mg, 2.18 mmol) in dichloromethane (10 mL) was added into the reaction and stirred for 2 h at 0°C. After completion of the reaction (monitored by TLC), water (10 mL) was added and extracted the compound into dichloromethane and the organic layer was dried over sodium sulphate, filtered and evaporated under vacuum to obtain crude compound-12 (1.35 g), which was further purified by silica gelcolumn chromatography (100-200 mesh) eluting with 15-20% ethyl acetate in hexane to afford Compound-12 as an off-white solid (200 mg isolated product).1H NMR (400 MHz, CDCl3): δ 8.32 (d, J= 2.0 Hz, 1H), 8.00 (dd, J= 8.4, 2.0 Hz, 1H), 7.87 (s, 1H), 6.94 (d, J= 8.4 Hz, 1H), 3.97 (s, 3H)

[0199] Compound 19: To a stirred solution of Compound-12 (500 mg, 1.53 mmol) in THF (5 mL) was added Int-6 (236 mg, 1.53 mmol), followed by the DABAL-Me3(1.96 g, 7.64 mmol), in 5 equal lots for 15 min, in a sealed tube. The resulting reaction contents were heated to 120°C and stirred for 4 h. After completion of the reaction (monitored by TLC), quenched with 1N HCl (1 mL) and extracted with ethyl acetate (10 mL), separated the organic layer, dried over sodium sulphate and filtered, evaporated under vacuum to obtain crude compound-19 (700 mg), which was further purified by Grace (Reverse phase) to afford Compound-19 (200 mg) as an off-white solid. Triturated the solid using IPA (2 mL), decanted and dried under vacuum at 40-45°C to afford Compound-19 as a pale-yellow solid (105 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.92 (d, J= 2.0 Hz, 1H), 8.43 (dd, J= 8.8, 2.0 Hz, 1H), 8.39 (d, J= 2.8 Hz, 1H), 8.34 (br s, 1H), 7.64-7.62 (m, 1H), 7.28 (s, 1H), 7.11-7.07 (m, 3H, 2H exchanged in D2O), 3.93-3.91 (m, 2H), 3.90 (s, 3H), 2.70-2.68 (m, 2H), 2.05-2.01 (m, 2H). Example 22 – Preparation of Compound 21

[0200] Compound 21 was prepared according to the following Scheme: was(50 mg, cat) at RT. After degassing the reaction mixture with nitrogen for 15 min, Pd(OAc)2(50 mg, 0.23 mmol) was added and degassed again for 10 min. The sealed tube was capped and resulting reaction contents were heated to 125°C and stirred for 16 h. After completion of the reaction (monitored by TLC), cooled to RT and filtered through celite bed, washed the celite bed with ethyl acetate (20 mL). The filtrate was washed with water (10 mL) and separated the organic layer, which was dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Compound-13 as an off-white solid (1.5 gramsisolated product).1H NMR (400 MHz, CDCl3): δ 8.56 (t, J= 1.6 Hz, 1H), 8.48 (d, J= 2.8 Hz, 1H), 7.68 (br d, J= 16.0 Hz, 1H), 7.57-7.53 (m, 1H), 6.52 (br d, J= 16.0 Hz, 1H), 3.84 (s, 3H).

[0202] Intermediate 14: To a solution of Compound-13 (1.7 g, 9.39 mmol) in methanol (17 mL) was added nickel chloride hexahydrate (0.67 g, 2.82 mmol) at 0°C. After stirring for 15 min, sodium borohydride (0.89 g, 23.48 mmol) was added portion-wise over a period of 15 min. The resulting reaction mixture was allowed to stir at RT for 2 h. After completion of the reaction (monitored by TLC), evaporated the solvent under vacuum at 40-45°C and partitioned the residue between 10% MeOH in DCM (30 mL) and water (10 mL). Separated the organic layer, dried over sodium sulphate and evaporated under vacuum to afford crude compound-14 (1.0 g), which was further purified by silica gel column chromatography (100-200 mesh) by eluting with 20-25% ethyl acetate in hexane to afford Compound-14 as brown oily compound (0.8 gram isolated product).1H NMR (400 MHz, CDCl3): δ 8.34-8.31 (m, 2H), 7.29-7.27 (m, 1H), 3.68 (s, 3H), 2.99 (t, J= 7.6 Hz, 2H), 2.66 (t, J= 7.6 Hz, 2H).

[0203] Intermediate 15: To a solution of Compound-14 (800 mg, 4.37 mmol) in dry THF (10 mL) was added CH3MgBr (1M in THF) (17.5 mL, 17.48 mmol) dropwise at 0°C and stirred for 15 min. The resulting reaction mixture was allowed to stir at RT for 2 h. After completion of the reaction (monitored by TLC), quench with sat. NH4Cl solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (5 mL), separated and dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Compound-15 as a brown semi-solid (0.7 gram isolated product).

[0204] Intermediate 16: To a solution of Compound-15 (100 mg, 0.54 mmol) in TFA (5 mL) was added chloro acetonitrile (0.06 mL, 1.08 mmol). The resulting reaction contents were heated to 70°C and stirred for 4 h. After completion of the reaction (monitored by TLC), quench with sat. sodium bicarbonate solution (10 mL) (until, pH-8) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (5 mL), separated and dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Compound-16 as a brown semi-solid (130 mg isolated product).

[0205] Intermediate E21: To a solution of Compound-16 (120 mg, 0.46 mmol) in ethanol (10 mL) was added thiourea (40 mg, 0.55 mmol) and acetic acid (0.3 mL, 2.5 vol). The resulting reaction contents were heated to 80°C and stirred for 16 h. After completion of the reaction (monitored by TLC), reaction mass was evaporated under vacuum and the obtained residue was partitioned between ethyl acetate (10 mL) and water (5 mL). The aq. layer was basified with aq. sodium hydroxide solution (until pH-8) and extracted with ethyl acetate (2 x 10 mL), combined the organic extracts and dried over sodium sulphate,filtered and evaporated under vacuum to afford crude Int-E21 as a brown semi-solid, which was used as such for the next step (130 mg isolated product).

[0206] Compound 21: To a stirred solution of Int-5 (Intermediate 5 of Example 1, 615 mg, 1.78 mmol) in DMF (3.2 mL) was added Int-E21 (320 mg, 1.78 mmol). After cooling to 0°C was added HATU (770 mg, 2.14 mmol), stirred for 10 min, followed by the addition of triethylamine (1.19 mL, 8.91 mmol). The result- ing reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL), combined organic phases were dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with 25-30% ethyl acetate in hexane to afford Compound-21 as a pale green semi-solid (160 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J= 2.0 Hz, 1H), 8.51 (s, 1H), 8.32 (d, J= 2.8 Hz, 1H), 8.30 (s, 1H), 8.18 (dd, J= 8.8, 2.0 Hz, 1H), 7.59-7.56 (m, 1H), 7.47 (s, 1H), 7.14 (d, J= 8.8 Hz, 1H), 3.90 (s, 3H), 2.67-2.63 (m, 2H), 2.13-2.07 (m, 2H), 1.42 (s, 6H). Example 23 – Preparation of Compound 22 and Compound 23

[0207] Compound 21 and Compound 23 were prepared according to the following Scheme:mL) was added DMF (cat), followed by the dropwise addition of oxalyl chloride (0.76 mL, 8.92 mmol) at 0°C. The resulting reaction mass was warmed to RT and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum to afford crude Compound-7B as a yellow color liquid (1 gram isolated product), which was used as such for the next reaction.

[0209] Intermediate 18A: To a stirred solution of Compound-7B (1.0 g, 7.63 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added (5-fluoropyridin-3-yl) boronic acid (1.16 g, 8.39 mmol), followed by the addition of potassium carbonate (3.1 g, 22.9 mmol). The reaction mixture was degassed with nitrogen for 15 min and PdCl2(dppf)DCM complex (620 mg, 0.76 mmol) was added, again degassed for 10 min. Then sealed tube was capped and resulting reaction contents were heated at 80°C for 16 h. Aftercompletion of the reaction (monitored by TLC), the reaction was cooled to RT and filtered through a celite pad. The filtrate was extracted with ethyl acetate (50 mL) and organic layer was dried over sodium sulphate and evaporated under vacuum to afford crude compound-18A (1.2 g), which was purified by silica gel column chromatography (100-200 mesh) eluting with 30-35% ethyl acetate in hexane to afford Compound-18A as a pale-yellow solid (980 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.51 (t, J= 2.8 Hz, 1H), 7.54-7.51 (m, 1H), 6.43 (s, 1H), 2.78-2.75 (m, 2H), 2.53 (t, J= 6.8 Hz, 1H), 2.24-2.17 (m, 2H).

[0210] Intermediate 18B: To a stirred solution of Compound-18A (1.0 g, 5.23 mmol) in methanol (10 mL) was added 20% Pd(OH)2(0.1 g, 0.52 mmol), at RT. The resulting reaction mixture was stirred under hydrogen pressure (60 psi) for 2 h. After completion of the reaction (monitored by TLC), the reaction was filtered through a celite pad. The filtrate was evaporated under vacuum to afford crude compound-18B (1.2 g), which was purified by silica gel column chromatography (100-200 mesh) eluting with 20-25% ethyl acetate in hexane to afford Compound-18B as a brown semi-solid (980 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J= 2.4 Hz, 1H), 8.34 (s, 1H), 7.34-7.28 (m, 1H), 3.13-3.06 (m, 1H), 2.65-2.60 (m, 1H), 2.53-2.50 (m, 2H), 2.44-2.36 (m, 1H), 2.22-2.14 (m, 2H), 1.92-1.79 (m, 2H).

[0211] Intermediate E22 (racemic): To a stirred solution of Compound-18B (360 mg, 1.86 mmol) in ethanol (10 mL) was added titanium isopropoxide (1.1 mL, 3.72 mmol), in a sealed tube at RT. After cooling the reaction to 0°C, 7M NH3in MeOH (2.6 mL, 18.6 mmol) was added dropwise. The resulting reaction mass was allowed to stir at RT for 16 h. After that, cooled the reaction mass to 0°C and sodium borohydride (105 mg, 2.79 mmol) was added and resulting reaction mass was warmed to RT and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction was filtered through a celite pad. The filtrate was evaporated under vacuum to afford crude Int-E22 as a pale yellow semi-solid (520 mg isolated product).

[0212] Intermediate 17 (racemic): To a stirred solution of Int-5 (Intermediate 5 of Example 1, 450 mg, 1.30 mmol) in DMF (4.5 mL) was added triethylamine (0.91 mL, 6.52 mmol) at 0°C, followed by the addition of Int-E22 (300 mg, 1.54 mmol). After stirring for 15 min at 0°C was added HATU (590 mg, 1.54 mmol), stirred for 10 min. The resulting reaction mixture was warmed to stir at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with25-30% ethyl acetate in hexane to afford Compound-17 as an off-white solid (360 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J= 2.4 Hz, 1H), 8.53 (s, 1H), 8.41-8.38 (m, 2H), 8.15-8.13 (m, 2H), 7.63-7.60 (m, 1H), 7.14-7.11 (m, 1H), 3.99-3.96 (m, 1H), 3.89 (s, 3H), 2.86-2.80 (m, 1H), 1.95-1.79 (m, 4H), 1.68-1.69 (m, 1H), 1.48-1.38 (m, 3H).

[0213] Compounds 22A, 22B, 23A and 23B: 1.0 (250 x4.6)5u; MP: CO2: Ethanol (100%) 80-20; BPR:102 KGF; flow: 3.0ml / min; UV: 280nm) to afford four isomers. Structures were verified by nOe analyses and the stereochemistry was arbitrarily assigned for the respective cis and trans components as follows: Isomer-1 (trans-A), Isomer-2 (cis-A), Isomer-3 (cis-B) and Isomer-4 (trans-B). Compound 22A:1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J= 2.0 Hz, 1H), 8.53 (s, 1H), 8.41-8.38 (m, 2H), 8.15 (dd, J= 8.4, 2.0 Hz, 1H), 8.11 (d, J= 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 7.12 (d, J= 8.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.89 (s, 3H), 2.86-2.80 (m, 1H), 1.99-1.79 (m, 4H), 1.68-1.59 (m, 1H), 1.53-1.38 (m, 3H). Compound 22B:1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J= 2.4 Hz, 1H), 8.54 (s, 1H), 8.41-8.39 (m, 2H), 8.17-8.12 (m, 2H), 7.64-7.60 (m, 1H), 7.12 (d, J= 9.2 Hz, 1H), 3.99-3.97 (m, 1H), 3.89 (s, 3H), 2.86-2.80 (m, 1H), 1.99-1.79 (m, 4H), 1.68-1.59 (m, 1H), 1.50-1.46 (m, 3H). Compound 23A:1H NMR (400 MHz, DMSO-d6): δ 8.75 (d, J= 2.4 Hz, 1H), 8.57 (s, 1H), 8.41-8.39 (m, 2H), 8.18 (dd, J= 8.8, 2.0 Hz, 1H), 8.01 (d, J= 7.2 Hz, 1H), 7.70-7.67 (m, 1H), 7.14 (d, J= 8.8 Hz, 1H), 4.26 (br s, 1H), 3.89 (s, 3H), 3.03 (br s, 1H), 1.951.91 (m, 2H), 1.87-1.83 (m, 2H), 1.63 (br s, 4H). Compound 23B:1H NMR (400 MHz, DMSO-d6): δ 8.75 (d, J= 2.4 Hz, 1H), 8.58 (s, 1H), 8.42 (br s, 2H), 8.18 (dd, J= 8.8, 2.0 Hz, 1H), 8.02 (d, J= 7.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.13 (dd, J= 8.8, 1.2 Hz, 1H), 4.26 (br s, 1H), 3.89 (s, 3H), 3.03 (br s, 1H), 1.98-1.91 (m, 2H), 1.88-1.83 (m, 2H), 1.63 (br s, 4H).Example 24 – Preparation of Compound 24

[0214] Compound 24 was prepared according to the following Scheme: [02 onitrile(5 mL) was added Boc anhydride (870 mg, 4.01 mmol) and DMAP (cat). The resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated under vacuum and the obtained residue was partitioned between 1N HCl (5 mL) and ethyl acetate (10 mL). The separated organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4,filtered and solvent was evaporated under reduced pressure to afford crude Compound-7b as a colorless gummy liquid (610 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 9.22 (d, J= 4.0 Hz, 1H), 7.95 (s, 1H), 7.85-7.81 (m, 1H), 7.54-7.37 (m, 2H), 7.26-7.17 (m, 1H), 1.47 (d, J= 1.6 Hz, 9H).

[0216] Intermediate 7c: To a stirred solution of Compound-7 (450 mg, 2.55 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added Compound-7b (600 mg, 2.55 mmol), followed by the addition of KCl (1.39 g, 10.07 mmol). Then degassed the reaction mixture with nitrogen for 15 min, Pd(PPh3)4(20 mg, 0.13 mmol) was added and again degassed for 10 min. The sealed tube was capped and resulting reaction contents were heated at 100°C for 16 h. After completion of the reaction (monitored by TLC), the reaction was cooled to RT and filtered through a celite pad. The filtrate was evaporated under vacuum and obtained residue was purified by silica gel column chromatography (100-200 mesh) eluting with 20-25% ethyl acetate in hexane to afford Compound-7c as a gummy semi-solid (810 mg isolated product).

[0217] Intermediate E24: A solution of Compound-7c (800 mg, 2.77 mmol) in 4M HCl in dioxane (4 mL) was stirred for 16 h at RT. After completion of the reaction (monitored by TLC), the precipitated solid was filtered and the solid was washed with dioxane (2 mL), dried under vacuum at 45-50°C to afford Int- E24 as a cream color solid (300 mg isolated product).1H NMR (400 MHz, DMSO-d6): δ 8.80 (t, J= 1.6 Hz, 1H), 8.69 (d, J= 2.8 Hz, 1H), 8.14-8.11 (m, 1H), 7.85-7.83 (m, 1H), 7.80 (t, J= 1.6 Hz, 1H), 7.65 (t, J= 7.6 Hz, 1H), 7.52-7.49 (m, 1H), 6.60-5.70 (m, 2H).

[0218] Compound 24: To a stirred solution of Int-5 (Intermediate 5 of Example 1, 200 mg, 0.58 mmol) in DMF (2.0 mL) was added triethylamine (0.57 mL, 4.05 mmol) at 0°C, followed by the addition of Int-E24(130 mg, 0.69 mmol), stirred for 15 min at 0°C was added HATU (264 mg, 0.69 mmol), stirred for 10 min. Then resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with 30-35% ethyl acetate in hexane to afford Compound-24 as an off-white solid (150 mg isolated product).1H NMR (400 MHz, DMSO- d6): δ 10.32 (s, 1H), 8.79 (t, J= 2.0 Hz, 1H), 8.70-8.69 (m, 2H), 8.61 (d, J= 2.4 Hz, 1H), 8.23 (dd, J= 8.4, 2.0 Hz, 1H), 8.20-8.19 (m, 1H), 8.07-8.00 (m, 2H), 7.56-7.51 (m, 2H), 7.18 (d, J= 9.2 Hz, 1H), 3.91 (s, 3H). Example 25 – Preparation of Compound 25

[0219] Compound 25 was prepared according to the following Scheme:

[0220] rboxylate 1 (1.0 g, 4.88 mmol, 1.0 eq) in DMF (8.0 mL) was added sodium hydride (60% w / w in mineral oil, 0.273 g, 6.83 mmol, 1.4 eq) at 0oC and allowed to stir for 30 min under N2atmosphere. SEM-Cl (0.952 mL, 5.37 mmol, 1.1 eq) was added at 0oC and allowed to stir overnight. Upon completion of the reaction (asconfirmed by LCMS analysis), the reaction mixture was quenched by saturated NH4Cl solution at 0oC and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 18 mL / min). The column was eluted using 10% ethylacetate in pet ether to afford methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazole-4-carboxylate 1b (1.15 g, 3.33 mmol, 68.4 % yield) as pale yellow gummy liquid .1H-NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 5.61 (s, 2H), 3.82 (s, 3H), 3.48 (t, J = 8.00 Hz, 2H), 0.82 (t, J = 7.60 Hz, 2H), -0.01 (t, J = Hz, 10H).

[0221] Intermediate 3: To a stirred solution of methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazole-4-carboxylate 1b (1.15 g, 3.43 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (1.436 g, 5.15 mmol, 1.5 eq) in dioxane (10.0 mL) and water (1.0 mL) was added potassium carbonate (0.948 g, 6.86 mmol, 2.0 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min and added PdCl2(dppf) (0.251 g, 0.343 mmol, 0.1 eq). The reaction mixture was heated to 80oC for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was diluted with ethyl acetate (10 mL), filtered through Celite and washed with ethylacetate (2 x 10 mL). Water (20 mL) was added to the filtrate and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 40-45% ethylacetate in pet-ether) to afford methyl 5-(4-methoxy-3- nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 3 (1.13 g, 2.485 mmol, 72.5 % yield) as brown gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.23 (t, J = 6.40 Hz, 2H), 8.03-8.00 (m, 1H), 7.42 (d, J = 9.20 Hz, 1H), 5.64 (s, 2H), 4.04 (t, J = 7.20 Hz, 3H), 3.76 (s, 3H), 3.50 (t, J = 8.00 Hz, 2H), 1.18 (t, J = 6.80 Hz, 2H), -0.02 (t, J = Hz, 9H).

[0222] Intermediate 4: To a stirred solution of methyl 5-(4-methoxy-3-nitrophenyl)-1-((2-(trimethyl- silyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 3 (1.39 g, 3.41 mmol, 1.0 eq) in ethanol (15.0 mL) and water (6.0 mL) was added ammonium chloride (1.460 g, 27.3 mmol, 8.0 eq) and iron (0.952 g, 17.06 mmol, 5.0 eq) under nitrogen atmosphere at RT. The reaction mixture was stirred at 85oC for 8 h. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was diluted using 10% MeOH in DCM (20 ml) and water (20 mL). The organic layer was separated and the aqueous layerwas extracted with 10% MeOH in DCM (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude methyl 5-(3-amino-4-methoxy- phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 4 (0.980 g, 2.53 mmol, 74.2 % yield) as black gummy liquid.

[0223] Intermediate 5: To a stirred solution of copper(I) iodide 4 (0.515 g, 2.70 mmol, 1.2 eq) in acetonitrile (8.0 mL) was added tert-butyl nitrite (0.279 g, 2.70 mmol, 1.2 eq) followed by a solution of methyl 5-(3-amino-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (0.850 g, 2.252 mmol, 1.0 eq) in Acetonitrile (8.0 mL) at 0oC. The resulting solution was stirred at 0 °C for 15 min. Then the reaction mixture was warmed to room temperature and stirred for overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was basified using saturated sodium bicarbonate solution (20 mL) and diluted with DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 30-40% ethylacetate in pet ether to afford methyl 5- (3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 5 (0.390 g, 0.702 mmol, 31.2 % yield)) as yellow gummy liquid.

[0224] Intermediate 6: To a stirred solution of methyl 5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethyl- silyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 5 (0.390 g, 0.799 mmol, 1.0 eq) in a mixture of MeOH (6.0 mL), THF (4.0 mL) and water (2.0 mL) at 0oC was added LiOH.H2O (0.076 g, 3.19 mmol, 4.0 eq) and allowed to stirred for overnight at RT. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was acidified with saturated citric acid solution (5.0 mL) and diluted using ethyl acetate (10.0 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4- carboxylic acid 6 (0.880 g, 1.552 mmol, 194 % yield) as off white solid.

[0225] Intermediate 7a: To a stirred solution of an 5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole-4-carboxylic acid 6 (0.090 g, 0.190 mmol, 1.0 eq) and 3-(5-fluoropyridin-3- yl)propan-1-amine 7 (Intermediate 6 of Example 1, 0.044 g, 0.285 mmol, 1.5 eq) in DMF (3.0 mL) was added DIPEA (0.166 mL, 0.949 mmol, 1.2 eq) followed by HATU (0.087 g, 0.228 mmol, 5.0 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon com- pletion of the reaction (as confirmed by LCMS analysis), ice cold water (10.0 mL) was added to the reactionmixture and diluted with ethylacetate (10.0 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford N-(3-(5-fluoropyridin-3-yl)propyl)-5-(3-iodo-4-meth- oxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide 7a (0.200 g, 0.263 mmol, 138 % yield) as pale yellow liquid.

[0226] Compound 25: To a stirred solution of an N-(3-(5-fluoropyridin-3-yl)propyl)-5-(3-iodo-4-meth- oxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide 7a (0.200 g, 0.328 mmol, 1.0 eq) in THF (5.0 mL) was added TBAF (1M in THF, 1.638 mL, 1.638 mmol, 5 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. The LCMS analysis indicated unreacted starting material. Additional 2.0 mL of TBAF was added to the reaction mixture at 0oC and allowed to stirred for 5 hours at RT. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to dryness. The obtained crude was purified by prep-HPLC (Column: X Bridge C18-150, 500 ul, Mobile phase: A: 0.1% FA in water, B: MeCN, Flow rate: 15 mL / min, Retention time: 10.2 min) to afford the final compound N-(3-(5-fluoropyridin-3- yl)propyl)-5-(3-iodo-4-methoxyphenyl)-1H-imidazole-4-carboxamide 25 (0.040 g, 0.083 mmol, 25.30 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.75 (s, 1H), 8.38 (t, J = 16.40 Hz, 3H), 8.12 (s, 1H), 7.90-7.87 (m, 1H), 7.79 (s, 1H), 7.67-7.63 (m, 1H), 7.06 (d, J = 8.40 Hz, 1H), 3.87 (s, 3H), 3.28-3.23 (m, 2H), 2.68 (t, J = 8.00 Hz, 2H), 1.87-1.80 (m, 2H). Example 26 – Preparation of Compound 27

[0227] Compound 27 was prepared according to the following Scheme:

[0228] y y .00 g, 14.27 mmol) in DCM (60.00 mL) was added copper (II) acetate (3.89 g, 21.41 mmol, 1.5 eq), pyridine (2.309 ml, 28.5 mmol, 2.0 eq) and (4-methoxyphenyl)boronic acid (4.34 g, 28.5 mmol, 2.0 eq) at 25 °C .The mixturewas stirred for overnight at 25 °C under oxygen atmosphere. Upon completion of reaction (as confirmed by TLC, 70% ethylacetate in pet ether, Rf of desired product 0.5 & LCMS analysis), the reaction mixture was concentrated under reduced pressure to afford the crude product as blue gummy liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 60% ethylacetate in pet ether) to afford ethyl 1-(4-methoxyphenyl)-1H-imidazole-2-carboxy- late 3 (1.00 g, 3.06 mmol, 21.45 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 7.56 (s, 1H), 7.35-7.32 (m, 2H), 7.22 (s, 1H), 7.04-7.01 (m, 2H), 4.15-4.10 (m, 2H), 3.82 (s, 3H), 1.14 (t, J = 9.60 Hz, 3H).

[0229] Intermediate 4: To a stirred solution of ethyl 1-(4-methoxyphenyl)-1H-imidazole-2- carboxylate 3 (1.00 g, 4.06 mmol, 1.0 eq) and chloroform (10.0 mL) in Trifluoroacetic acid (3.0 mL) was added silver trifluoroacetate (0.897 g, 4.06 mmol, 1.0 eq) and iodine (1.031 g, 4.06 mmol, 1.0 eq) and the reaction mixture was stirred at 25 °C for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure and basified to pH=12 using aqueous ammonia (30 solution, 10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with aq. Na2S2O3solution (2 x 40 mL), water ( 1 x 50 mL) followed by brine (1 x 50 mL). The organic layer was dried under anhydrous Na2SO4and concentrated under reduced pressure to afford the crude product. The crude product was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous TFA / MeCN mobile phase) to afford ethyl 1-(3- iodo-4-methoxyphenyl)-1H-imidazole-2-carboxylate 4 (1.00 g, 2.66 mmol, 65.5 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 7.86 (d, J = 3.20 Hz, 1H), 7.63 (d, J = 1.60 Hz, 1H), 7.45 (dd, J = 3.60, 11.80 Hz, 1H), 7.29 (d, J = 1.20 Hz, 1H), 7.09 (d, J = 12.00 Hz, 1H), 4.19-4.12 (m, 2H), 3.89 (s, 3H), 1.14 (t, J = 9.60 Hz, 3H).

[0230] Compound 27: A mixture of 3-(5-fluoropyridin-3-yl)propan-1-amine 7 (Intermediate 6 of Example 1, 0.414 g, 2.69 mmol, 2.5 eq) and DIPEA (0.478 ml, 2.69 mmol, 2.5 eq) in methanol (10 mL) was stirred at 25 °C under nitrogen atmosphere for 1 h. To the reaction mixture ethyl 1-(3-iodo-4- methoxyphenyl)-1H-imidazole-2-carboxylate 4 (0.4 g, 1.075 mmol, 1.0 eq) and calcium chloride (0.119 g, 1.075 mmol, 1.0 eq) were added under nitrogen atmosphere at 25 °C and the mixture was stirred at 25 °C for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to afford the crude product. The obtained crude was purified by prep-HPLC (Column: Agilent 50mm, 500 ul, Mobile phase: A: 10 Mm ammonium bicarbonate in water, B: MeCN, Flow rate: 15 mL / min, Retention time: 11.0 min) to afford the final compound 27 [N-(3-(5- fluoropyridin-3-yl)propyl)-1-(3-iodo-4-methoxyphenyl)-1H-imidazole-2-carboxamide (0.117 g, 0.243 mmol, 28.7 % yield)] as pale brown gummy solid.1H-NMR (400 MHz, DMSO-d6): δ 8.60 (t, J = 6.00 Hz,1H), 8.38 (d, J = 2.80 Hz, 1H), 8.32 (t, J = 1.60 Hz, 1H), 7.76 (d, J = 2.80 Hz, 1H), 7.63-7.60 (m, 1H), 7.48 (d, J = 0.80 Hz, 1H), 7.39-7.37 (m, 1H), 7.13 (d, J = 0.80 Hz, 1H), 7.05 (d, J = 8.80 Hz, 1H), 3.88 (s, 3H), 3.19-3.14 (m, 2H), 2.68-2.66 (m, 2H), 1.84-1.77 (m, 2H). Example 27 – Preparation of Compound 28

[0231] Compound 28 was prepared according to the following Scheme:

[0232] y . g, . ol, 1.0 eq) in methanol (15 mL) was added ethyl 2-oxoacetate (40% in toluene, 1.230 g, 4.82 mmol, 1.2 eq) and the resulting mixture heated at reflux for 3.5 h. The mixture was concentrated in vacuum and the resulting residue reconstituted in anhydrous ethanol (15.0 mL) and treated with potassium carbonate (1.110 g, 8.03 mmol, 2.0 eq) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene 1a (1.176 g, 6.02 mmol, 1.5 eq). The resulting mixture was heated at 65° C for 4 h under nitrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to dryness. Ice cold water (50 mL) was added to the residue and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 37-40 % ethyl acetate in pet-ether) to afford ethyl 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxylate 2 (0.810 g, 1.918 mmol, 47.8 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 0.80 Hz, 1H), 7.86(d, J = 2.40 Hz, 1H), 7.77 (d, J = 0.80 Hz, 1H), 7.47-7.44 (m, 1H), 7.09 (d, J = 8.80 Hz, 1H), 4.16-4.11 (m, 2H), 3.87 (t, J = 37.20 Hz, 3H), 1.15 (t, J = 6.80 Hz, 3H).

[0233] Intermediate 3: To a stirred solution of ethyl 1-(3-iodo-4-methoxyphenyl)-1H-imidazole- 5-carboxylate 2 (0.800 g, 2.150 mmol, 1.0 eq) in a mixture of ethanol (10.0 mL), THF (6.67 mL) and Water (3.33 mL) was added LiOH.H2O (0.206 g, 8.60 mmol, 4.0 eq) at 0oC and allowed to stir for overnight at RT. Upon completion of reaction (as confirmed by LCMS analysis), the reaction was concentrated under reduced pressure. The resulting residue was acidified with acetic acid (3.0 mL), concentrated under reduced pressure to afford the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C1840 µm, 870 g; flow rate: 25 mL / min; 35% HCOOH in water / MeCN mobile phase) to afford 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxylic acid 3 (0.720 g, 1.817 mmol, 84.5 % yield) as off white-solid.

[0234] Compound 28: To a stirred solution of an 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5- carboxylic acid 3 (0.250 g, 0.727 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine (Intermediate 6 of Example 1, 0.168 g, 1.090 mmol, 1.5 eq) in DMF (4.0 mL) was added DIPEA (0.469 g, 3.63 mmol, 5.0 eq) followed by HATU (0.331 g, 0.872 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to afford the crude. Ice cold water (20 mL) was added to the resulting crude and diluted with ethylacetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude . The obtained crude was purified by prep-HPLC (Column: XSELECT C18-250, 500 ul, Mobile phase: A: 10 mm Ammonium bicarbonate in water, B: MeCN, Flow rate: 14 mL / min, Retention time: 13.0 min) to afford N-(3-(5-fluoropyridin-3-yl)propyl)-1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxamide 28 (0.113 g, 0.232 mmol, 31.9 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.40-8.37 (m, 2H), 8.33 (t, J = 2.00 Hz, 1H), 7.90 (d, J = 0.80 Hz, 1H), 7.75 (d, J = 2.40 Hz, 1H), 7.62 (t, J = 2.00 Hz, 1H), 7.61- 7.58 (m, 1H), 7.37-7.34 (m, 1H), 7.06 (d, J = 8.80 Hz, 1H), 3.87 (s, 3H), 3.17-3.12 (m, 2H), 2.65 (t, J = 7.60 Hz, 2H), 1.78 (t, J = 7.20 Hz, 2H).Example 28 – Preparation of Compound 29

[0235] Compound 29 was prepared according to the following Scheme:

[0236] 4 mmol, 1.0eq) in glacial acetic acid (10.0 mL) was added ICl (0.442 ml, 8.81 mmol, 1.2 eq) at room temperature under nitrogen atmosphere and the resulting solution was stirred for overnight at 140oC. The reaction progress was monitored by TLC (15% ethylacetate in pet ether, Rf ~ 0.2). Upon completion of reaction, the reaction mixture was cooled to room temperature and poured into a solution of sodium metabisulfite (15.0 g) in ice cold water (250 mL). The suspension was stirred for 10 min, filtered, washed with water (20 mL) and air dried for 30 min. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 15% ethylacetate in pet ether to afford 3- iodo-4-methoxybenzaldehyde 2 (1.0 g, 2.98 mmol, 40.5 % yield) as off-white solid.1H-NMR (400 MHz, CDCl3): δ 9.85 (s, 1H), 8.33 (d, J = 2.00 Hz, 1H), 7.90-7.87 (m, 1H), 6.95 (d, J = 8.40 Hz, 1H), 4.00 (s, 3H).

[0237] Intermediate 4: To a stirred solution of 3-iodo-4-methoxybenzaldehyde 2 (0.8 g, 3.05 mmol, 1.0 eq) in DMF (10.0 ml) was added methyl cyanoacetate 3 (0.270 ml, 3.05 mmol, 1.0 eq), sodium azide (0.595 g, 9.16 mmol, 3.0 eq) and triethylamine hydrochloride (1.051 g, 7.63 mmol, 2.5 eq) at RT under nitrogen atmosphere and the resulting reaction mixture was stirred for overnight at 70oC. The reaction progress was monitored by TLC (20% Ethylacetate in pet ether Rf ~ 0.1). Upon completion of the reaction (as confirmed by TLC, 20% Ethylacetate in pet ether, Rf of product ~ 0.1), the reaction mixture was cooled to room temperature and quenched with ice cold saturated NaHCO3solution (45 mL) and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as yellow gummy liquid.The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 45-49 % ethylacetate in pet ether to afford methyl 5-(3-iodo-4- methoxyphenyl)-1H-1,2,3-triazole-4-carboxylate 4 (0.43 g, 1.132 mmol, 37.1 % yield) as yellow gummy oil.1H-NMR (400 MHz, DMSO-d6): δ 15.83 (d, J = 60.80 Hz, 1H), 8.23 (br s, 1H), 7.98 (d, J = 14.80 Hz, 1H), 7.82 (s, 1H), 7.13 (d, J = 8.40 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H).

[0238] Intermediate 5: To a stirred solution of methyl 5-(3-iodo-4-methoxyphenyl)-1H-1,2,3- triazole-4-carboxylate 4 (0.430 g, 1.197 mmol, 1.0 eq) in a mixture of methanol (9.0 ml), tetrahydrofuran (6.0 ml) and water (3.00 ml) was added lithium hydroxide (0.201 g, 4.79 mmol, 4.0 eq) at 0oC. the resulting solution was stirred for 10 min at 0oC. Then the reaction mixture was allowed to RT and stirred for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to dryness. The obtained residue was soluble in water (5 mL) and acidified with acetic acid until pH ~ 5-6 and concentrated under reduced pressure to afford compound. The obtained crude was purified by prep-HPLC (Column: Agilent 50mm, 500 ul, Mobile phase: A: 0.1% TFA in water, B: MeCN, Flow rate: 15 mL / min, Retention time: 8.0 min) to afford desired compound 5-(3-iodo- 4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylic acid 5 (0.255 g, 0.721 mmol, 60 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.52 (br s, 1H), 8.10 (br s, 1H), 7.07 (d, J = 8.80 Hz, 1H), 3.88 (s, 3H).

[0239] Compound 29: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)-1H-1,2,3-triazole-4- carboxylic acid 5 (0.2 g, 0.580 mmol, 1.0 eq), 3-(5-fluoropyridin-3-yl)propan-1-amine, HCl 7 (Intermediate 6 of Example 1, 0.166 g, 0.869 mmol, 1.5 eq) in DMF (3.5 ml) was added N,N-diisopropylethylamine (0.375 g, 2.90 mmol, 5.0 eq), EDC (0.167 g, 0.869 mmol, 1.5 eq) and HOBt (0.133 g, 0.869 mmol, 1.5 eq) at 0oC under nitrogen atmosphere and solution was stirred for overnight at room temperature. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (45 mL) was added to the reaction mixture, diluted with ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude compound. The obtained crude was purified by prep-HPLC (Column: SUNFIRE C-1819.1X250, 500 ul, Mobile phase: A: 0.1% FA in water, B: MeCN, Flow rate: 15 mL / min, Retention time: 10.1 min). The product containing fractions were combined and lyophilized to afford the TFA salt of 29 as off-white solid and the obtained TFA salt of 29 was basified with saturated aqueous solution of NaHCO3solution (4 mL), diluted with DCM (4 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 4 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford as yellow gummy liquid and the compound was lyophilized to afford final compound 29 [N-(3-(5-fluoropyridin-3-yl)propyl)-5-(3-iodo-4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxamide (0.045 g, 0.092 mmol, 15.8 % yield)] as pale beige solid.1H-NMR (400 MHz, DMSO-d6): 15.56 (br s, 1H), 8.61 (s, 1H), 8.42-8.35 (m, 3H), 7.98 (t, J = 6.80 Hz, 1H), 7.67-7.64 (m, 1H), 7.10 (d, J = 8.80 Hz, 1H), 3.88 (s, 3H), 3.28 (t, J = 6.40 Hz, 2H), 2.71-2.68 (m, 2H), 1.90-1.85 (m, 2H). Example 29 – Preparation of Compound 30

[0240] Compound 30 was prepared according to the following Scheme:

[0241] Intermediate 2: To a stirred solution of 4-bromo-1-methoxy-2-nitrobenzene 1 (5.5 g, 23.70 mmol, 1.0 eq) and bis(pinacolato)diboron (12.04 g, 47.4 mmol, 2. eq) in 1,4-dioxane (30.0 ml) was added potassium acetate (13.38 g, 136 mmol, 5.75 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min and added PdCl2(dppf) (0.520 g, 0.711 mmol, 0.03 eq). Then the mixture was degassed again with nitrogen for 10 min. The reaction mixture was heated to 100oC for overnight. The reaction progress was monitored by TLC (10% EtOAc in pet ether, Rf ~ 04). Upon completion of reaction, the reaction mixture was filtered through Celite, bed was washed with EtOAc (1 x 10 mL) and the filtrate was concentrated under reduced pressure to dryness. Water (150 mL) was added to the residue, diluted with ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 70 mL). The combined organic layer was washed with brine (1x 150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as black gummy liquid. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 12-14 % ethylacetate in pet ether) to afford 2-(4-methoxy-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (8.1 g, 23.06 mmol, 97 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.03 (d, J = 1.60 Hz, 1H), 7.90 (dd, J = 1.60, 8.40 Hz, 1H), 7.38 (d, J = 8.40 Hz, 1H), 3.96 (s, 3H), 1.30 (s, 12H).

[0242] Intermediate 4: To a stirred solution of 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane 2 (0.4 g, 1.433 mmol, 1.0 eq), ethyl 5-bromothiazole-4-carboxylate 3 (0.305 g, 1.290 mmol, 0.9 eq), K2CO3(0.396 g, 2.87 mmol, 2.0 eq) in mixture of 1,4-dioxane (4.0 mL) and water (0.5 mL) was degassed with nitrogen for 10 min. Then PdCl2(dppf) (10.49 mg, 0.014 mmol, 0.01 eq) was added to the mixture and degassed with nitrogen for 3h under nitrogen atmosphere. The reaction progress was monitored by LCMS analysis, Upon completion of reaction the reaction mixture was filtered through Celite and washed with EtOAc (1 x 10 mL). The filtrate was concentrated under reduced pressure to dryness. Ice cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as black gummy liquid. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 40-43 % ethylacetate in pet ether to afford ethyl 5-(4-methoxy-3-nitrophenyl)thiazole-4-carboxylate 4 (0.435 g, 1.344 mmol, 94 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.10 (d, J = 2.00 Hz, 1H), 7.82 (dd, J = 2.40, 8.80 Hz, 1H), 7.44 (d, J = 8.80 Hz, 1H), 4.22-4.17 (m, 2H), 3.99 (s, 3H), 1.15 (t, J = 7.20 Hz, 3H).

[0243] Intermediate 5: To a stirred solution of ethyl 5-(4-methoxy-3-nitrophenyl)thiazole-4- carboxylate 4 (0.415 g, 1.346 mmol, 1.0 eq) in a mixture of EtOH (10.0 ml) and water (2.00 ml) was added iron (0.376 g, 6.73 mmol, 5.0 eq) and ammonium chloride (0.864 g, 16.15 mmol, 12.0 eq) at RT under nitrogen atmosphere and solution was stirred for 8 h at 80oC. The reaction progress was monitored by LCMS analysis. Upon completion of the reaction, the reaction mixture was filtered through Celite and washed with EtOH (2 x 10 mL) and the filtrate was concentrated under reduced pressure to dryness. Water (25 mL) was added to the residue and diluted with DCM (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude ethyl 5-(3-amino-4-methoxyphenyl)thiazole-4-carboxylate 5 (0.260 g, 0.832 mmol, 61.8 % yield) as pale yellowgummy oil. The obtained crude compound was used for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 6.84 (d, J = 8.40 Hz, 1H), 6.76 (d, J = 2.00 Hz, 1H), 6.68-6.65 (m, 1H), 4.91 (s, 2H), 4.23-4.18 (m, 2H), 3.81 (s, 3H), 1.18 (t, J = 6.80 Hz, 3H).

[0244] Intermediate 6: To a stirred solution of ethyl 5-(3-amino-4-methoxyphenyl)thiazole-4- carboxylate 5 (0.16 g, 0.575 mmol, 1.0 eq) in Conc.HCl (2.0 ml) was added a solution of sodium nitrite (0.048 g, 0.690 mmol, 1.2 eq) in H2O (1.0 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 1.5 h. Then a solution of potassium iodide (0.382 g, 2.299 mmol, 4.0 eq) in H2O (1.0 mL) was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 3h. The reaction progress was monitored by TLC (60% ethylacetate in pet ether, Rf ~ 0.6). Upon completion of reaction, ice cold water (5 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1 x 5 mL). The combined organic layer was washed with saturated aqueous Na2S2O3(1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as yellow gummy solid. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 27-29 % ethylacetate in pet ether to afford ethyl 5-(3-iodo-4- methoxyphenyl)thiazole-4-carboxylate 6 (0.142 g, 0.365 mmol, 63.5 % yield) as pale yellow solid.1H- NMR (400 MHz, DMSO-d6): δ 9.11 (s, 1H), 7.92 (d, J = 2.00 Hz, 1H), 7.53 (dd, J = 2.00, 8.60 Hz, 1H), 7.07 (d, J = 8.40 Hz, 1H), 4.22-4.17 (m, 2H), 3.89 (s, 3H), 1.17 (t, J = 6.80 Hz, 3H).

[0245] Intermediate 7: To a stirred solution of ethyl 5-(3-iodo-4-methoxyphenyl)thiazole-4- carboxylate 6 (0.32 g, 0.822 mmol, 1.0 eq) in a mixture of ethanol (6.0 ml), Tetrahydrofuran (4.0 ml) and Water (2.00 ml) was added lithium hydroxide (0.138 g, 3.29 mmol, 4.0 eq) at 0oC. The resulting solution was stirred for 3h at room temperature. Reaction progress was monitored by TLC & LCMS analysis, upon completion of reaction, reaction mixture was concentrated under reduced pressure to dryness. The obtained residue was acidified with 1.5N HCl solution until pH ~4 and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude 5-(3-iodo-4-methoxyphenyl)thiazole-4-carboxylic acid 7 (0.28 g, 0.722 mmol, 88 % yield) as pale yellow solid. The obtained crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 12.97 (br s, 1H), 9.08 (s, 1H), 7.92 (d, J = 2.00 Hz, 1H), 7.53 (dd, J = 2.40, 8.60 Hz, 1H), 7.07 (d, J = 8.40 Hz, 1H), 3.88 (s, 3H).

[0246] Compound 30: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)thiazole-4-carboxylic acid 7 (0.28 g, 0.775 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine, HCl 8 (Intermediate 6 ofExample 1, 0.222 g, 1.163 mmol, 1.5 eq) in DMF (6.0 ml) was added N,N-diisopropylethylamine (0.406 ml, 2.326 mmol, 3.0 eq) followed by HATU (0.442 g, 1.163 mmol, 1.5 eq) at 0oC under nitrogen atmosphere and the resulting solution was stirred for 4h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 70% EtOAc in pet ether, Rf of the product ~ 0.5), ice cold water (50 mL) was added to the reaction mixture and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The crude compound was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous TFA / MeCN mobile phase) to afford the desired final compound N-(3-(5-fluoropyridin-3-yl)propyl)-5-(3-iodo-4-methoxyphenyl)thiazole-4- carboxamide 30 (0.180 g, 0.362 mmol, 46.7 % yield) as pale pink solid.1H-NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.55 (t, J = 6.00 Hz, 1H), 8.40 (d, J = 2.80 Hz, 1H), 8.34 (s, 1H), 7.97 (d, J = 2.00 Hz, 1H), 7.65- 7.63 (m, 1H), (dd, J = 3018.00, 8.40 Hz, 1H), 7.04 (d, J = 8.40 Hz, 1H), 3.87 (s, 3H), 3.26-3.21 (m, 2H), 2.65 (t, J = 7.60 Hz, 2H), 0.00-1.84 (m, 2H). Example 30 – Preparation of Compound 31

[0247] Compound 31 was prepared according to the following Scheme:

[0248] Intermediate 1a: To a stirred solution of furan-3-carboxylic acid 1 (2.0 g, 17.84 mmol, 1.0 eq) in THF (15 mL) was added n-BuLi (2.5M Solution in hexane, 14.28 mL, 35.7 mmol, 2.0 eq) at –78 °C under nitrogen atmosphere (during the addition, white precipitate formation was observed). The reaction mixture was stirred for 2 h at –78 °C, then bromine (1.011 mL, 19.63 mmol, 1.1 eq) was added dropwise. The reaction mixture was stirred for an additional 2 h at –78 °C under nitrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), ice cold 2N HCl aqueous solution (15.0 mL) was added to the reaction mixture, diluted with ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude .The obtained crude was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCO2H / MeCN mobile phase). Product containing fractions were combined and concentrated under reduced pressure to afford 2-bromofuran-3-carboxylic acid 1a (1.4 g, 7.29 mmol, 40.86 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1H), 7.89 (d, J = 2.00 Hz, 1H), 6.82 (d, J = 2.40 Hz, 1H.

[0249] Intermediate 1b: To a stirred solution of 2-bromofuran-3-carboxylic acid 1a (1.38 g, 7.23 mmol, 1.0 eq) in DMF (10 mL) was added potassium carbonate (3.00 g, 21.68 mmol, 3.0 eq) and methyl iodide (0.900 mL, 14.45 mmol, 2.0 eq) under nitrogen atmosphere at RT and the reaction mixture was allowed to stir for overnight. Upon completion of reaction (as confirmed by TLC analysis 15% ethylacetate in pet ether, Rf ~ 0.7), ice cold water (15 mL) was added to the reaction mixture and diluted with MTBE (10 mL). The organic layer was separated and the aqueous layer was extracted with MTBE (2 x 20 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude methyl 2-bromofuran-3-carboxylate 1b (1.4 g, 6.82 mmol, 94 % yield) as brown solid.1H-NMR (400 MHz, DMSO-d6): δ 7.93 (d, J = 2.80 Hz, 1H), 6.88 (d, J = 2.80 Hz, 1H), 3.79 (s, 3H).

[0250] Intermediate 3: To a stirred solution of methyl 2-bromofuran-3-carboxylate 1b (1.4 g, 6.83 mmol, 1.0 eq) and methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (2.86 g, 10.24 mmol, 1.5 eq) in a mixture of dioxane (15 mL) and water (1 mL) was added potassium carbonate (1.888 g, 13.66 mmol, 2.0 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min and PdCl2(dppf) (0.500 g, 0.683 mmol, 0.1 eq) was added. Then the mixture was purged again with nitrogen for 10 min and allowed to stirred at 80oC for overnight. Upon completion of reaction (as confirmed by TLC 15% ethylacetate in pet ether, Rf ~ 0.7), the reaction mixture was diluted with ethyl acetate (20 mL), filtered through celite bed, the bed was washed with ethyl acetate (2 x 10 mL) and icecold water (20 mL) was added to the filtrate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 10-15% ethyl acetate in pet-ether to afford methyl 2-(4-methoxy-3-nitrophenyl)furan-3-carboxylate 3 (1.4 g, 4.58 mmol, 67.1 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.57 (d, J = 2.40 Hz, 1H), 8.23-8.20 (m, 1H), 7.90 (d, J = 2.00 Hz, 1H), 7.51 (d, J = 8.80 Hz, 1H), 6.92 (d, J = 2.00 Hz, 1H), 4.01 (s, 3H), 3.82-3.76 (m, 3H).

[0251] Intermediate 4: To a stirred solution of methyl 2-(4-methoxy-3-nitrophenyl)furan-3- carboxylate 3 (1.4 g, 5.05 mmol 1.0 eq) in a mixture of ethanol (15.0 mL) and water (7.50 mL) was added ammonium chloride (2.161 g, 40.4 mmol, 8.0 eq) and iron (1.410 g, 25.2 mmol, 5.0 eq) under nitrogen atmosphere at RT. The reaction mixture was allowed to stir for 5 h at 85oC. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to dryness. The obtained residue was diluted using 10% MeOH in DCM (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 2-(3-amino-4-methoxyphenyl)furan-3-carboxylate 4 (1.13 g, 4.42 mmol, 88 % yield) as brown gummy liquid. The crude product was used for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 7.74 (d, J = 2.80 Hz, 1H), 7.23-7.19 (m, 2H), 6.88 (d, J = 11.20 Hz, 1H), 6.81 (d, J = 2.80 Hz, 1H), 4.88 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H).

[0252] Intermediate 5: To a stirred solution of methyl 2-(3-amino-4-methoxyphenyl)furan-3- carboxylate 4 (0.830 g, 3.36 mmol, 1.0 eq) in Conc.HCl (3.5 mL) was added a solution of sodium nitrite (0.278 g, 4.03 mmol, 1.2 eq) in water (1.0 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 30 minutes. Then a solution of potassium iodide (2.229 g, 13.43 mmol, 4.0 eq) in water (1.0 mL) added at 0oC. The reaction mixture was allowed to warm to room temperature and stirred for overnight. Upon completion of reaction (as confirmed by TLC analysis 50 % EtOAC in Pet ether, Rf ~ 0.5), the reaction mixture was basified using saturated sodium bicarbonate solution (20 mL) at 0oC and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude.The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 50 mL / min, eluted using 30 % ethyl acetate in pet-ether) to afford methyl 2-(3-iodo-4- methoxyphenyl)furan-3-carboxylate 5 (0.375 g, 0.946 mmol, 28.2 % yield) as yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.00 Hz, 1H), 7.97-7.94 (m, 1H), 7.82 (d, J = 2.00 Hz, 1H), 7.12 (d, J = 8.80 Hz, 1H), 6.87 (d, J = 2.00 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 3H).

[0253] Intermediate 6: To a stirred solution of methyl 2-(3-iodo-4-methoxyphenyl)furan-3- carboxylate 5 (0.470 g, 1.312 mmol, 1.0 eq) in mixture of methanol (20 mL), THF (13 mL) and water (7 mL) at 0oC was added LiOH.H2O (0.220 g, 5.25 mmol, 4.0 eq) and stirred for overnight at RT. Additional 4 equivalents of LiOH.H2O (0.220 g, 5.25 mmol) was added and reaction mixture was heated to 45oC for 2h. Upon completion of reaction (as confirmed by TLC analysis; 50% Ethyl acetate in pet. ether, Rf ~ 0.2), the reaction was concentrated under reduced pressure to dryness. The resulting residue was acidified with aqueous HCl (1.5 N, 10 mL) at 0oC till pH ~2 and extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with brine (1 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude 2-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.370 g, 1.075 mmol, 82 % yield) as pale yellow gummy solid.1H-NMR (400 MHz, DMSO-d6): δ 12.75 (s, 1H), 8.40 (d, J = 2.00 Hz, 1H), 8.00-7.91 (m, 1H), 7.78-7.75 (m, 1H), 7.13-7.02 (m, 1H), 6.83-6.81 (m, 1H), 3.90 (s, 3H).

[0254] Compound 31: To a stirred solution of an 2-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.390 g, 1.133 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine (Intermediate 6 of Example 1, 0.262 g, 1.700 mmol, 1.5 eq) in DMF (5.0 mL) was added DIPEA (0.732 g, 5.67 mmol, 5.0 eq) followed by HATU (0.517 g, 1.360 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (20 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The crude product was purified by prep-HPLC (Column: XSELECT C18-250, 500 ul, Mobile phase: A: 10 mm Ammonium bicarbonate in water, B: MeCN, Flow rate: 14 mL / min, Retention time: 13.0 min) to afford N- (3-(5-fluoropyridin-3-yl)propyl)-2-(3-iodo-4-methoxyphenyl)furan-3-carboxamide 31 (0.245 g, 0.508 mmol, 44.8 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.41-8.36 (m, 3H), 8.27 (t, J = 5.60 Hz, 1H), 7.92-7.90 (m, 1H), 7.75 (d, J = 2.00 Hz, 1H), 7.66-7.63 (m, 1H), 7.08 (d, J = 8.80 Hz, 1H), 6.86 (d, J = 2.00 Hz, 1H), 3.87 (s, 3H), 3.26-3.22 (m, 2H), 2.70 (t, J = 8.00 Hz, 2H), 1.84 (t, J = 7.20 Hz, 2H).Example 31 – Preparation of Compound 32

[0255] Compound 32 was prepared according to the following Scheme:

[0256] mol, 1.0 eq) in tetrahydrofuran (10 mL) was added iso-propylmagnesium chloride (2.0M sol in THF, 4.87 ml, 9.74 mmol, 1.1 eq) dropwise under 0oC for half an hour, then the reaction mixture was warmed to room temperature and stirred for 5 h. The reaction mixture was then cooled to 0oC, methyl chloroformate (0.823 ml, 10.63 mmol, 1.2 eq) in anhydrous tetrahydrofuran (10 mL) was added dropwise over a period of 10 min. The reaction mixture was warmed to room temperature and stirred for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 10% EtOAc in pet ether, Rfof the product ~ 0.3), saturated aqueous ammonium chloride solution (15 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as brown gummy liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230 – 400, flow rate 35 mL / min, eluted using 4-5% ethylacetate in pet-ether) to afford methyl 4-bromofuran-3-carboxylate 1b (1.1 g, 5.17 mmol, 58.4 % yield) as pale yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.49 (t, J = 1.20 Hz, 1H), 8.10 (t, J = 1.20 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 1H).

[0257] Intermediate 3: To a stirred solution of methyl 4-bromofuran-3-carboxylate 1b (0.900 g, 4.39 mmol.1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (2.451 g,8.78 mmol, 2.0 eq) in water (2 mL) and 1,4-dioxane (40 mL) was added K2CO3(1.213 g, 8.78 mmol, 2.0 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min, then added PdCl2(dppf) (0.321 g, 0.439 mmol, 0.1 eq). Then the mixture was purged again with nitrogen for 10 min. The reaction mixture was heated to 80oC for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 10% EtOAc in pet ether, Rfof the product ~ 0.2), the reaction mixture was filtered through Celite and washed with ethylacetate (2 x 30 mL). Ice cold water (45 mL) was added to the filtrate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude compound was purified by column chromatography (Isolera, silica mesh size 230 – 400, flow rate 20 mL / min, eluted using 9% ethylacetate in pet ether) to afford desired product methyl 4-(4-methoxy-3-nitrophenyl)furan-3-carboxylate 3 (0.760 g, 1.875 mmol, 42.7 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.49 (d, J = 1.60 Hz, 1H), 8.10 (d, J = 1.60 Hz, 1H), 8.03 (d, J = 2.40 Hz, 1H), 7.80-7.77 (m, 1H), 7.41-7.38 (m, 1H), 3.96 (s, 3H), 3.78 (s, 1H), 3.73 (d, J = 9.20 Hz, 2H).

[0258] Intermediate 4: To a stirred solution of methyl 4-(4-methoxy-3-nitrophenyl)furan-3- carboxylate 3 (0.700 g, 2.52 mmol, 1.0 eq) in methanol (40 mL) and water (5 mL) was added ammonium chloride (1.080 g, 20.20 mmol, 8.0 eq) and iron (0.705 g, 12.62 mmol.5.0 eq) under nitrogen atmosphere at RT. The reaction mixture was stirred for 4 h at 85oC. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.4 & LCMS analysis), the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was diluted with 10% methanol in DCM (20 mL) and water (25 mL) was added to the organic layer. The organic layer was separated and the aqueous layer was extracted with 10% methanol in DCM (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product methyl 4-(3-amino-4-methoxyphenyl)furan-3-carboxylate 4 (0.550 g, 1.907 mmol, 76 % yield) as brown gummy liquid. The crude compound was taken for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 8.39-8.36 (m, 1H), 7.85-7.80 (m, 1H), 6.79 (d, J = 8.40 Hz, 1H), 6.72-6.70 (m, 1H), 6.63-6.60 (m, 1H), 4.69 (d, J = 19.20 Hz, 2H), 3.76 (t, J = 4.00 Hz, 2H), 3.72 (d, J = 1.60 Hz, 3H).

[0259] Intermediate 5: To a stirred solution of methyl 4-(3-amino-4-methoxyphenyl)furan-3- carboxylate 4 (0.500 g, 2.022 mmol, 1.0 eq) in Conc.HCl (4.00 ml) was added a solution of sodium nitrite (0.167 g, 2.427 mmol, 1.2 eq) in water (2.00 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 1.5 h. Then a solution of potassium iodide (1.343 g, 8.09 mmol, 4.0 eq) in water (2.00 mL) was addeddropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.6), the reaction mixture was basified to pH=12 by using saturated sodium bicarbonate solution (10 mL) and diluted with DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layer was washed with saturated aqueous Na2S2O3(1 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as brown gummy liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230 – 400, flow rate 20 mL / min, eluted with 28% ethylacetate in pet ether) to afford desired product methyl 4-(3-iodo-4-methoxyphenyl)furan-3-carboxylate 5 (0.370 g, 1.019 mmol, 50.4 % yield) as yellow gummy solid.1H-NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 3.20 Hz, 1H), 8.00 (d, J = 3.60 Hz, 1H), 7.90 (d, J = 5.20 Hz, 1H), 7.50-7.47 (m, 1H), 7.05-7.02 (m, 1H), 3.86 (t, J = 2.00 Hz, 4H), 3.73 (t, J = 1.60 Hz, 4H).

[0260] Intermediate 6: To a stirred solution of methyl 4-(3-iodo-4-methoxyphenyl)furan-3- carboxylate 5 (0.370 g, 1.033 mmol, 1.0 eq) in a mixture of methanol (20 mL), THF (13.0 mL) and water (6.5 mL) was added LiOH.H2O (0.173 g, 4.13 mmol, 4.0 eq) at 0oC and stirred for overnight at RT and reaction mixture was heated to 45oC for 1h. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.0), the reaction mixture was concentrated under reduced pressure to dryness. The resulting residue was acidified with aqueous 1.5N HCl (10 mL) at 0oC till pH ~2, extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with brine (1 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product 4-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.330 g, 0.945 mmol, 92 % yield) as pale yellow solid. The crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 12.61 (s, 1H), 8.35 (d, J = 2.40 Hz, 1H), 7.95 (d, J = 2.00 Hz, 1H), 7.89 (d, J = 3.20 Hz, 1H), 7.52-7.48 (m, 1H), 7.03 (d, J = 11.60 Hz, 1H), 3.86 (s, 3H).

[0261] Compound 32: To a stirred solution of 4-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.330 g, 0.959 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine, HCl 7 (Intermediate 6 of Example 1, 0.274 g, 1.439 mmol, 1.5 eq) in DMF (6.0 ml) was added N,N-diisopropylethylamine (0.837 ml, 4.80 mmol, 5.0 eq) followed by HATU (0.547 g, 1.439 mmol, 1.5 eq) at 0oC under nitrogen atmosphere and the resulting solution was stirred for overnight at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 70% EtOAc in pet ether, Rfof the product ~ 0.2), ice cold water (50 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washedwith brine (1 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as pale brown gummy liquid. The obtained crude compound was purified by prep-HPLC (Column:Column:X-Bridge C8(50X4.6) mm,3.5μm, Mobile phase: A:10 mM Ammonium bicarbonate in water, B: Acetonitrile, Flow rate:1.0 mL / min, Retention time: 12.0 min) to afford N-(3-(5-fluoropyridin-3- yl)propyl)-4-(3-iodo-4-methoxyphenyl)furan-3-carboxamide 32 (0.22053 g, 0.458 mmol, 47.75 % yield) as pale brown gummy solid.1H-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.80 Hz, 1H), 8.35 (s, 1H), 8.27 (t, J = 5.60 Hz, 1H), 8.06 (d, J = 1.60 Hz, 1H), 7.97 (d, J = 1.60 Hz, 1H), 7.91 (d, J = 2.00 Hz, 1H), 7.64-7.61 (m, 1H), 7.51-7.48 (m, 1H), 7.01 (d, J = 8.40 Hz, 1H), 3.83 (s, 3H), 3.22-3.17 (m, 2H), 2.68 (t, J = 7.60 Hz, 2H), 1.96-1.75 (m, 2H). Example 32 – Preparation of Compound 33

[0262] Compound 33 was prepared according to the following Scheme: [026. g, 2.62 mmol, 1.0 eq) in DMF (10 mL) were added K2CO3(0.543 g, 3.93 mmol, 1.5 eq) and methyl iodide (0.327 ml, 5.24 mmol, 2.0 eq) at RT. The reaction mixture was stirred for overnight under nitrogen atmosphere.Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.6), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product methyl 3-bromofuran-2-carboxylate 1a (0.520 g, 2.54 mmol, 97 % yield) as pale yellow liquid. The crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 8.03 (d, J = 2.00 Hz, 1H), 6.96 (d, J = 2.00 Hz, 1H), 3.84-3.83 (m, 3H).

[0264] Intermediate 3: To a stirred solution of methyl 3-bromofuran-2-carboxylate 1a (1.77 g, 8.63 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5-trimethyl-1,3,2-dioxaborolane 2 (3.43 g, 12.95 mmol, 1.5 eq) in 1,4-dioxane (50 mL) and water (4.0 mL) was added potassium carbonate (1.790 g, 12.95 mmol, 1.5 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min and was added PdCl2(dppf) (0.632 g, 0.863 mmol, 0.1 eq). Then the mixture was purged again with nitrogen for 10 min and heated to 80oC for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.5), the reaction mixture was filtered through Celite bed and the filtrate was extracted with ethylacetate (2 x 30 mL). The combined organic layer was washed with brine (1 x 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product as brown gummy liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 20 mL / min, eluted using 45% ethylacetate in pet ether) to afford desired product methyl 3-(4-methoxy-3-nitrophenyl)furan-2-carboxylate 3 (4.2 g, 14.22 mmol, 165 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.24 (d, J = 2.80 Hz, 1H), 8.03 (d, J = 2.40 Hz, 1H), 7.98-7.93 (m, 1H), 7.43 (d, J = 12.00 Hz, 1H), 7.02 (d, J = 2.40 Hz, 1H), 4.07-3.96 (m, 3H), 3.93 (s, 1H), 3.78 (t, J = 10.80 Hz, 3H), 1.20-1.16 (m, 1H), 1.08 (s, 3H).

[0265] Intermediate 4: To a stirred solution of methyl 3-(4-methoxy-3-nitrophenyl)furan-2- carboxylate 3 (2.0 g, 7.21 mmol, 1.0 eq) in methanol (50 mL) and water (5 mL) was added ammonium chloride (4.63 g, 87 mmol, 12.0 eq) and iron (2.014 g, 36.1 mmol, 5.0 eq) under nitrogen atmosphere at RT. The reaction mixture was stirred for 2 h at 85oC. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.4), the reaction mixture was filtered through Celite and the filtrate was concentrated. Water ( 20 mL) was added to he resultant residue and extracted with 10% methanol in DCM (2 x 20 mL). The combined organic layer was washed with brine (1 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product as brown liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 30-40 % ethylacetate in pet-ether) to afford methyl 3-(3-amino-4-methoxyphenyl)furan-2-carboxylate 4 (1.40 g, 5.42 mmol, 75 % yield) as brown liquid.1H- NMR (400 MHz, DMSO-d6): δ 7.94-7.92 (m, 1H), 6.92 (t, J = 1.20 Hz, 1H), 6.88-6.82 (m, 2H), 6.76 (d, J = 2.00 Hz, 1H), 4.76 (s, 2H), 4.06-4.01 (m, 1H), 3.94 (s, 3H), 3.80 (s, 1H), 3.76 (t, J = 3.20 Hz, 3H), 1.08 (s, 2H).

[0266] Intermediate 5: To a stirred solution of methyl 3-(3-amino-4-methoxyphenyl)furan-2- carboxylate 4 (1.1 g, 4.45 mmol, 1.0 eq) in conc. HCl (4.0 mL) was added a solution of sodium nitrite (0.368 g, 5.34 mmol, 1.2 eq) in water (2.0 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 1.5h. Then a solution of potassium iodide (2.95 g, 17.80 mmol, 4.0 eq) in water (2.0 mL) added dropwisely over a period of 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 4h. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.6), the reaction mixture was basified to pH=12 with saturated NaHCO3solution (10 mL) and diluted with DCM (20 mL ). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layer was washed with saturated aqueous Na2S2O3(1 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as brown gummy liquid. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 20 mL / min). The column was eluted using 28% ethylacetate in pet ether to afford desired product methyl 3-(3-iodo-4-methoxyphenyl)furan-2-carboxylate 5 (1.15 g, 3.03 mmol, 68.2 % yield) as yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.11 (d, J = 2.00 Hz, 1H), 7.98 (d, J = 1.60 Hz, 1H), 7.68-7.65 (m, 1H), 7.06 (d, J = 8.80 Hz, 1H), 6.94 (d, J = 1.60 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 3H).

[0267] Intermediate 6: To a stirred solution of methyl 3-(3-iodo-4-methoxyphenyl)furan-2- carboxylate 5 (1.1 g, 3.07 mmol, 1.0 eq) in a mixture of methanol (20 mL), THF (13.0 mL) and water (6.5 mL) at 0oC was added LiOH.H2O (0.516 g, 12.29 mmol, 4.0 eq) and stirred for overnight at RT. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.1& LCMS analysis), the reaction was concentrated under reduced pressure. The resulting crude was acidified with aqueous 1.5 N HCl (10 mL), extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with brine (1 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-(3-iodo-4-methoxyphenyl)furan-2-carboxylic acid 6 (1.01 g, 2.83 mmol, 92 % yield) as off-white solid. The obtained crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 13.02 (s, 1H), 8.07 (d, J = 3.20 Hz, 1H), 7.92 (d, J = 2.00 Hz, 1H), 7.68-7.65 (m, 1H), 7.05 (d, J = 11.60 Hz, 1H), 6.88 (d, J = 2.00 Hz, 1H), 3.87 (s, 3H).

[0268] Compound 33: To a stirred solution of 3-(3-iodo-4-methoxyphenyl)furan-2-carboxylic acid 6 (0.500 g, 1.453 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine, HCl 7 (0.416 g, 2.180 mmol, 1.5 eq) in DMF (6.0 mL) was added N,N-diisopropylethylamine (1.269 ml, 7.27 mmol, 5.0 eq)followed by HATU (0.829 g, 2.180 mmol, 1.5 eq) at 0oC under nitrogen atmosphere and the resulting solution was stirred for overnight at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.4), ice cold water (50 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by prep-HPLC (Column:Column:X-Bridge C8(50X4.6)mm,3.5μm, Mobile phase: A:10 mM Ammonium bicarbonate in water, B: Acetonitrile, Flow rate:1.0 mL / min, Retention time: 12.0 min) to afford [N-(3-(5-fluoropyridin-3-yl)propyl)-3-(3-iodo-4-methoxyphenyl)furan- 2-carboxamide 33 (0.192 g, 0.399 mmol, 29.3 % yield)] as pale yellow gummy solid.1H-NMR (400 MHz, DMSO-d6): δ 8.41-8.38 (m, 2H), 8.35 (t, J = 2.00 Hz, 1H), 8.27 (d, J = 2.40 Hz, 1H), 7.85 (d, J = 1.60 Hz, 1H), 7.78-7.75 (m, 1H), 7.66-7.63 (m, 1H), 7.02 (d, J = 8.80 Hz, 1H), 6.91 (d, J = 2.00 Hz, 1H), 3.86 (s, 3H), 3.27- 3.22 (m, 2H), 2.68 (t, J = 8.00 Hz, 2H), 1.87-1.80 (m, 2H). Example 33 – Preparation of Compound 34

[0269] Compound 34 was prepared according to the following Scheme: [0, , .0 eq), 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (1.011 g, 3.62 mmol, 1.0 eq), K2CO3(1.001 g, 7.24 mmol, 2.0 eq) in mixture of 1,4-dioxane (10.0 mL) and water (0.5 mL) was degassed and purged with nitrogen for 10 min, then PdCl2(dppf) (0.027 g, 0.036 mmol, 0.01 eq) was added to the mixture and degassed and purged with nitrogen for 10 min. The resulting reaction mixture was stirred at 80 °C. for overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLCanalysis, 10% EtOAc in pet ether, Rfof the product ~ 0.1), the reaction mixture was filtered through Celite and washed with ethylacetate (1 x 10 mL). The filtrate was concentrated under reduced pressure to afford the crude as black gummy liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted with 16 % ethylacetate in pet-ether) to afford ethyl 4'-methoxy-3'-nitro-[1,1'-biphenyl]-2-carboxylate 3 (0.85 g, 2.81 mmol, 78 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 7.83-7.81 (m, 1H), 7.79 (d, J = 2.00 Hz, 1H), 7.68-7.64 (m, 1H), 7.61-7.58 (m, 1H), 7.56-7.52 (m, 1H), 7.48-7.46 (m, 1H), 7.42 (d, J = 8.80 Hz, 1H), 4.13-4.08 (m, 2H), 3.98 (s, 3H), 1.05 (t, J = 7.20 Hz, 3H).

[0271] Intermediate 4: To a stirred solution of ethyl 4'-methoxy-3'-nitro-[1,1'-biphenyl]-2- carboxylate 3 (0.85 g, 2.82 mmol, 1.0 eq) in a mixture of ethanol (15.0 mL) and water (3.00 mL) was added iron (0.788 g, 14.11 mmol, 5.0 eq) and ammonium chloride (1.811 g, 33.9 mmol, 12.0 eq) at RT under nitrogen atmosphere and solution was stirred for 8h at 80oC. Upon completion of the reaction (as confirmed by TLC analysis, 80% EtOAc in pet ether, Rfof the product ~ 0.5), the reaction mixture was filtered through Celite and washed with EtOH (2 x 10 mL) and the filtrate was concentrated under reduced pressure to dryness. Then saturated NaHCO3solution (45 mL) was added to the reaction mixture, diluted with DCM (50 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude compound ethyl 3'-amino-4'-methoxy-[1,1'- biphenyl]-2-carboxylate 4 (0.700 g, 2.58 mmol, 91 % yield) as pale yellow solid. The obtained crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 7.61-7.54 (m, 1H), 7.52 (d, J = 1.20 Hz, 1H), 7.42-7.35 (m, 2H), 6.82 (d, J = 8.40 Hz, 1H), 6.59 (d, J = 2.00 Hz, 1H), 6.45-6.43 (m, 1H), 4.79 (s, 2H), 4.10-4.03 (m, 2H), 3.79 (s, 3H), 1.02 (t, J = 7.20 Hz, 3H).

[0272] Intermediate 5: To a stirred solution of ethyl 3'-amino-4'-methoxy-[1,1'-biphenyl]-2- carboxylate 4 (0.4 g, 1.474 mmol, 1.0 eq) in conc. HCl (5.0 mL) was added a solution of sodium nitrite (0.122 g, 1.769 mmol, 1.2 eq) in water (2.00 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 1.5h. Then a solution of potassium iodide (0.979 g, 5.90 mmol, 4.0 eq) in water (2.00 mL) was added dropwise over a period of 10 min at 0oC. The reaction mixture was allowed to warm to room temperature and stirred for 3h. Upon completion of the reaction (as confirmed by TLC analysis, 0% EtOAc in pet ether, Rfof the product ~ 0.3 & LCMS analysis), ice cold water (5 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1 x 5 mL). The combined organic layer was washed with saturated aqueous Na2S2O3(1 X 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as yellowgummy solid. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 70-90 % ethylacetate in pet ether to afford ethyl 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxylate 5 (0.550 g, 1.425 mmol, 97 % yield) as pale yellow gummy solid.1H-NMR (400 MHz, DMSO-d6): δ 7.73-7.71 (m, 1H), 7.64 (d, J = 2.00 Hz, 1H), 7.61-7.58 (m, 1H), 7.50-7.46 (m, 1H), 7.43-7.41 (m, 1H), 7.33-7.30 (m, 1H), 7.07 (d, J = 8.40 Hz, 1H), 4.12-4.07 (m, 2H), 3.87 (s, 3H), 1.04 (t, J = 7.20 Hz, 3H).

[0273] Intermediate 6: To a stirred solution of ethyl 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2- carboxylate 5 (0.550 g, 1.439 mmol, 1.0 eq) in a mixture of ethanol (12 mL), THF (8.00 mL) and water (4.00 mL) at 0oC was added LiOH.H2O (0.242 g, 5.76 mmol,4.0 eq) and stirred for overnight at RT. The LCMS analysis indicated the presence of unreacted starting material, so 2 equivalents of LiOH.H2O was added and the reaction was continued by heating at 50 °C. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction was concentrated under reduced pressure. The resulting crude product was acidified with aqueous 1.5 N HCl (10 mL), extracted with ethyl acetate (2 x 15 mL) and washed with brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxylic acid 6 (0.436 g, 1.200 mmol, 83 % yield) as pale yellow solid. The crude compound was used for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 12.84 (s, 1H), 7.73-7.71 (m, 2H), 7.71-7.58 (m, 1H), 7.56-7.54 (m, 1H), 7.46-7.36 (m, 2H), 7.06-7.04 (m, 1H), 3.87 (s, 3H).

[0274] Compound 34: To a stirred solution of 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxylic acid 6 (0.400 g, 1.129 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine, HCl 7 (Intermediate 6 of Example 1, 0.258 g, 1.355 mmol, 1.2 eq) in DMF (6.0 mL) was added N,N-diisopropylethylamine (0.592 ml, 3.39 mmol, 3.0 eq) followed by HATU (0.644 g, 1.694 mmol, 1.5 eq) at 0oC under nitrogen atmosphere and the resulting solution was stirred for overnight at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc), ice cold water (50 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 X 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude compound as pale brown gummy liquid. The obtained crude was purified by prep-HPLC (Column: X-Bridge C8(50X4.6)mm, 3.5μm, Mobile phase: A:10mM Ammonium bicarbonate in water, B: Acetonitrile, Flow rate:1.0 mL / min, Retention time: 12.0 min) to afford N-(3-(5-fluoropyridin-3-yl)propyl)-3'-iodo-4'-methoxy-[1,1'-biphenyl]-2- carboxamide 34 (0.167 g, 0.340 mmol, 30.9 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ8.40 (d, J = 2.80 Hz, 1H), 8.25-8.21 (m, 2H), 7.77 (d, J = 2.00 Hz, 1H), 7.46-7.49 (m, 2H), 7.41-7.37 (m, 4H), 7.02 (d, J = 8.80 Hz, 1H), (s, 3H), 3.10 (q, J = 6.40 Hz, 2H), 2.42 (t, J = 8.00 Hz, 2H), 1.67-1.60 (m, 2H). Example 34 – Preparation of Compound 35

[0275] Compound 35 was prepared according to the following Scheme:

[0276] ol, 1.0 eq)) in DMF (20.0 mL) were added potassium carbonate (1.505 g, 10.89 mmol, 1.1 eq), methyl iodide (1.238 mL, 19.80 mmol, 2.0 eq) at RT. The reaction mixture was allowed to stirred at room temperature for overnight. Upon completion of reaction (as confirmed by TLC analysis, 50% ethylacetate in pet ether, Rf ~ 0.8), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (2 x 25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude methyl 2-bromonicotinate 1a (2.0 g, 7.47 mmol, 75 % yield) as pale yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.57-8.55 (m, 1H), 8.19-8.17 (m, 1H), 7.61-7.58 (m, 1H), 3.89 (s, 3H).

[0277] Intermediate 3: To a stirred solution of methyl 2-bromonicotinate 1a (2.330 g, 10.79 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (4.52 g, 16.18 mmol, 1.5 eq) in a mixture of dioxane (40.0 mL) and water (2.0 mL) was added potassium carbonate (2.98g, 21.57 mmol, 2.0 eq). The reaction mixture was degassed with nitrogen for 10 min and added PdCl2(dppf) (0.789 g, 1.079 mmol, 0.1 eq) . The mixture was purged again with nitrogen for 10 min and the reaction mixture was heated to 80oC for overnight. Upon completion of reaction (as confirmed by LCMS analysis), ice cold water (40 mL) was added to the reaction mixture, diluted with ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 40 mL / min, eluted using 33 % ethylacetate in pet-ether) to afford methyl 2-(4-methoxy-3-nitrophenyl)nicotinate 3 (2.350 g, 8.13 mmol, 75 % yield) as off-white solid.1H- NMR (400 MHz, DMSO-d6): δ 8.84-8.82 (m, 1H), 8.23-8.21 (m, 1H), 8.06 (d, J = 2.00 Hz, 1H), 7.82-7.79 (m, 1H), 7.58-7.55 (m, 1H), 7.45 (d, J = 8.80 Hz, 1H), 4.00 (s, 3H), 3.74 (s, 3H).

[0278] Intermediate 4: To a stirred solution of methyl 2-(4-methoxy-3-nitrophenyl)nicotinate 3 (1.15 g, 3.99 mmol, 1.0 eq) in a mixture of EtOH (40 mL) and Water (20 mL) was added ammonium chloride (1.707 g, 31.9 mmol, 8.0 eq) and iron (1.114 g, 19.95 mmol, 5.0 eq) under nitrogen atmosphere at RT. The reaction mixture was allowed to stir for 3 h at 85oC. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to dryness. The residue was diluted using 10% MeOH in DCM (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layer was washed with brine (2 x 20 mL) and NaHCO3(2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude methyl 2-(3-amino-4- methoxyphenyl)nicotinate 4 (1.22 g, 4.42 mmol, 111 % yield) as brown solid.1H-NMR (400 MHz, DMSO- d6): δ 8.72-8.71 (m, 1H), 8.00-7.98 (m, 1H), 7.41-7.38 (m, 1H), 6.92 (d, J = 2.40 Hz, 1H), 6.85 (d, J = 8.00 Hz, 1H), 6.69-6.66 (m, 1H), 4.85 (s, 2H), 3.81 (s, 3H), 3.70 (s, 3H).

[0279] Intermediate 5: To a stirred solution of methyl 2-(3-amino-4-methoxyphenyl)nicotinate 4 (1.22 g, 4.72 mmol, 1.0 eq) in Conc.HCl (4.0 mL) was added a solution of sodium nitrite (0.391 g, 5.67 mmol, 1.2 eq) in water (2.0 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 1.5 h. Then a solution of potassium iodide (3.14 g, 18.89 mmol, 4.0 eq) in water (2 mL) was added dropwise at 0 °C . The reaction mixture was allowed to warm to room temperature and stirred for 4h. Upon completion of reaction (as confirmed by TLC analysis 50 % EtOAC in pet-ether, Rf ~ 0.6), the reaction mixture was basified using saturated sodium bicarbonate solution (30 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The crude waspurified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 40 mL / min, eluted using 35% ethyl acetate in pet-ether) to afford methyl 2-(3-iodo-4-methoxyphenyl)nicotinate 5 (0.610 g, 1.289 mmol, 27.3 % yield) as brown gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.79-8.76 (m, 1H), 8.13- 8.07 (m, 1H), 7.94 (d, J = 2.00 Hz, 1H), 7.53-7.44 (m, 2H), 7.09 (d, J = 8.80 Hz, 1H), 3.90 (s, 3H), 3.72 (s, 3H).

[0280] Intermediate 6: To a stirred solution of methyl 2-(3-iodo-4-methoxyphenyl)nicotinate 5 (0.610 g, 1.652 mmol, 1.0 eq) in a mixture of MeOH (8.0 mL), THF (5.33 mL) and water (2.67 mL) at 0oC was added LiOH.H2O (0.158 g, 6.61 mmol, 4.0 eq) and stirred for overnight at rt. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure. The resulting crude product was acidified with HCl (4.0 M soln. in ethyl acetate, 3.0 mL), concentrated under reduced pressure to afford the crude product. The crude product was purified by reverse-phase column chromatography (Grace column: C18 40 µm, 870 g; flow rate: 20 mL / min; 0.1% TFA in water / MeCN mobile phase) to afford 2-(3-iodo-4-methoxyphenyl)nicotinic acid 6 (0.560 g, 1.542 mmol, 93.3 % yield) as pale brown solid.1H-NMR (400 MHz, DMSO-d6): δ 8.74-8.72 (m, 1H), 8.11-8.07 (m, 1H), 7.96 (d, J = 3.20 Hz, 1H), 7.58-7.51 (m, 1H), 7.48-7.44 (m, 1H), 7.10-7.00 (m, 1H), 3.89 (s, 3H).

[0281] Compound 35: To a stirred solution of 2-(3-iodo-4-methoxyphenyl)nicotinic acid 6 (0.460 g, 1.295 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine 7 (Intermediate 6 of Example 1, 0.300 g, 1.943 mmol, 1.5 eq) in DMF (10.0 mL) was added DIPEA (0.837 g, 6.48 mmol, 5.0 eq) followed by HATU (0.591 g, 1.554 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to afford the crude. Ice cold water (20 mL) was added to the resulting crude and diluted with ethylacetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude .The obtained crude was purified by prep-HPLC (Column: XSELECT C18-250, 500 ul, Mobile phase: A: 10 mm Ammonium bicarbonate in water, B: MeCN, Flow rate: 14 mL / min, Retention time: 13.0 min) to afford N-(3-(5- fluoropyridin-3-yl)propyl)-2-(3-iodo-4-methoxyphenyl)nicotinamide 35 (0.174 g, 0.353 mmol, 27.25%) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.69-8.68 (m, 1H), 8.46 (t, J = 5.20 Hz, 1H), 8.41 (d, J = 2.40 Hz, 1H), 8.27 (s, 1H), 8.06 (d, J = 2.00 Hz, 1H), 7.82-7.80 (m, 1H), 7.69-7.67 (m, 1H), 7.51-7.52 (m, 1H), 7.43-7.40 (m, 1H), 7.05 (d, J = 8.80 Hz, 1H), 3.82 (s, 3H), 3.33-3.14 (m, 2H), 2.52-2.47 (m, 2H), 1.72 (t, J = 8.00 Hz, 2H).Example 35 – Preparation of Compound 36

[0282] Compound 36 was prepared according to the following Scheme: [l, 1.0 eq) in DMF (25.0 mL) were added K2CO3(4.52 g, 32.7 mmol, 2.2 eq), methyl iodide (1.857 mL, 29.7 mmol, 2.0 eq) under nitrogen atmosphere. The reaction mixture was stirred for overnight at room temperature. Upon completion of the reaction (as confirmed by TLC analysis 20% EtOAC in pet-ether, Rf ~ 0.5), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (40 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude methyl 3- bromoisonicotinate 1a (1.3 g, 4.86 mmol, 32.8 % yield) as brown liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.71 (d, J = 4.80 Hz, 1H), 7.75-7.74 (m, 1H), 3.92 (s, 3H).

[0284] Intermediate 3: To a stirred solution of methyl 3-bromoisonicotinate 1a (0.400 g, 1.852 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (0.517 g, 1.852 mmol, 1.5 eq) in 1,4-dioxane (40 mL) and water (2 mL) was added potassium carbonate (0.256 g, 1.852mmol, 2.0 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min, then added PdCl2(dppf) (1.355 g, 1.852 mmol, 0.1 eq) and the mixture was purged again with nitrogen for additional 10 min. The reaction mixture was heated to 80oC for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 20 mL / min, eluted using 45% ethylacetate in pet-ether) to afford methyl 4-(4-methoxy-3-nitrophenyl)nicotinate 3 (0.296 g, 0.919 mmol, 49.6 % yield) as pale yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.78-8.75 (m, 2H), 7.94 (d, J = 2.00 Hz, 1H), 7.76 (d, J = 4.80 Hz, 1H), 7.70-7.67 (m, 1H), 7.46 (d, J = 8.40 Hz, 1H), 3.99 (s, 3H), 3.73 (s, 3H).

[0285] Intermediate 4: To a stirred solution of methyl 3-(4-methoxy-3-nitrophenyl)isonicotinate 3 (1.35 g, 4.68 mmol, 1.0 eq) in ethanol (30.0 mL) and water (15.0 mL) was added ammonium chloride (2.004 g, 37.5 mmol, 8.0 eq) and iron (1.308 g, 23.42 mmol, 5.0 eq) under nitrogen atmosphere at RT. The reaction mixture was allowed to stir at 85oC for 8 h. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite, the obtained filtrate was concentrated under reduced pressure to dryness. The residue was diluted using 10% MeOH in DCM (20 mL) and saturated aqueous NaHCO3solution (40 mL). The organic layer was separated and the aqueous layer was extracted with 10% MeOH in DCM (2 x 10 mL). The combined organic layer was washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude methyl 3-(3-amino-4-methoxyphenyl)isonicotinate 4 (1.15 g, 4.33 mmol, 93 % yield) as brown gummy liquid.

[0286] Intermediate 5: To a stirred solution of methyl 3-(3-amino-4-methoxyphenyl)isonicotinate 4 (1.15 g, 4.45 mmol, 1.0 eq) in Conc. HCl (4.0 mL) was added a solution of sodium nitrite (0.369 g, 5.34 mmol, 1.2 eq) in Water (2.0 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 1.5h. Then a solution of potassium iodide (2.96 g, 17.81 mmol, 4.0 eq) in Water (2.0 mL) was added dropwise at 0oC. The reaction mixture was allowed to warm to room temperature and stirred for 4h. Upon completion of the reaction (as confirmed by TLC analysis 50 % EtOAC in Pet ether, Rf ~ 0.5) the reaction mixture was basified by using saturated sodium bicarbonate solution until pH ~ 11 and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400,flow rate 50 mL / min, eluted using 30% ethylacetate in pet-ether) to afford methyl 3-(3-iodo-4- methoxyphenyl)isonicotinate 5 (0.360 g, 0.824 mmol, 18.52 % yield) as yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.72-8.69 (m, 2H), 7.77 (d, J = 2.40 Hz, 1H), 7.68-7.67 (m, 1H), 7.41-7.38 (m, 1H), 7.12-7.03 (m, 1H), 3.89 (s, 3H), 3.71 (s, 3H).

[0287] Intermediate 6: To a stirred solution of methyl 3-(3-iodo-4-methoxyphenyl)isonicotinate 5 (0.360 g, 0.975 mmol, 1.0 eq) in a mixture of MeOH (6.0 mL), THF (4.0 mL) and water (2.0 mL) at 0oC was added LiOH. H2O (0.093 g, 3.90 mmol, 4.0 eq) and allowed to stir for overnight at room temperature. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to dryness. The resulting residue was acidified with 1.5N HCl (3.0 mL), concentrated under reduced pressure to afford the crude. The crude compound was purified by reverse-phase column chromatography (Grace column: C1840 µm, 100 g; flow rate: 40 mL / min; 35% FA in water / MeCN mobile phase) to afford 3-(3-iodo-4-methoxyphenyl)isonicotinic acid 6 (0.200 g, 0.556 mmol, 57.0 % yield) as off white-solid.1H-NMR (400 MHz, DMSO-d6): δ 13.57 (s, 1H), 8.66 (t, J = 10.00 Hz, 2H), 7.79 (d, J = 2.80 Hz, 1H), 7.63 (d, J = 6.40 Hz, 1H), 7.44-7.41 (m, 1H), 7.10 (d, J = 11.20 Hz, 1H), 3.89 (s, 3H).

[0288] Compound 36: To a stirred solution of an 3-(3-iodo-4-methoxyphenyl)isonicotinic acid 6 (0.200 g, 0.563 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine 7 (0.130 g, 0.845 mmol, 1.5 eq) in DMF (2.0 mL) was added N,N-diisopropylethylamine (0.492 ml, 2.82 mmol, 5.0 eq) followed by HATU (0.257 g, 0.676 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), ice cold water (20 mL) was added to the reaction mixture and diluted with ethylacetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude .The obtained crude was purified by prep-HPLC (Column: XSELECT C18-250, 500 ul, Mobile phase: A: 10mm Ammonium bicarbonate in water, B: MeCN, Flow rate: 14 mL / min, Retention time: 13.0 min) to afford the final compound N-(3-(5-fluoropyridin-3-yl)propyl)-3-(3-iodo-4- methoxyphenyl)isonicotinamide 36 (0.087 g, 0.176 mmol, 31.2 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.63-8.61 (m, 2H), 8.47 (t, J = 5.60 Hz, 1H), 8.40 (d, J = 2.80 Hz, 1H), 8.25 (d, J = 1.60 Hz, 1H), 7.83 (d, J = 2.40 Hz, 1H), 7.51-7.46 (m, 2H), 7.41-7.39 (m, 1H), 7.07 (d, J = 8.40 Hz, 1H), 3.80 (s, 3H), 3.15-3.11 (m, 2H), 2.41 (d, J = 8.00 Hz, 2H), 1.69-1.61 (m, 2H).Example 36 – Preparation of Compound 37

[0289] Compound 37 was prepared according to the following Scheme:

[0290] Intermediate 1b: To a stirred solution of 4-chloronicotinic acid 1a (1.0 g, 6.35 mmol, 1.0 eq) in dichloromethane (10 mL) and DMF (0.2 mL) was added oxalyl chloride (1.389 mL, 15.87 mmol, 2.5 eq) dropwise at 0 °C. After addition, the mixture was stirred for 2 h at room temperature. Then cooled back to 0oC and MeOH (4.0 mL) was added slowly, and the clear solution was further stirred for 30 min. Upon completion of the reaction (as confirmed by TLC analysis, 30% EtOAc in pet ether, Rf~ 0.5), the reaction mixture was quenched with ice cold saturated NaHCO3solution (35 mL) at 0oC, diluted with DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude methyl 4-chloronicotinate 1b (1.2 g, 3.57 mmol, 56.2 % yield) as yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.99 (t, J = 6.40 Hz, 1H), 8.71 (d, J = 5.20 Hz, 1H), 7.74-7.73 (m, 1H), 3.91 (s, 3H).

[0291] Intermediate 3: To a stirred solution of methyl 4-chloronicotinate 1b (1.0 g, 5.83 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (2.440 g, 8.74 mmol, 1.5 eq) in a mixture of dioxane (20.0 mL) and water (2.0 mL) was added potassium carbonate (1.611 g, 11.66 mmol, 2.0 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10min, then added PdCl2(dppf) (0.426 g, 0.583 mmol, 0.1 eq) and the mixture was purged again with nitrogen for 10 min. The reaction mixture was heated to 80oC for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite and the filtrate was diluted with ethylacetate (2 x 15 mL) and water (25 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 20 mL / min). The column was eluted using 48-52% ethylacetate in pet ether to afford desired product methyl 4-(4-methoxy-3-nitrophenyl)nicotinate 3 (1.1 g, 3.14 mmol, 53.9 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.80 (d, J = 5.20 Hz, 1H), 7.96 (d, J = 2.00 Hz, 1H), 7.71-7.68 (m, 1H), 7.56 (d, J = 5.20 Hz, 1H), 7.47-7.41 (m, 1H), 4.10 (s, 3H), 3.73-3.70 (m, 3H).

[0292] Intermediate 4: To a stirred solution of methyl 4-(4-methoxy-3-nitrophenyl)nicotinate 3 (1.1 g, 3.82 mmol, 1.0 eq) in ethanol (15.0 mL) and water (5.0 mL) was added ammonium chloride (1.633 g, 30.5 mmol, 8.0 eq) and iron (1.066 g, 19.08 mmol, 5.0 eq) under nitrogen atmosphere at room temperature. The reaction mixture was allowed to stir at 85oC for 5 hours. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was filtered through Celite and the obtained filtrate was concentrated under reduced pressure to dryness. The obtained residue was diluted using 10% MeOH in DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with 10% MeOH in DCM (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude methyl 4-(3-amino-4-methoxyphenyl)nicotinate 4 (1.01 g, 3.89 mmol, 102 % yield) as brown gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.67 (d, J = 5.20 Hz, 1H), 7.42 (d, J = 5.20 Hz, 1H), 6.88 (d, J = 8.40 Hz, 1H), 6.66 (d, J = 2.00 Hz, 1H), 6.54 (d, J = 2.40 Hz, 1H), 4.92 (s, 2H), 3.81 (s, 3H), 3.69 (s, 3H).

[0293] Intermediate 5: To a stirred solution of methyl 4-(3-amino-4-methoxyphenyl)nicotinate 4 (1.01 g, 3.91 mmol, 1.0 eq) in Conc.HCl (4.0 mL) was added a solution of sodium nitrite (0.324 g, 4.69 mmol, 1.2 eq) in water (2.0 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 30 minutes. Then a solution of potassium iodide (2.60 g, 15.64 mmol, 4 eq) in Water (2.0 mL) was added dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 4h. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was basified using saturated sodium bicarbonate solution and diluted with DCM (20 mL ). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude was purified by columnchromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 30-35 % ethylacetate in pet-ether) to afford methyl 4-(3-iodo-4-methoxyphenyl)nicotinate 5 (0.330 g, 0.792 mmol, 20.26 % yield) as yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.86 (d, J = 16.00 Hz, 1H), 8.73 (d, J = 6.80 Hz, 1H), 7.78 (d, J = 3.20 Hz, 1H), 7.50 (t, J = 7.20 Hz, 1H), 7.42-7.39 (m, 1H), 7.11 (d, J = 11.60 Hz, 1H), 3.90 (s, 3H), 3.70 (d, J = 6.40 Hz, 3H).

[0294] Intermediate 6: To a stirred solution of methyl 4-(3-iodo-4-methoxyphenyl)nicotinate 4 (0.330 g, 0.894 mmol, 1.0 eq) in a mixture of MeOH (6 mL), THF (4 mL), water (2 mL) at 0oC was added LiOH.H2O (0.086 g, 3.58 mmol, 4.0 eq) and allowed to stir for 5 h at 45 °C. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction was concentrated under reduced pressure. The resulting crude was acidified with 1.5N HCl (3.0 mL), concentrated under reduced pressure to afford the crude .The crude compound was purified by reverse-phase column chromatography (Grace column: C1840 µm, 100 g; flow rate: 25 mL / min; 35% ammonium bicarbonate in water / MeCN mobile phase) to afford 4-(3-iodo-4- methoxyphenyl)nicotinic acid 6 (0.290 g, 0.698 mmol, 78.0 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.40 (s, 1H), 7.93 (d, J = 2.80 Hz, 1H), 7.56-7.53 (m, 1H), 7.25 (d, J = 5.60 Hz, 1H), 7.03 (t, J = 17.20 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 1H).

[0295] Compound 37: To a stirred solution of an 4-(3-iodo-4-methoxyphenyl)nicotinic acid 5 (0.290 g, 0.817 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine 7 (Intermediate 6 of Example 1, 0.189 g, 1.225 mmol, 1.5 eq) in DMF (5 mL) was added DIPEA (0.713 mL, 4.08 mmol, 5 eq) followed by HATU (0.373 g, 0.980 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), ice cold water was added to the reaction mixture and diluted with ethylacetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-HPLC (Column: XSELECT C18-250, 500 ul, Mobile phase: A: 10mm Ammonium bicarbonate in water, B: MeCN, Flow rate: 14 mL / min, Retention time: 13.0 min) to afford N-(3-(5-fluoropyridin-3-yl)propyl)-4-(3-iodo-4-methoxyphenyl)nicotinamide 37 (0.057 g, 0.114 mmol, 13.95 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.64 (d, J = 5.20 Hz, 1H), 8.56 (s, 1H), 8.50 (t, J = 6.00 Hz, 1H), 8.40 (d, J = 2.80 Hz, 1H), 8.27 (s, 1H), 7.86 (d, J = 2.00 Hz, 1H), 7.55-7.46 (m, 3H), 7.08 (d, J = 8.40 Hz, 1H), 3.81 (s, 3H), 3.18-3.14 (m, 2H), 2.52-2.46 (m, 2H), 1.73-1.66 (m, 2H).Example 37 – Preparation of Compound 38

[0296] Compound 38 was prepared according to the following Scheme:

[0297] . , . mol, 1.0 eq) in dichloromethane (10 mL) was added oxalyl chloride (1.592 mL, 18.56 mmol, 2.5 eq) as dropwise followed by addition of DMF (0.200 mL) at RT. The reaction mixture was allowed to stir for 2h at room temperature. Then the reaction mixture was cooled to 0oC and added methanol (10 mL) as dropwise under nitrogen atmosphere. The reaction mixture was stirred for 20 min. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.3 & LCMS analysis), reaction mixture was concentrated under reduced pressure to dryness and quenched with saturated NaHCO3solution (~55 mL) until pH ~ 10 at 0oC and diluted with ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 10-12 % ethylacetate in pet ether) to afford methyl 3-bromopicolinate 1a (1.3 g, 5.99 mmol, 81 % yield) as pale yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.64-8.62 (m, 1H), 8.27-8.25 (m, 1H), 7.55-7.52 (m, 1H), 3.91 (s, 3H).

[0298] Intermediate 3: To a stirred solution of methyl 3-bromopicolinate 1a (1 g, 4.63 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (1.938 g, 6.94 mmol, 1.5 eq) in 1,4-dioxane (50 mL) and water (4 mL), was added potassium carbonate (0.960 g, 6.94 mmol, 1.5 eq) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min and PdCl2(dppf) (0.339 g, 0.463 mmol, 0.1 eq) was added. The mixture was purged again with nitrogen for 10 min and heated to 80oC for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.2), the reaction mixture was filtered through Celite. Ice cold water (50 mL) was added to the filtrate, diluted with ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 20 mL / min, eluted using 45% ethylacetate in pet ether) to afford desired product methyl 3-(4- methoxy-3-nitrophenyl)picolinate 3 (1.5 g, 4.38 mmol, 95 % yield) as pale beige solid.1H-NMR (400 MHz, DMSO-d6): δ 8.68-8.66 (m, 1H), 8.03-8.00 (m, 1H), 7.92 (d, J = 3.20 Hz, 1H), 7.71-7.64 (m, 2H), 7.48 (d, J = 12.00 Hz, 1H), 3.99 (s, 3H), 3.74 (t, J = 14.00 Hz, 3H).

[0299] Intermediate 4: To a stirred solution of methyl 3-(4-methoxy-3-nitrophenyl)picolinate 3 (2.0 g, 6.94 mmol, 1.0 eq) in methanol (40 mL) and water (20.00 mL) was added ammonium chloride (2.97 g, 55.5 mmol, 8.0 eq) and iron (1.937 g, 34.7 mmol, 5.0 eq) under nitrogen atmosphere at RT. The reaction mixture was stirred for 2h at 85oC. Upon completion of the reaction (as confirmed by TLC analysis). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to dryness. The residue was basified to pH ~ 12 using aqueous 10% NaHCO3solution and diluted with ethylacetate (75 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (1 x 150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product methyl 3-(3-amino-4- methoxyphenyl)picolinate 4 (0.400 g, 1.469 mmol, 21% yield) as brown gummy liquid. The obtained crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 8.54-8.53 (m, 1H), 7.85-7.83 (m, 1H), 7.65-7.54 (m, 2H), 6.85 (t, J = 14.80 Hz, 1H), 6.65 (d, J = 2.00 Hz, 1H), 6.53-6.50 (m, 1H), 4.88 (s, 2H), 4.19-4.03 (s, 3H), 3.80 (s, 3H).

[0300] Intermediate 5: To a stirred solution of methyl 3-(3-amino-4-methoxyphenyl)picolinate 4 (0.400 g, 1.469 mmol, 1.0 eq) in Conc.HCl (2.0 mL) was added a solution of sodium nitrite (0.122 g, 1.763 mmol, 1.2 eq) in water (1.0 mL) at 0oC. The resulting diazonium salt was stirred at 0 °C for 1.5 h. Then a solution of potassium iodide (0.975 g, 5.88 mmol, 4.0 eq) in water (1.0 mL) was added dropwise over aperiod of 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 4h. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was basified with saturated NaHCO3(40 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layer was washed with saturated aqueous Na2S2O3(1 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude as brown gummy liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 20 mL / min). The column was eluted using 28% ethylacetate in pet ether to afford desired product methyl 3-(3-iodo-4-methoxyphenyl)picolinate 5 (0.211 g, 0.527 mmol, 35.9 % yield) as yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.61-8.60 (m, 1H), 7.96-7.94 (m, 1H), 7.75 (d, J = 2.40 Hz, 1H), 7.64-7.61 (m, 1H), 7.41-7.39 (m, 1H), 7.12 (d, J = 8.40 Hz, 1H), 4.21-4.15 (s, 3H), 3.88 (s, 3H).

[0301] Intermediate 6: To a stirred solution of methyl 3-(3-iodo-4-methoxyphenyl)picolinate 5 (0.211 g, 0.572 mmol, 1.0 eq) in a mixture of methanol (12 mL), THF (8.00 mL) and water (4.00 mL) at 0oC was added LiOH.H2O (0.096 g, 2.286 mmol, 4.0 eq) and stirred for overnight at RT. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.0 & LCMS analysis), the reaction mixture was concentrated under reduced pressure to dryness. The resulting residue was acidified with aqueous 1.5 N HCl (10 mL) until pH ~ 5, concentrated under reduced pressure to afford the crude product as yellow solid. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous TFA / MeCN mobile phase) to afford 3-(3-iodo-4-methoxyphenyl)picolinic acid 6 (0.150 g, 0.383 mmol, 68.0 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 8.58-8.56 (m, 1H), 7.91-7.87 (m, 1H), 7.81 (d, J = 2.80 Hz, 1H), 7.59-7.55 (m, 1H), 7.45-7.41 (m, 1H), 7.26 (s, 1H), 7.23 (s, 1H), 7.19-7.09 (m, 1H), 3.88 (s, 3H), 2.31 (s, 1H).

[0302] Compound 38: To a stirred solution of an 3-(3-iodo-4-methoxyphenyl)picolinic acid 6 (0.150 g, 0.422 mmol, 1.0 eq) and 3-(5-fluoropyridin-3-yl)propan-1-amine 7 (0.098 g, 0.634 mmol, 1.5 eq) in DMF (3.0 mL) was added DIPEA (0.369 ml, 2.112 mmol, 5.0 eq) followed by HATU (0.241 g, 0.634 mmol, 1.5 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rfof the product ~ 0.3 & LCMS analysis), ice cold water (10 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (1 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as brown gummy liquid.The crude compound was purified by prep-HPLC (Column:X-Bridge C8(50 x 4.6) mm,3.5μm, Mobile phase: A:10 mM Ammonium bicarbonate in water, B: Acetonitrile, Flow rate:1.0 mL / min, Retention time: 12.0 min) to afford final compound N-(3-(5-fluoropyridin-3-yl)propyl)-3-(3-iodo-4-methoxyphenyl)picolin- amide 38 (0.092 g, 0.187 mmol, 44.31 % yield) as pale orange solid.1H-NMR (400 MHz, DMSO-d6): δ 8.57- 8.55 (m, 2H), 8.40 (d, J = 2.40 Hz, 1H), 8.28 (t, J = 1.60 Hz, 1H), 7.86-7.84 (m, 1H), 7.80 (d, J = 2.40 Hz, 1H), 7.56-7.53 (m, 2H), 7.43-7.41 (m, 1H), 7.04 (d, J = 8.40 Hz, 1H), 3.82 (s, 3H), 3.19-3.14 (m, 2H), 2.55-2.50 (m, 2H), 1.77-1.69 (m, 2H). Example 38 – Preparation of Compound 39

[0303] Compound 39 was prepared according to the following Scheme:

[0304] . , .0 mmol, 1.0 eq) and imidazole (2.112 g, 31.0 mmol, 1.0 eq) in DCM (30.0 mL) was added iodine (9.45 g, 37.2 mmol, 1.2 eq) portion wise at 25 °C and allowed to stirred for 1 h. Then, a solution of tert-butyl (2- hydroxyethyl)carbamate 1 (5.0 g, 31.0 mmol, 1.0 eq) in DCM (10 mL) was added dropwise to the reaction mixture and allowed to stirred for 2 h at RT. Upon completion of the reaction (as confirmed by LCMS analysis), water (30 mL) was added to the reaction mixture and diluted with DCM (30 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layer was washed with sodium thiosulfate solution (2 x 15 mL), brine (1 x 50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude.The obtained crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 8-10 % ethylacetate in pet-ether) to afford tert-butyl (2-iodoethyl)carbamate 2 (5.3 g, 17.97 mmol, 57.9 % yield)as orange gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 7.15 (t, J = 5.20 Hz, 1H), 3.27-3.22 (m, 2H), 3.18-3.15 (m, 2H), 1.39 (s, 9H).

[0305] Intermediate 4: 5-bromoquinoline 3 (0.250 g, 1.202 mmol, 1.0 eq), zinc (0.236 g, 3.60 mmol, 3.0 eq, freshly activated with 1N HCl and dried), pyridine-26-bis(carboximidamide) dihydrochloride (0.057 g, 0.240 mmol, 0.2 eq), TBAI (0.133 g, 0.360 mmol, 0.3 eq) and NiCl2(dme) (0.053 g, 0.240 mmol, 0.2 eq) were stirred in RB under N2condition. The RB was then evacuated and backfilled with N2 (3 times) with the help of a 2-way adaptor. In another vial tert-butyl (2-iodoethyl)carbamate 2 (0.391 g, 1.442 mmol, 1.2 eq) was taken, evacuated and backfilled with N2, then separately degassed N,N-dimethylacetamide (6.0 mL) was added in vial containing alkyl iodide compound. The alkyl iodide solution was transferred to RB containing aryl iodide reaction mixture under N2. The reaction mixture was heated at 100 °C for 1 h under nitrogen atmosphere. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was quenched with water (20.0 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layer was dried over Na2SO4and concentrated to afford crude. The crude product was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / MeCN mobile phase) to afford tert-butyl (2-(quinolin-5-yl)ethyl)carbamate 4 (0.092 g, 0.332 mmol, 27.6 % yield) as pale yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 8.91-8.90 (m, 1H), 8.58 (d, J = 8.00 Hz, 1H), 7.90 (d, J = 8.00 Hz, 1H), 7.70-7.66 (m, 1H), 7.59-7.56 (m, 1H), 7.45 (d, J = 8.00 Hz, 1H), 6.99 (s, 1H), 3.23-3.17 (m, 4H), 1.37 (s, 9H).

[0306] Intermediate 5: To a stirred solution of tert-butyl (2-(quinolin-5-yl)ethyl)carbamate 4 (0.09 g, 0.330 mmol, 1.0 eq) in DCM (3.0 mL) was added HCl (4.0M sol in 1,4-dioxane, 1.487 mL, 5.95 mmol, 18.0 eq) at 0oC. The resulting solution was stirred for 2 h at RT. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was triturated with pet-ether (2 x 5 mL) and decanted the solvent, dried it under reduced pressure to afford 2-(quinolin-5-yl)ethan-1-amine, HCl 5 (0.07 g, 0.328 mmol, 99 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.06 (d, J = 3.60 Hz, 1H), 8.83 (d, J = 8.00 Hz, 1H), 8.06 (d, J = 8.00 Hz, 1H), 7.99 (s, 2H), 7.84 (t, J = 8.80 Hz, 1H), 7.79-7.77 (m, 1H), 7.63 (d, J = 7.20 Hz, 1H), 3.45 (t, J = 7.60 Hz, 4H). Compound 39: To a stirred solution of an 2-(quinolin-5-yl)ethan-1-amine, HCl 5 (0.07 g, 0.335 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 6 (Intermediate 5 of Example 1, 0.116 g, 0.335 mmol, 1.0 eq) in DMF (3.0 mL) was added DIPEA (0.293 mL, 1.677 mmol, 5.0 eq) followed by HATU (0.153 g, 0.403 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred atroom temperature for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), ice cold water (10 mL) was added to the resulting crude and diluted with ethylacetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted with 60-62 % ethylacetate in pet-ether to afford 5-(3-iodo-4-methoxyphenyl)-N- (2-(quinolin-5-yl)ethyl)oxazole-4-carboxamide 39 (0.043 g, 0.086 mmol, 21.48 % yield) as off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.92-8.90 (m, 1H), 8.79 (d, J = 2.40 Hz, 1H), 8.74 (d, J = 8.40 Hz, 1H), 8.65 (t, J = 6.00 Hz, 1H), 8.55 (s, 1H), 8.23-8.20 (m, 1H), 7.91 (d, J = 8.40 Hz, 1H), 7.71-7.67 (m, 1H), 7.59-7.56 (m, 1H), 7.51 (d, J = 6.40 Hz, 1H), 7.15 (d, J = 8.80 Hz, 1H), 3.91 (s, 3H), 3.61-3.56 (m, 2H), 3.33 (t, J = 6.80 Hz, 2H). Example 39 – Preparation of Compound 40

[0307] Compound 40 was prepared according to the following Scheme:

[0308] n erme a e : - romosoquno ne . g, . mmo, . eq , znc .236 g, 3.60 mmol, 3.0 eq, freshly activated with 1N HCl and dried), pyridine-26-bis(carboximidamide) dihydrochloride (0.057 g, 0.240 mmol, 0.2 eq), TBAI (0.133 g, 0.360 mmol, 0.3 eq) and NiCl2(dme) (0.053 g, 0.240 mmol, 0.2 eq) were stirred in RB under N2condition. The RB was then evacuated and backfilled with N2(3 times) with the help of a 2-way adaptor. In another vial tert-butyl (2-iodoethyl)carbamate 2(0.391 g, 1.442 mmol, 1.2 eq) was taken and evacuated and backfilled with N2, then separately degassed N,N-Dimethylaniline(6.0 mL) was added in vial containing alkyl iodide compound. The alkyl iodide solution was transferred to RB containing aryl iodide reaction mixture under N2. The reaction mixture was heated at 100 °C for 1h under nitrogen atmosphere. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford crude. The obtained crude compound was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / MeCN mobile phase) to afford desired product tert-butyl (2-(isoquinolin-5-yl)ethyl)carbamate 3 (0.095 g, 0.330 mmol, 27.4 % yield) as pale yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.55 (d, J = 4.00 Hz, 1H), 7.99 (d, J = 8.00 Hz, 2H), 7.61 (t, J = 0.00 Hz, 2H), 6.99 (t, J = 4.00 Hz, 1H), 3.34-3.24 (m, 2H), 3.23-3.16 (m, 2H), 1.36 (s, 9H).

[0309] Intermediate 4: To a stirred solution of tert-butyl (2-(isoquinolin-5-yl)ethyl)carbamate 3 (0.09 g, 0.330 mmol, 1.0 eq) in DCM (3.0 mL) was added HCl (4.0M sol in 1,4-dioxane, 1.487 mL, 5.95 mmol, 18.0 eq) at 0oC. The resulting solution was stirred for 2 h at RT under nitrogen atmosphere. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to afford the crude. The obtained crude compound was triturated with pet-ether (2 x 5 mL) and decant the solvent, dried it under reduced pressure to afford 2-(isoquinolin-5-yl)ethan-1-amine, HCl 4 (0.08 g, 0.276 mmol, 84 % yield) as off- white solid. Compound 40: To a stirred solution of 2-(isoquinolin-5-yl)ethan-1-amine, HCl 4 (0.08 g, 0.383mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 6 (Intermediate 5 of Example 1, 0.132 g, 0.383 mmol, 1.0 eq) in DMF (3.0 mL) was added DIPEA (0.335 mL, 1.917 mmol, 5.0 eq) followed by HATU (0.175 g, 0.460 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. Upon completion of the reaction (as confirmed by LCMS analysis), ice cold water (10 mL) was added to the resulting crude and diluted with ethylacetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 60-62 % ethylacetate in pet ether to afford 5-(3-iodo-4-methoxyphenyl)-N-(2-(isoquinolin-5-yl)ethyl)oxazole-4-carboxamide 40 (0.032 g, 0.064 mmol, 16.57 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.77 (d, J = 4.00 Hz, 1H), 8.64 (t, J = 4.00 Hz, 1H), 8.55 (t, J = 0.00 Hz, 2H), 8.22-8.19 (m, 1H), 8.16 (d, J = 4.00 Hz, 1H), 8.01 (d, J = 8.00 Hz, 1H), 7.68 (t, J = 0.00 Hz, 1H), 7.62 (t, J = 8.00 Hz, 1H), 7.15 (d, J = 8.00 Hz, 1H), 3.91 (s, 3H), 3.62-3.57 (m, 2H), 2.56-2.50 (m, 2H).Example 40 – Preparation of Compound 41

[0310] Compound 41 was prepared according to the following Scheme:

[0311] Intermediate 3: 8-bromoisoquinoline 1 (0.5 g, 2.403 mmol, 1.0 eq), zinc (0.471 g, 7.21 mmol, 3.0 eq) (freshly activated with 1N HCl and dried), pyridine-2 6-bis(carboximidamide) dihydrochloride (0.113 g, 0.481 mmol, 0.2 eq), TBAI (0.266 g, 0.721 mmol, 0.3 eq) and NiCl2(dme) (0.106 g, 0.481 mmol, 0.2 eq) were stirred in RB under N2condition. The RB was evacuated and backfilled with N2. In another vial tert-butyl (2-iodoethyl)carbamate 2 (0.782 g, 2.88 mmol, 1.2 eq) was taken and evacuated and backfilled with N2, then separately degassed DMA (6.00 mL) was added. The DMA solution was transferred to RB under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 1 h under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 40% EtOAc in pet ether, Rfof the product ~ 0.1 & LCMS analysis), the reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethylacetate (2 x 15 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / MeCN mobile phase) to afford tert-butyl (2-(isoquinolin-8- yl)ethyl)carbamate 3 (0.220 g, 0.752 mmol, 31.2 % yield) as pale yellow gummy liquid.1H-NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.52 (d, J = 5.60 Hz, 1H), 8.17 (s, 1H), 7.83 (t, J = 4.80 Hz, 2H), 7.71-7.67 (m, 1H),7.49 (d, J = 6.80 Hz, 1H), 7.02 (s, 1H), 3.27 (d, J = 2.40 Hz, 4H), 3.17 (s, 1H), 3.00-2.88 (m, 1H), 1.36 (d, J = 7.20 Hz, 9H).

[0312] Intermediate 4: To a stirred solution of tert-butyl (2-(isoquinolin-8-yl)ethyl)carbamate 3 (0.210 g, 0.771 mmol, 1.0 eq) in dichloromethane (3.0 mL) was added HCl (4.0M sol in 1,4-dioxane, 3.47 mL, 13.88 mmol, 18.0 eq) at 0oC. The resulting solution was stirred for 1.5 h at RT under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 60% EtOAc in pet ether, Rfof the product ~ 0.0), the reaction mixture was concentrated under reduced pressure to afford crude product. The crude compound was titurated with MTBE (2 x 3 mL) and decant the solvent, dried under reduced pressure to afford 2-(isoquinolin-8-yl)ethan-1-amine, HCl 4 (0.160 g, 0.731 mmol, 95 % yield) as off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 8.70 (t, J = 3.20 Hz, 1H), 8.48 (d, J = 6.40 Hz, 1H), 8.23 (d, J = 8.00 Hz, 3H), 8.12 (t, J = 8.40 Hz, 1H), 7.90 (d, J = 7.20 Hz, 1H), 3.96-3.57 (m, 2H), 3.21- 3.16 (m, 2H).

[0313] Compound 41: To a stirred solution of 2-(isoquinolin-8-yl)ethan-1-amine, HCl 4 (0.160 g, 0.767 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (Intermediate 5 of Example 1, 0.265 g, 0.767 mmol, 1.0 eq) in DMF (3.0 mL) was added DIPEA (0.682 ml, 3.83 mmol, 5.0 eq) followed by HATU (0.350 g, 0.920 mmol, 1.2 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 6 h. Upon completion of the reaction (as confirmed by TLC analysis, 60% EtOAc in pet ether, Rfof the product ~ 0.2), ice cold water (10 mL) was added to the resulting crude and diluted with ethylacetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude compound was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min). The column was eluted using 35-40% ethylacetate in pet ether to afford final compound 5-(3- iodo-4-methoxyphenyl)-N-(2-(isoquinolin-8-yl)ethyl)oxazole-4-carboxamide 41 (0.1962 g, 0.386 mmol, 50.3 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 8.75 (d, J = 2.40 Hz, 1H), 8.69 (t, J = 6.40 Hz, 1H), 8.53 (t, J = 5.60 Hz, 2H), 8.24-8.21 (m, 1H), 7.86-7.82 (m, 2H), 7.72-7.68 (m, 1H), 7.55 (d, J = 6.40 Hz, 1H), 7.15 (d, J = 8.80 Hz, 1H), 3.91 (s, 3H), 3.66-3.61 (m, 2H), 3.43 (t, J = 6.80 Hz, 2H), (t, J = Hz, 2H).Example 41 – Preparation of Compound 42

[0314] Compound 42 was prepared according to the following Scheme:

[0315] g, 4.50 mmol, 1.0 eq) in DMSO (10 mL) were added tetrabutylammonium bromide (0.073 g, 0.225 mmol, 0.05 eq) and sodium cyanide (0.441 g, 9.01 mmol, 2.0 eq) at 25 °C and allowed to stirred for overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc in pet ether, Rf of the product ~ 0.3), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic layer was washed with brine (1 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude compound. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted using 8-9 % ethylacetate in pet-ether) to afford desired product 2-(quinolin-8-yl)acetonitrile 2 (0.610 g, 3.60 mmol, 80 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.02-9.00 (m, 1H), 8.47-8.44 (m, 1H), 8.03-8.01 (m, 1H), 7.88 (t, J = 6.00 Hz, 1H), 7.67-7.63 (m, 2H), 4.49 (s, 2H).

[0316] Intermediate 3: To a stirred solution of 2-(quinolin-8-yl)acetonitrile 2 (0.60 g, 3.57 mmol, 1.0 eq) in a mixture of 7N methanolic ammonia (3.00 mL) and ethanol (5.0 mL) was added Raney nickel (0.022 g, 0.357 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for overnight under hydrogen atmosphere. Upon completion of the reaction (as confirmed by LCMS analysis & TLC analysis, 30% EtOAc in pet ether), the reaction mixture was filteredthrough Celite, washed with methanol (2 x 5 mL) and the filtrate was concentrated under reduced pressure to afford the desired crude product 2-(quinolin-8-yl)ethan-1-amine 3 (0.530 g, 2.89 mmol, 81 % yield) as pale yellow gummy liquid . The obtained crude compound was taken as such for next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 8.93-8.92 (m, 1H), 8.35-8.33 (m, 1H), 7.84-7.81 (m, 1H), 7.63-7.61 (m, 1H), 7.55-7.51 (m, 2H), 3.47-3.20 (m, 1H), 3.17 (s, 3H), 2.95-2.87 (m, 2H), 2.70-2.64 (m, 1H), 1.77 (t, J = 5.60 Hz, 1H), 1.44 (s, 1H), 1.06 (t, J = 6.80 Hz, 1H).

[0317] Compound 42: To a stirred solution of 2-(quinolin-8-yl)ethan-1-amine 3 (0.150 g, 0.869 mmol, 1.2 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4 (Intermediate 5 of Example 1, 0.250 g, 0.724 mmol, 1.0 eq) in DMF (6.0 ml) was added DIPEA (0.633 ml, 3.62 mmol, 5.0 eq) followed by HATU (0.413 g, 1.087 mmol, 1.5 eq) at 0oC under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 h. Upon completion of the reaction (as confirmed by LCMS analysis), ice cold water (20 mL) was added to the reaction mixture and diluted with ethylacetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (Isolera, silica mesh size 230 - 400, flow rate 35 mL / min, eluted with 35-40 % ethylacetate in pet-ether) to afford final compound 5-(3-iodo-4-methoxyphenyl)-N-(2-(quinolin-8-yl)ethyl)oxazole-4-carboxamide 42 (0.1363 g, 0.271 mmol, 37.43 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.99-8.98 (m, 1H), 8.75 (d, J = 2.00 Hz, 1H), 8.58 (t, J = 5.60 Hz, 1H), 8.51 (s, 1H), 8.39-8.36 (m, 1H), 8.19-8.16 (m, 1H), 7.88-7.85 (m, 1H), 7.67 (d, J = 6.00 Hz, 1H), 7.58-7.52 (m, 2H), 7.12 (d, J = 8.80 Hz, 1H), 3.90 (s, 3H), 3.71-3.66 (m, 2H), 3.50 (t, J = 7.20 Hz, 2H).Example 42 – Preparation of Compound 43 and Compound 44

[0318] Compound 43 and Compound 44 were prepared according to the following Scheme:

[0319] Intermediate 7B: To a stirred solution of Compound-7A (1.0 g, 8.9mL) was added DMF (cat), followed by the dropwise addition of oxalyl chloride (0.76 mL, 8.92 mmol) at 0°C. The resulting reaction mass was warmed to RT and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum to afford crude Intermediate 7B as a yellow color liquid, which was used as such for the next reaction.

[0320] Intermediate 18A: To a stirred solution of Intermediate 7B (1.0 g, 7.63 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added (5-fluoropyridin-3-yl) boronic acid (1.16 g, 8.39 mmol), followed by the addition of potassium carbonate (3.1 g, 22.9 mmol). The reaction mixture was degassed with nitrogen for 15 min and PdCl2(dppf)DCM complex (620 mg, 0.76 mmol) was added, again degassed for 10 min. Then sealed tube was capped and resulting reaction contents were heated at 80°C for 16 h. After completion of the reaction (monitored by TLC), the reaction was cooled to RT and filtered through a celite pad. The filtrate was extracted with ethyl acetate (50 mL) and organic layer was dried over sodium sulphate and evaporated under vacuum to afford crude compound-18A (1.2 g), which was purified by silica gel column chromatography (100-200 mesh) eluting with 30-35% ethyl acetate in hexane to afford Intermediate 18A (850 mg, 73% yield) as a pale-yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.76 (t, J= 1.6 Hz, 1H), 8.64 (d, J= 2.8 Hz, 1H), 8.09-8.05 (m, 1H), 6.53 (s, J= 1.2 Hz, 1H), 2.82-2.78 (m, 2H), 2.43-2.39 (m, 2H), 2.10-2.03 (m, 2H).

[0321] Intermediate 19A: To a stirred solution of Intermediate 18A (200 mg, 1.0 mmol) in THF (4 mL), was added R-tert-butyl sulfonamide (140 mg, 1.1 mmol), followed by the addition of titaniumtetraethoxide (1.07 g, 4.7 mmol), under nitrogen atmosphere. The resulting reaction mixture was heated to 70°C and stirred for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO3solution (5 mL) and stirred for 10 min. Then, filtered the reaction mixture through a celite bed and washed the bed with ethyl acetate (10 mL). The filtrate was subjected to layer separation and the organic layer was evaporated under vacuum to obtain 120 mg of imino compound as a yellow color liquid. Then, dissolved the obtained imino compound in THF (2.5 mL) and cooled to -78°C, DiBAL-H (1.0 M in toluene) (1.3 mL, 1.2 mmol) was added dropwise into the reaction mixture over a period of 10-15 min and stirred the reaction at -78°C for 2 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched using sat. NH4Cl solution (5 mL) and stirred for 10 min, followed by extraction with ethyl acetate (10 mL). Separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Compound-19 (300 mg), which was purified by silica-gel (100-200 mesh) column chromatography eluting with 2-4% methanol in DCM to afford Racemic Intermediate 19 (80 mg, 66% yield) as a yellow liquid. Following chiral preparative HPLC, Intermediate 19A was isolated with 99.33% enantiomeric purity.

[0322] Intermediate 20: To a stirred solution of Intermediate 19A (1 g, 3.3 mmol) in 1,4-dioxane (5 mL), was added 4M HCl in dioxane (20 mL) and resulting reaction mixture was stirred for 2-3 h. After completion of reaction (monitored by TLC), concentrated the reaction mixture under vacuum to obtain 1 g of Compound-20 as an off-white solid (HCl salt), which was further basified with aq. NaOH solution, followed by extraction into DCM (30 mL). Separated the organic layer and evaporated under vacuum to afford Intermediate 20 (650 mg, 100% crude yield) as free base.1H NMR (400 MHz, DMSO-d6): δ 8.52 (t, J= 2.0 Hz, 1H), 8.44 (d, J= 2.8 Hz, 1H), 7.74-7.70 (m, 1H), 6.23 (s, 1H), 2.27 (br s, 2H), 1.90-1.84 (m, 3H), 1.65-1.61 (m, 1H).

[0323] Intermediate 18: To a stirred solution of Intermediate 20 (600 mg, 3.0 mmol) in methanol (10 mL) was added 20% Pd(OH)2(1.2 g, 200% w / w), at RT. The resulting reaction mixture was stirred under hydrogen pressure (60 psi) for 16 h. After completion of the reaction (monitored by TLC), the reaction was filtered through a celite pad. The filtrate was evaporated under vacuum to afford Intermediate 18 (470 mg, 81% yield) an off-white liquid.

[0324] Compound 43 and Compound 44: Intermediate 10 (Intermediate 5 from Example 1, (670 mg, 1.9 mmol) was coupled with Intermediate 18 (450 mg, 2.3 mmol) using the general procedure for Compound 1 (Example 1) giving Intermediate 20A (Compound 43 / 44 mixture, 400 mg, 78% yield) as an off-white solid. Separation of the isomers by SFC chromatography yielded Compound 43 (158 mg) and Compound 44 (125 mg). Compound 431H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J= 2.4 Hz, 1H), 8.53 (s,1H), 8.41 (d, J= 2.8 Hz, 1H), 8.38 (t, J= 1.6 Hz, 1H), 8.16 (dd, J= 8.8, 2.0 Hz, 1H), 8.11 (d, J= 8.4 Hz, 1H), 7.63- 7.59 (m, 1H), 7.12 (d, J= 8.8 Hz, 1H), 3.99-3.97 (m, 1H), 3.89 (s, 3H), 2.83 (t, J= 12.0 Hz, 2H), 1.99-1.79 (m, 4H), 1.64 (q, J= 12.0 Hz, 2H), 1.53-1.38 (m, 3H). Compound 441H NMR (400 MHz, DMSO-d6): δ 8.76 (d, J= 2.0 Hz, 1H), 8.58 (s, 1H), 8.42-8.40 (m, 2H), 8.18 (dd, J= 8.8, 2.0 Hz, 1H), 8.01 (d, J= 7.6 Hz, 1H), 7.69-7.67 (m, 1H), 7.14 (d, J= 8.8 Hz, 1H), 4.27 (br s, 1H), 3.90 (s, 3H), 3.03 (br s, 1H), 1.99-1.91 (m, 2H), 1.88-1.83 (m, 2H), 1.63 (br s, 4H). Example 43 – General Preparation of Compounds 45-49

[0325] Compound 45-49 were prepared according to the following Scheme:

[0326] Genom Example 1, 0.58 mmol) and Amino compound (Intermediate 11-15, 0.69 mmol) in DMF (5 mL) was added HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL), separated the organic layer and washed with brine (5 mL) and the organic layer was dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with ethyl acetate in hexane to afford Compound 45-49. Example 44 – Preparation of Compound 45

[0327] Compound 45 was prepared according to Example 43 using Intermediate 10 (Intermediate 5 from Example 1, 300 mg, 0.87 mmol), Intermediate 11 (141 mg, 1.04 mmol), HATU (363 mg, 1.04 mmol) and triethylamine (0.6 mL, 4.35 mmol) in DMF (5 mL) giving the target compound (220 mg, 55% yield) as a white solid.1NMR (400 MHz, DMSO-d6): δ 8.79 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.43 (t, J=6.0 Hz 1H), 8.19 (dd, J=8.8, 2.8 Hz, 1H), 7.29-7.26 (m, 2H), 7.23-7.21 (m, 2H), 7.19-7.12 (m, 2H), 3.89 (s, 3H), 3.30-3.26 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 1.86-1.79 (m, 2H).Example 45 – Preparation of Compound 46

[0328] Compound 46 was prepared according to Example 43 using Intermediate 10 (Intermediate 5 from Example 1, 200 mg, 0.58 mmol), Intermediate 12 (103 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.90 mmol) in DMF (5 mL) giving the target compound (135 mg, 49% yield) as a white solid.1NMR (400 MHz, DMSO-d6): δ 8.79 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.40 (t, J=6.0 Hz 1H), 8.19 (dd, J=8.8, 2.4 Hz, 1H), 7.14-7.11 (m, 1H), 7.11-7.06 (m, 4H), 3.89 (s, 3H), 3.28-3.25 (m, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.32 (s, 3H), 1.81-1.78 (m, 2H). Example 46 – Preparation of Compound 47

[0329] Compound 47 was prepared according to Example 43 using Intermediate 10 (Intermediate 5 from Example 1, 200 mg, 0.58 mmol), Intermediate 13 (0.11 mL, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.90 mmol) in DMF (3 mL) giving the target compound (127 mg, 45% yield) as an off-white solid.1NMR (400 MHz, DMSO-d6): δ 8.79 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.40 (t, J=6.0 Hz 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 7.13 (d, J=8.8 Hz, 3H), 6.85-6.81 (m, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 3.29-3.24 (m, 2H), 2.54 (t, J=7.2 Hz, 2H), 1.82-1.75 (m, 2H). Example 47 – Preparation of Compound 48

[0330] Compound 48 was prepared according to Example 43 using Intermediate 10 (Intermediate 5 from Example 1, 200 mg, 0.58 mmol), Intermediate 14 (117 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.90 mol) in DMF (3 mL) giving the target compound (160 mg, 56% yield) as a white solid.1NMR (400 MHz, DMSO-d6): δ 8.79 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.40 (t, J=6.0 Hz 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.28-3.25 (m, 2H), 2.60 (t, J=7.2 Hz, 2H), 1.85-1.77 (m, 2H). Example 48 – Preparation of Compound 49

[0331] Compound 49 was prepared according to Example 43 using Intermediate 10 (Intermediate 5 from Example 1, 300 mg, 0.87 mmol), Intermediate 15 (0.16 mL, 1.04 mmol), HATU (363 mg, 1.04 mmol) and triethylamine (0.6 mL, 4.35 mol) in DMF (5 mL) giving the target compound (210 mg, 46% yield) as a white solid.1NMR (400 MHz, DMSO-d6): δ 8.80 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.43 (t, J=5.6 Hz 1H), 8.19 (dd, J=8.4, 2.0 Hz, 1H), 7.53-7.50 (m, 2H), 7.24 (dd, J=8.0, 1.6 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 3.28 (q, J=6.4 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.85-1.81 (m, 2H).Example 49 – General Synthetic Route for Preparation of Compounds 50-53 and Compounds 55-58he above scheme. As illustrated, carboxylic acid starting materials 1 were converted to acid chloride intermediates 2 on reaction with oxalyl chloride and catalytic DMF. Subsequent cyclization to oxazole Intermediates 4 occurred on reaction of Intermediates 2 with isocyanate 3. Ester hydrolysis of Intermediates 4 with NaOH yielded carboxylic acid Intermediates 5. Final coupling with amine Intermediate 6 gave the target compounds. Specific conditions and analytical data are described in Examples 50-60.

[0333] General Procedure for Preparation of Intermediate 2: To a stirred suspension of substituted benzoic acid (1) (1.79 mmol) in DCM (5 mL) was added oxalyl chloride (2.69 mmol), a few drops of DMF at 0 °C. The resulting reaction mixture was warmed to rt and stirred for 2 to 4 h. After completion of reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure in the presence of nitrogen atmosphere to get crude residue. The obtained crude residue of Intermediate 2 was used in the next step, as such, without any further purification.

[0334] General Procedure for Preparation of Intermediate 4: To a stirred solution of Intermediate 3 (1.79 mmol) in dry THF (5 mL) was added potassium tert-butoxide (5.37 mmol) portion-wise at 0 °C and stirred for 15 minutes. Thereafter, Intermediate 2 (1.79 mmol), dissolved in dry THF (5 mL), was added drop wise at same temperature into the reaction. The resulting reaction mixture was allowed to stir at RT for 2 to 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with sat. ammonium chloride (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with ethyl acetate in hexane to afford Intermediate 4.

[0335] General Procedure for Preparation of Intermediate 5: To a stirred solution of Intermediate 4 (0.34 mmol) in THF (5 mL) was added 1M NaOH solution (0.5 mL, 0.52 mmol) at 0 °C. The resulting reactionmass was allowed to stir at RT for 12 to 16 h. After completion of the reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was taken into water (5 mL) and extracted with ethyl acetate (10 mL), separated the organic layer, acidified the aqueous layer using 1 N HCl (pH 1-2), filtered the precipitated solid and washed with water (5 mL), dried the product under vacuum at 45-50°C to afford Intermediate 5.

[0336] General Procedure for Preparation of Compounds 50-53 and Compounds 55-58: To a stirred solution of Intermediate 5 (0.58 mmol) and Intermediate 6 (0.69 mmol) in DMF (5 mL) was added HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL), separated the organic layer and washed with brine (5 mL) and the organic layer was dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with ethyl acetate in hexane to afford the desired target compound. Example 50 – Preparation of Intermediate 6 from Example 49

[0337] Intermediate 6 from Example 49 was prepared according to the following Scheme:in triethylamine (120 mL) was added prop-2-yn-1-ol (7.6 g, 137.13 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2(2.38 g, 3.40 mmol), CuI (1.29 g, 6.85 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 100°C and stirred for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was filtered through a celite pad. The filter cake was thoroughly washed with DCM, the filtrate was evaporated under reduced pressure to get crude residue (21.0 g). The obtained residue was further purified by silica- gel (100-200 mesh) column chromatography eluting with 45-50% ethyl acetate in hexane to afford Intermediate 2 (8.6 grams, 83% yield) as a pale-yellow liquid.1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J=2.4 Hz, 1H), 8.51 (br s, 1H), 7.89-7.75 (m, 1H), 5.46 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 1H).

[0339] Intermediate 3: To a stirred suspension of palladium on carbon (10% wet) (1.8 g) in methanol (100 mL) was added 3-(5-fluoropyridin-3-yl) prop-2-yn-1-ol (2) (8.5 g, 56.23 mmol) at RT and the resulting reaction mixture was stirred under hydrogen pressure (60 Psi) for 16 h. After completion of reaction(monitored by TLC), the mixture was filtered through a celite pad. The filtered cake was thoroughly washed with MeOH (50 mL) and filtrate was evaporated under reduced pressure to get crude residue (8.2 g). The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with 50-55% ethyl acetate in hexane to afford Intermediate 3 (6.4 grams, 73% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=2.8 Hz, 1H), 8.32 (s, 1H), 7.61-7.57 (m, 1H), 4.53 (t, J=5.2 Hz, 1H), 3.41 (q, J=6.0 Hz, 2H)2.77 (t, J=5.2 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.77-1.70 (m, 2H).

[0340] Intermediate 4: To a stirred solution of Intermediate 3 (6.4 g, 41.29 mmol) in THF (120 mL) was added PPh3(21.6 g, 82.5 mmol) and phthalimide (12.0 g, 41.29 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (16.7 mL, 82.5 mmol) was added dropwise and the reaction mass was warmed to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using (50:50) ethyl acetate in hexane as eluent to afford Intermediate 4 (10.4 grams, 89% yield) as a pale-yellow solid.

[0341] Intermediate 6: To a stirred solution of Intermediate 4 (10.0 g, 35.17 mmol) and in MeOH (100 mL) was added N2H4.H2O (4.5 mL, 91.45 mmol) at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was washed with EtOAc and filtered. The filtrate was evaporated under reduced pressure to get crude residue and the obtained crude residue was further purified by silica gel column chromatography (100-200 mesh) using (5:10:85) (Aq. NH3: MeOH: DCM) as an eluent to afford Intermediate 6 (1.2 grams, 18.4% yield) as a colorless liquid.1H NMR (400 MHz, CDCl3): δ 8.40 (d, J=2.4 Hz, 2H), 8.34 (s, 1H), 7.65 (d, J=9.6 Hz, 1H), 2.77-2.67 (m, 4H), 1.91-1.87 (m, 2H). Example 51 – Preparation of Compound 50

[0342] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-Flurobenzoic acid (2.0 g, 14.28 mmol) and oxalyl chloride (1.84 mL, 21.42 mmol) in DCM (10 mL) giving the target compound (2.4 grams, 100% yield).

[0343] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (1.7 g, 15.13 mmol), potassium tert- butoxide (5.1 g, 45.40 mmol) and Intermediate 2 (2.4 g, 15.13 mmol) in dry THF (20 mL) giving the target compound (1.4 g, 39% yield) as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.05- 8.01 (m, 2H), 7.42-7.37 (m, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).

[0344] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (1.1 g, 4.68 mmol) and 1M NaOHsolution (7.0 mL, 7.02 mmol) in THF (12 mL) giving the target compound (0.9 g, 62% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.21 (br s, 1H), 8.53 (s, 1H), 8.08-8.04 (m, 2H), 7.37 (t, J= 8.8 Hz, 1H).

[0345] Compound 50: Compound 50 was prepared according to the general procedure for the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (300 mg, 1.45 mmol), Intermediate 6 (Example 50, 141 mg, 1.74 mmol), HATU (660 mg, 1.74 mmol) and triethylamine (1.0 mL, 7.25 mmol) in DMF (5 mL) giving the target compound (160 mg, 32% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.51 (t, J= 6.4 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.31-8.27 (m, 2H), 7.64 (d, J= 10.0 Hz, 1H), 7.35 (t, J= 8.8 Hz, 2H), 3.30-3.27 (m, 2H), 2.68 (t, J= 7.6 Hz, 2H), 1.88-1.85 (m, 2H). Example 52 – Preparation of Compound 51

[0346] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-(methylsulfonamido) benzoic acid (500 mg, 2.32 mmol) and oxalyl chloride (0.3 mL, 3.48 mmol) in DCM (5 mL) giving the target compound (0.6 gram, 100% yield).

[0347] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (0.29 g, 2.56 mmol), potassium tert- butoxide (0.87 g, 7.70 mmol) and Intermediate 2 (0.6 g, 2.56 mmol) in dry THF (10 mL) giving the target compound (0.41 g, 51% yield) as a pale-yellow solid.

[0348] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (0.4 g, 1.29 mmol) and 1M NaOH solution (1.9 mL, 1.9 mmol) in THF (5 mL) giving the target compound (0.25 g, 69% yield) as an off-white solid.

[0349] Compound 51: Compound 51 was prepared according to the general procedure for the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (200 mg, 0.71 mmol), Intermediate 6 (Example 50, 130 mg, 0.85 mmol), HATU (323 mg, 0.85 mmol) and triethylamine (0.5 mL, 3.55 mmol) in DMF (5 mL) giving the target compound (120 mg, 40% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 8.54 (s, 1H), 8.45 (t, J= 5.6 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J= 8.8 Hz, 2H), 7.64 (d, J= 10.0 Hz, 1H), 7.29 (d, J= 8.8 Hz, 2H), 3.29-3.26 (m, 2H), 3.07 (s, 3H), 2.68 (t, J= 7.6 Hz, 2H), 1.90-1.83 (m, 2H).Example 53 – Preparation of Compound 52

[0350] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-acetamidobenzoic acid (1.0 g, 5.58 mmol) and oxalyl chloride (0.71 mL, 8.37 mmol) in DCM (10 mL) giving the target compound (1.2 grams, 100% yield).

[0351] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (0.69 g, 6.07 mmol), potassium tert- butoxide (2.04 g, 18.21 mmol) and Intermediate 2 (1.2 g, 6.07 mmol) in dry THF (20 mL) giving the target compound (0.8 g, 48% yield) as a pale-yellow solid.

[0352] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (0.8 g, 2.91 mmol) and 1M NaOH solution (4.4 mL, 4.37 mmol) in THF (5 mL) giving the target compound (0.45 g, 63% yield) as an off-white solid.

[0353] Compound 52: Compound 52 was prepared according to the general procedure for the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (200 mg, 0.81 mmol), Intermediate 6 (Example 50, 150 mg, 0.97 mmol), HATU (370 mg, 0.97 mmol) and triethylamine (0.5 mL, 4.05 mmol) in DMF (5 mL) giving the target compound (170 mg, 55% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.52 (s, 1H), 8.44 (t, J= 5.6 Hz, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.35 (s, 1H), 8.17 (d, J= 8.8 Hz, 2H), 7.69 (d, J= 8.8 Hz, 2H), 7.64 (d, J= 10.4 Hz, 1H), 3.29-3.26 (m, 2H), 2.68 (t, J= 7.6 Hz, 2H), 2.07 (s, 3H), 1.90-1.83 (m, 2H). Example 54 – Preparation of Intermediate 5 of Compound 53

[0354] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-(tert-butoxycarbonyl)benzoic acid (500 mg, 2.25 mmol) and oxalyl chloride (0.3 mL, 3.37 mmol) in DCM (5 mL) giving the target compound (580 mg, 100% yield).

[0355] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (0.27 g, 2.41 mmol), potassium tert- butoxide (0.81 g, 7.22 mmol) and Intermediate 2 (0.58 g, 2.41 mmol) in dry THF (10 mL) giving the target compound (0.35 g, 46% yield) as a pale-yellow solid.

[0356] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (0.35 g, 1.10 mmol) and 1M NaOH solution (1.6 mL, 1.6 mmol) in THF (10 mL) giving the target compound (0.18 g, 57% yield) as an off-whitesolid.1H NMR (400 MHz, DMSO-d6): δ 13.33 (br s, 1H), 8.62 (s, 1H), 8.13 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H). Example 55 – Preparation of Compound 55

[0357] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-nitrobenzoic acid (2.0 g, 11.97 mmol) and oxalyl chloride (1.54 mL, 17.96 mmol) in DCM (20 mL) giving the target compound (2.4 grams, 100% yield).

[0358] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (1.46 g, 12.92 mmol), potassium tert- butoxide (4.4 g, 38.76 mmol) and Intermediate 2 (2.4 g, 12.92 mmol) in dry THF (20 mL) giving the target compound (1.3 g, 38% yield) as an off-white solid.

[0359] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (1.1 g, 4.19 mmol) and 1M NaOH solution (6.3 mL, 6.3 mmol) in THF (12 mL) giving the target compound (0.7 g, 71% yield) as an off-white solid.

[0360] Compound 55: Compound 55 was prepared according to the general procedure for the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (200 mg, 0.85 mmol), Intermediate 6 (Example 50, 157 mg, 1.02 mmol), HATU (389 mg, 1.02 mmol) and triethylamine (0.6 mL, 5.10 mmol) in DMF (5 mL) giving the target compound (170 mg, 58% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.67 (t, J= 5.6 Hz, 1H), 8.52 (d, J= 8.8 Hz, 1H), 8.39-8.34 (m, 4H), 7.64 (d, J= 10.0 Hz, 1H), 3.31-3.29 (m, 2H), 2.69 (t, J= 7.6 Hz, 2H), 1.92-1.87 (m, 2H). Example 56 – Preparation of Compound 56

[0361] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-acetylbenzoic acid (1.0 g, 6.09 mmol) and oxalyl chloride (0.78 mL, 9.14 mmol) in DCM (10 mL) giving the target compound (1.2 grams, 100% yield).

[0362] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (0.75 g, 6.57 mmol), potassium tert- butoxide (2.23 g, 19.71 mmol) and Intermediate 2 (1.2 g, 6.57 mmol) in dry THF (20 mL) giving the target compound (0.8 g, 47% crude yield) as a brown liquid.

[0363] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (0.75 g, 2.89 mmol) and 1M NaOH solution (4.3 mL, 4.3 mmol) in THF (10 mL) giving the target compound (0.32 g, 48% yield) as an off-white solid.

[0364] Compound 56: Compound 56 was prepared according to the general procedure for the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (240 mg, 1.04 mmol), Intermediate 6 (Example 50, 191 mg, 1.24 mmol), HATU (473 mg, 1.24 mmol) and triethylamine (0.73 mL, 5.20 mmol) in DMF (5 mL) giving the target compound (160 mg, 42% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.59 (t, J= 5.6 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.37 (s, 1H), 8.35 (s, 2H), 8.06 (d, J= 8.4 Hz, 2H), 7.66-7.63 (m, 1H), 3.30-3.28 (m, 2H), 2.69 (t, J= 7.6 Hz, 2H), 2.62 (s, 3H), 1.89-1.87 (m, 2H). Example 57 – Preparation of Compound 57

[0365] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-(methylsulfonyl)benzoic acid (1.0 g, 5.0 mmol) and oxalyl chloride (0.63 mL, 7.50 mmol) in DCM (10 mL) giving the target compound (1.2 grams, 100% yield).

[0366] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (0.62 g, 5.50 mmol), potassium tert- butoxide (1.85 g, 16.51 mmol) and Intermediate 2 (1.2 g, 5.50 mmol) in dry THF (20 mL) giving the target compound (0.7 g, 43% crude yield) as a brown liquid.

[0367] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (0.65 g, 2.20 mmol) and 1M NaOH solution (3.5 mL, 3.5 mmol) in THF (10 mL) giving the target compound (0.2 g, 43% yield) as an off-white solid.

[0368] Compound 57: Compound 57 was prepared according to the general procedure for the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (200 mg, 0.75 mmol), Intermediate 6 (Example 50, 138 mg, 0.90 mmol), HATU (341 mg, 0.90 mmol) and triethylamine (0.52 mL, 3.75 mmol) in DMF (5 mL) giving the target compound (130 mg, 43% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.63 (t, J= 5.6 Hz, 1H), 8.46 (d, J= 8.8 Hz, 2H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J= 8.4 Hz, 2H), 7.66-7.63 (m, 1H), 3.31-3.29 (m, 2H), 3.27 (s, 3H), 2.69 (t, J= 7.6 Hz, 2H), 1.91-1.84 (m, 2H).

[0369] Example 58 – Preparation of Intermediate 5 of Compound 58

[0370] Intermediate 2: Intermediate 2 was prepared according to the general procedure for the preparation of Intermediate 2 (Example 49), using 4-(N-(tert-butoxycarbonyl)sulfamoyl)benzoic acid (1.0 g, 3.3 mmol) and oxalyl chloride (0.43 mL, 4.97 mmol) in DCM (10 mL) giving the target compound (1.2 grams, 100% yield).

[0371] Intermediate 4: Intermediate 4 was prepared according to the general procedure for the preparation of Intermediate 4 (Example 49), using Intermediate 3 (0.43 g, 3.75 mmol), potassium tert- butoxide (1.26 g, 11.25 mmol) and Intermediate 2 (1.2 g, 3.75 mmol) in dry THF (20 mL) giving the target compound (0.6 g, 40% yield) as a pale-yellow liquid.

[0372] Intermediate 5: Intermediate 5 was prepared according to the general procedure for the preparation of Intermediate 5 (Example 49), using Intermediate 4 (0.6 g, 1.51 mmol) and 1M NaOH solution (3.2 mL, 3.2 mmol) in THF (10 mL) giving the target compound (0.22 g, 39% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.39 (s, 1H), 11.80 (s, 1H), 8.63 (s, 1H), 8.22 (d, J= 8.8 Hz, 2H), 8.00-7.97 (m, 2H). Example 59 – Preparation of Compound 53 and Compound 54

[0373] Compound 53 and Compound 54 were prepared according to the following Scheme:the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (Example 54, 200 mg, 0.69 mmol), Intermediate 6 (Example 50, 128 mg, 0.83 mmol), HATU (316 mg, 0.83 mmol) and triethylamine (0.49 mL, 3.45 mmol) in DMF (5 mL) giving the target compound (180 mg, 61% yield) as an off-white solid.

[0375] Compound 54: To a stirred solution of Intermediate 5A (180 mg, 0.42 mmol) in DCM (6 mL), was added TFA (2 mL) at RT and stirred for 4 h. After completion of reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford Compound 54 (180 mg, 88% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.21 (br s, 1H), 8.66 (s, 1H), 8.58 (t, J=6.0 Hz, 1H), 8.41 (d, J=2.8 Hz, 1H), 8.36 (s, 1H), 8.34 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H), 7.70-7.67 (m, 1H), 3.30 (q, J=6.8 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 1.89-1.86 (m, 2H).

[0376] Compound 53: To a stirred solution of Compound 54 (180 mg, 0.37 mmol) and ammonium chloride (78 mg, 1.12 mmol) in DMF (3 mL) was added HATU (222 mg, 0.45 mmol) and triethylamine (0.4 mL, 2.22 mmol) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL), separated the organic layer and washed with brine (5 mL) and the organiclayer was dried over anhydrous Na2SO4,filtered and evaporated to get 280 mg of crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with 30% ethyl acetate in hexane to afford Compound 53 (130 mg, 61% yield).1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.55 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.29 (d, J= 8.4 Hz, 1H), 8.08 (s, 1H), 7.97 (d, J= 8.8 Hz, 2H), 7.66-7.63 (m, 1H), 7.48 (s, 1H), 3.12-3.27 (m, 2H), 3.27 (s, 3H), 2.67 (t, J= 7.6 Hz, 2H), 1.91-1.84 (m, 2H). Example 60 – Preparation of Compound 58

[0377] Compound 58 was prepared according to the following Scheme:cedure for the preparation of target Compounds 50-53 and target Compounds 55-58 (Example 49), using Intermediate 5 (Example 58, 200 mg, 0.54 mmol), Intermediate 6 (Example 50, 102 mg, 0.65 mmol), HATU (247 mg, 0.65 mmol) and triethylamine (0.4 mL, 2.7 mmol) in DMF (5 mL) giving the target compound (130 mg, 48% yield) as an off-white solid.

[0379] Compound 58: To a stirred solution of Intermediate 5A (125 mg, 0.25 mmol) in dioxane (1 mL) was added 4M HCl in dioxane (3 mL) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), evaporated the reaction mixture under vacuum. The obtained crude compound was triturated with hexane (10 mL), to precipitate the solid and which was filtered, washed with hexane (5 mL) and dried under vacuum to afford Compound 58 (70 mg, 57% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.59 (t, J= 6.0 Hz, 1H), 8.39- 8.35 (m, 4H), 7.92 (d, J= 8.8 Hz, 2H), 8.08 (s, 1H), 7.67-7.64 (m, 1H), 7.48 (s, 2H), 3.28 (q, J= 6.8 Hz, 2H), 2.69 (t, J= 7.6 Hz, 2H), 1.91-1.84 (m, 2H).Example 61 – General Synthetic Route for Preparation of Compounds 59, 60, 62, 63, 75 and 77 me.As illustrated, carboxylic acid starting materials 1 were converted to acid chloride intermediates 2 on reaction with oxalyl chloride and catalytic DMF. Subsequent cyclization to oxazole Intermediates 4 occurred on reaction of Intermediates 2 with isocyanate 3. Ester hydrolysis of Intermediates 4 with NaOH yielded carboxylic acid Intermediates 5. Final coupling with amine Intermediate 6 gave the target compounds. Specific conditions and analytical data are described in Examples 62-67.

[0381] General Procedure for Preparation of Intermediate 2: To a stirred suspension of substituted benzoic acid (1) (1.79 mmol) in DCM (5 mL) was added oxalyl chloride (2.69 mmol), a few drops of DMF at 0 °C. The resulting reaction mixture was warmed to rt and stirred for 2 to 4 h. After completion of reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure in the presence of nitrogen atmosphere to get crude residue. The obtained crude residue of Intermediate 2 was used in the next step, as such, without any further purification.

[0382] General Procedure for Preparation of Intermediate 4: To a stirred solution of Intermediate 3 (1.79 mmol) in dry THF (5 mL) was added potassium tert-butoxide (5.37 mmol) portion-wise at 0 °C and stirred for 15 minutes. Thereafter Intermediate 2 (1.79 mmol) dissolved in dry THF (5 mL) was added drop wise at same temperature into the reaction. The resulting reaction mixture was allowed to stir at RT for 2 to 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with sat. ammonium chloride (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with ethyl acetate in hexane to afford Intermediate 4.

[0383] General Procedure for Preparation of Intermediate 5: To a stirred solution of Intermediate 4 (0.34 mmol) in THF (5 mL) was added 1M NaOH solution (0.5 mL, 0.52 mmol) at 0 °C. The resulting reaction mass was allowed to stir at RT for 12 to 16 h. After completion of the reaction (monitored by TLC), reactionmixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was taken into water (5 mL) and extracted with ethyl acetate (10 mL), separated the organic layer, acidified the aqueous layer using 1 N HCl (pH 1-2), filtered the precipitated solid and washed with water (5 mL), dried the product under vacuum at 45-50°C to afford Intermediate 5.

[0384] General Procedure for Preparation of Target Compounds 59, 60, 62, 63, 75 and 77: To a stirred solution of Intermediate 5 (0.58 mmol) and Intermediate 6 (Example 50, 0.69 mmol) in DMF (5 mL) was added HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL), separated the organic layer and washed with brine (5 mL) and the organic layer was dried over anhydrous Na2SO4,filtered and evaporated to get crude residue. The obtained crude residue was purified by silica gel column chromatography (100- 200 mesh) eluting with ethyl acetate in hexane to afford the target compounds. Example 62 – Preparation of Compound 59

[0385] Preparation of Intermediate 2: Intermediate 2 was prepared according to the general procedure for preparation of Intermediate 2 in Example 61 using 3-bromo-4-methoxybenzoic acid (1.0 g, 4.32 mmol) and oxalyl chloride (0.55 mL, 6.49 mmol) in DCM (5 mL) giving the desired compound (1.2 grams, 100% crude yield).

[0386] Preparation of Intermediate 4: Intermediate 4 was prepared according to the general procedure for preparation of Intermediate 4 in Example 61 using Intermediate 3 (0.54 g, 4.80 mmol), potassium tert-butoxide (1.7 g, 14.43 mmol) and Intermediate 2 (1.2 g, 4.80 mmol) in dry THF (12 mL) giving the desired compound (0.6 grams, 38% yield).

[0387] Preparation of Intermediate 5: Intermediate 5 was prepared according to the general procedure for preparation of Intermediate 5 in Example 61 using Intermediate 4 (0.5 g, 1.53 mmol) and 1M NaOH solution (1.96 mL, 1.96 mmol) in THF (5 mL) giving the desired compound (0.3 gram, 67% yield) as an off-white solid.

[0388] Preparation of Compound 59: Compound 59 was prepared according to the general procedure for preparation of target compounds in Example 61 using Intermediate 5 (200 mg, 0.67 mmol), Intermediate 6 (Example 50, 124 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) giving Compound 59 (94 mg, 29% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J= 2.0 Hz, 1H), 8.55 (s, 1H), 8.49 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.15 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.67-7.63 (m, 1H), 7.25 (d, J= 8.8 Hz, 1H), 3.92 (s, 3H), 3.31-3.27 (m, 2H), 2.68 (t, J= 7.2 Hz, 2H), 1.88-1.85 (m, 2H).Example 63 – Preparation of Compound 60

[0389] Preparation of Intermediate 2: Intermediate 2 was prepared according to the general procedure for preparation of Intermediate 2 in Example 61 using 3-chloro-4-methoxybenzoic acid (1 g, 5.36 mmol) and oxalyl chloride (0.69 mL, 8.04 mmol) in DCM (5 mL) giving the desired compound (1.2 grams, 100% crude yield).

[0390] Preparation of Intermediate 4: Intermediate 4 was prepared according to the general procedure for preparation of Intermediate 4 in Example 61 using Intermediate 3 (0.66 g, 5.85 mmol), potassium tert-butoxide (1.97 g, 17.55 mmol) and Intermediate 2 (1.2 g, 5.85 mmol) in dry THF (12 mL) giving the desired compound (0.41 grams, 38% yield).

[0391] Preparation of Intermediate 5: Intermediate 5 was prepared according to the general procedure for preparation of Intermediate 5 in Example 61 using Intermediate 4 (0.6 g, 2.13 mmol) and 1M NaOH (3.1 mL, 3.1 mmol) in THF (6 mL) giving the desired compound (0.33 gram, 61% yield) as an off- white solid.

[0392] Preparation of Compound 60: Compound 60 was prepared according to the general procedure for preparation of target compounds in Example 61 using Intermediate 5 (200 mg, 0.79 mmol), Intermediate 6 (Example 50, 145 mg, 0.95 mmol), HATU (360 mg, 0.95 mmol) and triethylamine (0.55 mL, 3.94 mmol) in DMF (2 mL) giving Compound 60 (94 mg, 30% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.53 (d, J= 2.0 Hz, 1H), 8.49 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.11 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 7.67-7.63 (m, 1H), 7.28 (d, J= 8.8 Hz, 1H), 3.93 (s, 3H), 3.31-3.27 (m, 2H), 2.68 (t, J= 7.6 Hz, 2H), 1.91-1.83 (m, 2H). Example 64 – Preparation of Compound 62

[0393] Preparation of Intermediate 2: Intermediate 2 was prepared according to the general procedure for preparation of Intermediate 2 in Example 61 using 4-acetyl-3-bromobenzoic acid (1.0 g, 4.11 mmol) and oxalyl chloride (0.53 mL, 6.17 mmol) in DCM (5 mL) giving the desired compound (1.2 grams, 100% crude yield).

[0394] Preparation of Intermediate 4: Intermediate 4 was prepared according to the general procedure for preparation of Intermediate 4 in Example 61 using Intermediate 3 (0.48 g, 4.20 mmol), potassium tert-butoxide (1.42 g, 12.62 mmol) and Intermediate 2 (1.1 g, 4.20 mmol) in dry THF (11 mL) giving the desired compound (0.61 grams, 43% yield).

[0395] Preparation of Intermediate 5: Intermediate 5 was prepared according to the general procedure for preparation of Intermediate 5 in Example 61 using Intermediate 4 (0.5 g, 1.48 mmol) and1M NaOH (2.2 mL, 2.2 mmol) in THF (5 mL) giving the desired compound (0.31 gram, 68% yield) as an off- white solid.

[0396] Preparation of Compound 62: Compound 62 was prepared according to the general procedure for preparation of target compounds in Example 61 using Intermediate 5 (200 mg, 0.64 mmol), Intermediate 6 (Example 50, 120 mg, 0.77 mmol), HATU (296 mg, 0.77 mmol) and triethylamine (0.45 mL, 3.22 mmol) in DMF (2 mL) giving Compound 62 (180 mg, 63% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.68 (s, 1H), 8.63 (t, J= 5.6 Hz, 1H), 8.38 (d, J= 2.0 Hz, 1H), 8.35 (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.65 (d, J= 10.0 Hz, 1H), 3.32-3.30 (m, 2H), 2.69 (t, J= 7.6 Hz, 2H), 2.61 (s, 3H), 1.91-1.84 (m, 2H). Example 65 – Preparation of Compound 63

[0397] Preparation of Intermediate 2: Intermediate 2 was prepared according to the general procedure for preparation of Intermediate 2 in Example 61 using 4-acetyl-3-chlorobenzoic acid (1 g, 5.03 mmol) and oxalyl chloride (0.65 mL, 7.55 mmol) in DCM (5 mL) giving the desired compound (1.2 grams, 100% crude yield).

[0398] Preparation of Intermediate 4: Intermediate 4 was prepared according to the general procedure for preparation of Intermediate 4 in Example 61 using Intermediate 3 (0.62 g, 5.53 mmol), potassium tert-butoxide (1.85 g, 16.58 mmol) and Intermediate 2 (1.2 g, 5.53 mmol) in dry THF (12 mL) giving the desired compound (0.55 grams, 33% yield).

[0399] Preparation of Intermediate 5: Intermediate 5 was prepared according to the general procedure for preparation of Intermediate 5 in Example 61 using Intermediate 4 (0.5 g, 1.71 mmol) and 1M NaOH (2.5 mL, 2.5 mmol) in THF (5 mL) giving the desired compound (0.29 gram, 63% yield) as an off- white solid.

[0400] Preparation of Compound 63: Compound 63 was prepared according to the general procedure for preparation of target compounds in Example 61 using Intermediate 5 (200 mg, 0.75 mmol), Intermediate 6 (Example 50, 139 mg, 0.90 mmol), HATU (344 mg, 0.90 mmol) and triethylamine (0.5 mL, 3.76 mmol) in DMF (2 mL) giving Compound 63 (85 mg, 28% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.63 (t, J= 6.0 Hz, 1H), 8.58 (d, J= 1.6 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.19 (dd, J= 8.4 Hz, 1.6 Hz, 1H), 7.84 (d, J= 8.4 Hz, 1H), 7.67-7.63 (m, 1H), 3.32-3.28 (m, 2H), 2.69 (t, J= 7.6 Hz, 2H), 2.62 (s, 2H), 1.91-1.84 (m, 2H). Example 66 – Preparation of Compound 75

[0401] Preparation of Intermediate 2: Intermediate 2 was prepared according to the general procedure for preparation of Intermediate 2 in Example 61 using 3-hydroxy-4-methoxybenzoic acid (1.0g, 5.94 mmol) and oxalyl chloride (0.76 mL, 8.92 mmol) in DCM (5 mL) giving the desired compound (1.2 grams, 100% crude yield).

[0402] Preparation of Intermediate 4: Intermediate 4 was prepared according to the general procedure for preparation of Intermediate 4 in Example 61 using Intermediate 3 (0.73 g, 6.43 mmol), potassium tert-butoxide (2.16 g, 19.29 mmol) and Intermediate 2 (1.2 g, 6.43 mmol) in dry THF (12 mL) giving the desired compound (0.58 grams, 34% yield).

[0403] Preparation of Intermediate 5: Intermediate 5 was prepared according to the general procedure for preparation of Intermediate 5 in Example 61 using Intermediate 4 (0.55 g, 2.09 mmol) and 1M NaOH (3.1 mL, 3.1 mmol) in THF (6 mL) giving the desired compound (0.3 gram, 61% yield) as an off- white solid.

[0404] Preparation of Compound 75: Compound 75 was prepared according to the general procedure for preparation of target compounds in Example 61 using Intermediate 5 (200 mg, 0.85 mmol), Intermediate 6 (Example 50, 145 mg, 1.02 mmol), HATU (360 mg, 1.02 mmol) and triethylamine (0.55 mL, 4.25 mmol) in DMF (2 mL) giving Compound 75 (120 mg, 38% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.48 (s, 1H), 8.42-8.39 (m, 2H), 8.37 (s, 1H), 8.75-8.71 (m, 2H), 7.68-7.65 (m, 1H), 7.04 (d, J= 8.4 Hz, 1H), 3.84 (s, 3H), 3.35-3.29 (m, 2H), 2.70 (t, J= 7.6 Hz, 2H), 1.90-1.86 (m, 2H). Example 67 – Preparation of Compound 77

[0405] Preparation of Intermediate 2: Intermediate 2 was prepared according to the general procedure for preparation of Intermediate 2 in Example 61 using 3-cyano-4-methoxybenzoic acid (500 mg, 2.82 mmol) and oxalyl chloride (0.78 mL, 4.23 mmol) in DCM (5 mL) giving the desired compound (1.2 grams, 100% crude yield).

[0406] Preparation of Intermediate 4: Intermediate 4 was prepared according to the general procedure for preparation of Intermediate 4 in Example 61 using Intermediate 3 (0.35 g, 3.07 mmol), potassium tert-butoxide (1.03 g, 9.20 mmol) and compound-2 (0.6 g, 3.07 mmol) in dry THF (6 mL) giving the desired compound (0.33 grams, 39% yield).

[0407] Preparation of Intermediate 5: Intermediate 5 was prepared according to the general procedure for preparation of Intermediate 5 in Example 61 using Intermediate 4 (0.32 g, 1.17 mmol) and 1M NaOH (1.76 mL, 7.76 mmol) in THF (5 mL) giving the desired compound (0.2 gram, 70% yield) as an off-white solid.

[0408] Preparation of Compound 77: Compound 77 was prepared according to the general procedure for preparation of target compounds in Example 61 using Intermediate 5 (200 mg, 0.82 mmol), Intermediate 6 (Example 50, 151 mg, 0.98 mmol), HATU (373 mg, 0.98 mmol) and triethylamine (0.57 mL,4.09 mmol) in DMF (2 mL) giving Compound 77 (150 mg, 48% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, J= 2.4 Hz, 1H), 8.59 (s, 1H), 8.54 (t, J= 5.6 Hz, 1H), 8.43 (dd, J= 9.2, 2.0 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 7.66-7.63 (m, 1H), 7.40 (d, J= 9.2 Hz, 2H), 3.99 (s, 3H), 3.32-3.28 (m, 2H), 2.68 (t, J= 7.6 Hz, 2H), 1.89-1.85 (m, 2H). Example 68 – Preparation of Compound 61

[0409] Compound 61 was prepared according to the following scheme:

[0410] Preparationo a stirred solution of Compound 19A (1 g, 4.06 mmol) in methanol (5 mL) was added thionyl chloride (0.6 mL, 8.13 mmol) dropwise for 30 min. The resulting reaction contents were heated for 16 h at 60-65°C. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under vacuum giving the desired compound (1 gram crude) which was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 8.48 (t, J= 1.2 Hz, 1H), 8.09 (d, J= 1.2 Hz, 1H), 3.90 (s, 3H).

[0411] Preparation of Intermediate 21A: To a stirred solution of Intermediate 20A (1.0 g, 3.84 mmol) in triethylamine (10 mL) was added Pd(PPh3)2Cl2(42 mg, 0.07 mmol) and degassed for 15 min, followed by the addition of trimethyl silyl acetylene (0.79 g, 6.92 mmol). Heated the reaction mixture to 75-80°Cand stirred for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was filtered through a celite pad. The filter cake was thoroughly washed with 10% MeOH in DCM, the filtrate was evaporated under reduced pressure to get crude residue (1.5 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 12-15% ethyl acetate in hexane to afford Intermediate 21A (0.66 gram, 62% yield) as a pale-yellow solid.

[0412] Preparation of Intermediate 22A: To a stirred solution of Intermediate 21A (0.66 g, 2.38 mmol) in ethyl acetate (50 mL) was added SnCl2•2H2O (42 mg, 0.07 mmol) and s...

Claims

CLAIMS What is claimed is:

1. An inhibitor of GSK-3β for therapeutic use, having the structure of Formula I: wherein, R1is L1-R5;R2is L2-R6; R3is H or C1-C6alkyl; R4is H or C1-C6alkyl; R5is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring or an 8-12 membered fused bicyclic aryl or heteroaryl ring system, wherein R5is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and -(CH2)s-R11; R6is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6is optionally substituted with 1-3 groups independently selected from - (C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2; R7is H, OR8or N(R8)2; each R8is independently H or -(C=O)p-(C1-C6alkyl); each R9is independently H, -(C=O)r-(C1-C6alkyl), or -(C=O)r-(CH2)x-(C3-C6cycloalkyl); each R10is independently H or C1-C6alkyl; each R11is independently H, OR12or N(R12)2; each R12is independently H or -(C=O)t-(C1-C6alkyl); each R13is independently H, -(C=O)v-(C1-C6alkyl), or S(O)2R14; each R14is independently H or C1-C6alkyl; L1is a direct link, -(CH2)n-, a 3-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring, wherein any carbon atom of L1is optionally substituted with one or two -(CH2)o-R7;L2is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2is optionally substituted with 1-2 C1-C6alkyl groups; X is O or N-R3; Y is O or N-R4; n is an integer from 1-5; o is 0 or an integer from 1-4; each p is independently 0 or 1; each q is independently 0 or 1; each r is independently 0 or 1; each s is independently 0 or an integer from 1-3; each t is independently 0 or 1; each u is independently 0 or 1; each v is independently 0 or 1; each w is independently 0 or 1 x is 0 or an integer from 1-3; and each stereogenic center is independently R, S or racemic.

2. The inhibitor of GSK-3β of Claim 1, having any one of the structures 2 through 101:3.met o o preparng an n tor o GS -3β or t erapeutc use, avng t e structure of Formula I: wherein,R1is L1-R5; R2is L2-R6; R3is H or C1-C6alkyl; R4is H or C1-C6alkyl; R5is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring or an 8- 12 membered fused bicyclic aryl or heteroaryl ring system, wherein R5is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6alkyl), F, Cl, Br, I, OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, CN, C(O)OR10, C(O)N(R10)2, S(O)2OR10, P(O)(OR10)2and -(CH2)s-R11; R6is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6alkyl), F, Cl, Br, I, NO2, OR13, SR13, S(O)R13, S(O)2R13, S(O)2N(R13)2, N(R13)2, CN, C(O)OR14, C(O)N(R14)2, S(O)2OR14and P(O)(OR14)2;R7is H, OR8, or N(R8)2; each R8is independently H or -(C=O)p-(C1-C6alkyl); each R9is independently H, -(C=O)r-(C1-C6alkyl), or -(C=O)r-(CH2)x-(C3-C6cycloalkyl); each R10is independently H or C1-C6alkyl; each R11is independently H, OR12or N(R12)2; each R12is independently H or -(C=O)t-(C1-C6alkyl); each R13is independently H, -(C=O)v-(C1-C6alkyl), or S(O)2R14; each R14is independently H or C1-C6alkyl; L1is a direct link, -(CH2)n-, a 3-7 membered cycloalkyl or heterocyclic ring, a 5-6 membered heteroaryl ring or a 6 membered aryl ring, wherein any carbon atom of L1is optionally substituted with one or two -(CH2)o-R7; L2is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2is optionally substituted with 1-2 C1-C6alkyl groups; X is O or N-R3; Y is O or N-R4; n is an integer from 1-5; o is 0 or an integer from 1-4; each p is independently 0 or 1; each q is independently 0 or 1; each r is independently 0 or 1; each s is independently 0 or an integer from 1-3; each t is independently 0 or 1; each u is independently 0 or 1; each v is independently 0 or 1; each w is independently 0 or 1 x is 0 or an integer from 1-3; and each stereogenic center is independently R, S or racemic; Comprising the steps of: (1) Reacting a compound of Formula II with a compound of Formula IV, wherein; a. A compound of Formula II is used without modification, or b. A compound of Formula II is converted to a carboxylic acid; and (2) Removing a protecting group from a compound of Formula IV if a protecting group is present; orComprising the steps of: (1) Reacting a compound of Formula III with a compound of Formula IV; and (2) Removing a protecting group from a compound of Formula IV if a protecting group is present; or II III IV wherein, all substitutions are defined according to a structure of Formula I, and wherein, R15is H, C1-C6alkyl or -(CH2)w-R16; R16is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R16is optionally substituted with 1-5 groups independently selected from F, NO2and OCH3; R17is a protecting group selected from the list comprising but not limited to acetyl, benzoyl, 4- nitrobenzoyl, benzyl, p-methoxybenzyl, tolyl, trityl, methoxymethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl dimethylsilyl, tert-butyl diphenylsilyl, tert-butyl carbamoyl (Boc), fluorenylmethylcarbamoyl (Fmoc) and benzylcarbamoyl (Cbz). w is 0 or 1. .

4. The method of preparing an inhibitor of GSK-3β of Claim 3, wherein said inhibitor has any one of the structures 2 through 101:

5. A method of treating a disorder comprising aberrant signaling of GSK-3, the method comprising administering to a subject in need thereof a therapeutically effective dose of a compound of claim 1.

6. The method of Claim 5, wherein the subject has a neurological disease and / or psychiatric disorder.

7. The method of Claim 6, wherein disease / disorder is selected from Alzheimer’s disease, frontotemporal dementia, behavioral complications of dementia, bipolar disorder, depression,schizophrenia, Parkinson’s disease, neuroinflammation, autism spectrum disorder, Fragile X syndrome, Pitt Hopkins syndrome, Rett syndrome, traumatic brain injury, stroke, acute spinal cord injury, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), neurofibromatosis type 1, neuronal ceroid lipofuscinosis, chronic pain, neuropathic pain, chemotherapy-induced neuropathy, and / or chemotherapy- induced cognitive impairment.

8. The method of Claim 5, wherein disease / disorder is selected from type 2 diabetes, diabetic retinopathy, diabetic neuropathy, diabetic macular edema, diabetic nephropathy, chronic kidney disease, polycystic kidney disease, and / or focal segmental glomerulosclerosis.

9. The method of Claim 5, wherein disease / disorder is selected from atherosclerosis, alopecia, bone and joint disorders including osteoarthritis and osteoporosis, inflammatory disorders including alcoholic hepatitis inflammatory bowel disease, and septic shock.

10. The method of Claim 5, wherein disease / disorder is selected from disorders of the eye including wet age-related macular degeneration, dry age-related macular degeneration, Fuch’s dystrophy, limbal cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, and Sjögren’s syndrome, and / or ear disorders including sensorineural hearing loss and conductive hearing loss.

11. The method of Claim 5, wherein disease / disorder is selected from pulmonary disorders including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, and / or cancers including melanoma, pancreatic cancer, prostate cancer, colon cancer, and leukemia, and / or short bowel syndrome, ischemia, inflammation, cardiovascular disease, congestive heart failure, dermatological disease, inflammation, or GM2 gangliosidosis.

12. The method of any one of the above Claims, wherein the compound is administered in an amount of about 32 to about 320 mg once daily of the compound, or about 16 to about 160 mg twice daily.

13. The method of any one of Claims 5 to 11, wherein the compound is administered in combination with lithium.

14. The method of any one of Claims 5 to 11, wherein the subject is non-responsive to lithium.

15. The method of Claim 13, wherein the subject is lithium responsive.

16. The method of Claim 13, wherein lithium is administered at a sub-effective dose based on monotherapy, and wherein the compound is administered at a sub-effective dose based on monotherapy.

17. The method of Claim 16, wherein the sub-effective dose of lithium is about 60 mg to about 600 mg once daily, or about 30 mg to about 300 mg twice daily.

18. The method of Claim 16, wherein a sub-effective dose of the compound is administered in about 8 to about 32 mg once daily, or about 4 to about 16 mg twice daily.

19. A method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful, comprising administering to a subject to be evaluated a therapeutically effective dose of the compound and evaluating the subject’s clinical response.

20. A method of establishing an appropriate therapeutic dose of the compound in a subject, comprising administering increasing doses of compound and assessing response using GSK-3 imaging or GSK-3 serology.

21. A method of treating a subject with Alzheimer’s disease, bipolar disorder, or depression who shows evidence of elevated GSK-3, comprising administering to the subject a therapeutically effective dose of a compound of claim 1 and evaluating and monitoring the subject using positron emission tomography (PET) or serology.

22. A method of establishing a diagnosis of bipolar disorder or other condition where GSK-3 inhibition is clinically useful, comprising administering to a subject to be evaluated a therapeutically effective dose of a compound of claim 1 with a therapeutically effective dose of lithium, and evaluating the subject’s clinical response.

23. The method of claim 21, wherein the dose of both the compound and lithium are sub-effective based on monotherapy.

24. A method of treating a subject with Alzheimer’s disease who has evidence of elevated GSK-3 beta activity, comprising administering to the subject a therapeutically effective dose of a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a therapeutically effective dose of lithium, and monitoring the subject using positron emission topography (PET).

25. The method of claim 24, wherein the dose of both the compound and lithium are sub-effective based on monotherapy.

26. A method of establishing an appropriate therapeutic dose of a compound of claim 1 in a subject, comprising administering increasing doses of the compound and lithium to the subject and assessing response using positron emission topography (PET).

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