WO2021231243A1 - Small molecule inhibitors of galectin-3 - Google Patents

Small molecule inhibitors of galectin-3 Download PDF

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Publication number
WO2021231243A1
WO2021231243A1 PCT/US2021/031479 US2021031479W WO2021231243A1 WO 2021231243 A1 WO2021231243 A1 WO 2021231243A1 US 2021031479 W US2021031479 W US 2021031479W WO 2021231243 A1 WO2021231243 A1 WO 2021231243A1
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Prior art keywords
mmol
alkyl
carboxylate
tert
triazol
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PCT/US2021/031479
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English (en)
French (fr)
Inventor
Prasada Rao JALAGAM
Susheel Jethanand NARA
Manoranjan Panda
Murugesan NATESAN
Pratik Devasthale
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to US17/998,261 priority Critical patent/US12286424B2/en
Priority to JP2022568549A priority patent/JP7677995B2/ja
Priority to EP21730348.6A priority patent/EP4149939A1/en
Priority to KR1020227042914A priority patent/KR20230009433A/ko
Priority to CN202180034243.5A priority patent/CN115551850A/zh
Publication of WO2021231243A1 publication Critical patent/WO2021231243A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals

Definitions

  • Galectin-3 (Gal-3) is a ⁇ -galactoside binding lectin of about 30 KDa (Cell 76: 597- 598), that is involved in the regulation of inflammatory and fibrotic processes. (Immunological Reviews 230: 160-171).
  • Gal-3 Under uncontrolled inflammation and pro- fibrotic condition, Gal-3 promotes fibroblast proliferation and transformation and mediates collagen production (Circulation 110:3121-3128). Gal-3 is localyzed in many cellular location such as cytoplasm, nucleus, and cell surface. Gal-3 is also secreted by various cell types, mainly macrophages and monocytes into the blood stream (J Pharmacol Exp Ther 351:336–343). There are multiple lines of evidence in the literature supporting the involment of Gal-3 in the development of fibrotic process in multiple organs such as xung (Am J. Respir. Crit. Care Med.185: 537-546), liver (PNAS 103:5060-5065) and kidney (Am. J. Pathol.172:288-298).
  • Gal-3 has also been identified as a biomarker for heart failure indicating that modulation of Gal-3 has potential uses in the treatment of heart failure (Curr. Heart Fail. Rep.7:1-8). Modulation of Gal-3 can be used in the treatment of cancer since Gal-3 is involved in cell growth and differentiation playing a critical role in angiogenic, apoptotic, and metastatic pathways (Galectin-3C: Human Lectin for Treatment of Cancer. ACS Symposium Series, Vol. 1115. Chapter 12, 195–23). Recently, Gal-3 inhibitors have proven to have positive effects when used in combination immunotherapy (Galectin Therapeutics. Press Release, February 7, 2017). Several publications and patent applications describe synthetic inhibitors of Gal-3 that are being explored as antifibrotic agents.
  • the present disclosure relates to compounds of the present invention, which inhibit Gal-3, and include pharmaceutically acceptable salts, compositions comprising such compounds, and methods using and making such compounds and compositions.
  • the present invention provides, inter alia, a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ar 1 is independently phenyl or naphthyl; and wherein each ring moiety is substituted with 1 to 5 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy; R 1 is independently selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; R 2 is independently selected from: , , , , , ; R 3 is independently selected from: -CH 2 OH, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy; Ar 2 is independently selected from phenyl, , , , and heteroaryl including from 5 to 10 ring atoms, wherein from 1 to 4 ring
  • R 1 is independently H or C 1-4 alkyl
  • R 2 is independently selected from: , , , , , , ;
  • R 3 is independently -CH 2 OH or C 1-4 alkyl
  • Ar 2 is independently selected from phenyl, , , , and heteroaryl including from 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R 4 ), O, and S; and wherein each ring moiety is substituted with 0 to 4 substituents selected from OH, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy,
  • R 2 is independently selected from: , , , , , .
  • R 1 is independently H or CH 3 .
  • R 1 is H.
  • R 1 is CH 3 .
  • the invention provides a compound selected from the exemplified examples or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound selected from the Examples 1 to 42 or a pharmaceutically acceptable salt thereof.
  • Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Terms with a hydrocarbon moiety include straight and branched isomers for the hydrocarbon portion which are composed of 1 to 6 carbons.
  • Halo includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl and “haloalkoxy” include all halogenated isomers from monohalo to perhalo.
  • Aryl means a monocyclic or bicyclic aromatic ring system having 5 to 12 carbon atoms wherein one or both of the rings are aromatic.
  • Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • Heteroaryl means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art. Combinations of substituents and bonding patterns are only those that result in stable compounds as understood by practitioners in the art.
  • Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art.
  • a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents.
  • anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • the invention includes all stereoisomeric forms of the compounds including enantiomers and diastereomers. Methods of making and separating stereoisomers are known in the art.
  • the invention includes all tautomeric forms of the compounds.
  • the invention includes atropisomers and rotational isomers.
  • the invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically- labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties. BIOLOGICAL METHODS Gal-3 ELISA Assay Materials: 1.
  • Coating Buffer Phosphate Buffered Saline (1x) - PBS
  • the Solution was prepared by dissolving the PBS packets procured from Sigma Aldrich (Catalogue No.: P3813-5x10Pak) – 1 Pack in 1Liter of Milli-Q water.
  • Fetal Bovine Serum. Invitrogen Catalogue No.: 26400-044-500mL).
  • Tween-20 Sigma Aldrich (Catalogue No.: P1379-250mL). 5.
  • TD-139 (EXT-001109-01-001): A small molecule synthesized in-house, used as an internal standard for the small molecule screening in hGalectin-3 neutralization binding assay.
  • A. Protocol a. Coating of Plate: The ASF at concentration 15nM was prepared in 1x PBS and was plated in the 96 well flat-bottom nunc plates (Nunc immuno plate, Maxisorp, Catalogue No.: 439454) according to the plate-map and was incubated overnight at 4°C after sealing the plates with a top-seal. b.
  • test compounds After spin drying the plates from previous washing, 100 ⁇ L of test compounds, at various concentrations as specified in the plate-map (pre-incubated with the hGalectin-3 or mGalectin-3 at concentration 15nM for 1h at Room Temperature-RT) were added onto the plate as per the plate map. The plates were run in duplicates for data duplication and reproducibility. These plates were incubated at RT for 1h and were washed for 5 times with wash buffer, spin dried and 100 ⁇ L of Streptavidin HRP (1:1000 dilutions) was added and incubated for 1h at room temperature and washed for 7 times with wash buffer. C.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating a patient afflicted with a disease or condition selected from fibrosis of organs (including liver, kidney, lung, heart and skin), liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder), cell proliferative diseases, cancers, and conditions (including solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)) and invasive metastasis of cancer cell), inflammatory diseases and conditions (including psoriasis, nephropathy, and pneumonia), gastrointestinal tract diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pan
  • Another aspect of the invention is a method of treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis and systemic sclerosis comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating fibrosis of organs (including liver, kidney, lung, heart and skin) comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder) comprising administering to a compound of the present invention to a patient.
  • liver diseases and conditions including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder
  • Another aspect of the invention is a method for treating cell proliferative diseases, cancers, and conditions (including solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)) and invasive metastasis of cancer cell) comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating inflammatory diseases and conditions (including psoriasis, nephropathy, and pneumonia) comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating gastrointestinal tract diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion) comprising administering to a compound of the present invention to a patient.
  • gastrointestinal tract diseases and conditions including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion
  • renal diseases and conditions comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating urinary tract-associated diseases and conditions (including benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, and symptoms derived from diabetes) comprising administering to a compound of the present invention to a patient.
  • urinary tract-associated diseases and conditions including benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebra
  • Another aspect of the invention is a method for treating lower urinary tract diseases and conditions (including obstruction of lower urinary tract), inflammatory diseases and conditions of lower urinary tract (including dysuria and frequent urination) comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating pancreatic diseases and conditions comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating abnormal angiogenesis- associated diseases and conditions (including arterial obstruction) comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating brain-associated diseases and conditions (including cerebral infarction and cerebral hemorrhage) comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating neuropathic pain and peripheral neuropathy comprising administering to a compound of the present invention to a patient.
  • Another aspect of the invention is a method for treating ocular diseases and conditions (including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring) comprising administering to a compound of the present invention to a patient.
  • ocular diseases and conditions including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring
  • the compounds of the invention may be used in the treatment and/or prophylaxis of conditions in which Gal-3 plays a role.
  • the compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a condition in which inhibition of the physiological activity of Gal-3 is useful, such as diseases in which a Gal-3 receptor participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.
  • the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
  • “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of pain.
  • “Patient” means a person afflicted with pain and suitable for therapy as understood by practitioners in the field.
  • compositions comprised of a therapeutically effective amount of a compound of the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
  • a therapeutically effective amount is that which is needed to provide a meaningful patient benefit.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions.
  • compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington’s Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA (1985).
  • Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit. Liquid compositions are usually in dosage unit ranges.
  • the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.
  • LCMS Conditions Method A: Column: Ascentis Express C18 (50x2.1mm), 2.7 ⁇ m; Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH 4 OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH 4 OAc; Temperature: 50°C; Gradient: 0- 100% B over 3 minutes.
  • Method B Column: Ascentis Express C18(50x2.1mm), 2.7 ⁇ m; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature:50°C; Gradient:0-100% B over 3 minutes; Flow: 1.1ml/min.
  • Prep-HPLC conditions Method A: Column: Waters XBridge C18, 19 x 150 mm, 5- ⁇ mparticles; Mobile Phase A: 10-mM ammonium acetate; Mobile Phase B: acetonitrile; Gradient: 15-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min.
  • Method B Column: X-Bridge Phenyl, 250 x 19 mm ID, 5 ⁇ ; Mobile Phase A: 10mM NH 4 OAc in water; Mobile Phase B: Acetonitrile; Gradient: 0-100% B over 18 minutes, then a 5 minute hold at 100% B; Flow: 17 mL/min.
  • Method C Column: Sunfire C18, 150 x 19 mm ID, 5 ⁇ ; Mobile Phase A: 10mM NH 4 OAc in water; Mobile Phase B: Acetonitrile; Gradient: 0-100% B over 18 minutes, then a 5 minute hold at 100% B; Flow: 17 mL/min.
  • Method D Waters XBridge C18, 19 x 150 mm, 5- ⁇ m particles; Mobile Phase A: 0.1% trifluoroacetic acid; Mobile Phase B: acetonitrile; Gradient: 8-32% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 15 mL/min.
  • Method E Column: Inertsil ODS, 150 x 4.6 mm, 5 ⁇ ; Mobile Phase A: 10mM NH 4 OAc in water; Mobile Phase B: Acetonitrile; Gradient: 0-100% B over 18 minutes, then a 5 minute hold at 100% B; Flow: 17 mL/min.
  • Method F Column: Kinetex C18 (250 * 21.2 ID) 5 micron; Mobile Phase A: 10mM NH 4 OAc in water; Mobile Phase B: Acetonitrile; Gradient: 0-100% B over 13 minutes, then a 5 minute hold at 100% B; Flow: 17 mL/min. Synthesis of carboxylic acid intermediate: Step 1.
  • Triflic anhydride (8.48 mL, 50.2 mmol) was added drop-wise over a period of 15 min under argon and the mixture was stirred for 1 h at - 15°C. The reaction mixture was allowed to reach rt over a period of 2 h. Acetyl chloride (4.76 mL, 66.9 mmol) was added at 0 °C, and the mixture was allowed to warm to rt and stirred for 10 h. DCM (300 mL) was added, and the solution was washed with 0.7 N HCl (150 mL), saturated sodium bicarbonate (2x 100 mL) and brine solution. The organic layer was separated and dried over sodium sulfate.
  • reaction mixture was diluted with EtOAc (500 mL), washed with water (4 x 200 mL), dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified via chromatography in silica gel (60 - 100 % EtOAc in n-hexane) to yield the title compound (15 g, 42.6 mmol, 64 %) as a yellow solid.
  • reaction mixture was allowed to warm to rt and stirred for 2 h. Then, the reaction mixture was diluted with DCM (200 mL), washed with aq.0.7 N HCl (50 mL), aq.NaHCO 3 (2x 50 mL), brine solution and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified via chromatography in silica gel (30 - 80 % EtOAc in n-hexane) to yield the title compound (1.2 g, 2.477 mmol, 38 %) as a solid.
  • Reaction mixture was degassed with nitrogen for 10 min and heated to 80 °C for 1h.
  • the reaction mixture was cooled to RT and diluted with water (60 ml) and DCM (50 ml) and stir for 1 h.
  • Reaction mixture was filtered through celite pad, washed with DCM (100 ml), filtrate taken for further workup.
  • the organic layer separated out and aqueous layer was re-extracted with DCM (2 x 100 ml), combined organic layer was washed with water (400 ml), brine (100 ml), dried the organic layer over sodium sulfate and concentrated under reduced pressure.
  • Step-3 Synthesis of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol- 1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid: To a stirred solution of (4aR,6R,7R,8R,8aR)-methyl 8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1- yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (1.3 g, 2.8 mmol) in Tetrahydrofuran (50 mL) and Water (50 mL) was added lithium hydroxide (0.33 g, 13.85 mmol) and stirred at rt for 1 h.
  • Step-1 Synthesis of (4aR,6S,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol- 1-yl)-6-(hydroxymethyl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol: To stirred suspension of (4aR,6R,7R,8S,8aR)-methyl 7-acetoxy-8-(4-(3-fluorophenyl)-1H-1,2,3- triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (2 g, 4.02 mmol) in tetrahydrofuran (100 mL), LiBH 4 (6.03 mL, 12.06 mmol, 2M in THF) was added drop wise under Ar at 0 °C.
  • Step-4 Synthesis of 2-((4aR,6S,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3- triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)acetic acid: 10 mL sealed tube was charged with 2-((4aR,6S,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H- 1,2,3-triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6- yl)acetonitrile (0.24 g, 0.550 mmol), EtOH (4 mL), 6N KOH (Aq) (2.75 mL, 16.50 mmol) and vial was sealed.
  • reaction mixture was heated at 100 °C for overnight. Reaction mixture was cooled to rt, solvent was removed under reduced pressure to give the crude residue. The crude residue was neutralized with aq.1.5 N HCl (5 mL) and extracted with EtOAc (3X75 mL).
  • Example 9 The crude product was purified by preparative HPLC [Method A] to afford Example 9 as a brown solid (11.5 mg, 36% yield).
  • LC-MS, [M+H] + 554.2.
  • LCMS Conditions -Method A, t R 1.085 min.
  • Step-1 Synthesis of tert-butyl 4-(3-hydroxy-4-nitrophenyl)piperazine-1- carboxylate: To a solution of 5-fluoro-2-nitrophenol (0.5 g, 3.18 mmol) in DMF (5 mL), tert-butyl piperazine-1-carboxylate (1.186 g, 6.37 mmol) and K 2 CO 3 (0.880 g, 6.37 mmol) were added sequentially at room temperature and the reaction mixture was heated at 80 °C for overnight. The reaction mixture was cooled to room temperature, quenched with ice cold water and extracted with EtOAc (3X50 mL).
  • reaction mixture was filtered through Celite pad, washed with EtOAc (40 mL) and filtrate was evaporated under reduced pressure to afford tert-butyl 4-(4-amino-3-hydroxyphenyl)piperazine-1-carboxylate as a wine red solid (170 mg, 94%) which was as such taken for next step without further purification.
  • Example 10 was purified by preparative HPLC (Method F) to yielded Example 10 as an off white solid (1.5 mg, 6 % yield).
  • LC-MS, [M+H] + 555.2.
  • LCMS Conditions -Method F, t R 0.892 min.
  • Example 12 (14.5 mg, 0.027 mmol, 50.4 % yield) as an off white solid. ).
  • Step-1 Synthesis of tert-butyl 4-((4-(benzyloxy)phenyl)carbamoyl)piperazine-1- carboxylate: To a stirred solution of 4-(benzyloxy)aniline (0.8 g, 4.02 mmol) in DCM (10 mL).1,1'-carbonyldiimidazole (1.107 g, 6.83 mmol) was added and stirred for 14 h at room temperature. Then tert-butyl piperazine-1-carboxylate (1.271 g, 6.83 mmol) was added and stirred for another 14 h. Reaction mixture was diluted with DCM (20 mL), filtered through Celite pad and washed with excess of DCM.
  • N-(4-hydroxyphenyl) piperazine-1-carboxamide, HCl To an ice cooled stirred solution of tert-butyl 4-((4-hydroxyphenyl)carbamoyl)piperazine-1- carboxylate (0.07 g, 0.218 mmol) in DCM (1 mL), 4N HCl in dioxane (0.5 mL, 2.000 mmol) was added and stirred for 2 h. Solvent was removed under reduced pressure and dried to afford N-(4-hydroxyphenyl) piperazine-1-carboxamide, HCl (0.04 g, 0.155 mmol, 71.3 % yield) as a pale yellow solid which was as such taken for next step without further purification.
  • Step-4 Synthesis of 4-((2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol- 1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-carbonyl)-N-(4- hydroxyphenyl)piperazine-1-carboxamide: To a stirred solution of Then (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-carboxylic acid (0.02 g, 0.057 mmol) in DMF (2 mL), DIPEA (0.5 mL, 2.86 mmol), HA
  • Step-1 Synthesis of (1S,4S)-tert-butyl 5-(4-methoxyphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate: Dried vial was charged with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.2 g, 1.009 mmol), 1-bromo-4- methoxybenzene (0.283 g, 1.513 mmol), sodium tert-butoxide (0.291 g, 3.03 mmol), BINAP (0.126 g, 0.202 mmol), Toluene (5 mL) and reaction mixture was degassed nitrogen for 10 min .
  • Example 23 Synthesis of methyl (4-((1S,4S)-5-((2R,3R,4S,5R,6R)-4-(4-(3- fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)carbamate
  • Step-1 Synthesis of (1S,4S)-tert-butyl 5-(4-nitrophenyl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate: To a stirred solution of (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (1.405 g, 7.09 mmol) in DMF (5 mL), K 2 CO 3 (0.98 g, 7.09 mmol) and 1-fluoro-4-nitrobenzene (0.5 g, 3.54 mmol) were added sequentially at room temperature. Then the reaction mixture was heated at 80 °C for overnight.
  • Step-2 Synthesis of N-(4-((1S, 4S)-2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) methane sulfonamide hydrochloride: Prepared in a similar fashion as described in Example 20, Step-4 using afford (1S,4S)-tert-butyl 5-(4-(methylsulfonamido)phenyl)-2,5- diazabicyclo [2.2.1]heptane-2-carboxylate (65 mg, 0.18 mmol) to afford N-(4-((1S, 4S)-2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) methane sulfonamide hydrochloride ( 53.5 mg, quantitative) as an off white solid which was as such taken for next step without purification.
  • Step-1 Synthesis of (1S,4S)-tert-butyl 5-(4-(benzyloxy)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate: Dried vial was charged with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.5 g, 2.52 mmol), 1-(benzyloxy)-4- bromobenzene (0.995 g, 3.78 mmol), sodium tert-butoxide (0.727 g, 7.57 mmol), BINAP (0.314 g, 0.504 mmol), Toluene (15 mL) and reaction mixture was degassed with nitrogen for 10 min .
  • Example 26 Synthesis of ((1S,4S)-5-(1H-indol-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)((2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)methanone
  • Step-1 Synthesis of (1S,4S)-tert-butyl 5-(1H-indol-5-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate: To a stirred solution of (1S,4S)-tertbutyl 2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (141 mg, 0.709 mmol) in Toluene (5 mL), was added tri-t- butylphosphine (6.52 mg, 0.032 mmol), sodium tert-butoxide (93 mg, 0.967 mmol) and 5- bromo-1-(tert-butyldimethylsilyl)-1H-indole (200 mg, 0.645 mmol) sequentially.
  • reaction mixture was degassed with Ar for 10 min and Pd(OAc) 2 (7.24 mg, 0.032 mmol) was added and reaction mixture was heated at 110 °C for 14h.
  • the reaction mixture was cooled to room temperature, filtered through Celite pad, washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to give crude residue.
  • the crude residue was purified by flash chromatography (50-80 % EtOAc in pet ether) to afford of (1S,4S)-tert-butyl 5-(1H-indol-5-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (50 mg, 0.16 mmol, 25% yield).
  • Step-3 Synthesis of ((1S,4S)-5-(1H-indol-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)((2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)methanone: To a stirred solution of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-carboxylic acid (25 mg, 0.071 mmol) in DMF (1.0 mL), 5-((1S,4S)-2,5-diazabicyclo[2.2.1
  • Example 27 Synthesis of 2-((2S,3R,4R,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1- yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1-((1S,4S)-5-(4- methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone Step-1.
  • Example 28 was prepared in an analogous fashion to Examples 27, substituting (1S,4S)-2-(4-methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride with the appropriate piperazine fragment in the synthetic sequence.
  • Example 32 was prepared in an analogous fashion to Examples 27, substituting 1- bromo-4-methoxybenzene with the appropriate aryl bromide in the synthetic sequence.
  • Step-1 Synthesis of tert-butyl 4-(4-(benzyloxy) phenyl)-1,4-diazepane-1- carboxylate: To a stirred solution of 1-(benzyloxy)-4-bromobenzene (0.2 g, 0.760 mmol) in Toluene (5 mL), was added BINAP (0.095 g, 0.152 mmol), sodium tert-butoxide (0.219 g, 2.280 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (0.228 g, 1.140 mmol) sequentially.
  • BINAP 0.095 g, 0.152 mmol
  • sodium tert-butoxide 0.219 g, 2.280 mmol
  • tert-butyl 1,4-diazepane-1-carboxylate 0.228 g, 1.140 mmol
  • reaction mixture was degassed with Ar for 10 min and Pd 2 (dba) 3 (0.070 g, 0.076 mmol) was added and reaction mixture was heated at 80 °C for 14 h.
  • the reaction mixture was cooled to room temperature, filtered through Celite pad, washed with EtOAc and the filtrate was concentrated under reduced pressure to give crude residue.
  • the crude residue was purified by flash chromatography (0 - 30 % EtOAc in pet ether) to afford tert-butyl 4-(4-(benzyloxy) phenyl)-1,4-diazepane-1-carboxylate (0.2 g, 0.523 mmol, 68.8 % yield).
  • Step-1 Synthesis of 1-benzyl 2-methyl 4-(4-(benzyloxy)phenyl)piperazine-1,2- dicarboxylate: A mixture of 1-benzyl 2-methyl piperazine-1,2-dicarboxylate (2 g, 7.19 mmol), (4-(benzyloxy)phenyl)boronic acid (3.3 g, 14.37 mmol) and copper (II) acetate (1.30 g, 7.19 mmol) in dichloromethane (60 mL) was added pyridine (1.2 mL, 14.37 mmol) and 2 g of 4A molecular sieves. The reaction mixture was stirred at room temperature for 48 h under oxygen atmosphere.
  • Step-5 Synthesis of tert-butyl 2-(hydroxymethyl)-4-(4-hydroxyphenyl)piperazine- 1-carboxylate: To a solution of tert-butyl 4-(4-(benzyloxy)phenyl)-2-(hydroxymethyl) piperazine-1-carboxylate (80 mg, 0.201 mmol, enantiomer-1) in MeOH (2 mL) was added Pd/C (10% on carbon (10.68 mg, 0.100 mmol) and stirred under H 2 atm (1 atm pressure) by using hydrogen bladder for 3 h.
  • Example 34b Prepared in a similar fashion as described for Example 34a, by using enantiomer 2 in Step-4 as the starting material.
  • Example 35a and Example 35b ((2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3- triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)(3- (hydroxymethyl)-4-(4-hydroxyphenyl)piperazin-1-yl)methanone Step-1.
  • Example 35b Prepared in a similar fashion as described for Example 35a, by using tert-butyl 4-(4-(benzyloxy)phenyl)-3-(hydroxymethyl)piperazine-1-carboxylate, enantiomer 2 as the starting material in Step 3.
  • Step-1 Synthesis of (2R, 5S)-tert-butyl 4-(4-(benzyloxy)phenyl)-2,5-dimethyl piperazine-1-carboxylate: Dried vial was charged with trans-tert-butyl 2,5-dimethyl piperazine-1-carboxylate (0.5 g, 2.333 mmol), 1-(benzyloxy)-4-bromobenzene (0.921 g, 3.50 mmol), potassium tert-butoxide (0.39 g, 3.50 mmol), tri-tert-butylphosphine (0.024 g, 0.117 mmol), toluene (5 mL) and reaction mixture was degassed with nitrogen for 10 min.
  • Example 37b Prepared in a similar fashion as described for Example 37a, by using (2R, 5S)-tert-butyl 4-(4-(benzyloxy)phenyl)-2,5-dimethylpiperazine-1-carboxylate enantiomer 2 as the starting material in Step 2.
  • Step-1 Synthesis of (3aR,6aS)-tert-butyl 5-(p-tolyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate: To a stirred solution of cis-2-boc-hexahydropyrrolo[3,4- c]pyrrole (250 mg, 1.178 mmol) in toluene (5 mL), was added BINAP (147 mg, 0.236 mmol), sodium tert-butoxide (340 mg, 3.53 mmol) and 1-bromo-4-methylbenzene (242 mg, 1.413 mmol) sequentially.
  • BINAP 147 mg, 0.236 mmol
  • sodium tert-butoxide 340 mg, 3.53 mmol
  • 1-bromo-4-methylbenzene 242 mg, 1.413 mmol
  • reaction mixture was degassed with Ar for 10 min and tris(dibenzylideneacetone)dipalladium(0) (108 mg, 0.118 mmol) was added and reaction mixture was heated at 80 °C for 14h.
  • the reaction mixture was cooled to rt, filtered through Celite pad, washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to give crude residue.
  • the crude residue was purified by flash chromatography (20 - 25%% EtOAc in pet ether) to afford of 3aR,6aS)-tert-butyl 5-(p- tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (110 mg, 0.36 mmol, 30% yield).
  • Example 39a and Example 39b (2R,3R,4R,5R,6S)-4-(4-(3-fluorophenyl)-1H-1,2,3- triazol-1-yl)-2-(hydroxymethyl)-6-((2-(hydroxymethyl)-4-(4-hydroxyphenyl)piperazin-1- yl)methyl)tetrahydro-2H-pyran-3,5-diol ((2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)(2-(hydroxymethyl)-4-(4- hydroxyphenyl)piperazin-1-yl)methanone, example 34a (10 mg, 0.018 mmol) was suspended in borane tetrahydrofuran complex (
  • Example 39a (2R,3R,4R,5R,6S)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-((2- (hydroxymethyl)-4-(4-hydroxyphenyl)piperazin-1-yl)methyl)tetrahydro-2H-pyran-3,5- diol, Isomer 1 (0.4 mg, 0.755 ⁇ mol, 4 % yield).
  • Example 40a and Example 40b (2R,3R,4R,5R,6S)-4-(4-(3-fluorophenyl)-1H-1,2,3- triazol-1-yl)-2-(hydroxymethyl)-6-((3-(hydroxymethyl)-4-(4-hydroxyphenyl)piperazin-1- yl)methyl)tetrahydro-2H-pyran-3,5-diol Step-1.
  • Step-3 A mixture of (4aR,6S,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol- 1-yl)-6-((3-(hydroxymethyl)-4-(4-hydroxyphenyl)piperazin-1-yl)methyl)-2-phenyl hexahydropyrano[3,2- d][1,3]dioxin-7-ol (20 mg, 0.032 mmol) and acetic acid(70% in water) (10 mL) was heated at 75°C for 16 h. The reaction mixture was cooled to rt and solvent was removed under reduced pressure to give crude residue.
  • Example 40a (2R,3R,4R,5R,6S)-4- (4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-((3-(hydroxymethyl)-4- (4-hydroxyphenyl)piperazin-1-yl)methyl)tetrahydro-2H-pyran-3,5-diol, Isomer 1 (2.4 mg, 4.44 ⁇ mol, 14 % yield) as a pure product.
  • Example 40b Prepared in a similar fashion as described for Example 40a, by using ((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2- phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)(3-(hydroxymethyl)-4-(4- hydroxyphenyl)piperazin-1-yl)methanone Isomer-2 as the starting material in Step 2.
  • Example 42 was prepared in an analogous fashion to Example 41, substituting 2- bromo-5-nitropyridine with 5-bromo-2-nitropyridine in the synthetic sequence.

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