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WO2025015045A1 - Inhibitors of glycogen synthase kinase 3 for therapeutic use - Google Patents

Inhibitors of glycogen synthase kinase 3 for therapeutic use Download PDF

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Publication number
WO2025015045A1
WO2025015045A1 PCT/US2024/037383 US2024037383W WO2025015045A1 WO 2025015045 A1 WO2025015045 A1 WO 2025015045A1 US 2024037383 W US2024037383 W US 2024037383W WO 2025015045 A1 WO2025015045 A1 WO 2025015045A1
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mmol
compound
independently
alkyl
afford
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Pablo LAPUERTA
Daniel E. Levy
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4m Therapeutics Inc
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4m Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients

Definitions

  • 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.
  • 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
  • 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 of cancer.
  • 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.
  • PF-04802367 also known as PF-367
  • OCMs oxazole carboxamides
  • compound 1 is not suitable to serve as an inhibitor of GSK-30 for therapeutic use.
  • 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.
  • the invention is directed to an inhibitor of GSK-30 for therapeutic use, having the structure of Formula I:
  • R 1 is L 1 -R 5 ;
  • R 2 is L 2 -R 6 ;
  • R 3 is H or C 1 -C 6 alkyl;
  • R 4 is H or C 1 -C 6 alkyl;
  • 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.
  • 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.
  • FIG. 1 shows a diagram of the therapeutic window for a drug on a graph of % maximum effect versus drug concentration.
  • FIG. 2 shows the radioactivity time curves of a related C 11 compound in rhesus monkey.
  • FIG. 3 shows the concentrations in plasma, brain and CSF hourly after injection of 50 mg/kg of a related compound in mice.
  • 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.
  • 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).
  • AMP dextroamphetamine
  • Li - AMP Lithium 100 mg/kg followed by AMP
  • Compound 56 followed by AMP Compound 56 followed by AMP
  • Compound 56 was administered at 10 mg/kg administered via intraperitoneal injection, and the AMP was administered one hour later.
  • the time 0-120 minutes reflects the timing of administration of AMP.
  • the term “about” generally includes up to plus or minus 10% of the indicated number.
  • “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.
  • “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.
  • 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,
  • a short half-life in a therapeutic agent 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the kinase hinge region is a region critical to binding of ATP – the natural kinase substrate.
  • the hinge region provides a hydrogen bond donor and a hydrogen bond acceptor – both being generally presented as part of the kinase protein backbone.
  • 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.
  • the hydrogen bond donor of the inhibitor will form a hydrogen bond with the hydrogen bond acceptor of the kinase hinge region.
  • the hydrogen bond acceptor of the inhibitor will form a hydrogen bond with the hydrogen bond donor of the kinase hinge region.
  • the hinge region is defined as the amino acid sequence connecting C-terminal lobe to the N-terminal lobe.
  • Hinge region binding alone is generally insufficient for development of a suitable kinase inhibiting therapeutic as all kinases possess hinge regions.
  • 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.
  • the compounds of the present invention utilize amides, amidines, acylated heteroaromatic groups, aminopyridines, aminopyrimidines and related structures as hinge region binders.
  • 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.
  • halogen refers, in one embodiment to F, in another embodiment to Cl, in another embodiment to Br, and in another embodiment to I.
  • 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.
  • 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.
  • the heterocyclic group is a 3-12 membered ring.
  • the heterocyclic group is a 6 membered ring.
  • the heterocyclic group is a 5-7 membered ring.
  • the heterocyclic group is a 4-8 membered ring.
  • 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.
  • the heterocyclic group may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring.
  • the heterocyclic group is a saturated ring.
  • the heterocyclic ring is an unsaturated ring.
  • 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.
  • 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.
  • the heteroaryl group is a 5-14 membered ring.
  • the heteroaryl group is a 5 membered ring.
  • the heteroaryl group is a 6 membered ring.
  • the heteroaryl group is a bicyclic ring structure containing 9 atoms.
  • the heteroaryl group is a bicyclic ring structure containing 10 atoms.
  • 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.
  • 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 from suitable 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • 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
  • 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.
  • a biomarker such as a blood test, tumor biopsy result, or PET imaging study
  • 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.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci- 4 alkyl)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.
  • 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.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-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.
  • 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.
  • R 1 is L 1 -R 5 .
  • R 2 is L 2 -R 6 .
  • R 3 is H or C 1 -C 6 alkyl. In some embodiments, R 3 is H. In some embodiments, R 3 is C 1 -C 6 alkyl.
  • R 4 is H or C 1 -C 6 alkyl. In some embodiments, R 4 is H.
  • R 4 is C 1 -C 6 alkyl.
  • R 5 is a 5-membered heteroaryl ring. In some embodiments, R 5 is a 6-membered aryl ring, a 6-membered heteroaryl ring. In some embodiments, R 5 is a 6-membered heteroaryl ring. In some embodiments, R 5 is an 8-12 membered fused bicyclic aryl or heteroaryl ring system. In some embodiments, R 5 is unsubstituted.
  • R 6 is a 5-6 membered heteroaryl ring. In some embodiments, R 6 is a 6-membered aryl ring. In some embodiments, R 6 is a 6-membered heteroaryl ring. In some embodiments, R 6 is unsubstituted.
  • R 7 is H, OR 8 or N(R 8 ) 2 .
  • R 7 is H.
  • R 7 is OR 8 .
  • R 7 is N(R 8 ) 2 .
  • each R 11 is independently H, OR 12 or N(R 12 ) 2 . In some embodiments, at least one of R 11 is H. In some embodiments, at least one of R 11 is OR 12 . In some embodiments, at least one of R 11 is N(R 12 ) 2 . In some embodiments, at least two of R 11 are H. In some embodiments, at least two of R 11 are OR 12 . In some embodiments, at least two of R 11 are N(R 12 ) 2 . In some embodiments, each R 11 is the same.
  • each R 11 is different.
  • At least one of R 14 is C 1 -C 6 alkyl. In some embodiments, at least two of R 14 are H. In some embodiments, at least two of R 14 are C 1 -C 6 alkyl. In some embodiments, each R 14 is the same. In some embodiments, each R 14 is different. [0058] As defined generally above, L 1 is a direct link, -(CH 2 ) 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 L 1 is optionally substituted with -(CH 2 ) o -R 7 .
  • L 1 is a direct link. In some embodiments, L 1 is -(CH 2 ) n -. In some embodiments, L 1 is a 3-7 membered cycloalkyl ring. In some embodiments, L 1 is a 4-7 membered heterocyclic ring. In some embodiments, L 1 is a 6 membered aryl ring. In some embodiments, L 1 is unsubstituted. In some embodiments, any carbon atom of L 1 is may be substituted with one or two -(CH 2 ) o -R 7 .
  • L 2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L 2 is optionally substituted with 1-2 C 1 -C 6 alkyl groups.
  • L 2 is a 5-6 membered heteroaryl ring.
  • L 2 is a 6-membered aryl ring.
  • L 2 is a 6-membered heteroaryl ring.
  • L 2 is unsubstituted.
  • L 2 is substituted with 1-2 C 1 -C 6 alkyl groups.
  • X is O or N-R 3 .
  • X is O. In some embodiments, X is N-R 3 .
  • Y is O or N-R 4 . In some embodiments, Y is O. In some embodiments, Y is N-R 4 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. In some 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.
  • 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.
  • 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.
  • R 1 is L 1 -R 5 ;
  • R 2 is L 2 -R 6 ;
  • R 3 is H or C 1 -C 6 alkyl;
  • R 4 is H or C 1 -C 6 alkyl;
  • 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 subst itutions are defined according to a structure of Formula I, and wherein, R 15 is H, C 1 -C 6 alkyl or -(CH 2 ) w -R 16 ; R 16 is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R 16 is optionally substituted with 1-5 groups independently selected from F, NO 2 and OCH 3 ; R 17 is a protecting group selected from the list comprising but not limited to acetyl, benzoyl,
  • R 15 is H, C 1 -C 6 alkyl or -(CH 2 ) w -R 16 . In some embodiments, R 15 is H. In some embodiments, R 15 is C 1 -C 6 alkyl. In some embodiments, R 15 is -(CH 2 ) w -R 16 . [0076] As defined generally above, R 16 is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R 16 is optionally substituted with 1-5 groups independently selected from F, NO2 and OCH3. In some embodiments, R 16 is a 5-membered heteroaryl group.
  • R 16 is a 6-membered aryl group optionally substituted with 1-5 groups independently selected from F, NO 2 and OCH 3 .
  • R 16 is a 6-membered heteroaryl group, wherein, R 16 is optionally substituted with 1-5 groups independently selected from F, NO 2 and OCH 3 .
  • R 17 is 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).
  • R 17 is acetyl.
  • R 17 is benzoyl. In some embodiments, R 17 is 4-nitrobenzoyl. In some embodiments, R 17 is benzyl. In some embodiments, R 17 is p-methoxybenzyl. In some embodiments, R 17 is tolyl. In some embodiments, R 17 is trityl. In some embodiments, R 17 is methoxymethyl. In some embodiments, R 17 is trimethylsilyl. In some embodiments, R 17 is triethylsilyl. In some embodiments, R 17 is triisopropylsilyl. In some embodiments, R 17 is tert-butyl dimethylsilyl. In some embodiments, R 17 is tertbutyl diphenylsilyl.
  • R 17 is tert-butyl carbamoyl (Boc). In some embodiments, R 17 is fluorenylmethylcarbamoyl (Fmoc). In some embodiments, R 17 is benzylcarbamoyl (Cbz). In some embodiments, R 17 is a suitable protecting group for a hydroxyl functional group. In some embodiments, R 17 is a suitable protecting group for an amine functional group.
  • suitable protecting groups for hydroxyl groups and amines are generally available in the relevant literature and represented in books such as "Protective Groups in Organic Synthesis" (Wiley, Greene and Wuts).
  • w is 0 or 1. In some embodiments, w is 0. In some embodiments, w is 1.
  • 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.
  • coupling reactions are often facilitated by amine bases including, but not limited to, triethylamine, diisopropyl ethylamine, N-methylmorpholine and pyridine.
  • esters and amides are formed by combining activated esters of carboxylic acids with alcohols or amines.
  • activated esters include, but are not limited to, acylimidazoles, nitrophenyl esters, pentafluorophenyl esters, succinimidyl esters and the like.
  • amidines are formed by combining nitriles with amines.
  • 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).
  • exemplary compounds of Formula I include compounds 2-101:
  • 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.
  • 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.
  • alopecia 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,
  • 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).
  • the compounds in the present disclosure can also be administered in combination with lithium.
  • the subject is non-responsive to lithium.
  • 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.
  • the sub-effective dose of lithium is about 60 mg to about 600 mg QD, or about 30 mg to about 300 mg BID.
  • 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.
  • 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.
  • 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.
  • PET positron emission tomography
  • 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.
  • the dose of both a compound of Formula I and lithium are sub-effective based on monotherapy.
  • 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 the subject 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).
  • the dose of both a compound of Formula I and lithium are sub-effective based on monotherapy.
  • 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).
  • PET positron emission topography
  • Example 2 General Scheme for the Preparation of Compounds 2-10
  • 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.
  • 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.
  • Example 4 – Preparation of Compound 3 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.
  • Example 5 Preparation of Compound 4
  • Compound 4 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.
  • 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.
  • 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.
  • 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.
  • Example 8 Preparation of Compound 7
  • Compound 7 was prepared according to the general Scheme in Example 2 and through the numbered intermediate structures illustrated therein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 K 2 CO 3 LiOH.HO O 2 DMF THF O mL), 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.
  • 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).
  • Example 13 – Preparation of Compound 11 [0150] Compound 11 was prepared according to the following Scheme: [0151] Interme -ol 1 (1.415 ml, 10.93 mmol, 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.
  • 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.
  • 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 ⁇ m, 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.
  • Example 14 – Preparation of Compound 12 [0153] Compound 12 was prepared according to the following Scheme: NHBoc Cl N 2 NHBoc M [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 PdCl 2 (PPh 3 ) 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.
  • 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 ⁇ m, 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 NaHCO 3 solution (75 mL) was added to the residue, followed by DCM (70 mL).
  • 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.
  • 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.
  • 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 ⁇ m, 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.
  • Example 16 – Preparation of Compound 14 [0163] Compound 14 was prepared according to the following Scheme: [0 g, 5.23 mmol, 1.0 eq) in THF (12.0 ml) was added BH 3 .THF (1.0 M sol in THF, 15.69 ml, 15.69 mmol, 3.0 eq) at 0 o C 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 0 o C and stirred for 10 min.
  • 1N HCl solution 10 mL
  • 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.
  • 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 POCl 3 (2.67 ml, 28.6 mmol, 10.0 eq) as dropwise and the reaction mixture was heated at 110 o C for overnight under nitrogen atmosphere. Upon completion of reaction (as confirmed by LCMS analysis), the reaction mixture was concentrated under reduced pressure to dryness.
  • 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.
  • reaction mixture was stirred at room temperature for 4 h.
  • 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 Na 2 SO 4 , 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.
  • 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 CH 3 CN (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 POCl 3 (3.33 ml, 35.7 mmol, 2.0 eq), then allowed to stirred at 50 °C for overnight.
  • 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 Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product.
  • reaction mixture degassed with nitrogen for additional 5 min and heated to 80 °C under nitrogen atmosphere for 4h.
  • 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 Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product.
  • reaction mixture Upon completion of reaction (as confirmed by TLC, 30% ethylacetate in pet ether, R f of desired product 0.1), the reaction mixture was quenched with sat. aq. sodium potassium tartrate solution (3 mL) very carefully at -10 o C 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 Na 2 SO 4 , 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.
  • 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.
  • reaction mixture was allowed to RT and stirred for overnight.
  • 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 Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product.
  • Example 19 – Preparation of Compound 17 [0186] Compound 17 was prepared according to the following Scheme: [0187 added 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 0 o C. 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.
  • 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.
  • 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.
  • Example 20 – Preparation of Compound 18 [0191] Compound 18 was prepared according to the following Scheme: was added triethyl amine (0.47 mL, 3.40 mmol) and cooled to 0°C, followed by the addition of Boc 2 O (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).
  • Example 21 – Preparation of Compound 19 [0196] Compound 19 was prepared according to the following Scheme: N F mg, 1.34 mmol) in methanol (10 mL) was added 7M NH 3 in 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).
  • 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).
  • 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.
  • 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 Na 2 SO 4, filtered and solvent was evaporated under reduced pressure to afford crude Compound-7b as a colorless gummy liquid (610 mg isolated product).
  • 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 0 o C and allowed to stir for 30 min under N 2 atmosphere. SEM-Cl (0.952 mL, 5.37 mmol, 1.1 eq) was added at 0 o C and allowed to stir overnight.
  • reaction mixture was quenched by saturated NH 4 Cl solution at 0 o C 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 Na 2 SO 4 , 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 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 80 o C 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 Na 2 SO 4 , 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.
  • 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 Na 2 SO 4 , 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).
  • 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 Na 2 SO 4 , 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.
  • 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 reaction mixture 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).
  • 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 mixture was stirred for overnight at 25 °C under oxygen atmosphere.
  • 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.
  • the crude product was purified by reverse-phase column chromatography (Grace column: C1840 ⁇ m, 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 Na 2 SO 4 , 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.
  • Example 28 – Preparation of Compound 29 [0235] Compound 29 was prepared according to the following Scheme: [0236] 4 mmol, 1.0 eq) 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 140 o C. 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 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.
  • TFA salt of 29 was basified with saturated aqueous solution of NaHCO 3 solution (4 mL), diluted with DCM (4 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 4 mL).
  • Example 29 – Preparation of Compound 30 [0240] Compound 30 was prepared according to the following Scheme: [024 1] 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.
  • reaction mixture was degassed with nitrogen for 10 min and added PdCl 2 (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 100 o C 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).
  • PdCl 2 dppf
  • 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.
  • 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 Na 2 SO 4 , 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.
  • the crude compound was purified by reverse-phase column chromatography (Grace column: C1840 ⁇ m, 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.
  • reaction mixture was stirred for an additional 2 h at –78 °C under nitrogen atmosphere.
  • 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).
  • reaction mixture was degassed with nitrogen for 10 min and PdCl 2 (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 80 o C for overnight.
  • 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 ice cold water (20 mL) was added to the filtrate.
  • 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 0 o C and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 20 mL).
  • 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.
  • 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 0 o C 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 0 o C, 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.
  • iso-propylmagnesium chloride 2.0M sol in THF, 4.87 ml, 9.74 mmol, 1.1 eq
  • reaction mixture was degassed with nitrogen for 10 min, then added PdCl 2 (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 80 o C for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 10% EtOAc in pet ether, R f of 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).
  • PdCl 2 dppf
  • 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 obtained crude compound was purified by prep-HPLC (Column:Column:X-Bridge C8(50X4.6) mm,3.5 ⁇ m, 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.
  • 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 K 2 CO 3 (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, R f of the product ⁇ 0.6), ice cold water (15 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL).
  • the obtained crude was purified by prep-HPLC (Column:Column:X-Bridge C8(50X4.6)mm,3.5 ⁇ m, 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.
  • 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), K 2 CO 3 (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 PdCl 2 (dppf) (0.027 g, 0.036 mmol, 0.01 eq) was added to the mixture and degassed and purged with nitrogen for 10 min.
  • dppf 0.027 g, 0.036 mmol, 0.01 eq
  • 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.
  • the combined organic layer was washed with saturated aqueous Na 2 S 2 O 3 (1 X 50 mL), dried over Na 2 SO 4 , 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 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.
  • the obtained crude was purified by prep-HPLC (Column: X-Bridge C8(50X4.6)mm, 3.5 ⁇ m, 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.
  • 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 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.
  • 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 Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude.
  • 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).
  • 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 K 2 CO 3 (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 reaction mixture was degassed with nitrogen for 10 min, then added PdCl 2 (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 80 o C for overnight.
  • 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 Na 2 SO 4 , 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.
  • 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 Na 2 SO 4 , 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.
  • reaction mixture was degassed with nitrogen for 10 min, then added PdCl 2 (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 80 o C for overnight.
  • 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).
  • 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 Na 2 SO 4 , 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 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.
  • 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 ⁇ m, 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.
  • 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.
  • 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 0 o C and added methanol (10 mL) as dropwise under nitrogen atmosphere. The reaction mixture was stirred for 20 min.
  • reaction mixture was concentrated under reduced pressure to dryness and quenched with saturated NaHCO 3 solution ( ⁇ 55 mL) until pH ⁇ 10 at 0 o C 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 Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product.
  • 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 NaHCO 3 (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 Na 2 S 2 O 3 (1 x 30 mL), dried over Na 2 SO 4 , 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 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 ⁇ m, 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.
  • the crude compound was purified by prep-HPLC (Column:X-Bridge C8(50 x 4.6) mm,3.5 ⁇ m, 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.
  • 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.
  • the combined organic layer was washed with sodium thiosulfate solution (2 x 15 mL), brine (1 x 50 mL) and dried over Na 2 SO 4 , 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.
  • the combined organic layer was dried over Na 2 SO 4 and concentrated to afford crude.
  • the crude product was purified by reverse-phase column chromatography (Grace column: C1840 ⁇ m, 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.
  • 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.
  • 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 NiCl 2 (dme) (0.106 g, 0.481 mmol, 0.2 eq) were stirred in RB under N 2 condition.
  • the RB was evacuated and backfilled with N2.
  • tert-butyl (2-iodoethyl)carbamate 2 (0.782 g, 2.88 mmol, 1.2 eq) was taken and evacuated and backfilled with N 2 , 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.
  • the crude compound was purified by reverse-phase column chromatography (Grace column: C1840 ⁇ m, 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.
  • 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 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.
  • Example 43 – General Preparation of Compounds 45-49 [0325] Compound 45-49 were prepared according to the following Scheme: [0326] Gen om 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 49 General Synthetic Route for Preparation of Compounds 50-53 and Compounds 55-58 he above scheme.
  • 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.
  • 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 Na 2 SO 4, 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(PPh 3 ) 2 Cl 2 (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.
  • 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).
  • 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.
  • 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 NaOH solution (7.0 mL, 7.02 mmol) in THF (12 mL) giving the target compound (0.9 g, 62% yield) as an off-white solid.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • Example 54 Preparation of Intermediate 5 of Compound 53
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • Example 58 – Preparation of Intermediate 5 of Compound 58 [0369]
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Na 2 SO 4, 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).
  • 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).
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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 (1.0 g, 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).
  • 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.
  • 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).
  • Example 68 – Preparation of Compound 61 [0409] Compound 61 was prepared according to the following scheme: [0410] Preparation o 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.
  • Compound 61 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 29A (45 mg, 0.13 mmol), Intermediate 6 (Example 50, 23 mg, 0.15 mmol), HATU (58 mg, 0.15 mmol) and triethylamine (0.1 mL, 0.63 mmol) in DMF (2 mL) giving the desired product (15 mg, 24% yield) as an off-white solid.
  • Example 69 – Preparation of Compound 64 [0421] Compound 64 was prepared according to the following scheme: ine (Intermediate 35, 2.0 g, 11.36 mmol) in triethylamine (20 mL) was added (R)-but-3-yn-2-ol (1.59 g, 22.72 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh 3 ) 2 Cl 2 (0.4 g, 0.57 mmol), CuI (0.21 g, 1.14 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 100°C and stirred for 16 h.
  • Compound 64 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 39 (116 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (150 mg, 52% yield) as an off-white solid.
  • Example 70 – Preparation of Compound 65 [0427] Compound 65 was prepared according to the following scheme: ine (Intermediate 35, 2.0 g, 11.36 mmol) in triethylamine (20 mL) was added (S)-but-3-yn-2-ol (1.59 g, 22.72 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh 3 ) 2 Cl 2 (0.4 g, 0.57 mmol), CuI (0.21 g, 1.14 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 100°C and stirred for 16 h.
  • Compound 65 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 43 (116 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (143 mg, 50% yield) as an off-white solid.
  • Example 71 – Preparation of Compound 66 [0433] Compound 66 was prepared according to the following scheme: ) in MeOH (10 mL) was added the Bestmann-Ohira reagent (1.0 g, 4.36 mmol) at RT. Then cooled the reaction mixture to 0-5°C and added K 2 CO 3 (1.08 g, 7.84 mmol). Later, gradually warmed the reaction to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH 4 Cl solution and extracted with hexane.
  • Compound 66 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 160 mg, 0.46 mmol), Intermediate 5B (101 mg, 0.55 mmol), HATU (211 mg, 0.55 mmol) and triethylamine (0.32 mL, 2.31 mmol) in DMF (2 mL) giving the target compound (63 mg, 26% yield) as a pale-blue solid.
  • Example 72 – Preparation of Compound 67 [0439] Compound 67 was prepared according to the following scheme: mol) in MeOH (9 mL) was added the Bestmann-Ohira reagent (0.9 g, 4.71 mmol) at RT. Then cooled the reaction mixture to 0-5°C and added K 2 CO 3 (0.97 g, 7.05 mmol). Later, gradually warmed the reaction to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH 4 Cl solution and extracted with hexane.
  • Compound 67 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 270 mg, 0.78 mmol), Intermediate 5A (170 mg, 0.94 mmol), HATU (357 mg, 0.94 mmol) and triethylamine (0.55 mL, 3.9 mmol) in DMF (2 mL) giving the target compound (51 mg, 13% yield) as a pale-blue solid.
  • Example 73 – Preparation of Compound 68 [0445] Compound 68 was prepared according to the following scheme: [0 hod described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 54 (98 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (138 mg, 48% yield) as a off-white solid.
  • Example 74 – Preparation of Compound 69 [0447] Compound 68 was prepared according to the following scheme: [04 hod described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 55 (87 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (150 mg, 57% yield) as a off-white solid.
  • Example 75 – Preparation of Compound 70 [0449] Compound 70 was prepared according to the following scheme: hod described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 56 (103 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (130 mg, 47% yield) as a off-white solid.
  • Intermediate 5 from Example 1, 200 mg, 0.58 mmol
  • Intermediate 56 103 mg, 0.69 mmol
  • HATU 264 mg, 0.69 mmol
  • triethylamine 0.4 mL, 2.89 mmol
  • Example 76 – Preparation of Compound 71 Compound 71 was prepared according to the following scheme: [0452] Preparation of Intermediate 71: Compou od described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 57 (114 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (130 mg, 45% yield) as a off-white solid.
  • Intermediate 5 from Example 1, 200 mg, 0.58 mmol
  • Intermediate 57 114 mg, 0.69 mmol
  • HATU 264 mg, 0.69 mmol
  • triethylamine 0.4 mL, 2.89 mmol
  • Example 77 – Preparation of Compound 72 [0453] Compound 72 was prepared according to the following scheme: od described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 58 (117 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (120 mg, 42% yield) as a off-white solid.
  • Intermediate 5 from Example 1, 200 mg, 0.58 mmol
  • Intermediate 58 117 mg, 0.69 mmol
  • HATU 264 mg, 0.69 mmol
  • triethylamine 0.4 mL, 2.89 mmol
  • Example 78 – Preparation of Compound 73 [0455] Compound 73 was prepared according to the following scheme: ion in oil, 0.3 g, 13.79 mmol) in THF (50 mL) was added drop wise of diethyl (cyanomethyl)phosphonate (1.4 g, 12.07 mmol) at 0-5°C and stirred for 1 h, followed by the addition of Intermediate 59A (2.0 g, 11.43 mmol), portion-wise for 15-20 min at 0-5°C. Then, gradually warmed the resulting reaction mixture to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH 4 Cl solution and extracted with ethyl acetate.
  • Example 79 – Preparation of Compound 76 [0459] Compound 76 was prepared according to the following scheme: , e 1, 600 mg, 1.45 mmol) in methanol (9 mL) was added Et 3 N (0.89 mL, 7.26 mmol) in a sealed tube and degassed with nitrogen for 10-15 min. PdCl 2 (dppf) (92 mg, 0.14 mmol) and X-Phos (119 mg, 0.29 mmol) were added and degassed again for 10-15. The resulting reaction mixture was heated to 65-70°C and stirred for 6 h under carbon monoxide (CO) pressure (50 psi).
  • CO carbon monoxide
  • Example 80 – Preparation of Compound 74 [0462] Compound 74 was prepared according to the following scheme: 50 mmol) in toluene (10 mL) was added DIPEA (0.8 mL, 4.51 mmol), followed by dropwise addition of diphenyl phosphoryl azide (0.4 mL, 1.80 mmol) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 30 min. Then, t-BuOH (3 mL) was added and heated the resulting reaction mass at 75-80°C for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to 45-50°C and evaporated under reduced pressure to get crude residue (1.2 g).
  • Compound 78 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (250 mg, 0.77 mmol), Intermediate 6 (Example 50, 141 mg, 0.92 mmol), HATU (351 mg, 0.92 mmol) and triethylamine (0.54 mL, 3.84 mmol) in DMF (2.5 mL) giving the target compound (84 mg, 24% yield) as a off-white solid.
  • Example 83 – Preparation of Compound 79 Compound 79 was prepared according to the Scheme in Example 81 with the added step of converting a nitrile into an amide as illustrated in the Scheme below. [0475] the general procedure described in Example 81, using 3-bromo-4-cyanobenzoic acid (2 g, 8.47 mmol) and oxalyl chloride (1.1 mL, 12.71 mmol) in DCM (20 mL)giving the target compound (2.4 grams, 100% crude yield).
  • Intermediate 5A was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (1.0 g, 3.41 mmol), Intermediate 6 (Example 50, 0.63 g, 4.09 mmol), HATU (1.56 g, 4.09 mmol) and triethylamine (2.4 mL, 17.06 mmol) in DMF (10 mL) giving the target compound (0.95 g, 67% yield) as a off-white solid.
  • Example 84 – Preparation of Compound 80 [0480] Compound 80 was prepared from Compound 79 according to the following Scheme: ) in AcOH (4.5 mL) was added tert-butyl nitrite (0.36 mL, 3.21 mmol). The resulting reaction contents were heated to 75-80°C and maintained for 16 h. After completion of the reaction (monitored by TLC), cooled to 50-55°C and evaporated the solvent under vacuum to afford crude compound (550 mg). The obtained crude residue was purified by prep-HPLC. Evaporated the pure fractions under vacuum to afford final Compound 80 (42 mg, 9.3% yield) as an off-white solid.
  • Example 85 – Preparation of Compound 81 Compound 81 was prepared according to the Scheme in Example 81. [0483] Preparation of Intermediate 2: Intermediate 2 was synthesized according to the general procedure described in Example 81, using 3-bromo-4-(methylsulfonyl)benzoic acid (2 g, 11.17 mmol) and oxalyl chloride (0.93 mL, 16.75 mmol) in DCM (20 mL) giving the target compound (1.2 grams, 100% crude yield).
  • Compound 81 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (200 mg, 0.58 mmol), Intermediate 6 (Example 50, 106 mg, 0.69 mmol), HATU (263 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (130 mg, 46% yield) as a off-white solid.
  • Example 86 – Preparation of Compound 82 [0487] Compound 82 was prepared according to the following Scheme: 0 g, 11.36 mmol) in triethylamine (20 mL) was added (R)-But-3-yn-2-ol (1.59 g, 22.72 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh 3 ) 2 Cl 2 (0.4 g, 0.57 mmol), CuI (0.21 g, 1.13 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 100°C and stirred for 16 h.
  • 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 (2.3 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 Compound-26 (1.8 grams, 93% yield) as a pale-yellow liquid.
  • Compound 82 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 200 mg, 0.67 mmol), Intermediate 29 (135 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) giving the target compound (112 mg, 37% yield) as an off-white solid.
  • Example 87 – Preparation of Compounds 83 and 84 [0493] Compounds 83 and 84 were prepared according to the following Scheme: ne (120 mL) was added ethyl 2-(diethoxy phosphoryl) propanoate (17.1 g, 72.0 mmol) dropwise at 0-5°C. After stirring for 30-40 min, Intermediate 38B (6.0 g, 48.0 mmol) in toluene (60 mL) was added dropwise into the reaction for 20-30 min. The resulting reaction contents were heated to 110°C and stirred for 2 h.
  • Compound 83 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 150 mg, 0.50 mmol), Intermediate 45D (101 mg, 0.60 mmol), HATU (230 mg, 0.60 mmol) and triethylamine (0.35 mL, 2.51 mmol) in DMF (1.5 mL) giving the target compound (28 mg, 12% yield) as an off-white solid.
  • Compound 84 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 140 mg, 0.47 mmol), Intermediate 45C (94 mg, 0.56 mmol), HATU (214 mg, 0.56 mmol) and triethylamine (0.32 mL, 2.35 mmol) in DMF (1.5 mL) giving the target compound (32 mg, 15% yield) as an off-white solid.
  • Example 88 – Preparation of Compound 85 [0505] Compound 85 was prepared according to the following Scheme: l) in dry THF (300 mL), was added triethylamine (20.6 mL, 146.38 mmol) at -20°C and stirred for 15 min, thereafter was added acryloyl chloride (6.1 mL, 73.19 mmol) at same temperature and stirred for 40 min. After that LiCl (3.3 g, 78.82 mmol) and Intermediate 38 (10 g, 56.3 mmol) were added, and the resulting white suspension was stirred at RT for 16 h.
  • Compound 85 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 350 mg, 1.20 mmol), Compound 43 (250 mg, 1.44 mmol), HATU (550 mg, 1.44 mmol) and triethylamine (0.8 mL, 6.04 mmol) in DMF (10 mL) followed by purification using Normal phase Prep conditions, afforded Compound 85 (130 mg, 24% yield) as an off-white solid.
  • Example 89 – Preparation of Compound 86 [0513] Compound 86 was prepared according to the following Scheme: hod described for preparation of Intermediate 39 (Example 88) using acrylic acid (5.5 mL, 78.82 mmol), triethyl amine (20.6 mL, 146.38 mmol), acryloyl chloride (6.1 mL, 73.19 mmol), LiCl (3.3 g, 78.82 mmol) and Intermediate 30 (10 g, 56.3 mmol) in dry THF (300 mL) to afford Intermediate 44 (7.0 grams, 53% yield) as a pale-yellow solid.
  • Intermediate 45 was prepared according to the method described for preparation of Intermediate 40 (Example 88) using Intermediate 44 (3.0 g, 12.97 mmol), 3- bromo-5-fluoropyridine (2.2 g, 12.97 mmol), palladium acetate (145 mg, 0.64 mmol) and o-tolyl phosphine (789 mg, 2.59 mmol) in Et 3 N (30 mL) to afford Intermediate 45 (2.4 grams, 55% yield) as a pale- yellow solid.
  • Intermediate 49B was prepared according to the method described for preparation of Intermediate 49A (Example 88) using Intermediate 45 (2.0 g, 6.13 mmol), copper(I) bromide dimethyl sulfide complex (1.8 g, 9.20 mmol), methyl magnesium bromide (1M in THF, 18.4 mL, 18.4 mmol), BF 3 •EtO (1.14 g, 9.20 mmol) in THF (30 mL) to afford Intermediate 49B (800 mg, 38% yield) as a pale-yellow solid.
  • Compound 86 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 115 mg, 0.38 mmol), Intermediate 48 (70 mg, 0.46 mmol), HATU (176 mg, 0.46 mmol) and triethylamine (0.26 mL, 1.93 mmol) in DMF (3 mL), followed by purification using Normal phase Prep conditions (Same as Compound 85), to afford Compound 86 (47 mg, 27% yield) as an off-white solid.
  • Example 90 – Preparation of Compound 87 [0521] Compound 87 was prepared according to the following Scheme: ribed for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 200 mg, 0.67 mmol), Intermediate 5A (110 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) to afford Compound 87 (110 mg, 39% yield) as an off-white solid.
  • Example 91 – Preparation of Compound 101 [0523] Compound 101 was prepared according to the following Scheme: .03 mmol) in toluene (30 mL) was added trimethylphosphono acetate (3.3 mL, 21.02 mmol) dropwise for 15- 20 min at 0°C, then. warmed the reaction to RT and stirred for 1 h. Intermediate 114 (3.0 g, 14.01 mmol) in toluene (30 mL) was added dropwise into the reaction mixture for 20-30 min. The resulting reaction contents were heated to 110°C and stirred for 16 h.
  • reaction mixture was cooled to RT, quenched with 1N HCl and extracted with ethyl acetate. Separated the organic layer, dried over sodium sulphate and evaporated under reduced pressure to get crude residue (5.5 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 5-10% ethyl acetate in hexane to afford Intermediate 115 (4.2 grams, 60% yield) as an off- white solid.
  • Example 92 – Preparation of Compound 88 [0529] Compound 88 was prepared according to the following Scheme: p py y (60) (2.0 g, 10.28 mmol) in triethylamine (20 mL) was added (R)-But-3-yn-2-ol (1.63 mL, 20.57 mmol) in a sealed tube and then reaction mixture was degassed for 15 min by using of nitrogen gas. Then, Pd(PPh 3 ) 2 Cl 2 (0.36 g, 0.51 mmol), CuI (0.19 g, 1.03 mmol) were added and continued the degassed for 15 min. The resulting reaction mixture was heated to 90°C and stirred for 16 h.
  • 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 (1.9 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 61 (0.85 gram, 56% yield) as a pale-yellow liquid.
  • Compound 88 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 200 mg, 0.67 mmol), Int-64 (120 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) giving Compound 88 (170 mg, 59% yield) as an off-white solid.
  • Example 93 – Preparation of Compound 89 [0535] Compound 89 was prepared according to the following Scheme: 60) (2.0 g, 10.28 mmol) in triethylamine (20 mL) was added (S)-But-3-yn-2-ol (1.63 mL, 20.57 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh 3 ) 2 Cl 2 (0.36 g, 0.51 mmol), CuI (0.19 g, 1.03 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 90°C and stirred for 16 h.
  • 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 (1.8 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 65 (0.9gram, 60% yield) as a pale-yellow liquid.
  • Example 94 – Preparation of Compound 90 [0541] Compound 90 was prepared according to the following Scheme: [0542] Preparation of Compound 90: Compound 90 wa ribed for preparation of Compound 1 (Example 1) using 5-(3-cyano-4-methoxyphenyl)oxazole-4-carboxylic acid (200 mg, 0.82 mmol), Intermediate 5A (Intermediate 4 from Example 13, 135 mg, 0.98 mmol), HATU (373 mg, 0.98 mmol) and triethylamine (0.57 mL, 4.09 mmol) in DMF (2 mL) to afford Compound 90 (115 mg, 38% yield) as an off-white solid.
  • Example 95 – Preparation of Compound 91 Compound 91 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-acetylphenyl)oxazole-4-carboxylic acid (200 mg, 0.86 mmol), Intermediate 5A (Intermediate 4 from Example 13, 151 mg, 1.04 mmol), HATU (392 mg, 1.04 mmol) and triethylamine (0.56 mL, 4.32 mmol) in DMF (2 mL) to afford Compound 91 (135 mg, 45% yield) as an off-white solid.
  • Example 96 – Preparation of Compound 92 Compound 92 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-(methylsulfonyl)phenyl)oxazole-4-carboxylic acid (200 mg, 0.75 mmol), Intermediate 5A (Intermediate 4 from Example 13, 122 mg, 0.90 mmol), HATU (341 mg, 0.90 mmol) and triethylamine (0.52 mL, 3.74 mmol) in DMF (2 mL) to afford Compound 92 (140 mg, 48% yield) as an off-white solid.
  • Example 97 – Preparation of Compound 93 Compound 93 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-acetyl-3-bromophenyl)oxazole-4-carboxylic acid (150 mg, 0.48 mmol), Intermediate 5A (Intermediate 4 from Example 13, 79 mg, 0.58 mmol), HATU (220 mg, 0.58 mmol) and triethylamine (0.33 mL, 2.42 mmol) in DMF (2 mL) to afford Compound 93 (100 mg, 48% yield) as an off-white solid.
  • Example 98 – Preparation of Compound 94 Compound 94 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-acetamido-3-bromophenyl)oxazole-4-carboxylic acid (250 mg, 0.77 mmol), Intermediate 5A (Intermediate 4 from Example 13, 126 mg, 0.92 mmol), HATU (351 mg, 0.92 mmol) and triethylamine (0.54 mL, 3.84 mmol) in DMF (2.5 mL) to afford Compound 94 (87 mg, 26% yield) as an off-white solid.
  • Example 99 – Preparation of Compound 95 and Compound 96 [0547] Preparation of Compound 95 and Compound 96 were achieved using methods that generally followed the same protocols for preparation of Compound 79 and Compound 80 as described in Examples 81, 83 and 84 by replacing Intermediate 6 with Intermediate 5A (Intermediate 4 from Example 13).
  • Example 100 – Preparation of Compound 97 Compound 97 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(3-bromo-4-(methylsulfonyl)phenyl)oxazole-4- carboxylic acid (200 mg, 0.58 mmol), Intermediate 5A (Intermediate 4 from Example 13, 94 mg, 0.69 mmol), HATU (263 mg, 0.59 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) to afford Compound 97 (140 mg, 52% yield) as an off-white solid.
  • Example 101 – Preparation of Compound 98 [0551] Compound 98 was prepared according to the following Scheme: ) in MeOH (10 mL) was added Ohira-Bestmann reagent (1.0 g, 4.36 mmol) at RT. Cooled the reaction to 0-5°C and added K 2 CO 3 (1.08 g, 7.84 mmol). Gradually brought the reaction to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH 4 Cl solution and extracted with hexane.
  • reaction mixture was heated to 90-95 °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 (820 mg). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 10-12% ethyl acetate in hexane to afford Intermediate 89 (280 mg, 41% yield) as a brown semi-solid.
  • Compound 98 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 170 mg, 0.57 mmol), Intermediate 91 (113 mg, 0.68 mmol), HATU (260 mg, 0.68 mmol) and triethylamine (0.4 mL, 2.85 mmol) in DMF (1.7 mL) giving Compound 98 (66 mg, 25% yield) as an off-white solid.
  • Intermediate 10 Intermediate 5 from Example 62, 170 mg, 0.57 mmol
  • Intermediate 91 113 mg, 0.68 mmol
  • HATU 260 mg, 0.68 mmol
  • triethylamine 0.4 mL, 2.85 mmol
  • Any of compounds 2-101 can be formulated as a pharmaceutically acceptable salt and/or solvate thereof.
  • the presently disclosed compounds, compositions and treatment methods also have use in veterinary applications for improving the health and well-being of livestock and companion animals by treating conditions they suffer from that respond to treatment with a GSK-3 ⁇ inhibitor.
  • CRMP2 phosphorylation is a direct and specific result of GSK3- ⁇ activity.
  • CRMP2 phosphorylation (pCRMP2) in post-mortem human brain tissue is abnormally high unless the person was taking lithium at the time of death.
  • OCM-51 requires a concentration of about 1 micromole to reduce pCRMP2 by at least 20%, while Compounds 13, 56, and 59 provide >20% reductions at concentrations of 0.1 micromolar or less.
  • Compound 56 was shown effective in a rodent model of lithium pharmacology, indicating its potential to cross the blood brain barrier and last long enough in the brain to impact animal behavior (FIG. 5).
  • Compound 56 was administered to adult male Wistar rats one hour before dextroamphetamine (AMP).
  • AMP dextroamphetamine

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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 USE
CROSS-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 of cancer. 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:
Figure imgf000004_0001
[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:
Figure imgf000004_0002
I
Wherein,
R1 is L1-R5; R2 is L2-R6; R3 is H or C1-C6 alkyl; R4 is H or C1-C6 alkyl; R5 is 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 R5 is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6 alkyl), 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)2 and -(CH2)s-R11; R6 is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6 is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2; R7 is H, OR8 or N(R8)2; each R8 is independently H or -(C=O)p-(C1-C6 alkyl); each R9 is independently H, -(C=O)r-(C1-C6 alkyl), or -(C=O)r-(CH2)x-(C3-C6 cycloalkyl); each R10 is independently H or C1-C6 alkyl; each R11 is independently H, OR12 or N(R12)2; each R12 is independently H or -(C=O)t-(C1-C6 alkyl); each R13 is independently H, -(C=O)v-(C1-C6 alkyl), or S(O)2R14; each R14 is independently H or C1-C6 alkyl; L1 is 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 L1 is optionally substituted with one or two -(CH2)o-R7; L2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2 is optionally substituted with 1-2 C1-C6 alkyl 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 C11 compound 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/kg administered 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, tertiary butylacetic 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, and the 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,
Figure imgf000009_0001
R1 is L1-R5; R2 is L2-R6; R3 is H or C1-C6 alkyl; R4 is H or C1-C6 alkyl; R5 is 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 R5 is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6 alkyl), 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)2 and -(CH2)s-R11; R6 is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6 is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2; R7 is H, OR8, or N(R8)2; each R8 is independently H or -(C=O)p-(C1-C6 alkyl); each R9 is independently H, -(C=O)r-(C1-C6 alkyl), or -(C=O)r-(CH2)x-(C3-C6 cycloalkyl); each R10 is independently H or C1-C6 alkyl; each R11 is independently H, OR12 or N(R12)2; each R12 is independently H or -(C=O)t-(C1-C6 alkyl); each R13 is independently H, -(C=O)v-(C1-C6 alkyl), or S(O)2R14; each R14 is independently H or C1-C6 alkyl; L1 is 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 L1 is optionally substituted with one or two -(CH2)o-R7; L2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2 is optionally substituted with 1-2 C1-C6 alkyl 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, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., 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 another embodiment, 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 from suitable 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 that differ 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 a 13C- or 14C-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, 1 1
Figure imgf000014_0001
R is L -R5; R2 is L2-R6; R3 is H or C1-C6 alkyl; R4 is H or C1-C6 alkyl; R5 is 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 R5 is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6 alkyl), 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)2 and -(CH2)s-R11; R6 is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6 is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2; R7 is H, OR8 or, N(R8)2; each R8 is independently H or -(C=O)p-(C1-C6 alkyl); each R9 is independently H, -(C=O)r-(C1-C6 alkyl), or -(C=O)r-(CH2)x-(C3-C6 cycloalkyl); each R10 is independently H or C1-C6 alkyl; each R11 is independently H, OR12 or N(R12)2; each R12 is independently H or -(C=O)t-(C1-C6 alkyl); each R13 is independently H, -(C=O)v-(C1-C6 alkyl), or S(O)2R14; each R14 is independently H or C1-C6 alkyl; L1 is 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 L1 is optionally substituted with one or two -(CH2)o-R7; L2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2 is optionally substituted with 1-2 C1-C6 alkyl 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, R1 is L1-R5. [0045] As defined generally above, R2 is L2-R6. [0046] As defined generally above, R3 is H or C1-C6 alkyl. In some embodiments, R3 is H. In some embodiments, R3 is C1-C6 alkyl. [0047] As defined generally above, R4 is H or C1-C6 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is C1-C6 alkyl. [0048] As defined generally above, R5 is 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 R5 is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6 alkyl), 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)2 and -(CH2)s-R11. In some embodiments, R5 is a 5-membered heteroaryl ring. In some embodiments, R5 is a 6-membered aryl ring, a 6-membered heteroaryl ring. In some embodiments, R5 is a 6-membered heteroaryl ring. In some embodiments, R5 is an 8-12 membered fused bicyclic aryl or heteroaryl ring system. In some embodiments, R5 is unsubstituted. In some embodiments, R5 is substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6 alkyl), 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)2 and -(CH2)s-R11. [0049] As defined generally above, R6 is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6- membered heteroaryl ring, wherein R6 is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2. In some embodiments, R6 is a 5-6 membered heteroaryl ring. In some embodiments, R6 is a 6-membered aryl ring. In some embodiments, R6 is a 6-membered heteroaryl ring. In some embodiments, R6 is unsubstituted. In some embodiments, R6 substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2. [0050] As defined generally above, R7 is H, OR8 or N(R8)2. In some embodiments, R7 is H. In some embodiments, R7 is OR8. In some embodiments, R7 is N(R8)2. [0051] As defined generally above, each R8 is independently H or -(C=O)p-(C1-C6 alkyl). In some embodiments, at least one of R8 is H. In some embodiments, at least one of R8 is -(C=O)p-(C1-C6 alkyl). In some embodiments, each R8 is the same. In some embodiments, each R8 is different. [0052] As defined generally above, each R9 is independently H, -(C=O)r-(C1-C6 alkyl), or -(C=O)r-(CH2)x- (C3-C6 cycloalkyl). In some embodiments, at least one of R9 is H. In some embodiments, at least one of R9 is -(C=O)r-(C1-C6 alkyl). In some embodiments, at least one of R9 is -(C=O)r-(CH2)x-(C3-C6 cycloalkyl). In some embodiments, at least two of R9 are H. In some embodiments, at least two of R9 are -(C=O)r-(C1-C6 alkyl). In some embodiments, at least two of R9 is -(C=O)r-(CH2)x-(C3-C6 cycloalkyl). In some embodiments, each R9 is the same. In some embodiments, each R9 is different. [0053] As defined generally above, each R10 is independently H or C1-C6 alkyl. In some embodiments, at least one of R10 is H. In some embodiments, at least one of R10 is C1-C6 alkyl. In some embodiments, at least two of R10 are H. In some embodiments, at least two of R10 are C1-C6 alkyl. In some embodiments, each R10 is the same. In some embodiments, each R10 is different. [0054] As defined generally above, each R11 is independently H, OR12 or N(R12)2. In some embodiments, at least one of R11 is H. In some embodiments, at least one of R11 is OR12. In some embodiments, at least one of R11 is N(R12)2. In some embodiments, at least two of R11 are H. In some embodiments, at least two of R11 are OR12. In some embodiments, at least two of R11 are N(R12)2. In some embodiments, each R11 is the same. In some embodiments, each R11 is different. [0055] As defined generally above, each R12 is independently H or -(C=O)t-(C1-C6 alkyl). In some embodiments, at least one of R12 is H. In some embodiments, at least one of R12 is -(C=O)t-(C1-C6 alkyl). In some embodiments, each R12 is the same. In some embodiments, each R12 is different. [0056] As defined generally above, each R13 is independently H, -(C=O)v-(C1-C6 alkyl), or S(O)2R14. In some embodiments, at least one of R13 is H. In some embodiments, at least one of R13 is -(C=O)v-(C1-C6 alkyl). In some embodiments, at least one of R13 is S(O)2R14. In some embodiments, at least two of R13 are H. In some embodiments, at least two of R13 are -(C=O)v-(C1-C6 alkyl). In some embodiments, at least two of R13 are S(O)2R14. In some embodiments, each R13 is the same. In some embodiments, each R13 is different. [0057] As defined generally above, each R14 is independently H or C1-C6 alkyl. In some embodiments, at least one of R14 is H. In some embodiments, at least one of R14 is C1-C6 alkyl. In some embodiments, at least two of R14 are H. In some embodiments, at least two of R14 are C1-C6 alkyl. In some embodiments, each R14 is the same. In some embodiments, each R14 is different. [0058] As defined generally above, L1 is 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 L1 is optionally substituted with -(CH2)o-R7. In some embodiments, L1 is a direct link. In some embodiments, L1 is -(CH2)n-. In some embodiments, L1 is a 3-7 membered cycloalkyl ring. In some embodiments, L1 is a 4-7 membered heterocyclic ring. In some embodiments, L1 is a 6 membered aryl ring. In some embodiments, L1 is unsubstituted. In some embodiments, any carbon atom of L1 is may be substituted with one or two -(CH2)o-R7. [0059] As defined generally above, L2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2 is optionally substituted with 1-2 C1-C6 alkyl groups. In some embodiments, L2 is a 5-6 membered heteroaryl ring. In some embodiments, L2 is a 6-membered aryl ring. In some embodiments, L2 is a 6-membered heteroaryl ring. In some embodiments, L2 is unsubstituted. In some embodiments, L2 is substituted with 1-2 C1-C6 alkyl 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. In some 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 thereof
Figure imgf000019_0001
wherein, R1 is L1-R5; R2 is L2-R6; R3 is H or C1-C6 alkyl; R4 is H or C1-C6 alkyl; R5 is 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 R5 is optionally substituted with 1-3 groups independently selected from –(C=O)q-(C1-C6 alkyl), 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)2 and –(CH2)s-R11; R6 is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6 is optionally substituted with 1-3 groups independently selected from –(C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2; R7 is H, OR8 ,or N(R8)2; each R8 is independently H or –(C=O)p-(C1-C6 alkyl); each R9 is independently H, -(C=O)r-(C1-C6 alkyl), or –(C=O)r-(CH2)x-(C3-C6 cycloalkyl); each R10 is independently H or C1-C6 alkyl; each R11 is independently H, OR12 or N(R12)2; each R12 is independently H or –(C=O)t-(C1-C6 alkyl); each R13 is independently H, -(C=O)v-(C1-C6 alkyl), or S(O)2R14; each R14 is independently H or C1-C6 alkyl; L1 is 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 L1 is optionally substituted with – (CH2)o-R7; L2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2 is optionally substituted with 1-2 C1-C6 alkyl 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 subst
Figure imgf000021_0001
itutions are defined according to a structure of Formula I, and wherein, R15 is H, C1-C6 alkyl or -(CH2)w-R16; R16 is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R16 is optionally substituted with 1-5 groups independently selected from F, NO2 and OCH3; R17 is 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, R15 is H, C1-C6 alkyl or -(CH2)w-R16. In some embodiments, R15 is H. In some embodiments, R15 is C1-C6 alkyl. In some embodiments, R15 is -(CH2)w-R16. [0076] As defined generally above, R16 is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R16 is optionally substituted with 1-5 groups independently selected from F, NO2 and OCH3. In some embodiments, R16 is a 5-membered heteroaryl group. In some embodiments, R16 is a 6-membered aryl group optionally substituted with 1-5 groups independently selected from F, NO2 and OCH3. In some embodiments, R16 is a 6-membered heteroaryl group, wherein, R16 is optionally substituted with 1-5 groups independently selected from F, NO2 and OCH3. [0077] As defined generally above, R17 is 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, R17 is acetyl. In some embodiments, R17 is benzoyl. In some embodiments, R17 is 4-nitrobenzoyl. In some embodiments, R17 is benzyl. In some embodiments, R17 is p-methoxybenzyl. In some embodiments, R17 is tolyl. In some embodiments, R17 is trityl. In some embodiments, R17 is methoxymethyl. In some embodiments, R17 is trimethylsilyl. In some embodiments, R17 is triethylsilyl. In some embodiments, R17 is triisopropylsilyl. In some embodiments, R17 is tert-butyl dimethylsilyl. In some embodiments, R17 is tertbutyl diphenylsilyl. In some embodiments, R17 is tert-butyl carbamoyl (Boc). In some embodiments, R17 is fluorenylmethylcarbamoyl (Fmoc). In some embodiments, R17 is benzylcarbamoyl (Cbz). In some embodiments, In some embodiments, R17 is a suitable protecting group for a hydroxyl functional group. In some embodiments, R17 is 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:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
[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 the subject 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:
Figure imgf000028_0001
[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 afford crude 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:
Figure imgf000031_0001
[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 hexane to 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 (400 MHz, 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 K2CO3 LiOH.HO O 2 DMF THF O
Figure imgf000037_0002
mL), 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
Figure imgf000037_0001
, 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, 10.93
Figure imgf000038_0001
mmol, 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 0 oC 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 N 2 NHBoc M [0
Figure imgf000039_0001
, , 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 NaHCO3 solution (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 0 oC. 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 0 oC 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 (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]
Figure imgf000041_0001
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, Rf of 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 by column 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 0 oC. 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 0 oC 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: [0
Figure imgf000043_0001
g, 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 0 oC 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 0 oC and stirred for 10 min. Then saturated aqueous NaHCO3 solution (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 0 oC 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 NaHCO3 solution (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 0 oC 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:
Figure imgf000045_0001
[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 110 oC 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 NaHCO3 solution (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 NaHCO3 solution (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 0 oC 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 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: 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]
Figure imgf000048_0001
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 35 mL/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/cm2 overnight. Upon completion of reaction (as confirmed by TLC, 60% ethylacetate in pet ether, Rf of 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, Rf of desired product 0.1), the reaction mixture was quenched with sat. aq. sodium potassium tartrate solution (3 mL) very carefully at -10 oC 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 0 oC 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, Rf of desired product 0.5 & LCMS analysis), ice cold saturated aq. NaHCO3 solution (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 to afford 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, Rf of 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 0 oC 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: [0187
Figure imgf000052_0001
added 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 0 oC. 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 NaHCO3 solution 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 0 oC 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: was
Figure imgf000054_0001
added 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), 3.1
Figure imgf000054_0002
93.17 (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 the solvent 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 F
Figure imgf000055_0001
mg, 1.34 mmol) in methanol (10 mL) was added 7M NH3 in 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 gel column 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
Figure imgf000056_0001
(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 grams isolated 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:
Figure imgf000058_0001
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. 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 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 NH3 in 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 with 25-30% 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 x
Figure imgf000060_0002
4.6)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), 1.95
Figure imgf000060_0001
1.91 (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
Figure imgf000061_0001
(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]
Figure imgf000062_0001
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 0 oC and allowed to stir for 30 min under N2 atmosphere. SEM-Cl (0.952 mL, 5.37 mmol, 1.1 eq) was added at 0 oC and allowed to stir overnight. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was quenched by saturated NH4Cl solution at 0 oC 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 85 oC 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 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 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 0 oC. 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 0 oC 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 0 oC 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 reaction mixture 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 0 oC 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 0 oC 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]
Figure imgf000065_0001
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 mixture was 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. Na2S2O3 solution (2 x 40 mL), water ( 1 x 50 mL) followed by brine (1 x 50 mL). The organic layer was dried under anhydrous Na2SO4 and 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]
Figure imgf000067_0001
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 0 oC 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 0 oC 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, 1.0
Figure imgf000069_0001
eq) 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 140 oC. 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 70 oC. 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 NaHCO3 solution (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 0 oC. the resulting solution was stirred for 10 min at 0 oC. 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 0 oC 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 NaHCO3 solution (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: [024
Figure imgf000071_0001
1] 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 100 oC 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 (1 x 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 80 oC. 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 yellow gummy 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 0 oC. 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 0 oC. 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 of Example 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 0 oC 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:
Figure imgf000074_0001
[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 80 oC 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 ice cold 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 85 oC. 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 0 oC. 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 0 oC. 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 0 oC 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 0 oC 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 45 oC 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 0 oC 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 0 oC 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]
Figure imgf000078_0001
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 0 oC 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 0 oC, 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, Rf of 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 80 oC for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 10% EtOAc in pet ether, Rf of 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 85 oC. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rf of 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 0 oC. 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 added dropwise 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, Rf of 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 0 oC and stirred for overnight at RT and reaction mixture was heated to 45 oC for 1h. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rf of 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 0 oC 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 0 oC 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, Rf of 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 washed with 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
Figure imgf000081_0001
. 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, Rf of 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 80 oC for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rf of 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 85 oC. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rf of 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 0 oC. 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, Rf of the product ~ 0.6), the reaction mixture was basified to pH=12 with saturated NaHCO3 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 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 0 oC 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, Rf of 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 0 oC 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, Rf of 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
Figure imgf000084_0001
, , .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 TLC analysis, 10% EtOAc in pet ether, Rf of 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 80 oC. Upon completion of the reaction (as confirmed by TLC analysis, 80% EtOAc in pet ether, Rf of 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 NaHCO3 solution (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 0 oC. 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 0 oC. 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, Rf of 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 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 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 0 oC 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 0 oC 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): δ 8.40 (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]
Figure imgf000087_0001
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 (2.98 g, 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 80 oC 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 85 oC. 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 0 oC. 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 was purified 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 0 oC 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 0 oC 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: [
Figure imgf000090_0001
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, 1.852 mmol, 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 80 oC 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 85 oC 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 NaHCO3 solution (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 0 oC. 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 0 oC. 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 0 oC 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 0 oC 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:
Figure imgf000093_0001
[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 0 oC 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 NaHCO3 solution (35 mL) at 0 oC, 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 10 min, 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 80 oC 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 85 oC 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 0 oC. 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 column chromatography (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 0 oC 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 0 oC 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]
Figure imgf000096_0001
. , . 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 0 oC 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, Rf of the product ~ 0.3 & LCMS analysis), reaction mixture was concentrated under reduced pressure to dryness and quenched with saturated NaHCO3 solution (~55 mL) until pH ~ 10 at 0 oC 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 80 oC for overnight. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc in pet ether, Rf of 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 85 oC. 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% NaHCO3 solution 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 0 oC. 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 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 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 0 oC 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, Rf of 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 0 oC 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, Rf of 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]
Figure imgf000099_0001
. , .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 N2 condition. 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 Na2SO4 and 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 0 oC. 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 0 oC 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 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]
Figure imgf000101_0001
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 N2 condition. 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 Na2SO4 and 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 0 oC. 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 0 oC 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:
Figure imgf000103_0001
[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 N2 condition. 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, Rf of 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 Na2SO4 and 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 0 oC. 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, Rf of 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 0 oC 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, Rf of 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]
Figure imgf000105_0001
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 filtered through 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 0 oC 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, 8.9
Figure imgf000107_0001
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 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 titanium tetraethoxide (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. NaHCO3 solution (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] Gen
Figure imgf000109_0001
om 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 55-58
Figure imgf000111_0001
he 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 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 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:
Figure imgf000112_0001
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 NaOH solution (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-white solid. 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:
Figure imgf000118_0001
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 organic layer 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:
Figure imgf000119_0001
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.
Figure imgf000120_0001
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), 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. [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) and 1M 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 (1.0 g, 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] Preparation
Figure imgf000125_0001
o 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°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 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 stirred at RT for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched into ice cold water. Adjusted the pH to ^8 by addition of sat. NaHCO3 solution. Separated the organic layer and washed with water. Separated the organic layer was dried over sodium sulphate, filtered and evaporated under vacuum to get crude Intermediate 22A (450 mg) and which was further purified by using of silica-gel (100- 200 mesh) column chromatography eluting with 15-20% ethyl acetate in hexane to afford Intermediate 22A (0.34 gram, 55% yield). [0413] Preparation of Intermediate 23A: To a stirred solution of Intermediate 22A (0.34 g, 1.94 mmol) in acetonitrile (5 mL) was added t-Bu-ONO (354 mg, 4.85 mmol) and CuI (523 mg, 3.88 mmol), followed by the addition of KI (228 mg, 1.94 mmol) and stirred at RT for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was partitioned between ethyl acetate and water. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude compd-23A (700 mg) and which was further purified by silica-gel (100-200 mesh) column chromatography eluting with 5-8% ethyl acetate in hexane to afford Intermediate 23A (0.35 gram, 71% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J= 1.6 Hz, 1H), 7.92 (dd, J= 8.0, 1.6 Hz, 1H), 7.61 (d, J= 8.0 Hz, 1H), 3.86 (s, 3H), 0.29 (s, 9H). [0414] Preparation of Intermediate 24A: To a stirred solution of Intermediate 23A (0.15 g, 0.42 mmol) in THF (10 mL) was added TBAF (1M in THF) (2.5 mL, 2.51 mmol) dropwise for 5-10 min at RT and stirred for 1 h. After completion of reaction (monitored by TLC), the reaction mixture was partitioned between ethyl acetate and brine. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude compd-24A (180 mg), which was further purified by silica-gel (100-200 mesh) column chromatography eluting with 7-10% ethyl acetate in hexane to afford Intermediate 24A (80 mg 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J= 1.6 Hz, 1H), 7.94 (dd, J= 8.0, 1.6 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 4.86 (s, 1H), 3.86 (s, 3H). [0415] Preparation of Intermediate 25A: A stirred solution of Intermediate 24A (1.0 g, 3.49 mmol) in formic acid (40 mL) was heated to 100°C and stirred for 36 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to RT and later cooled to 0-5°C, where it was quenched with sat. NaHCO3 solution, until pH^8. Then extracted the aq layer with ethyl acetate, separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude compd-25A (1.2 g), which was further purified by silica-gel (100-200 mesh) column chromatography eluting with 4-6% ethyl acetate in hexane to afford Intermediate 25A (700 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J= 1.2 Hz, 1H), 8.03 (dd, J= 8.0, 1.6 Hz, 1H), 7.75 (d, J= 8.0 Hz, 1H), 3.88 (s, 3H), 2.58 (s, 3H). [0416] Preparation of Intermediate 26A: To a solution of Intermediate 25A (700 mg, 2.41 mmol) in THF (7 mL) and water (3 mL) was added LiOH.H2O (116 mg, 2.89 mmol) and stirred for 1 h at RT. After completion of reaction (monitored by TLC), the reaction mixture was partitioned between ethyl acetate and water. Separated the layers and adjusted the pH of aq layer to ^2, using 1N HCl. The resulting aq. layer was extracted with ethyl acetate. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to afford Intermediate 26A (500 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J= 1.2 Hz, 1H), 8.01 (dd, J= 8.0, 1.6 Hz, 1H), 7.72 (d, J= 7.6 Hz, 1H), 2.58 (s, 3H). [0417] Preparation of Intermediate 27A: Intermediate 27A was prepared according to the method described for preparation of Intermediate 2 of Example 1 using Intermediate 26A (400 mg, 1.37 mmol) and oxalyl chloride (0.17 mL, 2.07 mmol) in DCM (5 mL) giving the desired product (500 mg, 100% crude yield). [0418] Preparation of Intermediate 28A: Intermediate 28A was prepared according to the method described for preparation of Intermediate 4 of Example 1 using Intermediate 27A (500 mg, 1.62 mmol), potassium tert-butoxide (545 mg, 4.87 mmol) and Intermediate 6 (Example 50, 184 mg, 1.62 mmol) in dry THF (5 mL) giving the desired product (110 mg, 16% yield). [0419] Preparation of Intermediate 29A: Intermediate 29A was prepared according to the method described for preparation of Intermediate 5 of Example 1 using Intermediate 28A (100 mg, 0.26 mmol) and 1M NaOH solution (0.39 mL, 0.39 mmol) in THF (2 mL) as an off-white solid. giving the desired product (45 mg, 49% yield) as an off-white solid. [0420] Preparation of Compound 61: Compound 61 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 29A (45 mg, 0.13 mmol), Intermediate 6 (Example 50, 23 mg, 0.15 mmol), HATU (58 mg, 0.15 mmol) and triethylamine (0.1 mL, 0.63 mmol) in DMF (2 mL) giving the desired product (15 mg, 24% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.91 (d, J= 1.6 Hz, 1H), 8.67 (s, 1H), 8.61 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.35 (s, 1H), 8.27 (dd, J= 8.4 Hz, 1.6 Hz, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.67-7.64 (m, 1H), 3.33-3.28 (m, 2H), 2.69 (t, J= 7.2 Hz, 2H), 2.59 (s, 3H), 1.89-1.85 (m, 2H). Example 69 – Preparation of Compound 64 [0421] Compound 64 was prepared according to the following scheme: ine
Figure imgf000128_0001
(Intermediate 35, 2.0 g, 11.36 mmol) in triethylamine (20 mL) was added (R)-but-3-yn-2-ol (1.59 g, 22.72 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (0.4 g, 0.57 mmol), CuI (0.21 g, 1.14 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 (2.3 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 36 (1.8 grams, 93% yield). [0423] Preparation of Intermediate 37: To a stirred suspension of palladium on carbon (10% wet) (360 mg) in methanol (30 mL) was added Intermediate 36 (1.8 g, 10.90 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 (1.9 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 37 (1.6 grams, 88% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=2.4 Hz, 1H), 8.32 (s, 1H), 7.60-7.57 (m, 1H), 4.54 (d, J=4.8 Hz, 1H), 3.62-3.56 (m, 1H), 2.78-2.51 (m, 2H), 1.66-1.60 (m, 2H), 1.09 (d, J=6.4 Hz, 3H). [0424] Preparation of Intermediate 38: To a stirred solution of Intermediate 37 (1.5 g, 8.87 mmol) in THF (15 mL) was added PPh3 (4.68 g, 17.75 mmol) and phthalimide (1.3 g, 8.87 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (3.49 mL, 17.75 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 38 (2.3 grams, 88% yield) as a pale-yellow solid. [0425] Preparation of Intermediate 39: To a stirred solution of Intermediate 38 (2.0 g, 6.71 mmol) and in MeOH (20 mL) was added N2H4•H2O (0.86 mL, 17.44 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 the residue. The obtained 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 39 (0.55 gram, 65% crude yield) as a colorless liquid. [0426] Preparation of Compound 64: Compound 64 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 39 (116 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (150 mg, 52% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.77 (d, J= 2.4 Hz, 1H), 8.54 (s, 1H), 8.37 (d, J= 2.8 Hz, 1H), 8.32 (s, 1H), 8.20 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 8.16 (s, 1H), 7.63-7.59 (m, 1H), 7.14 (d, J= 8.8 Hz, 1H), 4.07-4.00 (m, 1H), 3.90 (s, 3H), 2.71- 2.62 (m, 2H), 1.99-1.91 (m, 1H), 1.89-1.77 (m, 1H), 1.18 (d, J= 6.4 Hz, 3H). Example 70 – Preparation of Compound 65 [0427] Compound 65 was prepared according to the following scheme:
Figure imgf000129_0001
ine (Intermediate 35, 2.0 g, 11.36 mmol) in triethylamine (20 mL) was added (S)-but-3-yn-2-ol (1.59 g, 22.72 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (0.4 g, 0.57 mmol), CuI (0.21 g, 1.14 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 (2.3 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 45-50% ethyl acetate in hexane giving Intermediate 40 (1.8 grams, 93% yield). [0429] Preparation of Intermediate 41: To a stirred suspension of palladium on carbon (10% wet) (360 mg) in methanol (30 mL) was added Intermediate 40 (1.8 g, 10.90 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 (1.9 g). The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with 50-55% ethyl acetate in hexane giving Intermediate 41 (1.5 grams, 81% yield) as an off-white solid. [0430] Preparation of Intermediate 42: To a stirred solution of Intermediate 41 (1.5 g, 8.87 mmol) in THF (15 mL) was added PPh3 (4.68 g, 17.75 mmol) and phthalimide (1.3 g, 8.87 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (3.49 mL, 17.75 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 giving Intermediate 42 (2 g, 76% yield) as a pale-yellow solid. [0431] Preparation of Intermediate 43: To a stirred solution of Intermediate 42 (2.0 g, 6.71 mmol) and in MeOH (20 mL) was added N2H4•H2O (0.86 mL, 17.44 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 the residue and the obtained 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 43 (along with the presence of a non-polar impurity) as a colorless liquid (0.50 gram, 44% crude yield), which was used in the next step as such. [0432] Preparation of Compound 65: Compound 65 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 43 (116 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (143 mg, 50% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.77 (d, J= 2.0 Hz, 1H), 8.54 (s, 1H), 8.37 (d, J= 2.8 Hz, 1H), 8.32 (s, 1H), 8.19 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 8.16 (s, 1H), 7.63-7.59 (m, 1H), 7.13 (d, J= 9.2 Hz, 1H), 4.07-4.00 (m, 1H), 3.90 (s, 3H), 2.71- 2.62 (m, 2H), 1.99-1.91 (m, 1H), 1.89-1.77 (m, 1H), 1.18 (d, J= 6.8 Hz, 3H). Example 71 – Preparation of Compound 66 [0433] Compound 66 was prepared according to the following scheme: ) in
Figure imgf000131_0001
MeOH (10 mL) was added the Bestmann-Ohira reagent (1.0 g, 4.36 mmol) at RT. Then cooled the reaction mixture to 0-5°C and added K2CO3 (1.08 g, 7.84 mmol). Later, gradually warmed the reaction to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH4Cl solution and extracted with hexane. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under reduced pressure to get crude residue (0.92 gram, 93% crude yield), which was used as such for the next reaction. [0435] Preparation of Intermediate 3B: To a stirred solution of 3-bromo-5-fluoropyridine (350 mg, 1.98 mmol) in triethylamine (9.2 mL) was added Intermediate 2B (895 mg, 3.97 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (69 mg, 0.04 mmol), CuI (37 mg, 0.19 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 90-95 °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 (1.4 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 10-12% ethyl acetate in hexane giving Intermediate 3B (870 mg, 68% yield) as a brown semi-solid. [0436] Preparation of Intermediate 4B: To a stirred suspension of palladium on carbon (10% wet, 180 mg) in methanol (8.7 mL) was added Intermediate 3B (870 mg, 2.71 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 (10 mL) and filtrate was evaporated under reduced pressure to giving Intermediate 4B (860 mg, 99% crude yield) as a crude yellow semi-solid residue. [0437] Preparation of Intermediate 5B: To a stirred solution of Intermediate 4B (430 mg, 1.34 mmol) in ethanol (15 mL) was added 2N HCl (10 mL) and refluxed at 85-90°C for 2 h. After completion of reaction (monitored by TLC), cooled to RT and partitioned between ethyl acetate and water. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to give Intermediate 5B (101 mg, 40% yield) as a brown gummy liquid. [0438] Preparation of Compound 66: Compound 66 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 160 mg, 0.46 mmol), Intermediate 5B (101 mg, 0.55 mmol), HATU (211 mg, 0.55 mmol) and triethylamine (0.32 mL, 2.31 mmol) in DMF (2 mL) giving the target compound (63 mg, 26% yield) as a pale-blue solid. 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J= 2.0 Hz, 1H), 8.54 (s, 1H), 8.36 (d, J= 2.4 Hz, 1H), 8.32 (s, 1H), 8.20 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.62-7.59 (m, 1H), 7.14 (d, J= 8.8 Hz, 1H), 4.83 (t, J= 5.6 Hz, 1H), 3.99- 3.97 (m, 1H), 3.90 (s, 3H), 3.53-3.48 (m, 1H), 3.45-3.39 (m, 1H), 2.71-2.60 (m, 2H), 1.94-1.85 (m, 2H). Example 72 – Preparation of Compound 67 [0439] Compound 67 was prepared according to the following scheme:
Figure imgf000132_0001
mol) in MeOH (9 mL) was added the Bestmann-Ohira reagent (0.9 g, 4.71 mmol) at RT. Then cooled the reaction mixture to 0-5°C and added K2CO3 (0.97 g, 7.05 mmol). Later, gradually warmed the reaction to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH4Cl solution and extracted with hexane. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under reduced pressure to get crude residue (0.84 gram, 100% crude yield), which was used as such for the next reaction. [0441] Preparation of Intermediate 3A: To a stirred solution of 3-bromo-5-fluoropyridine (350 mg, 1.98 mmol) in triethylamine (9.2 mL) was added Intermediate 2A (824 mg, 3.66 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (86 mg, 0.12 mmol), CuI (46 mg, 0.24 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 90-95 °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 (1.1 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 10-12% ethyl acetate in hexane giving Intermediate 3A (610 mg, 52% yield) as a yellow liquid. [0442] Preparation of Intermediate 4A: To a stirred suspension of palladium on carbon (10% wet, 165 mg) in methanol (6.5 mL) was added Intermediate 3A (650 mg, 2.03 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 (10 mL) and filtrate was evaporated under reduced pressure to giving Intermediate 4A (600 mg, 100% crude yield) as a yellow semi-solid. [0443] Preparation of Intermediate 5A: To a stirred solution of Intermediate 4A (600 mg, 1.87 mmol) in ethanol (15 mL) was added 2N HCl (10 mL) and refluxed at 85-90°C for 2 h. After completion of reaction (monitored by TLC), cooled to RT and partitioned between ethyl acetate and water. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to give Intermediate 5A (170 mg, 50% yield) as a brown gummy liquid. [0444] Preparation of Compound 67: Compound 67 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 270 mg, 0.78 mmol), Intermediate 5A (170 mg, 0.94 mmol), HATU (357 mg, 0.94 mmol) and triethylamine (0.55 mL, 3.9 mmol) in DMF (2 mL) giving the target compound (51 mg, 13% yield) as a pale-blue solid. 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J= 2.0 Hz, 1H), 8.54 (s, 1H), 8.36 (d, J= 2.8 Hz, 1H), 8.32 (s, 1H), 8.20 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 8.02 (d, J= 8.8 Hz, 1H), 7.63-7.60 (m, 1H), 7.14 (d, J= 8.8 Hz, 1H), 4.88 (t, J= 5.6 Hz, 1H), 4.01- 3.95 (m, 1H), 3.90 (s, 3H), 3.55-3.49 (m, 2H), 2.75-2.66 (m, 2H), 1.94-1.85 (m, 2H). Example 73 – Preparation of Compound 68 [0445] Compound 68 was prepared according to the following scheme: [0 hod
Figure imgf000134_0001
described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 54 (98 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (138 mg, 48% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.75 (d, J= 2.4 Hz, 1H), 8.52 (s, 1H), 8.50 (t, J= 6.0 Hz, 1H), 8.40 (d, J= 2.8 Hz, 1H), 8.33 (s, 1H), 8.15 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.12 (d, J= 8.8 Hz, 1H), 3.89 (s, 3H), 3.56 (q, J= 6.8 Hz, 2H), 2.93 (t, J= 6.8 Hz, 2H). Example 74 – Preparation of Compound 69 [0447] Compound 68 was prepared according to the following scheme: [04
Figure imgf000134_0002
hod described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 55 (87 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (150 mg, 57% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.10 (t, J= 6.0 Hz, 1H), 8.76 (d, J= 2.0 Hz, 1H), 8.56 (s, 1H), 8.46 (d, J= 2.8 Hz, 1H), 8.44 (s, 1H), 8.19 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.13 (d, J= 8.8 Hz, 1H), 4.52 (d, J= 6.0 Hz, 1H), 3.89 (s, 3H). Example 75 – Preparation of Compound 70 [0449] Compound 70 was prepared according to the following scheme: hod
Figure imgf000135_0001
described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 56 (103 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (130 mg, 47% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J= 2.0 Hz, 1H), 8.53 (s, 1H), 8.42 (t, J= 6.4 Hz, 1H), 8.19 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 7.17-7.12 (m, 2H), 7.03-6.97 (m, 3H), 3.89 (s, 3H), 3.32-3.26 (m, 2H), 2.57 (t, J= 7.6 Hz, 1H), 2.27 (s, 3H), 1.85-1.77 (m, 2H). Example 76 – Preparation of Compound 71 [0451] Compound 71 was prepared according to the following scheme: [0452] Preparation of Intermediate 71: Compou
Figure imgf000135_0002
od described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 57 (114 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (130 mg, 45% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J= 2.0 Hz, 1H), 8.55 (s, 1H), 8.44 (t, J= 6.0 Hz, 1H), 8.21 (dd, J= 8.8, 2.0 Hz, 1H), 7.20 (t, J= 8.0 Hz, 1H), 7.15 (d, J= 8.8 Hz, 1H), 6.82-6.80 (m, 2H), 6.77-6.74 (m, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.34-3.28 (m, 2H), 2.61 (t, J= 7.6 Hz, 2H), 1.86-1.83 (m, 2H). Example 77 – Preparation of Compound 72 [0453] Compound 72 was prepared according to the following scheme: od
Figure imgf000136_0002
described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 200 mg, 0.58 mmol), Intermediate 58 (117 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (120 mg, 42% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.79 (d, J= 2.0 Hz, 1H), 8.53 (s, 1H), 8.44 (t, J= 6.0 Hz, 1H), 8.19 (dd, J= 8.8, 2.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.24-7.19 (m, 2H), 7.13 (d, J= 8.8 Hz, 1H), 3.89 (s, 3H), 3.31-3.26 (m, 2H), 2.63 (t, J= 8.0 Hz, 2H), 1.87-1.79 (m, 2H). Example 78 – Preparation of Compound 73 [0455] Compound 73 was prepared according to the following scheme:
Figure imgf000136_0001
ion in oil, 0.3 g, 13.79 mmol) in THF (50 mL) was added drop wise of diethyl (cyanomethyl)phosphonate (1.4 g, 12.07 mmol) at 0-5°C and stirred for 1 h, followed by the addition of Intermediate 59A (2.0 g, 11.43 mmol), portion-wise for 15-20 min at 0-5°C. Then, gradually warmed the resulting reaction mixture to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH4Cl solution and extracted with ethyl acetate. Separated the organic layer, dried over sodium sulphate and evaporated under reduced pressure to get crude residue (1.3 g), which was further purified by silica gel column chromatography (100-200 mesh) using 3-5% ethyl acetate in hexane as an eluent giving Intermediate 59B (1 gram, 44% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.87-7.81 (m, 2H), 7.77-7.75 (m, 1H), 7.46 (d, J= 8.0 Hz, 1H), 6.60 (br d, J= 16.4 Hz, 1H). [0457] Preparation of Intermediate 59: To a stirred solution of Intermediate 59B (0.6 g, 3.03 mmol) in methanol (12 mL) was added Raney Ni (120 mg, 20% w/w) 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 (10 mL) and filtrate was evaporated under reduced pressure to get crude residue (630 mg). The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) eluting with 5-7% methanol in DCM giving Intermediate 59 (220 mg, 35% yield) as a yellow oil. [0458] Preparation of Compound 73: Compound 73 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (from Example 1, 310 mg, 0.89 mmol), Intermediate 59 (219 mg, 1.08 mmol), HATU (410 mg, 1.08 mmol) and triethylamine (0.4 mL, 4.49 mmol) in DMF (5 mL) giving the target compound (120 mg, 25% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.79 (d, J= 2.0 Hz, 1H), 8.53 (s, 1H), 8.48 (t, J= 6.0 Hz, 1H), 8.19 (dd, J= 8.8, 2.0 Hz, 1H), 7.48 (dd, J= 8.0, 2.4 Hz, 1H), 7.38 (dd, J= 8.0, 1.6 Hz, 1H), 7.29 (t, J= 8.0 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 3.89 (s, 3H), 3.35-3.30 (m, 2H), 2.79 (t, J= 8.0 Hz, 2H), 1.87-1.80 (m, 2H). Example 79 – Preparation of Compound 76 [0459] Compound 76 was prepared according to the following scheme:
Figure imgf000137_0001
, e 1, 600 mg, 1.45 mmol) in methanol (9 mL) was added Et3N (0.89 mL, 7.26 mmol) in a sealed tube and degassed with nitrogen for 10-15 min. PdCl2(dppf) (92 mg, 0.14 mmol) and X-Phos (119 mg, 0.29 mmol) were added and degassed again for 10-15. The resulting reaction mixture was heated to 65-70°C and stirred for 6 h under carbon monoxide (CO) pressure (50 psi). After completion of reaction (monitored by TLC), the reaction mixture was cooled to RT and filtered through a celite pad. The filter cake was thoroughly washed with methanol, the filtrate was evaporated under reduced pressure to get crude residue (670 mg). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 20-25% ethyl acetate in hexane giving Intermediate 75A (450 mg, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.54-8.49 (m, 2H), 8.47-8.43 (m, 2H), 8.38 (d, J=2.8 Hz, 1H), 8.35 (s, 1H), 7.67-7.63 (m, 1H), 7.30 (d, J=9.2 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.30-3.27 (m, 2H), 2.70-2.66 (m, 2H), 1.91-1.83 (m, 2H). [0461] Preparation of Compound 76: To a stirred solution of Intermediate 75A (450 mg, 1.09 mmol) in THF (6 mL) was added 1N NaOH solution (1.6 mL, 1.6 mmol)) at RT and stirred for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was partitioned between ethyl acetate and water. Separated the aq layer, adjusted the pH of aq layer to ^2, using 1N HCl and extracted with ethyl acetate. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under reduced pressure giving Compound 80 (300 mg, 69% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 8.55-8.54 (m, 2H), 8.46 (t, J=6.0 Hz, 1H), 8.41-8.35 (m, 3H), 7.66-7.63 (m, 1H), 7.26 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.33-3.27 (m, 2H), 2.68 (t, J=7.6 Hz, 1H), 1.90-1.83 (m, 2H). Example 80 – Preparation of Compound 74 [0462] Compound 74 was prepared according to the following scheme: 50
Figure imgf000138_0001
mmol) in toluene (10 mL) was added DIPEA (0.8 mL, 4.51 mmol), followed by dropwise addition of diphenyl phosphoryl azide (0.4 mL, 1.80 mmol) at 0°C. The resulting reaction mixture was warmed to RT and stirred for 30 min. Then, t-BuOH (3 mL) was added and heated the resulting reaction mass at 75-80°C for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to 45-50°C and evaporated under reduced pressure to get crude residue (1.2 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 5-8% ethyl acetate in hexane giving Intermediate 63A (155 mg, 22% yield). [0464] Preparation of Compound 74: To a solution of Intermediate 63A (150 mg, 0.32 mmol) in 1,4- dioxane (2 mL) was added 4M HCl in dioxane (1 mL) at 0°C. Then, warmed the resulting reaction mixture to RT and stirred for 4 h. After completion of reaction, by TLC, evaporated the reaction mixture under vacuum to afford compound-78 as its HCl salt. Partitioned the residue between DCM and water. Added sat NaHCO3 solution, until aq layer showed pH^8. After stirring for 30 min, separated the organic layer, dried over sodium sulphate and evaporated under vacuum to afford crude compound-78 (130 mg), which was further purified by silica-gel (100-200 mesh) column chromatography eluting with 4-5% MeOH in DCM to afford Compound 74 (30 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.41 (t, J=2.8 Hz, 1H), 8.71-8.35 (m, 2H), 7.68-7.65 (m, 1H), 7.58 (dd, J=8.4, 2.4 Hz, 1H), 7.46 (d, J= 2.0 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 4.90 (s, 2H), 3.84 (s, 3H), 3.34-3.27 (m, 2H), 2.72-2.68 (m, 2H), 1.92-1.84 (m, 2H). Example 81 – General Synthetic Route for Preparation of Intermediates 5 of Compounds 78-81 ted,
Figure imgf000139_0001
substituted benzoic acids 1 were converted to acid chlorides 2 on reaction with oxalyl chloride and DMF. Subsequent conversion to oxazoles 4 occurred on reaction of acid chlorides 2 with isocyanate 3. Ester hydrolysis of intermediates 4 on reaction with sodium hydroxide gave carboxylic acids 5. Final compounds were prepared on coupling of carboxylic acids 5 with intermediate 6 (Example 50) using HBTU. General procedures are in the following paragraphs. [0466] Benzoyl Chloride Intermediates 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. [0467] Substituted Ethyl-Phenyloxazole-4-Carboxylate Intermediates 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. [0468] Substituted Phenyloxazole-4-Carboxylic Acid Intermediates 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), 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. Example 82 – Preparation of Compound 78 [0469] Compound 78 was prepared according to the Scheme in Example 80. [0470] Preparation of Intermediate 2: Intermediate 2 was synthesized according to the general procedure described in Example 81, using 4-acetamido-3-bromobenzoic acid (2.0 g, 7.75 mmol) and oxalyl chloride (0.99 mL, 11.62 mmol) in DCM (20 mL) giving the target compound (2.3 grams, 100% crude yield). [0471] Preparation of Intermediate 4: Intermediate 4 was synthesized according to the general procedure described in Example 81, using Intermediate 3 (0.94 g, 8.31 mmol), potassium tert-butoxide (2.8 g, 24.95 mmol) and Intermediate 2 (2.3 g, 8.31 mmol) in dry THF (12 mL) giving the target compound (0.69 g, 76% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.58 (s, 1H), 8.35 (d, J= 1.6 Hz, 1H), 7.90-7.85 (m, 2H), 4.30 (q, J= 7.2 Hz, 2H), 2.13 (s, 3H), 1.29 (t, J= 7.2 Hz, 3H). [0472] Preparation of Intermediate 5: Intermediate 5 was synthesized according to the general procedure described in Example 81, using Intermediate 4 (1.0 g, 2.83 mmol) and LiOH•H2O (0.24 g, 5.66 mmol) in THF (20 mL) and water (5 mL) giving the target compound (1.0 gram, 34% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.26 (s, 1H), 9.58 (s, 1H), 8.54 (s, 1H), 8.36 (d, J= 1.6 Hz, 1H), 7.94 (dd, J= 8.4, 2.0 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 2.13 (s, 3H). [0473] Preparation of Compound 78: Compound 78 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (250 mg, 0.77 mmol), Intermediate 6 (Example 50, 141 mg, 0.92 mmol), HATU (351 mg, 0.92 mmol) and triethylamine (0.54 mL, 3.84 mmol) in DMF (2.5 mL) giving the target compound (84 mg, 24% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.73 (d, J= 2.0 Hz, 1H), 8.60 (s, 1H), 8.54 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.08 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 7.83-7.81 (m, 1H), 7.67-7.63 (m, 1H), 3.32-3.28 (m, 2H), 2.69 (t, J= 7.6 Hz, 2H), 1.89-1.85 (m, 2H). Example 83 – Preparation of Compound 79 [0474] Compound 79 was prepared according to the Scheme in Example 81 with the added step of converting a nitrile into an amide as illustrated in the Scheme below. [0475] the general
Figure imgf000141_0001
procedure described in Example 81, using 3-bromo-4-cyanobenzoic acid (2 g, 8.47 mmol) and oxalyl chloride (1.1 mL, 12.71 mmol) in DCM (20 mL)giving the target compound (2.4 grams, 100% crude yield). [0476] Preparation of Intermediate 4: Intermediate 4 was synthesized according to the general procedure described in Example 81, using Intermediate 3 (1.1 g, 9.73 mmol), potassium tert-butoxide (3.3 g, 29.20 mmol) and Intermediate 2 (2.4 g, 5.85 mmol) in dry THF (25 mL) giving the target compound (1.4 g, 41% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.52 (t, J= 0.8 Hz, 1H), 8.12 (d, J= 0.8 Hz, 2H), 4.31 (q, J= 7.2 Hz, 2H), 1.29 (t, J= 7.2 Hz, 3H). [0477] Preparation of Intermediate 5: Intermediate 5 was synthesized according to the general procedure described in Example 81, using Intermediate 4 (3.0 g, 9.34 mmol) and LiOH•H2O (0.46 g, 18.69 mmol) in THF (20 mL) and water (5 mL) giving the target compound (2.2 grams, 81% yield) as an off-white solid. [0478] Preparation of Intermediate 5A: Intermediate 5A was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (1.0 g, 3.41 mmol), Intermediate 6 (Example 50, 0.63 g, 4.09 mmol), HATU (1.56 g, 4.09 mmol) and triethylamine (2.4 mL, 17.06 mmol) in DMF (10 mL) giving the target compound (0.95 g, 67% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.73 (d, J= 2.0 Hz, 1H), 8.60 (s, 1H), 8.54 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.08 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 7.83-7.81 (m, 1H), 7.67-7.63 (m, 1H), 3.32-3.28 (m, 2H), 2.69 (t, J= 7.6 Hz, 2H), 1.89-1.85 (m, 2H). [0479] Preparation of Compound 79: To a stirred solution of Intermediate 5A (200 mg, 0.46 mmol) in DMSO (2 mL) was added potassium carbonate (167 mg, 1.21 mmol), followed by 30% hydrogen peroxide (0.07 mL, 3.03 mmol) and stirred for 2 h at RT. 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 2-4% MeOH in DCM. Evaporated the pure fractions under vacuum to afford final Compound 79 (110 mg, 52% yield) as an off-white solid. 1H NMR (400 MHz, DMSO- d6): δ 8.65 (d, J= 2.0 Hz, 2H), 8.59 (t, J= 6.0 Hz, 1H), 8.39-8.35 (m, 2H), 8.16 (dd, J= 8.0, 1.6 Hz, 1H), 7.96 (s, 1H), 7.67-7.64 (m, 2H), 7.52 (d, J= 8.0 Hz, 1H), 3.32-3.28 (m, 2H), 2.69 (t, J= 7.6 Hz, 2H), 1.91-1.84 (m, 2H). Example 84 – Preparation of Compound 80 [0480] Compound 80 was prepared from Compound 79 according to the following Scheme: ) in
Figure imgf000142_0001
AcOH (4.5 mL) was added tert-butyl nitrite (0.36 mL, 3.21 mmol). The resulting reaction contents were heated to 75-80°C and maintained for 16 h. After completion of the reaction (monitored by TLC), cooled to 50-55°C and evaporated the solvent under vacuum to afford crude compound (550 mg). The obtained crude residue was purified by prep-HPLC. Evaporated the pure fractions under vacuum to afford final Compound 80 (42 mg, 9.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.56 (s, 1H), 8.76 (d, J= 1.6 Hz, 1H), 8.68 (s, 1H), 8.63 (t, J= 6.0 Hz, 1H), 8.39 (d, J= 2.8 Hz, 1H), 8.35 (s, 1H), 8.21 (dd, J= 8.0, 1.6 Hz, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.67-7.64 (m, 1H), 3.33-3.28 (m, 2H), 2.69 (t, J= 8.0 Hz, 2H), 1.89- 1.85 (m, 2H). Example 85 – Preparation of Compound 81 [0482] Compound 81 was prepared according to the Scheme in Example 81. [0483] Preparation of Intermediate 2: Intermediate 2 was synthesized according to the general procedure described in Example 81, using 3-bromo-4-(methylsulfonyl)benzoic acid (2 g, 11.17 mmol) and oxalyl chloride (0.93 mL, 16.75 mmol) in DCM (20 mL) giving the target compound (1.2 grams, 100% crude yield). [0484] Preparation of Intermediate 4: Intermediate 4 was synthesized according to the general procedure described in Example 81, using Intermediate 3 (0.92 g, 8.14 mmol), potassium tert-butoxide (2.73 g, 24.42 mmol) and Intermediate 2 (2.4 g, 8.14 mmol) in dry THF (25 mL) giving the target compound (0.8 g, 27% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.56 (t, J= 1.6 Hz, 1H), 8.22-8.16 (m, 2H), 4.33 (q, J= 7.2 Hz, 2H), 1.30 (t, J= 7.2 Hz, 3H). [0485] Preparation of Intermediate 5: Intermediate 5 was synthesized according to the general procedure described in Example 81, using Intermediate 4 (0.8 g, 2.14 mmol) and LiOH•H2O (0.27 g, 6.41 mmol) in THF (4 mL) and water (1.6 mL) giving the target compound (0.5 gram, 68% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J= 1.2 Hz, 1H), 8.64 (s, 1H), 8.23-8.17 (m, 2H), 3.43 (s, 3H). [0486] Preparation of Compound 81: Compound 81 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 5 (200 mg, 0.58 mmol), Intermediate 6 (Example 50, 106 mg, 0.69 mmol), HATU (263 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) giving the target compound (130 mg, 46% yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (d, J= 1.6 Hz, 1H), 8.74 (s, 1H), 8.69 (t, J= 5.6 Hz, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.36-8.33 (m, 2H), 8.17 (d, J= 8.4 Hz, 1H), 7.66-7.63 (, 1H), 3.42 (s, 3H), 3.31-3.29 (m, 2H), 2.69 (t, J= 8.0 Hz, 2H), 2.61 (s, 3H), 1.89-1.86 (m, 2H). Example 86 – Preparation of Compound 82 [0487] Compound 82 was prepared according to the following Scheme:
Figure imgf000143_0001
0 g, 11.36 mmol) in triethylamine (20 mL) was added (R)-But-3-yn-2-ol (1.59 g, 22.72 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (0.4 g, 0.57 mmol), CuI (0.21 g, 1.13 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 (2.3 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 Compound-26 (1.8 grams, 93% yield) as a pale-yellow liquid. [0489] Preparation of Intermediate 27: To a stirred suspension of palladium on carbon (10% wet) (360 mg) in methanol (30 mL) was Intermediate 26 (1.8 g, 10.90 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 (1.9 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 27 (1.6 grams, 88% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J= 2.8 Hz, 1H), 8.32 (s, 1H), 7.60-7.57 (m, 1H), 4.53 (d, J= 4.8 Hz, 1H), 3.62-3.54 (m, 1H), 2.77-2.62 (m, 2H), 1.65-1.59 (m, 2H), 1.08 (d, J= 6.0 Hz, 3H). [0490] Preparation of Intermediate 28: To a stirred solution of Intermediate 27 (1.5 g, 8.87 mmol) in THF (15 mL) was added PPh3 (4.68 g, 17.75 mmol) and phthalimide (1.3 g, 8.87 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (3.49 mL, 17.75 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 (7.9 g). 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 28 (2.3 grams, 100% yield) as a pale- yellow solid. [0491] Preparation of Intermediate 29: To a stirred solution of Compound-28 (2.0 g, 6.71 mmol) and in MeOH (20 mL) was added N2H4•H2O (0.86 mL, 17.44 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 (1.54 g). 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 29 (0.55gram, 65% crude yield) as a colorless liquid. [0492] Preparation of Compound 82: Compound 82 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 200 mg, 0.67 mmol), Intermediate 29 (135 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) giving the target compound (112 mg, 37% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 8.55 (s, 1H), 8.36 (d, J= 2.0 Hz, 1H), 8.31 (s, 1H), 8.20-8.14 (m, 2H), 7.61 (d, J= 9.6 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 4.05-4.02 (m, 1H), 3.92 (s, 3H), 2.67-2.62 (m, 2H), 1.97-1.92 (m, 1H), 1.82-1.78 (m, 1H), 1.18 (d, J= 2.4 Hz, 3H). Example 87 – Preparation of Compounds 83 and 84 [0493] Compounds 83 and 84 were prepared according to the following Scheme:
Figure imgf000145_0001
ne (120 mL) was added ethyl 2-(diethoxy phosphoryl) propanoate (17.1 g, 72.0 mmol) dropwise at 0-5°C. After stirring for 30-40 min, Intermediate 38B (6.0 g, 48.0 mmol) in toluene (60 mL) was added dropwise into the reaction for 20-30 min. The resulting reaction contents were heated to 110°C and stirred for 2 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to RT, quenched with 1N HCl and extracted with ethyl acetate. Separated the organic layer, dried over sodium sulphate and evaporated under reduced pressure to get crude residue (7.1 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 10-15% ethyl acetate in hexane to afford Intermediate 39B (5.0 grams, 60%yield) as an off-white solid. [0494] Preparation of Intermediate 40B: Intermediate 40B was synthesized according to the general procedure for the preparation of Intermediates 5 described in Example 81, using Intermediate 39B (5.0 g, 23.90 mmol) and LiOH•H2O (1.94 g, 47.8 mmol) in THF (50 mL) and water (12 mL) giving the target compound (2.8 grams, 65% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 8.56 (d, J= 2.8 Hz, 2H), 7.86 (d, J= 10.0 Hz, 1H), 7.58 (s, 1H), 2.04 (s, 3H). [0495] Preparation of Intermediate 41C: A suspension of Intermediate 40B (2.5 g, 13.8 mmol) in SOCl2 (8.0 mL, 110.5 mmol) was stirred at 80°C for 2 h. After the reaction became clear, cooled to 50-55°C and evaporated the solvent under vacuum. Then, dissolved the obtained residue in DCM (40 mL) and triethyl amine (8.75 mL, 69.0 mmol) was added, followed by the addition of (S)-4-benzyloxazolidin-2-one (2.21 g, 13.8 mmol) and LiCl (2.64 g, 69.0 mmol). The resulting reaction mixture was stirred for another 2 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to RT, quenched with 1N HCl and extracted with DCM. Separated the organic layer and washed with water. Separated and the organic layer over sodium sulphate and evaporated under reduced pressure to get crude residue (3.9 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 15-18% ethyl acetate in hexane to afford Intermediate 41C (2.8 grams, 60% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.46-8.42 (m, 2H), 7.48-7.45 (m, 1H), 7.38-7.30 (m, 3H), 7.26-7.23 (m, 2H), 6.77 (s, 1H), 4.80-4.75 (m, 1H), 4.36-4.31 (m, 1H), 4.26-4.23 (m, 1H), 3.40 (dd, J= 13.6, 3.2 Hz, 1H), 2.91 (dd, J= 13.6, 2.8 Hz, 1H), 2.18 (d, J= 1.6 Hz, 3H). [0496] Preparation of Intermediates 42C and 42D: To a stirred suspension of palladium hydroxide on carbon (20%) (0.2 g) in IPA (5 mL) and toluene (5 mL), was added Intermediate 41C (1.0 g, 2.94 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 reaction 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 (970 mg). The obtained crude residue was purified by prep-HPLC to afford 360 mg of Major product (Intermediate 42C) and 290 mg of Minor product (Intermediate 42D) as off- white solids. [0497] Preparation of Intermediate 43C: To a stirred solution of Intermediate 42C (350 mg, 1.02 mmol), in dry THF (20 mL) was added LAH (2 M in THF) (1.52 mL, 3.04 mmol) at 0°C, the resulting solution was stirred at same temperature for 1.5 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl (30 mL) and aqueous layer was extracted with EtOAc (3 x 30 mL). Combined the organic layers, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude compound (200 mg) which was purified by column chromatography using silica gel (100-200 mesh) as the stationary phase, eluting with 3% MeOH in DCM. Collected the pure fractions and evaporated under vacuum to afford desired Intermediate 43C (190 mg) as a pale-yellow gummy liquid. [0498] Preparation of Intermediate 43D: To a stirred solution of Intermediate 42D (290 mg, 0.85 mmol), in dry THF (15 mL) was added LAH (2 M in THF) (1.26 mL, 2.52 mmol) at 0°C, the resulting solution was stirred at same temperature for 1.5 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl (20 mL) and aqueous layer was extracted with EtOAc (3 x 20 mL). Combined the organic layers, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude compound (200 mg) which was purified by column chromatography using silica gel (100-200 mesh) as the stationary phase, eluting with 3% MeOH in DCM and collected the pure fractions, evaporated under vacuum to afford desired Intermediate 43D (160 mg) as a pale-yellow gummy liquid. [0499] Preparation of Intermediate 44C: To a stirred solution of Intermediate 43C (190 mg, 1.12 mmol) in THF (1.9 mL) was added PPh3 (578 mg, 2.25 mmol) and phthalimide (161 mg, 1.12 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (0.42 mL, 2.25 mmol) was added dropwise, 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 2.8 g. The obtained crude residue was purified by silica gel column chromatography (100- 200 mesh) using 15-20% ethyl acetate in hexane as eluent to obtain Intermediate 44C (510 mg) as a gummy liquid. [0500] Preparation of Intermediate 44D: To a stirred solution of Intermediate 43D (160 mg, 0.95 mmol) in THF (1.6 mL) was added PPh3 (494 mg, 1.89 mmol) and phthalimide (138 mg, 0.95 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (0.36 mL, 1.89 mmol) was added dropwise, 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 2.8 g. The obtained crude residue was purified by silica gel column chromatography (100- 200 mesh) using 15-20% ethyl acetate in hexane as eluent to afford Intermediate 44D (400 mg) as a gummy liquid. [0501] Preparation of Intermediate 45C: To a stirred solution of Intermediate 44C (510 mg, 1.71 mmol) in MeOH (5.1 mL) was added N2H4.H2O (0.20 mL, 4.45 mmol) at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to get crude residue. The obtained crude residue was suspended in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to get crude residue (190 mg) 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 obtain Intermediate 45C (94 mg) as a yellow gummy liquid. [0502] Preparation of Intermediate 45D: To a stirred solution of Intermediate 44D (400 mg, 1.34 mmol) in MeOH (4 mL) was added N2H4•H2O (0.17 mL, 3.48 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 suspended in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to get crude residue (210 mg) 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 obtain Intermediate 45D (107 mg) as a yellow gummy liquid. [0503] Preparation of Compound 83: Compound 83 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 150 mg, 0.50 mmol), Intermediate 45D (101 mg, 0.60 mmol), HATU (230 mg, 0.60 mmol) and triethylamine (0.35 mL, 2.51 mmol) in DMF (1.5 mL) giving the target compound (28 mg, 12% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.46-8.43 (m, 2H), 8.33-8.29 (m, 2H), 7.81 (s, 1H), 7.41-7.35 (m, 1H), 7.29 (s, 1H), 6.98 (d, J= 8.4 Hz, 1H), 3.95 (s, 3H), 3.49-3.42 (m, 1H), 3.38-3.31 (m, 1H), 2.86-2.82 (m, 1H), 2.50- 2.44 (m, 1H), 2.15-2.09 (m, 1H), 0.96 (d, J= 6.4 Hz, 3H). [0504] Preparation of Compound 84: Compound 84 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 140 mg, 0.47 mmol), Intermediate 45C (94 mg, 0.56 mmol), HATU (214 mg, 0.56 mmol) and triethylamine (0.32 mL, 2.35 mmol) in DMF (1.5 mL) giving the target compound (32 mg, 15% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.46-8.43 (m, 2H), 8.32 (s, 1H), 8.28 (s, 1H), 7.81 (s, 1H), 7.39-7.37 (m, 1H), 7.28 (s, 1H), 6.98 (d, J= 8.4 Hz, 1H), 3.95 (s, 3H), 3.49-3.42 (m, 1H), 3.38-3.31 (m, 1H), 2.86-2.81 (m, 1H), 2.50-2.44 (m, 1H), 2.15-2.09 (m, 1H), 0.96 (d, J= 6.8 Hz, 3H). Example 88 – Preparation of Compound 85 [0505] Compound 85 was prepared according to the following Scheme:
Figure imgf000148_0001
l) in dry THF (300 mL), was added triethylamine (20.6 mL, 146.38 mmol) at -20°C and stirred for 15 min, thereafter was added acryloyl chloride (6.1 mL, 73.19 mmol) at same temperature and stirred for 40 min. After that LiCl (3.3 g, 78.82 mmol) and Intermediate 38 (10 g, 56.3 mmol) were added, and the resulting white suspension was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), partitioned between ethyl acetate (750 mL) and chilled water (300 mL). Separated the org layer and extracted the aq. layer with ethyl acetate (500 mL). Separated and combined the organic layers, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude compound (10.72 g) which was further purified by silica-gel (100-200 mesh) column chromatography eluting with 15-20% ethyl acetate in hexane to afford Intermediate 39 (6.5 g, 50% yield) as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.32 (m, 3H), 7.31-7.19 (m, 3H), 6.45 (dd, J = 16.8, 1.6 Hz, 1H), 5.98 (dd, J = 10.4, 1.6 Hz, 1H), 4.73-4.70 (m, 1H), 4.36 (t, J = 8.8 Hz, 1H), 4.23-4.20 (m, 1H), 3.07-2.94 (m, 1H), 2.52-2.49 (m, 1H). [0507] Preparation of Intermediate 40: A stirred solution of Intermediate 39 (3.0 g, 12.97 mmol), 3- bromo-5-fluoropyridine (2.2 g, 12.97 mmol) in Et3N (30 mL) in sealed tube was degassed with nitrogen for 20 min. Thereafter palladium acetate (145 mg, 0.64 mmol) and o-tolyl phosphine (789 mg, 2.59 mmol) were added. The resulting reaction mixture was heated to 90°C and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, quenched with saturated NH4Cl (30 mL) and aqueous layer was extracted with EtOAc (2 x 50 mL). Combined the organic layers, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Intermediate 40 (3.5 g), which was purified by column chromatography using silica gel (100-200 mesh) as the stationary phase, eluting with 15% ethyl acetate in hexane and collected the pure fractions and evaporated under vacuum to afford desired Intermediate 40 (3.1 grams, 70% yield) as a pale-yellow solid. [0508] Preparation of Intermediate 49A: To a stirred suspension of copper(I) bromide dimethyl sulfide complex (1.5 g, 7.36 mmol), in dry THF was added methyl magnesium bromide (1 M in THF, 14.7 mL, 14.7 mmol) at -40°C. The resulting yellow colored solution was stirred at same temperature for 1h. Thereafter BF3•EtO complex (1g, 1.5 eq) was added at same temperature and stirred for 30 min, after that Compound-40 (1.6 g, 4.90 mmol) dissolved in dry THF (25 mL) was added at same temperature, the resulting orange colored solution was warmed to -20°C and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was warmed to 0°C, quenched with saturated NH4Cl solution and aqueous layer was extracted with EtOAc (2 x 50 mL). Combined the organic layers, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude Int-49A (3.0 g), which was purified by reverse phase column chromatography (Biotage instrument, C-18 (60 g column) using CH3CN/H2O, eluting with 50 % CH3CN in H2O, Collected the pure fractions and evaporated under vacuum to afford desired Intermediate 49A (750 mg, 34% yield) as a pale-yellow solid. [0509] Preparation of Intermediate 41: To a stirred solution of Intermediate 49A (2.5 g, 7.30 mmol), in dry THF (100 mL) was added LAH (2 M in THF) (11.5 mL, 21.9 mmol) at 0°C, the resulting pale-yellow colored solution was stirred at same temperature for 1.5 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl (30 mL) and aqueous layer was extracted with EtOAc (3 x 50 mL). Combined the organic layers, dried over sodium sulphate, filtered and evaporated under vacuum to afford crude compound (3.3 g) which was purified by column chromatography using silica gel (100-200 mesh) as the stationary phase, eluting with 3% MeOH in DCM and collected the pure fractions and evaporated under vacuum to afford desired Intermediate 41 (920 mg) as a pale-yellow gummy liquid. [0510] Preparation of Intermediate 42: To a stirred solution of Intermediate 41 (920 mg, 5.44 mmol) in THF (20 mL) was added PPh3 (2.8 g, 10.88 mmol) and phthalimide (800 mg, 5.44 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (2.1 mL, 10.88 mmol) was added dropwise, 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 2.8 g. 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 42 (1.1gram) as a yellow solid. [0511] Preparation of Intermediate 43: To a stirred solution of Intermediate 42 (1.0 g, 3.34 mmol) in MeOH (10 mL) was added N2H4•H2O (0.4 mL, 8.69 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 the residue. The obtained crude residue was suspended in DCM and filtered. The filtrate was evaporated under reduced pressure to get the crude and the obtained crude product was purified by silica gel column chromatography (100-200 mesh) using (5:10:85) (Aq. NH3: MeOH: DCM) as an eluent to afford Intermediate 43 (450 mg, 80% yield) as a brown liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J= 2.8 Hz, 1H), 8.36 (t, J= 1.6 Hz, 1H), 7.66-7.63 (m, 1H), 2.99-2.94 (m, 1H), 2.49-2.43 (m, 2H), 1.65 (q, J= 7.2 Hz, 2H), 1.22 (d, J= 7.2 Hz, 3H). [0512] Preparation of Compound 85: Compound 85 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 350 mg, 1.20 mmol), Compound 43 (250 mg, 1.44 mmol), HATU (550 mg, 1.44 mmol) and triethylamine (0.8 mL, 6.04 mmol) in DMF (10 mL) followed by purification using Normal phase Prep conditions, afforded Compound 85 (130 mg, 24% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J= 2.0 Hz, 1H), 8.54 (s, 1H), 8.43-8.36 (m, 3H), 8.15 (dd, J= 8.8, 2.0 Hz, 1H), 7.69-7.65 (m, 1H), 7.24 (d, J= 9.2 Hz, 1H), 3.92 (s, 3H), 3.29-3.09 (m, 2H), 2.91-2.86 (m, 1H), 1.92-1.81 (m, 2H), 1.25 (d, J= 7.2 Hz, 3H).
Example 89 – Preparation of Compound 86 [0513] Compound 86 was prepared according to the following Scheme: hod
Figure imgf000151_0001
described for preparation of Intermediate 39 (Example 88) using acrylic acid (5.5 mL, 78.82 mmol), triethyl amine (20.6 mL, 146.38 mmol), acryloyl chloride (6.1 mL, 73.19 mmol), LiCl (3.3 g, 78.82 mmol) and Intermediate 30 (10 g, 56.3 mmol) in dry THF (300 mL) to afford Intermediate 44 (7.0 grams, 53% yield) as a pale-yellow solid. [0515] Preparation of Intermediate 45: Intermediate 45 was prepared according to the method described for preparation of Intermediate 40 (Example 88) using Intermediate 44 (3.0 g, 12.97 mmol), 3- bromo-5-fluoropyridine (2.2 g, 12.97 mmol), palladium acetate (145 mg, 0.64 mmol) and o-tolyl phosphine (789 mg, 2.59 mmol) in Et3N (30 mL) to afford Intermediate 45 (2.4 grams, 55% yield) as a pale- yellow solid. [0516] Preparation of Intermediate 49B: Intermediate 49B was prepared according to the method described for preparation of Intermediate 49A (Example 88) using Intermediate 45 (2.0 g, 6.13 mmol), copper(I) bromide dimethyl sulfide complex (1.8 g, 9.20 mmol), methyl magnesium bromide (1M in THF, 18.4 mL, 18.4 mmol), BF3•EtO (1.14 g, 9.20 mmol) in THF (30 mL) to afford Intermediate 49B (800 mg, 38% yield) as a pale-yellow solid. [0517] Preparation of Intermediate 46: Intermediate 46 was prepared according to the method described for preparation of Intermediate 41 (Example 88) using Intermediate 49B (400 mg, 2.5 mmol), LAH (2 M in THF) (1.75 mL, 3.50 mmol) in dry THF (20 mL) to afford Intermediate 46 (135 mg, 45% yield) as a pale-yellow gummy liquid. [0518] Preparation of Intermediate 47: Intermediate 47 was prepared according to the method described for preparation of Intermediate 42 (Example 88) using Intermediate 46 (135 mg, 0.79 mmol), phthalimide (118 mg, 0.79 mmol), DIAD (322 mg, 1.59 mmol), PPh3 (490 mg, 1.59 mmol in dry THF (5 mL) to afford Intermediate 47 (230 mg, 99% yield) as a green solid. [0519] Preparation of Intermediate 48: Intermediate 48 was prepared according to the method described for preparation of Intermediate 43 (Example 88) using Intermediate 47 (230 mg, 0.77 mmol), N2H4.H2O (0.1 mL, 2.00 mmol) in MeOH (2 mL) to afford Intermediate 48 (70 mg, 54% yield) as a brown liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J= 2.8 Hz, 1H), 8.34 (s, 1H), 7.65-7.60 (m, 1H), 2.99-2.93 (m, 1H), 2.39 (t, J= 7.2 Hz, 2H), 1.66-1.60 (m, 2H), 1.20 (d, J= 7.2 Hz, 3H). [0520] Preparation of Compound 86: Compound 86 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 115 mg, 0.38 mmol), Intermediate 48 (70 mg, 0.46 mmol), HATU (176 mg, 0.46 mmol) and triethylamine (0.26 mL, 1.93 mmol) in DMF (3 mL), followed by purification using Normal phase Prep conditions (Same as Compound 85), to afford Compound 86 (47 mg, 27% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J= 2.0 Hz, 1H), 8.54 (s, 1H), 8.42-8.37 (m, 3H), 8.15 (dd, J= 8.8, 2.0 Hz, 1H), 7.68-7.66 (m, 1H), 7.24 (d, J= 8.8 Hz, 1H), 3.92 (s, 3H), 3.26-3.11 (m, 2H), 2.91-2.86 (m, 1H), 1.87-1.85 (m, 2H), 1.25 (d, J= 6.8 Hz, 3H). Example 90 – Preparation of Compound 87 [0521] Compound 87 was prepared according to the following Scheme:
Figure imgf000152_0001
ribed for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 200 mg, 0.67 mmol), Intermediate 5A (110 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) to afford Compound 87 (110 mg, 39% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J= 2.4 Hz, 1H), 8.54 (s, 1H), 8.52-8.46 (m, 1H), 8.44 (dd, J= 4.8, 1.6 Hz, 2H), 8.15 (dd, J= 4.8, 2.0 Hz, 1H), 7.26-7.24 (m, 3H), 3.92 (s, 3H), 2.32-3.37 (m, 2H), 2.63 (t, J= 8.0 Hz, 2H), 1.87-1.83 (m, 2H). Example 91 – Preparation of Compound 101 [0523] Compound 101 was prepared according to the following Scheme: .03
Figure imgf000153_0001
mmol) in toluene (30 mL) was added trimethylphosphono acetate (3.3 mL, 21.02 mmol) dropwise for 15- 20 min at 0°C, then. warmed the reaction to RT and stirred for 1 h. Intermediate 114 (3.0 g, 14.01 mmol) in toluene (30 mL) was added dropwise into the reaction mixture for 20-30 min. The resulting reaction contents were heated to 110°C and stirred for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to RT, quenched with 1N HCl and extracted with ethyl acetate. Separated the organic layer, dried over sodium sulphate and evaporated under reduced pressure to get crude residue (5.5 g). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 5-10% ethyl acetate in hexane to afford Intermediate 115 (4.2 grams, 60% yield) as an off- white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J= 2.0 Hz, 1H), 7.58 (d, J= 16.0 Hz, 1H), 7.45-7.41 (m, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.31 (d, J= 16.0 Hz, 1H), 3.93 (s, 3H), 3.79 (s, 3H). [0525] Preparation of Intermediate 116: To a stirred solution of NOBF4 (8.6 g, 73.80 mmol) in DCM (10 mL), pyridine (6.0 mL, 73.80 mmol) was added at -35°C to -40°C. After stirring for 20-30 min, Intermediate 115 (2.0 g, 7.38 mmol) in DCM (10 mL) was added dropwise and maintained at -35°C to - 40°C for 4 days. After completion of reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with DCM. Separated the organic layer, dried over sodium sulphate and evaporated under reduced pressure to get crude residue (1.8 g). The obtained residue was further purified by silica- gel (100-200 mesh) column chromatography eluting with 5-10% ethyl acetate in hexane to afford Intermediate 116 (0.6 gram, 24% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J= 2.0 Hz, 1H), 7.55 (dd, J= 8.8, 2.4 Hz, 1H), 7.28 (d, J= 8.8 Hz, 1H), 3.94 (s, 3H), 3.80 (s, 3H). [0526] Preparation of Intermediate 117: A solution of Intermediate 116 (0.6 g, 1.82 mmol) in trimethyl phosphite (6.0 mL) was stirred at 100°C for 16 h. After completion of reaction (monitored by TLC), cooled to RT, quenched with 1N HCl and extracted with ethyl acetate. Separated the organic layer, dried over sodium sulphate and evaporated under reduced pressure to get crude residue (510 mg). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 5-10% ethyl acetate in hexane to afford Intermediate 117 (0.35 grams, 61% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (d, J= 2.0 Hz, 1H), 7.84 (dd, J= 8.4, 2.0 Hz, 1H), 7.29 (d, J= 8.4 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H). [0527] Preparation of Intermediate 118: Intermediate 118 was synthesized according to the general procedure for the preparation of Intermediate 5 described in Example 81, using Intermediate 117 (350 mg, 1.12 mmol) and LiOH•H2O (105 mg, 2.79 mmol) in THF (6 mL) and water (6 mL) giving the target compound (280 mg, 84% yield) as an off-white solid. [0528] Preparation of Compound 101: To a stirred solution of Intermediate 118 (300 mg, 1.00 mmol) in DCM (3 mL), was added morpholine (0.11 mL, 0.90 mmol), followed by the addition of Isobutyl chloroformate (0.13 mL, 1.00 mmol). After stirring for 4 h, Intermediate 5A (Intermediate 4 from Example 13, 180 mg, 1.20 mmol) was added and stirred for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with DCM. Separated the organic layer, dried over sodium sulphate and evaporated under reduced pressure to get crude residue (370 mg). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 2-3% MeOH in DCM to afford Compound 101 (120 mg, 28% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.35 (t, J= 5.6 Hz, 1H), 8.45 (dd, J= 4.4, 1.6 Hz, 2H), 8.07 (d, J= 2.4 Hz, 1H), 7.85 (dd, J= 8.8, 2.4 Hz, 1H), 7.30 (d, J= 8.8 Hz, 1H), 7.23 (d, J= 6.0 Hz, 2H), 3.92 (s, 3H), 3.35-3.30 (m, 2H), 2.64 (t, J= 8.0 Hz, 2H), 1.87-1.84 (m, 2H). Example 92 – Preparation of Compound 88 [0529] Compound 88 was prepared according to the following Scheme:
Figure imgf000154_0001
p py y (60) (2.0 g, 10.28 mmol) in triethylamine (20 mL) was added (R)-But-3-yn-2-ol (1.63 mL, 20.57 mmol) in a sealed tube and then reaction mixture was degassed for 15 min by using of nitrogen gas. Then, Pd(PPh3)2Cl2 (0.36 g, 0.51 mmol), CuI (0.19 g, 1.03 mmol) were added and continued the degassed for 15 min. The resulting reaction mixture was heated to 90°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 (1.9 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 61 (0.85 gram, 56% yield) as a pale-yellow liquid. [0531] Preparation of Intermediate 62: To a stirred suspension of palladium on carbon (10% wet) (360 mg) in methanol (30 mL) was added Intermediate 61 (1.8 g, 10.90 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 (1.9 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 62 (0.85 gram, 56% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (dd, J= 4.4, 1.6 Hz, 2H), 7.22 (d, J= 6.0 Hz, 1H), 4.51 (d, J= 4.8 Hz, 1H), 3.62-3.53 (m, 1H), 2.69-2.66 (m, 1H), 2.62-2.55 (m, 1H), 1.64-1.59 (m, 2H), 1.08 (d, J= 6.0 Hz, 3H). [0532] Preparation of Intermediate 63: To a stirred solution of Intermediate 62 (0.6 g, 3.97 mmol) in THF (15 mL) was added PPh3 (2.08 g, 7.94 mmol) and phthalimide (0.58 g, 3.97 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (1.57 mL, 7.94 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 (2.5 g). 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 63 (1.8 grams, 100% crude yield) as a pale-yellow solid. [0533] Preparation of Intermediate 64: To a stirred solution of Intermediate 63 (1.8 g, 6.42 mmol) and in MeOH (20 mL) was added N2H4•H2O (0.5 mL, 16.71 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 (0.4 g). 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 64 (0.25 gram, 26% yield) as a colorless liquid. 1H NMR (400 MHz, DMSO- d6): δ 8.43 (dd, J= 4.4, 1.6 Hz, 2H), 7.23 (d, J= 5.6 Hz, 2H), 2.80-2.75 (m, 1H), 2.64-2.59 (m, 2H), 1.58-1.53 (m, 2H), 1.02 (d, J= 6.4 Hz, 3H). [0534] Preparation of Compound 88: Compound 88 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 200 mg, 0.67 mmol), Int-64 (120 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) giving Compound 88 (170 mg, 59% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J= 2.0 Hz, 1H), 8.56 (s, 1H), 8.42 (dd, J= 4.41.6 Hz, 2H), 8.21-8.14 (m, 2H), 7.26-7.22 (m, 3H), 4.07-4.00 (m, 1H), 3.92 (s, 3H), 2.67-2.57 (m, 2H), 1.97-1.88 (m, 1H), 1.82-1.74 (m, 1H), 1.18 (d, J= 5.2 Hz, 3H). Example 93 – Preparation of Compound 89 [0535] Compound 89 was prepared according to the following Scheme:
Figure imgf000156_0001
60) (2.0 g, 10.28 mmol) in triethylamine (20 mL) was added (S)-But-3-yn-2-ol (1.63 mL, 20.57 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (0.36 g, 0.51 mmol), CuI (0.19 g, 1.03 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 90°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 (1.8 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 65 (0.9gram, 60% yield) as a pale-yellow liquid. [0537] Preparation of Intermediate 66: To a stirred suspension of palladium on carbon (10% wet) (360 mg) in methanol (30 mL) was added Intermediate 65 (0.9 g, 6.12 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 (30 mL) and filtrate was evaporated under reduced pressure to get crude residue (0.85 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 66 (0.65 gram, 71% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (dd, J= 4.4, 1.6 Hz, 2H), 7.22 (d, J= 6.0 Hz, 2H), 4.51 (d, J= 4.8 Hz, 1H), 3.62-3.56 (m, 1H), 2.69-2.60 (m, 2H), 1.64-1.58 (m, 2H), 1.08 (d, J= 6.4 Hz, 3H). [0538] Preparation of Intermediate 67: To a stirred solution of Intermediate 66 (0.6 g, 3.97 mmol) in THF (15 mL) was added PPh3 (2.08 g, 7.94 mmol) and phthalimide (0.58 g, 3.97 mmol) sequentially at RT and stirred for 10 min. Thereafter the reaction mixture was cooled to 0°C, DIAD (1.57 mL, 7.94 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 (2.5 g). 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 67 (2.0 grams, 100% crude yield) as a pale-yellow solid. [0539] Preparation of Intermediate 68: To a stirred solution of Intermediate 67 (2.0 g, 7.14 mmol) and in MeOH (20 mL) was added N2H4•H2O (0.56 mL, 18.57 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 (0.7 g). 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 68 (0.3 gram, 28% yield) as a colorless liquid. 1H NMR (400 MHz, DMSO- d6): δ 8.43 (dd, J= 4.4, 0.8 Hz, 2H), 7.23 (d, J= 5.6 Hz, 2H), 2.80-2.75 (m, 1H), 2.64-2.57 (m, 2H), 1.59-1.53 (m, 2H), 1.02 (d, J= 6.4 Hz, 3H). [0540] Preparation of Compound 89: Compound 89 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 200 mg, 0.67 mmol), Int-68 (120 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol) and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) giving Compound 89 (180 mg, 62% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J= 2.0 Hz, 1H), 8.56 (s, 1H), 8.42 (d, J= 5.6 Hz, 2H), 8.21-8.14 (m, 2H), 7.26-7.22 (m, 3H), 4.07-4.00 (m, 1H), 3.92 (s, 3H), 2.67-2.59 (m, 2H), 1.97-1.88 (m, 1H), 1.82-1.74 (m, 1H), 1.18 (d, J= 2.4 Hz, 3H). Example 94 – Preparation of Compound 90 [0541] Compound 90 was prepared according to the following Scheme:
Figure imgf000158_0001
[0542] Preparation of Compound 90: Compound 90 wa ribed
Figure imgf000158_0002
for preparation of Compound 1 (Example 1) using 5-(3-cyano-4-methoxyphenyl)oxazole-4-carboxylic acid (200 mg, 0.82 mmol), Intermediate 5A (Intermediate 4 from Example 13, 135 mg, 0.98 mmol), HATU (373 mg, 0.98 mmol) and triethylamine (0.57 mL, 4.09 mmol) in DMF (2 mL) to afford Compound 90 (115 mg, 38% 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= 6.0 Hz, 1H), 8.45-8.41 (m, 3H), 7.40 (d, J= 8.8 Hz, 1H), 7.26-7.25 (m, 2H), 3.99 (s, 3H), 3.33-3.27 (m, 2H), 2.63 (t, J= 7.6 Hz, 2H), 1.87-1.83 (m, 2H). Example 95 – Preparation of Compound 91 [0543] Preparation of Compound 91: Compound 91 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-acetylphenyl)oxazole-4-carboxylic acid (200 mg, 0.86 mmol), Intermediate 5A (Intermediate 4 from Example 13, 151 mg, 1.04 mmol), HATU (392 mg, 1.04 mmol) and triethylamine (0.56 mL, 4.32 mmol) in DMF (2 mL) to afford Compound 91 (135 mg, 45% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.61-8.56 (m, 1H), 8.45 (dd, J= 4.4, 1.6 Hz, 1H), 8.36 (d, J= 8.4, 1H), 8.06 (d, J= 8.8 Hz, 1H), 7.27 (d, J= 6.0 Hz, 1H), 3.33-3.28 (m, 2H), 2.67-2.64 (m, 2H), 2.62 (s, 3H), 1.90-1.83 (m, 2H). Example 96 – Preparation of Compound 92 [0544] Preparation of Compound 92: Compound 92 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-(methylsulfonyl)phenyl)oxazole-4-carboxylic acid (200 mg, 0.75 mmol), Intermediate 5A (Intermediate 4 from Example 13, 122 mg, 0.90 mmol), HATU (341 mg, 0.90 mmol) and triethylamine (0.52 mL, 3.74 mmol) in DMF (2 mL) to afford Compound 92 (140 mg, 48% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.63 (t, J= 6.0 Hz, 1H), 8.47- 8.43 (m, 4H), 8.05 (dd, J= 7.2, 2.0 Hz, 2H), 7.26 (dd, J= 4.8, 1.6 Hz, 2H), 3.32-3.30 (m, 2H), 3.27 (s, 3H), 2.64 (t, J= 7.6 Hz, 2H), 1.88-1.84 (m, 2H). Example 97 – Preparation of Compound 93 [0545] Preparation of Compound 93: Compound 93 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-acetyl-3-bromophenyl)oxazole-4-carboxylic acid (150 mg, 0.48 mmol), Intermediate 5A (Intermediate 4 from Example 13, 79 mg, 0.58 mmol), HATU (220 mg, 0.58 mmol) and triethylamine (0.33 mL, 2.42 mmol) in DMF (2 mL) to afford Compound 93 (100 mg, 48% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.72 (d, J= 1.6 Hz, 1H), 8.68 (s, 1H), 8.63 (t, J= 6.0 Hz, 1H), 8.43 (d, J= 6.0 Hz, 2H), 8.23 (dd, J= 8.0, 1.6 Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.26 (d, J= 5.6 Hz, 1H), 3.32-3.28 (m, 2H), 2.67-2.65 (m, 2H), 2.64 (s, 3H), 1.90-1.84 (m, 2H). Example 98 – Preparation of Compound 94 [0546] Preparation of Compound 94: Compound 94 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(4-acetamido-3-bromophenyl)oxazole-4-carboxylic acid (250 mg, 0.77 mmol), Intermediate 5A (Intermediate 4 from Example 13, 126 mg, 0.92 mmol), HATU (351 mg, 0.92 mmol) and triethylamine (0.54 mL, 3.84 mmol) in DMF (2.5 mL) to afford Compound 94 (87 mg, 26% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.72 (d, J= 2.0 Hz, 1H), 8.59 (s, 1H), 8.54 (t, J= 6.0 Hz, 1H), 8.44 (dd, J= 4.8, 1.6 Hz, 2H), 8.08 (dd, J= 8.4, 2.0 Hz, 1H), 7.81 (d, J= 8.8 Hz, 1H), 7.26 (d, J= 6.0 Hz, 1H), 3.31-3.29 (m, 2H), 2.65-2.61 (m, 2H), 2.12 (s, 3H), 1.89-1.82 (m, 2H). Example 99 – Preparation of Compound 95 and Compound 96 [0547] Preparation of Compound 95 and Compound 96 were achieved using methods that generally followed the same protocols for preparation of Compound 79 and Compound 80 as described in Examples 81, 83 and 84 by replacing Intermediate 6 with Intermediate 5A (Intermediate 4 from Example 13). [0548] Compound 95: 1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 2H), 8.59 (t, J= 5.6 Hz, 1H), 8.44 (d, J= 5.2 Hz, 1H), 8.16 (d, J= 7.6 Hz, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.26 (d, J= 4.8 Hz, 2H), 3.32-3.28 (m, 2H), 2.64 (t, J= 7.2 Hz, 2H), 1.98-1.84 (m, 2H). [0549] Compound 96: 1H NMR (400 MHz, DMSO-d6): δ 13.66 (s, 1H), 8.76 (d, J= 1.2 Hz, 1H), 8.70-8.65 (m, 4H), 8.21 (dd, J= 8.0, 1.6 Hz, 1H), 7.86 (d, J= 6.0 Hz, 1H), 7.75 (d, J= 8.4 Hz, 2H), 3.33 (q, J= 6.8 Hz, 2H), 2.84 (t, J= 7.6 Hz, 2H), 1.94-1.91 (m, 2H). Example 100 – Preparation of Compound 97 [0550] Preparation of Compound 97: Compound 97 was prepared according to the method described for preparation of Compound 1 (Example 1) using 5-(3-bromo-4-(methylsulfonyl)phenyl)oxazole-4- carboxylic acid (200 mg, 0.58 mmol), Intermediate 5A (Intermediate 4 from Example 13, 94 mg, 0.69 mmol), HATU (263 mg, 0.59 mmol) and triethylamine (0.4 mL, 2.89 mmol) in DMF (2 mL) to afford Compound 97 (140 mg, 52% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (d, J= 1.6 Hz, 1H), 8.73 (s, 1H), 8.71-8.69 (m, 1H), 8.44 (dd, J= 4.4, 1.6 Hz, 2H), 8.34 (dd, J= 8.4, 2.0 Hz, 1H), 8.17 (d, J= 8.4 Hz, 1H), 7.26-7.25 (m, 2H), 3.42 (s, 3H), 3.32-3.29 (m, 2H), 2.64 (t, J= 8.4 Hz, 2H), 1.88-1.84 (m, 2H). Example 101 – Preparation of Compound 98 [0551] Compound 98 was prepared according to the following Scheme: ) in
Figure imgf000160_0001
MeOH (10 mL) was added Ohira-Bestmann reagent (1.0 g, 4.36 mmol) at RT. Cooled the reaction to 0-5°C and added K2CO3 (1.08 g, 7.84 mmol). Gradually brought the reaction to RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with sat. NH4Cl solution and extracted with hexane. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under reduced pressure to get crude residue (0.92 gram, 93% crude yield), which was used as such for the next reaction. [0553] Preparation of Intermediate 89: To a stirred solution of 4-Iodopyridine (440 mg, 2.78 mmol) in triethylamine (4.4 mL) was added Intermediate 88 (763 mg, 4.17 mmol) in a sealed tube and the reaction mixture was degassed for 15 min using nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (79 mg, 0.14 mmol), CuI (43 mg, 0.28 mmol) were added and degassed for 15 min. The resulting reaction mixture was heated to 90-95 °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 (820 mg). The obtained residue was further purified by silica-gel (100-200 mesh) column chromatography eluting with 10-12% ethyl acetate in hexane to afford Intermediate 89 (280 mg, 41% yield) as a brown semi-solid. [0554] Preparation of Intermediate 90: To a stirred suspension of palladium on carbon (10% wet) (50 mg) in methanol (3.0 mL) was added Intermediate 89 (280 mg, 0.93 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 (10 mL) and filtrate was evaporated under reduced pressure to afford crude residue (250 mg, 88% crude yield) as a yellow semi-solid. [0555] Preparation of Intermediate 91: To a stirred solution of Intermediate 90 (250 mg, 0.82 mmol) in ethanol (10 mL) was added 2N HCl (7.5 mL) and refluxed at 85-90°C for 2 h. After completion of reaction (monitored by TLC), cooled to RT and partitioned between ethyl acetate and water. Separated the organic layer, dried over sodium sulphate, filtered and evaporated under vacuum to give Intermediate 91 (170 mg, 100% crude yield) as a brown liquid, which was used as such for the next reaction. [0556] Preparation of Compound 98: Compound 98 was prepared according to the method described for preparation of Compound 1 (Example 1) using Intermediate 10 (Intermediate 5 from Example 62, 170 mg, 0.57 mmol), Intermediate 91 (113 mg, 0.68 mmol), HATU (260 mg, 0.68 mmol) and triethylamine (0.4 mL, 2.85 mmol) in DMF (1.7 mL) giving Compound 98 (66 mg, 25% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, J= 2.0 Hz, 1H), 8.56 (s, 1H), 8.42 (d, J= 6.0 Hz, 1H), 8.16 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.27-7.23 (m, 3H), 4.84 (t, J= 5.6 Hz, 1H), 4.01-3.95 (m, 1H), 3.92 (s, 3H), 3.54-3.49 (m, 1H), 3.46-3.40 (m, 1H), 2.69-2.59 (m, 2H), 1.94-1.84 (m, 2H). [0557] Any of compounds 2-101 can be formulated as a pharmaceutically acceptable salt and/or solvate thereof. [0558] The presently disclosed compounds, compositions and treatment methods also have use in veterinary applications for improving the health and well-being of livestock and companion animals by treating conditions they suffer from that respond to treatment with a GSK-3β inhibitor. Example 102 – Compounds 13, 56, and 59 in vitro and in vivo data [0559] Testing showed that the compounds are superior to OCM-51 in reducing CRMP2 phosphorylation in living human brain cells, the reduction of which indicates a level of GSK3-β inhibition that is relevant to treatment of psychiatric and neurological disorders (FIG.4). CRMP2 phosphorylation is a direct and specific result of GSK3-β activity. CRMP2 phosphorylation (pCRMP2) in post-mortem human brain tissue is abnormally high unless the person was taking lithium at the time of death. OCM-51 requires a concentration of about 1 micromole to reduce pCRMP2 by at least 20%, while Compounds 13, 56, and 59 provide >20% reductions at concentrations of 0.1 micromolar or less. [0560] Compound 56 was shown effective in a rodent model of lithium pharmacology, indicating its potential to cross the blood brain barrier and last long enough in the brain to impact animal behavior (FIG. 5). Compound 56 was administered to adult male Wistar rats one hour before dextroamphetamine (AMP). The effects of Compound 56 on positive appetitive vocalizations over the next two hours were equal to or better than those of a full therapeutic dose of lithium. [0561] It will be understood by those of ordinary skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the various embodiments of the present invention described herein are illustrative only and are not intended to limit the scope of the present invention.

Claims

CLAIMS What is claimed is: 1. An inhibitor of GSK-3β for therapeutic use, having the structure of Formula I: wherein, R1 is L1-R5;
Figure imgf000163_0001
R2 is L2-R6; R3 is H or C1-C6 alkyl; R4 is H or C1-C6 alkyl; R5 is 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 R5 is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6 alkyl), 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)2 and -(CH2)s-R11; R6 is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6 is optionally substituted with 1-3 groups independently selected from - (C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2; R7 is H, OR8 or N(R8)2; each R8 is independently H or -(C=O)p-(C1-C6 alkyl); each R9 is independently H, -(C=O)r-(C1-C6 alkyl), or -(C=O)r-(CH2)x-(C3-C6 cycloalkyl); each R10 is independently H or C1-C6 alkyl; each R11 is independently H, OR12 or N(R12)2; each R12 is independently H or -(C=O)t-(C1-C6 alkyl); each R13 is independently H, -(C=O)v-(C1-C6 alkyl), or S(O)2R14; each R14 is independently H or C1-C6 alkyl; L1 is 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 L1 is optionally substituted with one or two -(CH2)o-R7; L2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2 is optionally substituted with 1-2 C1-C6 alkyl 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:
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
3.
Figure imgf000167_0001
met o o preparng an n tor o GS -3β or t erapeutc use, avng t e structure of Formula I: wherein,
Figure imgf000167_0002
R1 is L1-R5; R2 is L2-R6; R3 is H or C1-C6 alkyl; R4 is H or C1-C6 alkyl; R5 is 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 R5 is optionally substituted with 1-3 groups independently selected from -(C=O)q-(C1-C6 alkyl), 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)2 and -(CH2)s-R11; R6 is a 5-6 membered heteroaryl ring, a 6-membered aryl or a 6-membered heteroaryl ring, wherein R6 is optionally substituted with 1-3 groups independently selected from -(C=O)u-(C1-C6 alkyl), 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)2OR14 and P(O)(OR14)2; R7 is H, OR8 , or N(R8)2; each R8 is independently H or -(C=O)p-(C1-C6 alkyl); each R9 is independently H, -(C=O)r-(C1-C6 alkyl), or -(C=O)r-(CH2)x-(C3-C6 cycloalkyl); each R10 is independently H or C1-C6 alkyl; each R11 is independently H, OR12 or N(R12)2; each R12 is independently H or -(C=O)t-(C1-C6 alkyl); each R13 is independently H, -(C=O)v-(C1-C6 alkyl), or S(O)2R14; each R14 is independently H or C1-C6 alkyl; L1 is 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 L1 is optionally substituted with one or two -(CH2)o-R7; L2 is a 5-6 membered heteroaryl ring, a 6-membered aryl ring or a 6-membered heteroaryl ring, wherein L2 is optionally substituted with 1-2 C1-C6 alkyl 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 II III IV wherein, all substitutions are defined according to a structure of Formula I, and wherein, R15 is H, C1-C6 alkyl or -(CH2)w-R16; R16 is a 5-membered heteroaryl group, a 6-membered aryl group or a 6-membered heteroaryl group, wherein, R16 is optionally substituted with 1-5 groups independently selected from F, NO2 and OCH3; R17 is 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:
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
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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WO2006091737A1 (en) * 2005-02-24 2006-08-31 Kemia, Inc. Modulators of gsk-3 activity
US20110008468A1 (en) * 2009-02-27 2011-01-13 Haggarty Stephen J Uses of chemicals to modulate GSK-3 signaling for treatment of bipolar disorder and other brain disorders
US20210095275A1 (en) * 2018-01-12 2021-04-01 Roche Innovation Center Copenhagen A/S Oligonucleotides for modulating gsk3b expression

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006091737A1 (en) * 2005-02-24 2006-08-31 Kemia, Inc. Modulators of gsk-3 activity
US20110008468A1 (en) * 2009-02-27 2011-01-13 Haggarty Stephen J Uses of chemicals to modulate GSK-3 signaling for treatment of bipolar disorder and other brain disorders
US20210095275A1 (en) * 2018-01-12 2021-04-01 Roche Innovation Center Copenhagen A/S Oligonucleotides for modulating gsk3b expression

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