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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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KETOROLAC


KetorolacKetorolac.svg

Ketorolac

  • Molecular FormulaC15H13NO3
  • Average mass255.269 Da
1H-Pyrrolizine-1-carboxylic acid, 5-benzoyl-2,3-dihydro-
413572 [Beilstein]
5-(Phenylcarbonyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
5-Benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid
74103-06-3 [RN]
 Ketorolac
CAS Registry Number: 74103-06-3
CAS Name: 5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
Additional Names: 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid
Manufacturers’ Codes: RS-37619
Molecular Formula: C15H13NO3
Molecular Weight: 255.27
Percent Composition: C 70.58%, H 5.13%, N 5.49%, O 18.80%
Literature References: Prostaglandin biosynthesis inhibitor. Prepn and separation of isomers: BE 856681; J. M. Muchowski, A. F. Kluge, US 4089969 (both 1978 to Syntex). Alternate processes: J. M. Muchowski, R. Greenhouse, US 4347186 (1982 to Syntex); F. Franco et al., J. Org. Chem. 47, 1682 (1982); J. B. Doherty, US 4496741 (1985 to Merck & Co.). Absolute configuration: A. Guzman et al., J. Med. Chem. 29, 589 (1986). Structure-activity relationships: J. M. Muchowski et al., ibid. 28, 1037 (1985). Pharmacology and analgesic, anti-inflammatory profile of ketorolac and its tromethamine salt: W. H. Rooks et al., Agents Actions12, 684 (1982); eidem, Drugs Exp. Clin. Res. 11, 479 (1985). Clinical comparison with acetaminophen in post-operative pain: H. J. McQuay et al., Clin. Pharmacol. Ther. 39, 89 (1986).
Properties: Crystals from ethyl acetate + ether, mp 160-161°. uv max in methanol: 245, 312 nm (e 7080, 17400). pKa 3.49 ±0.02. LD50 orally in mice: ~200 mg/kg (Rooks).
Melting point: mp 160-161°
pKa: pKa 3.49 ±0.02
Absorption maximum: uv max in methanol: 245, 312 nm (e 7080, 17400)
Toxicity data: LD50 orally in mice: ~200 mg/kg (Rooks)
Derivative Type: (±)-Form tromethamine salt
CAS Registry Number: 74103-07-4
Trademarks: Acular (Allergan); Dolac (Syntex); Lixidol (Farmitalia); Tarasyn (Syntex); Toradol (Syntex); Toratex (Syntex)
Molecular Formula: C19H24N2O6
Molecular Weight: 376.40
Percent Composition: C 60.63%, H 6.43%, N 7.44%, O 25.50%
Derivative Type: (+)-Form
Properties: Crystals from hexane + ethyl acetate, mp 174° (Guzman); also reported as mp 154-156° (Muchowski, Kluge). [a]D+173° (c = 1 in methanol).
Melting point: mp 174° (Guzman); mp 154-156° (Muchowski, Kluge)
Optical Rotation: [a]D +173° (c = 1 in methanol)
Derivative Type: (-)-Form
Properties: Crystals from hexane + ethyl acetate, mp 169-170° (Guzman); also reported as mp 153-155° (Muchowski, Kluge). [a]D-176° (c = 1 in methanol).
Melting point: mp 169-170° (Guzman); mp 153-155° (Muchowski, Kluge)
Optical Rotation: [a]D -176° (c = 1 in methanol)
Therap-Cat: Analgesic; anti-inflammatory.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylcarboxylic Acids.

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain.[1]Specifically it is recommended for moderate to severe pain.[2] Recommended duration of treatment is less than six days.[1] It is used by mouth, by injection into a vein or muscle, and as eye drops.[1][2] Effects begin within an hour and last for up to eight hours.[1]

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea.[1] Serious side effects may include stomach bleedingkidney failureheart attacksbronchospasmheart failure, and anaphylaxis.[1] Use is not recommended during the last part of pregnancy or during breastfeeding.[1] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2) thereby decreasing prostaglandins.[1][3]

Ketorolac was patented in 1976 and approved for medical use in 1989.[4][1] It is avaliable as a generic medication.[2] In the United Kingdom it costs the NHS less than a £ per injectable dose as of 2019.[2] In the United States the wholesale cost of this amount is about 1.50 USD.[5] In 2016 it was the 296th most prescribed medication in the United States with more than a million prescriptions.[6]

Medical uses

Ketorolac is used for short-term management of moderate to severe pain.[7]It is usually not prescribed for longer than five days.[8][9][10][11] Ketorolac is effective when administered with paracetamol to control pain in neonates because it does not depress respiration as do opioids.[12] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.[11] Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.[13]

Ketorolac is used for short-term pain control not lasting longer than five days, and can be administered orally, by intramuscular injection, intravenously, and by nasal spray.[8] Ketorolac is initially administered by intramuscular injection or intravenously.[7] Oral therapy is only used as a continuation from the intramuscular or intravenous starting point.[8][12]

Ketorolac is used during eye surgery help with pain.[14] Ketorolac is effective in treating ocular itching.[15] The ketorolac ophthalmic formulation is associated with a decreased development of macular edema after cataract surgery and is more effective alone rather than as an opioid/ketorolac combination treatment.[16][17] Ketorolac has also been used to manage pain from corneal abrasions.[18]

During treatment with ketorolac, clinicians monitor for the manifestation of adverse effects and side effects. Lab tests, such as liver function tests, bleeding time, BUNserum creatinine and electrolyte levels are often used and help to identify potential complications.[8][9]

Contraindications

Ketorolac is contraindicated in those with hypersensitivity, allergies to the medication, cross-sensitivity to other NSAIDs, prior to surgery, history of peptic ulcer disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular bleeding, nasal polypsangioedema, and asthma.[8][9] Recommendations exist for cautious use of ketorolac in those who have experienced cardiovascular disease, myocardial infarction, stroke, heart failurecoagulation disorders, renal impairment, and hepatic impairment.[8][9]

Adverse effects

Though uncommon, potentially fatal adverse effects are strokemyocardial infarctionGI bleedingStevens-Johnson Syndrometoxic epidermal necrolysis and anaphylaxis. A less serious and more common (>10%) side effect is drowsiness. Infrequent (<1%) side effects are paresthesia, prolonged bleeding timeinjection site pain, purpurasweatingabnormal thinking, increased production of tearsedemapallordry mouthabnormal tasteurinary frequencyincreased liver enzymesitching and others. Ketorolac can cause premature constriction of the ductus arteriosis in an infant during the third trimester of pregnancy.[8][9] Platelet function is decreased related to the use of ketorolac.[19]

The practice of restricting treatment with ketorolac is due to its potential to cause kidney damage.[20]

Interactions

Ketorolac can interact with other medications. Probenecid can increase the probability of having an adverse reaction or experiencing a side effect when taken with ketorolac. Pentoxifylline can increase the risk of bleeding. When aspirin is taken at the same time as ketorolac, the effectiveness is decreased. Problematic GI effects are additive and become more likely if potassium supplements, aspirin, other NSAIDS, corticosteroids, or alcohol is taken at the same time. The effectiveness of antihypertensives and diuretics can be lowered. The use of ketorolac can increase serum lithium levels to the point of toxicity. Toxicity to methotrexate is more likely if ketorolac is taken at the same time. The risk of bleeding increases with the concurrent medications clopidogrelcefoperazonevalproic acidcefotetaneptifibatidetirofiban, and copidine. Anticoagulants and thrombolytic medications also increase the likelihood of bleeding. Medications used to treat cancer can interact with ketorolac along with radiation therapy. The risk of toxicity to the kidneys increases when ketorolac is taken with cyclosporine.[8][9]

Interactions with ketorolac exist with some herbal supplements. The use of Panax ginsengclovegingerarnicafeverfewdong quaichamomile, and Ginkgo biloba increases the risk of bleeding.[8][9]

Mechanism of action

The primary mechanism of action responsible for ketorolac’s anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.[21] Ketorolac has been assessed to be a relatively higher risk NSAID when compared to aceclofenac, celecoxib, and ibuprofen.[13] It is considered a first-generation NSAID.[19]

History

In the US, ketorolac was the only widely available intravenous NSAID for many years; an IV form of paracetemol, which is not an NSAID, became available in Europe in 2009 and then in the US.[12]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular around 2006.[citation needed]

In 2007, there were concerns about the high incidence of reported side effects. This led to restriction in its dosage and maximum duration of use. In the UK, treatment was initiated only in a hospital, although this was not designed to exclude its use in prehospital care and mountain rescue settings.[7] Dosing guidelines were published at that time.[22]

Concerns over the high incidence of reported side effects with ketorolac trometamol led to its withdrawal (apart from the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide.[23]

The eye-drop formulation was approved by the FDA in 1992.[24] An intranasal formulation was approved by the FDA in 2010[25] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.

Synthesis

DOI: 10.1021/jo00348a014

Image result for Ketorolac SYNTHESIS

1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-benzoyl-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Ketorolac

2-Methylthiopyrrole (I) is benzoylated with N,N-dimethylbenzamide (II) to produce 5-benzoyl-2-methylthiopyrrole (III) in the presence of POCl3 in refluxing CH2Cl2, and the yielding product is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) in the presence of NaH in DMF giving compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol.Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

SYN

DE 2731678; ES 460706; ES 470214; FR 2358406; FR 2375234; GB 1554075

The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol – water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol – water.

SYN2

The benzoylation of 2-methylthiopyrrole (I) with N,N-dimethylbenzamide (II) by means of POCl3 in refluxing CH2Cl2 gives 5-benzoyl-2-methylthiopyrrole (III), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) by means of NaH in DMF yielding compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2 affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol. Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

References

  1. Jump up to:a b c d e f g h i “Ketorolac Tromethamine Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  2. Jump up to:a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1144, 1302–1303. ISBN 9780857113382.
  3. ^ “DailyMed – ketorolac tromethamine tablet, film coated”dailymed.nlm.nih.gov. Retrieved 14 April 2019.
  4. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 521. ISBN 9783527607495.
  5. ^ “NADAC as of 2019-02-27”Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
  6. ^ “The Top 300 of 2019”clincalc.com. Retrieved 22 December 2018.
  7. Jump up to:a b c Mallinson, Tom (2017). “A review of ketorolac as a prehospital analgesic”Journal of Paramedic Practice9 (12): 522–526. doi:10.12968/jpar.2017.9.12.522. Retrieved 2 June 2018.
  8. Jump up to:a b c d e f g h i Vallerand, April H. (2017). Davis’s Drug Guide for Nurses. Philadelphia: F.A. Davis Company. p. 730. ISBN 9780803657052.
  9. Jump up to:a b c d e f g Physician’s Desk Reference 2017. Montvale, New Jersey: PDR, LLC. 2017. pp. S–474–5. ISBN 9781563638381.
  10. ^ “Ketorolac-tromethamine”The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  11. Jump up to:a b Henry, p. 291.
  12. Jump up to:a b c Martin, Lizabeth D; Jimenez, Nathalia; Lynn, Anne M (2017). “A review of perioperative anesthesia and analgesia for infants: updates and trends to watch”F1000Research6: 120. doi:10.12688/f1000research.10272.1ISSN 2046-1402PMC 5302152PMID 28232869.
  13. Jump up to:a b Schwier, Nicholas; Tran, Nicole (2016). “Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis”Pharmaceuticals9 (2): 17. doi:10.3390/ph9020017ISSN 1424-8247PMC 4932535PMID 27023565.
  14. ^ Saenz-de-Viteri, Manuel; Gonzalez-Salinas, Roberto; Guarnieri, Adriano; Guiaro-Navarro, María Concepción (2016). “Patient considerations in cataract surgery – the role of combined therapy using phenylephrine and ketorolac”Patient Preference and Adherence10: 1795–1801. doi:10.2147/PPA.S90468ISSN 1177-889XPMC 5029911PMID 27695298.
  15. ^ Karch, Amy (2017). Focus on nursing pharmacology. Philadelphia: Wolters Kluwer. p. 272. ISBN 9781496318213.
  16. ^ Lim, Blanche X; Lim, Chris HL; Lim, Dawn K; Evans, Jennifer R; Bunce, Catey; Wormald, Richard; Wormald, Richard (2016). “Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery”Cochrane Database Syst Rev11: CD006683. doi:10.1002/14651858.CD006683.pub3PMID 27801522.
  17. ^ Sivaprasad, Sobha; Bunce, Catey; Crosby-Nwaobi, Roxanne; Sivaprasad, Sobha (2012). “Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery”. Cochrane Database Syst Rev (2): CD004239. doi:10.1002/14651858.CD004239.pub3PMID 22336801.
  18. ^ Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, Ghandour O, McCormick R, Walsh CD, Amayem A, Lang E, Harrison N (2017). “Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions”. Cochrane Database Syst Rev5: CD009781. doi:10.1002/14651858.CD009781.pub2PMID 28516471.
  19. Jump up to:a b Henry, p. 279.
  20. ^ Henry, p. 280.
  21. ^ Lee, I. O.; Seo, Y. (2008). “The Effects of Intrathecal Cyclooxygenase-1, Cyclooxygenase-2, or Nonselective Inhibitors on Pain Behavior and Spinal Fos-Like Immunoreactivity”. Anesthesia & Analgesia106 (3): 972–977, table 977 contents. doi:10.1213/ane.0b013e318163f602PMID 18292448.
  22. ^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4.
  23. ^ Committee on the Safety of Medicines, Medicines Control Agency: Ketorolac: new restrictions on dose and duration of treatment. Current Problems in Pharmacovigilance:June 1993; Volume 19 (pages 5-8).
  24. ^ “Ketorolac ophthalmic medical facts from”. Drugs.com. Retrieved 2013-10-06.
  25. ^ “Sprix Information from”. Drugs.com. Retrieved 2013-10-06.

Bibliography

External links

Ketorolac
Ketorolac.svg
Ketorolac ball-and-stick.png
Clinical data
Trade names Toradol, Acular, Sprix, others
Synonyms Ketorolac tromethamine
AHFS/Drugs.com Monograph
MedlinePlus a693001
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration
By mouth, IMIV, eye drops
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% (All routes)
Metabolism Liver
Elimination half-life 3.5 h to 9.2 h, young adults;
4.7 h to 8.6 h, elderly (mean age 72)
Excretion Kidney: 91.4% (mean)
Biliary: 6.1% (mean)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.110.314 Edit this at Wikidata
Chemical and physical data
Formula C15H13NO3
Molar mass 255.27 g/mol g·mol−1
3D model (JSmol)
Chirality Racemic mixture

//////////Ketorolac,

Cavosonstat (N-91115)


Cavosonstat.png

Cavosonstat (N-91115)

CAS 1371587-51-7

C16H10ClNO3, 299.71 g/mol

UNII-O2Z8Q22ZE4, O2Z8Q22ZE4, NCT02589236; N91115-2CF-05; SNO-6

3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid

Treatment of Chronic Obstructive Pulmonary Diseases (COPD), AND Cystic fibrosis,  Nivalis Therapeutics, phase 2

The product was originated at Nivalis Therapeutics, which was acquired by Alpine Immune Sciences in 2017. In 2018, Alpine announced the sale and transfer of global rights to Laurel Venture Capital for further product development.

In 2016, orphan drug and fast track designations were granted to the compound in the U.S. for the treatment of cystic fibrosis.

  • Originator N30 Pharma
  • Developer Nivalis Therapeutics
  • Class Small molecules
  • Mechanism of Action Cystic fibrosis transmembrane conductance regulator modulators; Glutathione-independent formaldehyde dehydrogenase inhibitors; Nitric oxide stimulants
  • Orphan Drug Status Yes – Cystic fibrosis
  • 20 Jul 2018 Laurel Venture Capital acquires global rights for cavosonstat from Alpine Immune Sciences
  • 20 Jul 2018 Laurel Venture Capital plans a phase II trial for Asthma
  • 24 Jun 2018 Biomarkers information updated

 Cavosonstat, alos known as N91115) an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.

cavosonstat-n91115Cavosonstat (N91115) was an experimental therapy being developed by Nivalis Therapeutics. Its primary mechanism of action was to inhibit the S-nitrosoglutathione reductase (GSNOR) enzyme and to stabilize cystic fibrosis transmembrane regulator (CFTR) protein activity. A press release published in February announced the end of research for this therapy in cystic fibrosis (CF) patients with F508del mutations. The drug, which did not meet primary endpoints in a Phase 2 trial, had been referred to as the first of a new class of compounds that stabilizes the CFTR activity.

History of cavosonstat

During preclinical studies, N91115 (later named cavosonstat) demonstrated an improvement in cystic fibrosis transmembrane regulator (CFTR) stability.

Phase 1 study was initiated in 2014 to evaluate the safety, tolerability, and pharmacokinetics (how a drug is processed in the body) of the drug in healthy volunteers. Later that year, the pharmacokinetics of the drug were assessed in another Phase 1 trial involving CF patients with F508del mutation suffering from pancreatic insufficiency. Results were presented a year later by Nivalis, revealing good tolerance and safety in study participants.

A second, much smaller Phase 2 study (NCT02724527) assessed cavosonstat as an add-on therapy to ivacaftor (Kalydeco). This double-blind, randomized, placebo-controlled study included 19 participants who received treatment with cavosonstat (400 mg) added to Kalydeco or with placebo added to Kalydeco. The primary objective was change in lung function from the study’s start to week 8. However, the treatment did not demonstrate a benefit in lung function measures or in sweat chloride reduction at eight weeks (primary objective). As a result, Nivalis decided not to continue development of cavosonstat for CF treatment.

The U.S. Food and Drug Administration (FDA) had granted cavosonstat both fast track and orphan drug designations in 2016.

How cavosonstat works

The S-nitrosoglutathione (GSNO) is a signaling molecule that is present in high concentrations in the fluids of the lungs or muscle tissues, playing an important role in the dilatation of the airways. GSNO levels are regulated by the GSNO reductase (GSNOR) enzyme, altering CFTR activity in the membrane. In CF patients, GSNO levels are low, causing a loss of the airway function.

Cavosonstat’s mechanism of action is achieved through GSNOR inhibition, which was presumed to control the deficient CFTR protein. Preclinical studies showed that cavosonstat restored GSNO levels.

PATENT
WO 2012083165

The chemical compound nitric oxide is a gas with chemical formula NO. NO is one of the few gaseous signaling molecules known in biological systems, and plays an important role in controlling various biological events. For example, the endothelium uses NO to signal surrounding smooth muscle in the walls of arterioles to relax, resulting in vasodilation and increased blood flow to hypoxic tissues. NO is also involved in regulating smooth muscle proliferation, platelet function, and neurotransmission, and plays a role in host defense. Although NO is highly reactive and has a lifetime of a few seconds, it can both diffuse freely across membranes and bind to many molecular targets. These attributes make NO an ideal signaling molecule capable of controlling biological events between adjacent cells and within cells.

[0003] NO is a free radical gas, which makes it reactive and unstable, thus NO is short lived in vivo, having a half life of 3-5 seconds under physiologic conditions. In the presence of oxygen, NO can combine with thiols to generate a biologically important class of stable NO adducts called S-nitrosothiols (SNO’s). This stable pool of NO has been postulated to act as a source of bioactive NO and as such appears to be critically important in health and disease, given the centrality of NO in cellular homeostasis (Stamler et al., Proc. Natl. Acad. Sci. USA, 89:7674-7677 (1992)). Protein SNO’s play broad roles in the function of cardiovascular, respiratory, metabolic, gastrointestinal, immune, and central nervous system (Foster et al., Trends in Molecular Medicine, 9 (4): 160-168, (2003)). One of the most studied SNO’s in biological systems is S-nitrosoglutathione (GSNO) (Gaston et al., Proc. Natl. Acad. Sci. USA 90: 10957-10961 (1993)), an emerging key regulator in NO signaling since it is an efficient trans-nitrosating agent and appears to maintain an equilibrium with other S-nitrosated proteins (Liu et al., Nature, 410:490-494 (2001)) within cells. Given this pivotal position in the NO-SNO continuum, GSNO provides a therapeutically promising target to consider when NO modulation is pharmacologically warranted.

[0004] In light of this understanding of GSNO as a key regulator of NO homeostasis and cellular SNO levels, studies have focused on examining endogenous production of GSNO and SNO proteins, which occurs downstream from the production of the NO radical by the nitric oxide synthetase (NOS) enzymes. More recently there has been an increasing understanding of enzymatic catabolism of GSNO which has an important role in governing available concentrations of GSNO and consequently available NO and SNO’s.

[0005] Central to this understanding of GSNO catabolism, researchers have recently identified a highly conserved S-nitrosoglutathione reductase (GSNOR) (Jensen et al., Biochem J., 331 :659-668 (1998); Liu et al., (2001)). GSNOR is also known as glutathione-dependent formaldehyde dehydrogenase (GSH-FDH), alcohol dehydrogenase 3 (ADH-3) (Uotila and Koivusalo, Coenzymes and Coƒactors., D. Dolphin, ed. pp. 517-551 (New York, John Wiley & Sons, (1989)), and alcohol dehydrogenase 5 (ADH-5). Importantly GSNOR shows greater activity toward GSNO than other substrates (Jensen et al., (1998); Liu et al., (2001)) and appears to mediate important protein and peptide denitrosating activity in bacteria, plants, and animals. GSNOR appears to be the major GSNO-metabolizing enzyme in eukaryotes (Liu et al., (2001)). Thus, GSNO can accumulate in biological compartments where GSNOR activity is low or absent (e.g. , airway lining fluid) (Gaston et al., (1993)).

[0006] Yeast deficient in GSNOR accumulate S-nitrosylated proteins which are not substrates of the enzyme, which is strongly suggestive that GSNO exists in equilibrium with SNO-proteins (Liu et al., (2001)). Precise enzymatic control over ambient levels of GSNO and thus SNO-proteins raises the possibility that GSNO/GSNOR may play roles across a host of physiological and pathological functions including protection against nitrosative stress wherein NO is produced in excess of physiologic needs. Indeed, GSNO specifically has been implicated in physiologic processes ranging from the drive to breathe (Lipton et al., Nature, 413: 171-174 (2001)) to regulation of the cystic fibrosis transmembrane regulator (Zaman et al., Biochem Biophys Res Commun, 284:65-70 (2001)), to regulation of vascular tone, thrombosis, and platelet function (de Belder et al., Cardiovasc Res.; 28(5):691-4 (1994)), Z. Kaposzta, et al., Circulation; 106(24): 3057 – 3062, (2002)) as well as host defense (de Jesus-Berrios et al., Curr. Biol., 13: 1963-1968 (2003)). Other studies have found that GSNOR protects yeast cells against nitrosative stress both in vitro (Liu et al., (2001)) and in vivo (de Jesus-Berrios et al., (2003)).

[0007] Collectively, data suggest GSNO as a primary physiological ligand for the enzyme S-nitrosoglutathione reductase (GSNOR), which catabolizes GSNO and

consequently reduces available SNO’s and NO in biological systems (Liu et al., (2001)), (Liu et al., Cell, 116(4), 617-628 (2004)), and (Que et al., Science, 308, (5728): 1618-1621 (2005)). As such, this enzyme plays a central role in regulating local and systemic bioactive NO. Since perturbations in NO bioavailability has been linked to the pathogenesis of numerous disease states, including hypertension, atherosclerosis, thrombosis, asthma, gastrointestinal disorders, inflammation, and cancer, agents that regulate GSNOR activity are candidate therapeutic agents for treating diseases associated with NO imbalance.

[0008] Nitric oxide (NO), S-nitrosoglutathione (GSNO), and S-nitrosoglutathione reductase (GSNOR) regulate normal lung physiology and contribute to lung pathophysiology. Under normal conditions, NO and GSNO maintain normal lung physiology and function via their anti-inflammatory and bronchodilatory actions. Lowered levels of these mediators in pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) may occur via up-regulation of GSNOR enzyme activity. These lowered levels of NO and GSNO, and thus lowered anti-inflammatory capabilities, are key events that contribute to pulmonary diseases and which can potentially be reversed via GSNOR inhibition.

[0009] S-nitrosoglutathione (GSNO) has been shown to promote repair and/or regeneration of mammalian organs, such as the heart (Lima et al., 2010), blood vessels (Lima et al., 2010) skin (Georgii et al., 2010), eye or ocular structures (Haq et al., 2007) and liver (Prince et al., 2010). S-nitrosoglutathione reductase (GSNOR) is the major catabolic enzyme of GSNO. Inhibition of GSNOR is thought to increase endogenous GSNO.

[0010] Inflammatory bowel diseases (IBD’s), including Crohn’s and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal (GI) tract, in which NO, GSNO, and GSNOR can exert influences. Under normal conditions, NO and GSNO function to maintain normal intestinal physiology via anti-inflammatory actions and maintenance of the intestinal epithelial cell barrier. In IBD, reduced levels of GSNO and NO are evident and likely occur via up-regulation of GSNOR activity. The lowered levels of these mediators contribute to the pathophysiology of IBD via disruption of the epithelial barrier via dysregulation of proteins involved in maintaining epithelial tight junctions. This epithelial barrier dysfunction, with the ensuing entry of micro-organisms from the lumen, and the overall lowered anti-inflammatory capabilities in the presence of lowered NO and GSNO, are key events in IBD progression that can be potentially influenced by targeting GSNOR.

[0011] Cell death is the crucial event leading to clinical manifestation of

hepatotoxicity from drugs, viruses and alcohol. Glutathione (GSH) is the most abundant redox molecule in cells and thus the most important determinant of cellular redox status. Thiols in proteins undergo a wide range of reversible redox modifications during times of exposure to reactive oxygen and reactive nitrogen species, which can affect protein activity. The maintenance of hepatic GSH is a dynamic process achieved by a balance between rates of GSH synthesis, GSH and GSSG efflux, GSH reactions with reactive oxygen species and reactive nitrogen species and utilization by GSH peroxidase. Both GSNO and GSNOR play roles in the regulation of protein redox status by GSH.

[0012] Acetaminophen overdoses are the leading cause of acute liver failure (ALF) in the United States, Great Britain and most of Europe. More than 100,000 calls to the U.S. Poison Control Centers, 56,000 emergency room visits, 2600 hospitalizations, nearly 500 deaths are attributed to acetaminophen in this country annually. Approximately, 60% recover without needing a liver transplant, 9% are transplanted and 30% of patients succumb to the illness. The acetaminophen-related death rate exceeds by at least three-fold the number of deaths due to all other idiosyncratic drug reactions combined (Lee, Hepatol Res 2008; 38 (Suppl. 1):S3-S8).

[0013] Liver transplantation has become the primary treatment for patients with fulminant hepatic failure and end-stage chronic liver disease, as well as certain metabolic liver diseases. Thus, the demand for transplantation now greatly exceeds the availability of donor organs, it has been estimated that more than 18 000 patients are currently registered with the United Network for Organ Sharing (UNOS) and that an additional 9000 patients are added to the liver transplant waiting list each year, yet less than 5000 cadaveric donors are available for transplantation.

[0014] Currently, there is a great need in the art for diagnostics, prophylaxis, ameliorations, and treatments for medical conditions relating to increased NO synthesis and/or increased NO bioactivity. In addition, there is a significant need for novel compounds, compositions, and methods for preventing, ameliorating, or reversing other NO-associated disorders. The present invention satisfies these needs.

Schemes 1-6 below illustrate general methods for preparing analogs.

[00174] For a detailed example of General Scheme 1 see Compound IV-1 in Example 1.

[00175] For a detailed example of Scheme 2, A conditions, see Compound IV-2 in Example 2.

[00176] For a detailed example of Scheme 2, B conditions, see Compound IV-8 in Example 8.

[00177] For a detailed example of Scheme 3, see Compound IV-9 in Example 9.

[00178] For a detailed example of Scheme 4, Route A, see Compound IV-11 in Example 11.

[00179] For a detailed example of Scheme 4, Route B, see Compound IV-12 in Example 12.

[00180] For a detailed example of Scheme 5, Compound A, see Compound IV-33 in Example 33.

[00181] For a detailed example of Scheme 5, Compound B, see Compound IV-24 in Example 24.

[00182] For a detailed example of Scheme 5, Compound C, see Compound IV-23 in Example 23.

Example 8: Compound IV-8: 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid

[00209] Followed Scheme 2, B conditions:

[00210] Step 1: Synthesis of 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid:

[00211] A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1) (200 mg, 1.04 mmol), 4-carboxy-2-chlorophenylboronic acid (247 mg, 1.24 mmol) and K2CO3(369 mg, 2.70 mmol) in DEGME / H2O (7.0 mL / 2.0 mL) was degassed three times under N2 atmosphere. Then PdCl2(dppf) (75 mg, 0.104 mmol) was added and the mixture was heated to 110 °C for 3 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, yield 46%) as a yellow solid, which was used for the next step without further purification.

[00212] Step 2: Synthesis of Compound IV-8: To a suspension of 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, 0.479 mmol) in anhydrous CH2Cl2 (5 mL) was added AlCl3 (320 mg, 2.40 mmol). The reaction mixture was refluxed overnight. The mixture was quenched with saturated NH4Cl (10 mL) and the aqueous layer was extracted with CH2Cl2 / MeOH (v/v=10: l, 30 mL x3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive) to give 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (25 mg, yield 18%). 1H NMR (DMSO, 400 MHz): δ 10.20 (brs, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.10-8.00 (m, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 6.4, 2.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), MS (ESI): m/z 299.9 [M+H]+.

PATENT
WO 2012048181
PATENT
WO 2012170371

REFERENCES

1: Donaldson SH, Solomon GM, Zeitlin PL, Flume PA, Casey A, McCoy K, Zemanick ET,
Mandagere A, Troha JM, Shoemaker SA, Chmiel JF, Taylor-Cousar JL.
Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic
fibrosis adults homozygous for F508DEL-CFTR. J Cyst Fibros. 2017 Feb 13. pii:
S1569-1993(17)30016-4. doi: 10.1016/j.jcf.2017.01.009. [Epub ahead of print]
PubMed PMID: 28209466.

//////////Cavosonstat, N-91115, Orphan Drug Status, NCT02589236, N91115-2CF-05,  SNO-6, PHASE 2, N30 Pharma, Nivalis Therapeutics, CYSTIC FIBROSIS, FAST TRACK

O=C(O)C1=CC=C(C2=NC3=CC=C(O)C=C3C=C2)C(Cl)=C1

Deutivacaftor


2D chemical structure of 1413431-07-8

Ivacaftor D9.png

Structure of DEUTIVACAFTOR

Deutivacaftor

RN: 1413431-07-8
UNII: SHA6U5FJZL

N-[2-tert-butyl-4-[1,1,1,3,3,3-hexadeuterio-2-(trideuteriomethyl)propan-2-yl]-5-hydroxyphenyl]-4-oxo-1H-quinoline-3-carboxamide

Molecular Formula, C24-H28-N2-O3, Molecular Weight, 401.552

Synonyms

  • CTP-656
  • D9-ivacaftor
  • Deutivacaftor
  • Ivacaftor D9
  • UNII-SHA6U5FJZL
  • VX-561
  • WHO 10704

Treatment of Cystic Fibrosis

  • Originator Concert Pharmaceuticals
  • Class Amides; Aminophenols; Antifibrotics; Organic deuterium compounds; Quinolones; Small molecules
  • Mechanism of Action Cystic fibrosis transmembrane conductance regulator stimulants
  • Orphan Drug Status Yes – Cystic fibrosis
  • Phase II Cystic fibrosis
  • 15 Apr 2019 Vertex Pharmaceuticals plans a phase II trial for Cystic fibrosis in April 2019 , (EudraCT2018-003970-28), (NCT03911713)
  • 11 Apr 2019 Vertex Pharmaceuticals plans a phase II trial for Cystic Fibrosis (Combination therapy) in May 2019 (NCT03912233)
  • 24 Oct 2018 Vertex Pharmaceuticals plans a phase II trial for Cystic fibrosis (with gating mutation) in the US in the first half of 2019

Patent

WO 2012158885

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=A7EFB561D919F34531D65DF294F8D74C.wapp1nB?docId=WO2012158885&tab=PCTDESCRIPTION&queryString=%28+&recNum=99&maxRec=1000

Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, nonradioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res, 1985, 14: 1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol, 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem., 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

[9] This invention relates to novel derivatives of ivacaftor, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a CFTR (cystic fibrosis transmembrane conductance regulator) potentiator.

[10] Ivacaftor, also known as VX-770 and by the chemical name, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, acts as a CFTR potentiator. Results from phase III trials of VX-770 in patients with cystic fibrosis carrying at least one copy of the G551D-CFTR mutation demonstrated marked levels of improvement in lung function and other key indicators of the disease including sweat chloride levels, likelihood of pulmonary exacerbations and body weight. VX-770 is also currently in phase II clinical trials in combination with VX-809 (a CFTR corrector) for the oral treatment of cystic fibrosis patients who carry the more common AF508-CFTR mutation. VX-770 was granted fast track designation and orphan drug designation by the FDA in 2006 and 2007, respectively.

[11] Despite the beneficial activities of VX-770, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

Patent

US 20140073667

Patent

JP 2014097964

PATENT

WO 2018183367

https://patentscope.wipo.int/search/zh/detail.jsf?docId=WO2018183367&tab=PCTDESCRIPTION&office=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A61K%22&sortOption=%E5%85%AC%E5%B8%83%E6%97%A5%E9%99%8D%E5%BA%8F&queryString=&recNum=555&maxRec=186391

The use according to embodiment 1, comprising administering to the patient an effect amount of (N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-l, 1, 1,3, 3,3-d6)phenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (Compound Il-d):

Il-d

PATENT

WO 2019018395,

CONTD…………………………..

//////////////////deutivacaftor, Orphan Drug Status, Cystic fibrosis, CTP-656, D9-ivacaftor, Deutivacaftor, Ivacaftor D9, UNII-SHA6U5FJZL, VX-561, WHO 10704, PHASE 2

[2H]C([2H])([2H])C(c1cc(c(NC(=O)C2=CNc3ccccc3C2=O)cc1O)C(C)(C)C)(C([2H])([2H])[2H])C([2H])([2H])[2H]

VX-659, Bamocaftor potassium


VX-659 Chemical Structure

VX-659, BAMOCAFTOR

N-(Benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

3-Pyridinecarboxamide, N-(phenylsulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethyl-1-pyrrolidinyl]-

N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide

CAS Number 2204245-48-5
UNII: 8C7XEW3K7S
BAMOCAFTOR
M. Wt 591.65
Formula C28H32F3N5O4S

str1

2D chemical structure of 2204245-47-4

Bamocaftor potassium

CAS 2204245-47-4

Molecular Formula C28 H31 F3 N5 O4 S . K
 Molecular Weight 629.735

VX-659
VX-659 potassium salt
VY7D8MTV72 (UNII code)

WHO 11167

3-Pyridinecarboxamide, N-(phenylsulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethyl-1-pyrrolidinyl]-, potassium salt (1:1)

Potassium (benzenesulfonyl)[6-(3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carbonyl]azanide

PHASE 2 CYSTIC FIBRIOSIS , VERTEX

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) (DeltaF508 Mutant) Correctors

Bamocaftor potassium is a CFTR channel (DeltaF508-CFTR Mutant) corrector in phase II clinical trials at Vertex, in patients with CF who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene, or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to tezacaftor, ivacaftor, or tezacaftor/ivacaftor and also in combination with tezacaftor and VX-561 in F508del/MF in patients with cystic fibrosis.

The compound is also developed by the company as a fixed-dose combination of VX-659, tezacaftor and ivacaftor.

Vertex Pharmaceuticals is developing a combination regimen comprising VX-659, a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector, with tezacaftor and ivacaftor, as a triple fixed-dose combination tablet. In March 2019, Vertex planned to file an NDA in the US in 3Q19 concurrently in patients aged 12 years or older with one F508del mutation and one minimal function mutation and in patients with two F508del mutations for either the VX-659 or VX-445 triple combination regimen; the regimen selected for a regulatory filing would be based on final 24-week data.

PATENT

WO 2018064632

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018064632

Example 4: Synthesis of Compounds 1-65

[00229] Synthetic Example 1: Synthesis of N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide (Compound 1)

[00230] Part A: Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride

[00231] Step 1: Synthesis of methyl-2,4-dimethyl-4-nitro-pentanoate

[00232] Tetrahydrofuran (THF, 4.5 L) was added to a 20 L glass reactor and stirred under N2 at room temperature. 2-Nitropropane (1.5 kg. 16.83 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.282 kg, 8.42 mol) were then charged to the reactor, and the jacket temperature was increased to 50 °C. Once the reactor contents were close to 50 °C, methyl methacrylate (1.854 kg, 18.52 mol) was added slowly over 100 minutes. The reaction temperature was maintained at or close to 50 °C for 21 hours. The reaction mixture was concentrated in vacuo then transferred back to the reactor and diluted with methyl tert-butyl ether (MTBE) (14 L). 2 M HC1 (7.5 L) was added, and this mixture was stirred for 5 minutes then allowed to settle. Two clear layers were visible – a lower yellow aqueous phase and an upper green organic phase. The aqueous layer was removed, and the organic layer was stirred again with 2 M HC1 (3 L). After separation, the HC1 washes were recombined and stirred with MTBE (3 L) for 5 minutes. The aqueous layer was removed, and all of the organic layers were combined in the reactor and stirred with water (3 L) for 5 minutes. After separation, the organic layers were concentrated in vacuo to afford a cloudy green oil. This was dried with MgSC and filtered to afford methyl-2,4-dimethyl-4-mtro-pentanoate as a clear green oil (3.16 kg, 99% yield). 1H NMR (400 MHz, Chloroform-d) δ 3.68 (s, 3H), 2.56 – 2.35 (m, 2H), 2.11 – 2.00 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.19 (d, J= 6.8 Hz, 3H). [00233] Step 2: Synthesis of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate

[00234] A reactor was charged with purified water (2090 L; 10 vol) and then potassium phosphate monobasic (27 kg, 198.4 moles; 13 g/L for water charge). The pH of the reactor contents was adjusted to pH 6.5 (± 0.2) with 20% (w/v) potassium carbonate solution. The reactor was charged with racemic methyl-2,4-dimethyl-4-nitro-pentanoate (209 kg; 1104.6 moles), and Palatase 20000L lipase (13 L, 15.8 kg; 0.06 vol).

[00235] The reaction mixture was adjusted to 32 ± 2 °C and stirred for 15-21 hours, and pH 6.5 was maintained using a pH stat with the automatic addition of 20% potassium carbonate solution. When the racemic starting material was converted to >98% ee of the S-enantiomer, as determined by chiral GC, external heating was switched off. The reactor was then charged with MTBE (35 L; 5 vol), and the aqueous layer was extracted with MTBE (3 times, 400-1000L). The combined organic extracts were washed with aqueous Na2CO3 (4 times, 522 L, 18 % w/w 2.5 vol), water (523 L; 2.5 vol), and 10% aqueous NaCl (314 L, 1.5 vol). The organic layer was concentrated in vacuo to afford methyl (2S)-2,4-dimethyl-4-nitro-pentanoate as a mobile yellow oil (>98% ee, 94.4 kg; 45 % yield).

[00236] Step 3: Synthesis of (3S)-3,5,5-trimethylpyrrolidin-2-one

[00237] A 20 L reactor was purged with N2. The vessel was charged sequentially with DI water-rinsed, damp Raney® Ni (2800 grade, 250 g), methyl (2S)-2,4-dimethyl-4-nitro-pentanoate (1741g, 9.2 mol), and ethanol (13.9 L, 8 vol). The reaction was stirred at 900 rpm, and the reactor was flushed with H2 and maintained at -2.5 bar. The reaction mixture was then warmed to 60 °C for 5 hours. The reaction mixture was cooled and filtered to remove Raney nickel, and the solid cake was rinsed with ethanol (3.5 L, 2 vol). The ethanolic solution of the product was combined with a second equal sized batch and concentrated in vacuo to reduce to a minimum volume of ethanol (-1.5 volumes). Heptane (2.5 L) was added, and the suspension was concentrated again to -1.5 volumes. This was repeated 3 times; the resulting suspension was cooled to 0-5 °C, filtered under suction, and washed with heptane (2.5 L). The product was dried under vacuum for 20 minutes then transferred to drying trays and dried in a vacuum oven at 40 °C overnight to afford (3S)-3,5,5-trimethylpyrrolidin-2-one as a white crystalline solid (2.042 kg, 16.1 mol, 87 %). 1H NMR (400 MHz, Chloroform-d) δ 6.39 (s, 1H), 2.62 (ddq, J = 9.9, 8.6, 7.1 Hz, 1H), 2.17 (dd, J = 12.4, 8.6 Hz, 1H), 1.56 (dd, J = 12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H).

[00238] Step 4: Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride

[00239] A glass lined 120 L reactor was charged with lithium aluminium hydride pellets (2.5 kg, 66 mol) and dry THF (60 L) and warmed to 30 °C. The resulting suspension was charged with (S)-3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over 2 hours while maintaining the reaction temperature at 30 to 40 °C. After complete addition, the reaction temperature was increased to 60 – 63 °C and maintained overnight. The reaction mixture was cooled to 22 °C, then cautiously quenched with the addition of ethyl acetate (EtOAc) (1.0 L, 10 moles), followed by a mixture of THF (3.4 L) and water (2.5 kg, 2.0 eq), and then a mixture of water (1.75 kg) with 50 % aqueous sodium hydroxide (750 g, 2 equiv water with 1.4 equiv sodium hydroxide relative to aluminum), followed by 7.5 L water. After the addition was complete, the reaction mixture was cooled to room temperature, and the solid was removed by filtration and washed with THF (3 x 25 L). The filtrate and washings were combined and treated with 5.0 L (58 moles) of aqueous 37% HCl (1.05 equiv.) while maintaining the temperature below 30°C. The resultant solution was concentrated by vacuum distillation to a slurry. Isopropanol (8 L) was added and the solution was concentrated to near dryness by vacuum distillation. Isopropanol (4 L) was added, and 1he product was slurried by warming to about 50 °C. MTBE (6 L) was added, and the

slurry was cooled to 2-5 °C. The product was collected by filtration and rinsed with 12 L MTBE and dried in a vacuum oven (55 °C/300 torr/N2 bleed) to afford (4S)-2,2,4- trimethylpyrrolidine’HCl as a white, crystalline solid (6.21 kg, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (br d, 2H), 3.33 (dd, J = 11.4, 8.4 Hz, 1H), 2.75 (dd, / = 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, J= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, J = 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J= 6.6 Hz, 3H).

[00240] Part B: Synthesis of N-(benzenesulfonyl)-6-[3-[2-[l- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-l-yl]pyridine-3-carboxamide

[00241] Synthesis of starting materials:

[00242] Synthesis of tert-Butyl 2,6-dichloropyridine-3-carboxylate

[00243] A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol) in THF (210 mL) was treated successively with di-tert-butyl dicarbonate (17 g, 77.89 mmol) and 4-(dimethylamino)pyridine (3.2 g, 26.19 mmol) and stirred overnight at room temperature. At this point, HC1 IN (400 mL) was added, and the mixture was stirred vigorously for about 10 minutes. The product was extracted with ethyl acetate (2x300mL), and the combined organic layers were washed with water (300 mL) and brine (150 mL) and dried over sodium sulfate and concentrated under reduced pressure to give 12.94 g (96% yield) of tert- butyl 2,6-dichloropyndine-3-carboxylate as a colorless oil. ESI-MS m/z calc. 247.02, found 248.1 (M+l) +; Retention time: 2.27 minutes. 1H NMR (300 MHz, CDC13) ppm 1.60 (s, 9H), 7.30 (d, .7=7.9 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H).

[00244] Synthesis of tert-Butyl 3-oxo-2,3-dihydro-lH-pyrazole-l-carboxylate

[00245] A 50L reactor was started, and the jacket was set to 20 °C, with stirring at 150 rpm, reflux condenser (10 °C) and nitrogen purge. MeOH (2.860 L) and methyl (E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added, and the reactor was capped. The reaction was heated to an internal temperature of 40 °C, and the system was set to hold jacket temperature at 40 °C. Hydrazine hydrate (1300 g of 55 %w/w, 22.31 mol) was added portion wise via addition funnel over 30 min. The reaction was heated to 60 °C for 1 h. The reaction mixture was cooled to 20 °C and triethyamine (2.483 kg, 3.420 L, 24.54 mol) was added portion-wise, maintaining reaction temperature <30 °C. A solution of Boc anhydride (di-tert-butyl dicarbonate) (4.967 kg, 5.228 L. 22.76 mol) in MeOH (2.860 L) was added portion-wise maintaining temperature <45 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction solution was partially concentrated to remove MeOH, resulting in a clear, light amber oil. The resulting oil was transferred to the 50L reactor, stirred and water (7.150 L) and heptane (7.150 L) were added. The additions caused a small amount of the product to precipitate. The aqueous layer was drained into a clean container, and the interface and heptane layer were filtered to separate the solid (product). The aqueous layer was transferred back to the reactor, and the collected solid was placed back into the reactor and mixed with the aqueous layer. A dropping funnel was added to the reactor and loaded with acetic acid (1.474 kg, 1.396 L, 24.54 mol) and added dropwise. The jacket was set to 0 °C to absorb the quench exotherm. After the addition was complete (pH=5), the reaction mixture was stirred for 1 h. The solid was collected by filtration and washed with water (7.150 L), and washed a second time with water (3.575 L). The crystalline solid was transferred into a 20L rotovap bulb, and heptane (7.150 L) was added. The mixture was slurried at 45 °C for 30 mins, and 1-2 volumes of solvent were distilled off The slurry in the rotovap flask was filtered, and the solids were washed with heptane (3.575 L). The solid was further dried in vacuo (50 °C, 15 mbar) to give tert-butyl 5-oxo-lH-pyrazole-2-carboxylate (2921 g, 71%) as a coarse, crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.98 (d, J= 2.9 Hz, 1H), 5.90 (d, J= 2.9 Hz, 1H), 1.54 (s, 9H).

[00246] Synthesis of 2-[l-(trifluoromethyl)cyclopropyl]ethanol

[00247] To a solution of lithium aluminum hydride (293 mg, 7.732 mmol) in THF (10.00 mL) in an ice-bath, 2-[l-(trifluoromethyl)cyclopropyl]acetic acid (1.002 g, 5.948 mmol) in THF (3.0 mL) was added dropwise over a period of 30 minutes keeping the reaction temperature below 20 ° C. The mixture was allowed to gradually warm to ambient temperature and was stirred for 18 h. The mixture was cooled with an ice-bath and sequentially quenched with water (294 mg, 295 μL, 16.36 mmol), NaOH (297 μL of 6 M, 1.784 mmol), and then water (884.0 μL, 49.07 mmol) to afford a granular solid in the mixture. The solid was filtered off using celite, and the precipitate was washed with ether. The filtrate was further dried with MgSO4 and filtered and concentrated in vacuo to afford the product with residual THF and ether. The mixture was taken directly into the next step without further purification.

[00248] Step 1: tert-Butyl 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate

[00249] rerf-Butyl 5-oxo-lH-pyrazole-2-carboxylate (1.043 g, 5.660 mmol), 2-[l-(trifluoromethyl)cyclopropyl]ethanol (916 mg, 5.943 mmol), and triphenyl phosphine (1.637 g, 6.243 mmol) were combined in THF (10.48 mL) and the reaction was cooled in an ice-bath. Diisopropyl azodicarboxylate (1.288 g, 1.254 mL, 6.368 mmol) was added dropwise to the reaction mixture, and the reaction was allowed to warm to room temperature for 16 hours. The mixture was evaporated, and the resulting material was partitioned between ethyl acetate (30 mL) and IN sodium hydroxide (30 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0- 30%) to give tert-butyl 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate (1.03 g, 57%). ESI-MS m/z calc. 320.13, found 321.1 (M+l) +; Retention time: 0.72 minutes.

[00250] Step 2: 3-[2-[l-(Trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole

[00251] terr-Butyl-3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate (1.03 g, 3.216 mmol) was dissolved in dichloromethane (10.30 mL) with trifluoroacetic acid (2.478 mL, 32.16 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was evaporated, and the resulting oil was partitioned between ethyl acetate (10 mL) and a saturated sodium bicarbonate solution.

The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated to give 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (612 mg, 86%). ESI-MS m/z calc. 220.08, found 221.0 (M+1) +; Retention time: 0.5 minutes. ¾ NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.50 (t, J = 2.1 Hz, 1H), 5.63 (t, J= 2.3 Hz, 1H), 4.14 (t, J= 7.1 Hz, 2H), 2.01 (t, J= 7.1 Hz, 2H), 0.96 – 0.88 (m, 2H), 0.88 -0.81 (m, 2H).

[00252] Step 3: tert- Butyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridine-3-carboxylate

[00253] tert-Butyl 2,6-dichloropyridine-3-carboxylate (687 mg, 2.770 mmol), 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (610 mg, 2.770 mmol), and freshly ground potassium carbonate (459 mg, 3.324 mmol) were combined in anhydrous DMSO (13.75 mL). l,4-diazabicyclo[2.2.2]octane (DABCO (1,4-diazabicyclo[2.2.2]octane), 62 mg, 0.5540 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (20 mL) and stirred for 15 minutes. The resulting solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and concentrated to give ferf-butyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (1.01 g, 84%). ESI-MS m/z calc. 431.12, found 432.1 (M+1) +; Retention time: 0.88 minutes.

[00254] Step 4: 2-Chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid

[00255] tert-Butyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (1.01 g, 2.339 mmol) and trifluoroacetic acid (1.8 mL, 23.39 mmol) were combined in dichloromethane (10 mL) and heated at 40 °C for 3 h. The reaction was concentrated. Hexanes were added, and the mixture was concentrated again to give 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (873 mg, 99%) ESI-MS m/z calc. 375.06, found 376.1 (M+l)+; Retention time: 0.69 minutes.

[00256] Step 5: N-(Benzenesulfonyl)-2-chloro-6-[3- [2- [1-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridine-3-carboxamide

[00257] A solution of 2-chloro-6-[3-[2-[l- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (0.15 g, 0.3992 mmol) and carbonyl diimidazole (77 mg, 0,4790 mmol) in THF (2.0 mL) was stirred for one hour, and benzenesulfonamide (81 mg, 0.5190 mmol) and DBU (72 μL, 0.4790 mmol) were added. The reaction was stirred for 16 hours, acidified with 1 M aqueous citric acid, and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-5%) to give N-(benzenesulfonyl)-2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyndine-3-carboxamide (160 mg, 78%). ESI-MS m/z calc. 514.07, found 515.1 (M+l)+; Retention time: 0.74 minutes.

[00258] Step 6: N-(Benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl] ethoxy] pyrazol-l-yl] -2- [(4S)-2,2,4-trimethylpyrrolidin-l-yl] pyridine-3-carboxamide

[00259] A mixture of N-(benzenesulfonyl)-2-chloro-6-[3-[2-[l -(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridine-3-carboxamide (160 mg, 0.3107 mmol), (4S)-2,2,4-trimethylpyrrolidine hydrochloride salt (139 mg, 0.9321 mmol), and potassium carbonate (258 mg, 1.864 mmol) in DMSO (1.5 mL) was stirred at 130 °C for 17 hours. The reaction mixture was acidified with 1 M aqueous citric acid and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to yield a crude product that was purified by reverse-phase HPLC utilizing a gradient of 10-99% acetonitrile in 5 mM aqueous HCI to yield N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide (87 mg, 47%). ESI-MS mJz calc. 591.21, found 592.3 (M+l) +; Retention time: 2.21 minutes. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.04 – 7.96 (m, 2H), 7.81 (d, J= 8.2 Hz, 1H), 7.77 – 7.70 (m, 1H), 7.70 – 7.62 (m, 2H), 6.92 (d, J= 8.2 Hz, 1H), 6.10 (d, J= 2.8 Hz, 1H), 4.31 (t, J= 7.0 Hz, 2H), 2.42 (t, J = 10.5 Hz, 1H), 2.28 (dd, J = 10.2, 7.0 Hz, 1H), 2.17 – 2.01 (m, 3H), 1.82 (dd, J= 11.9, 5.5 Hz, 1H), 1.52 (d, .7= 9.4 Hz, 6H), 1.36 (t, J= 12.1 Hz, 1H), 1.01 – 0.92 (m, 2H), 0.92 – 0.85 (m, 2H), 0.65 (d, J = 6.3 Hz, 3H). pKa: 4.95±0.06.

Alternate synthesis of 2-Chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid

[00263] Step 1: ethyl 3-hydroxy-lH-pyrazole-4-carboxylate

[00264] A mixture of EtOH (20.00 L, 10 vol) and diethyl 2-(ethoxymethylene)propanedioate (2000 g, 9.249 mol, 1.0 equiv) was added under nitrogen purge a to a 50 L reactor equipped with a reflux condenser (10 °C) and the jacket set to 40 °C. The mixture was stirred, and then hydrazine hydrate (538.9 g of 55 %w/w, 523.7 mL of 55 %w/w, 9.249 mol, 1.00 equiv) was added in portions via an addition funnel. Once the addition was complete, the reaction was heated to 75 °C for 22 h to afford a solution of ethy l 3-hydroxy-lH-pyrazole-4-carboxylate that was used directly in the next step.

[00265] Step 2: l-(tert-butyl) 4-ethyl 3-hydroxy-lH-pyrazole-l,4-dicarboxylate

[00266] The solution of ethyl 3-hydroxy-lH-pyrazole-4-carboxylate was cooled from 75 °C to 40 °C, then triethylamine (TEA) (46.80 g, 64.46 mL, 462.5 mmol, 0.05 eq.) was added. A solution of Boc anhydride (2.119 kg, 9.711 mol 1.05 equiv) in EtOH (2.000 L, 1 equiv) was added to the reactor over 35 min. The mixture was stirred for 4 hours to complete the reaction; then water (10.00 L, 5.0 vol) was added over 15 mins. The resulting mixture was cooled to 20 °C to complete crystallization of the product. The crystals were allowed to age for 1 hour, then the mixture was filtered. The solid was washed with a mixture of EtOH (4.000 L, 2.0 vol) and water (2.000 L, 1 0 vol) The solid was then dried in vacuo to afford l-(tert-butyl)-4-ethyl-3-hydroxy-lH-pyrazole-1,4-dicarboxylate (1530 g, 65%) as colorless, fine needle, crystalline solid. ‘H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.40 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.56 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).

[00267] Step 3: l-(tert-butyl) 4-ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-l,4-dicarboxylate

[00268] A 5L reactor was started with the jacket set to 40 °C, stirring at 450 rpm, reflux condenser at room temperature and nitrogen purge. The vessel was charged with toluene (1.0L, 10.0 vol), 2-[l-(tnfluoromethyl)cyclopropyl]ethanol (lOO.Og, 648.8 mmol, 1.0 equiv), and l-(tert-butyl) 4-ethyl 3-hydroxy-lH-pyrazole-l,4-dicarboxylate (166.3 g, 648.8 mmol), and the mixture was stirred. The reaction mixture was charged with triphenyl phosphine (195.7 g, 746.1 mmol, 1.15 equiv), then the reactor was set to maintain an internal temperature of 40 °C. Diisopropyl azoldicarboxylate (150.9 g, 746.1 mmol, 1.15 equiv) was added into an addition funnel and was added to the

reaction while maintaining the reaction temperature between 40 and 50 °C (addition was exothermic, exotherm addition controlled), and stirred for a total of 2.5 hours. Once the reaction was deemed complete by HPLC, heptane was added (400 mL, 4 vol), the solution was cooled to 20 °C over 60 minutes, and the bulk of tnphenylphosphine oxide-DIAD complex (TPPO-DIAD) crystallized out. Once at room temp, the mixture was filtered, and the solid was washed with heptane (400 mL, 4.0 vol) and pulled dry. The filtrate was used in the next step as a solution in toluene-heptane without further purification.

[00269] Step 4: ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylate

[00270] A 500mL reactor was started with the jacket set to 40 °C, stirring at 450 rpm, reflux condenser at room temp, and nitrogen purge. The vessel was charged with a toluene solution consisting of approximately 160 mmol, 65.0 g of 1 -(tert-buty 1) 4-ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-l,4-dicarboxylate in 3 vol of toluene (prepared by concentrating a 25% portion of filtrate from previous reaction down to 4 volumes in a rotovap). The reaction was set to maintain an internal temperature at 40 °C and KOH (33.1 g, 1.5 eq. of aqueous 45 % KOH solution) was added in one portion, resulting in a mild exothermic addition, while CO2 was generated upon removal of the protecting group. The reaction proceeded for 1.5 hr, monitored by HPLC, with the product partially crystallizing during the reaction. Heptane (160 mL, 2.5 vol) was added to the reaction mixture and the reaction was cooled to room temperature over 30 minutes. The resulting mixture was filtered, and the solid was washed with heptane (80.00 mL, 1.25 vol), pulled dry, then dried in vacuo (55 °C, vacuum). 52.3 g of ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylate was obtained as a crude, colorless solid that was used without further purification.

[00271] Step 5: 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylic acid

[00272] A 500mL reactor was started with the jacket set to 40 °C, stirring at 450 rpm, reflux condenser at room temp, and nitrogen purge. The vessel was charged with methanol (150.0 mL, 3.0 vol), a solution of ethyl 3-(2-(l-(triiluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylate (50.0 g, 171.1 mmol, 1.0 equiv), and the reaction was stirred to suspend the solids. The reactor was set to maintain internal temperature at 40 °C. To the mixture was added KOH (96 g of aqueous 45 % KOH, 1.71 mol, 10.0 equiv) in portions maintaining the internal temperature <50 °C. Once addition was complete, the reaction was set to maintain temperature at 50 °C, and the reaction proceeded for 23 hours, monitored by HPLC. Once complete the reaction was cooled to 10 °C then partially concentrated on a rotary evaporator to remove most of the MeOH. The resulting solution was diluted with water (250 mL, 5.0 vol) and 2-Me-THF (150 mL, 3.0 vol), and transferred to the reactor, stirred at room temp, then stopped, and layers were allowed to separate. The layers were tested, with remaining TPPO-DIAD complex in the organic layer and product in the aqueous layer. The aqueous layer was washed again with 2-Me-THF (100 mL, 2.0 vol), the layers separated, and the aqueous layer returned to the reactor vessel. The stirrer was started and set to 450 rpm, and the reactor jacket was set to 0 °C. The pH was adjusted to pH acidic by addition of 6M aqueous HC1 (427mL, 15 equiv) portion wise, maintaining the internal temperature between 10 and 30 °C. The product began to crystallize close to pH neutral and was accompanied with strong off-gassing, and so the acid was added slowly, and then further added to reach pH 1 once the off-gassing had ended. To the resulting suspension was added 2-Me-THF (400 mL, 8.0 vol), and the product was allowed to dissolve into the organic layer. Stirring was stopped, the layers were separated, and the aqueous layer was returned to the reactor, stirred and re-extracted with 2-Me-THF (100 mL, 2.0 vol). The organic lay ers were combined in the reactor and stirred at room temperature, washed with brine (lOOmL, 2 vols), dried over Na2S04, filtered through celite, and the solid was washed with 2-Me-THF (50 mL, 1.0 vol). The filtrate was transferred to a clean rotovap flask, stirred, warmed to 50 °C and heptane (200 mL, 4.0 vol) added, and then partially concentrated with the addition of heptane (300 mL, 6.0 vol) and then seeded with 50mg of 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylic acid), and the product crystallized during solvent removal. The distillation was stopped when the bulk of the 2-Me-THF had distilled off. The bath heater was turned off, the vacuum removed, and the mixture was allowed to stir and cool to room temperature. The mixture was filtered (slow speed) and the solid was washed with heptane (100 mL, 2.0 vol), and the solid was collected and dried in vacuo (50 °C, rotovap). 22.47 g of 3-(2-(l-(triiluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylic acid was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d) δ 12.45 (s, 2H), 8.01 (s, 1H), 4.26 (t, J = 7.0 Hz, 2H), 2.05 (t, J= 7.0 Hz, 2H), 0.92 (m, 4H).

[00273] Step 6: 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole

[00274] A mixture of toluene (490.0 mL), 3-(2-(l- (triiluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylic acid (70.0 g, 264.9 mmol), and DMSO (70.00 mL) was placed in a reactor and heated to 100 °C with stirring. DBU (approximately 20.16 g, 19.80 mL, 132.4 mmol) was added to the reactor over 15 min. The mixture was stirred for 20 h to complete the reaction and then cooled to 20 °C. The mixture was washed with water (350.0 mL), then 0.5N aq HC1 (280.0 mL), then water (2 x 140.0 mL), and lastly with bnne (210.0 mL). The organic layer was dried with Na2S04, and then activated charcoal (5 g, Darco 100 mesh) was added to the stirred slurry. The dried mixture was filtered through celite, and the solid was washed with toluene (140.0 mL) and then pulled dry. The filtrate was concentrated in a rotovap (50 °C, vac) to afford 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-

pyrazole (30.89 g, 53%) as an amber oil. 1H NMR (400 MHz, DMSO-4,) δ 11.87 (s, 1H), 7.50 (d, J= 2.4 Hz, 1H), 5.63 (d, 7= 2.4 Hz, 1H), 4.23 – 4.06 (m, 2H), 2.01 (t, J= 7.1 Hz, 2H), 1.00 – 0.77 (m, 4H).

[00275] Step 7: ethyl 2-chloro-6-[3-[2-[l- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate

[00276] A mixture of DMF (180.0 mL), ethyl 2,6-dichloropyridine-3-carboxylate (approximately 29.97 g, 136.2 mmol), 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (30.0 g, 136.2 mmol), and K2CO3, (325 mesh, approximately 24.48 g, 177.1 mmol) was added to a stirred reactor at 20 °C. DABCO (approximately 2.292 g, 20.43 mmol) was then added to the reactor, and the mixture was stirred at 20 °C for 1 hour, and then the temperature was increased to 30 °C, and the mixture stirred for 24 hours to complete the reaction. The mixture was cooled to 20 °C; then water (360 mL) was added slowly. The mixture was then drained from the reactor and the solid was isolated by filtration. The solid was then washed with water (2 x 150 mL), and then the solid was dried under vacuum at 55 °C to afford ethyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (51.37 g, 93%) as a fine, beige colored solid. 1H NMR (400 MHz, DMSO-c4) δ 8.44 (d, J= 2.9 Hz, 1H), 8.41 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 8.5 Hz, 1H), 6.21 (d, J= 2.9 Hz, 1H), 4.34 (m, 4H), 2.09 (t, J= 7.1 Hz, 2H), 1.34 (t, J= 7.1 Hz, 3H), 1.00 – 0.84 (m, 4H).

[00277] Step 8: 2-Chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid

[00278] A solution of ethyl 2-chloro-6-[3-[2-[l- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (50.0 g, 123.8 mmol) in THF (300.0 mL) was prepared in a reactor at 20 °C. EtOH (150.0 mL) was added, followed by aqueous NaOH (approximately 59.44 g of 10 %w/w, 148.6 mmol). The mixture was stirred for 1 hour to complete the reaction; then aq IN HCl (750.0 mL) was slowly added. The resulting suspension was stirred for 30 mm at 10 °C, and then the solid was isolated by filtration. The solid was washed with water (150 mL then 2 x 100 mL) and then pulled dry by vacuum. The solid was then further dried under vacuum with heating to afford 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (42.29 g, 91%). 1H NMR (400 MHz, DMSO-d 6) 5 13.63 (s, 1H), 8.48 – 8.35 (m, 2H), 7.73 (d, J= 8.4 Hz, 1H), 6.20 (d, J= 2.9 Hz, 1H), 4.35 (t, J = 7.1 Hz, 2H), 2.09 (t, J= 7.1 Hz, 2H), 1.01 – 0.82 (m, 4H).

PATENT

WO2018227049

Follows on from WO2018227049 , claiming a composition comprising this compound and at least one of tezacaftor, ivacaftor, deutivacaftor or lumacaftor, useful for treating CF.

PATENT

WO-2019079760

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019079760&tab=PCTDESCRIPTION&maxRec=1000

Novel crystalline forms of the compound, the potassium salt of which is presumed to be VX-659 , Such as Forms A, B, C, D, E, H and M , processes for their preparation and compositions comprising them are claimed. Also claimed are their use for treating cystic fibrosis, and compositions comprising VX-659, ivacaftoR,  lumacaftor and tezacaftor .

This application claims priority to U.S. Provisional Application No.

62/574,677, filed October 19, 2017; U.S. Provisional Application No. 62/574,670, filed October 19, 2017; and U.S. Provisional Application No. 62/650,057, filed March 29, 2018, the entire contents of each of which are expressly incorporated herein by reference in their respective entireties.

[0002] Disclosed herein are crystalline forms of Compound I and pharmaceutically acceptable salts thereof, which are modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), compositions comprising the same, methods of using the same, and processes for making the same.

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.

[0004] In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61 :863 :870; and Kerem, B-S. et al. (1989) Science 245: 1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is

commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and traffic to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild-type CFTR, i.e., CFTR having no mutations. In addition to impaired trafficking, the mutation results in defective channel gating.

Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). The channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up-or down-regulated to alter anion secretion and modify disease progression and/or severity.

[0007] CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six

transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple

phosphorylation sites that regulate channel activity and cellular trafficking.

[0008] Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+-K+-ATPase pump and CI- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via CI channels, resulting in a vectorial transport. Arrangement of Na+/2C17K+ co-transporter, Na+-K+– ATPase pump and the basolateral membrane K+ channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

[0009] Compound I and pharmaceutically acceptable salts thereof are potent CFTR modulators. Compound I is N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide, and has the following structure:

Example 1: Synthesis of N-(benzenesulfonyl)-6-[3-[2-[l- (trifluoromethyl)cyclopropyl] ethoxy] pyrazol-l-yl]-2- [(4S)-2,2,4- trimethylpyrrolidin-l-yl]pyridine-3-carboxamide (Compound I)

Part A: Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride

° THF, Base

N02 1 “* N02 | -k/ B) HC

Step 1: Synthesis of methyl-2,4-dimethyl-4-nitro-pentanoate

[00381] Tetrahydrofuran (THF, 4.5 L) was added to a 20 L glass reactor and stirred under N2 at room temperature. 2-Nitropropane (1.5 kg, 16.83 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.282 kg, 8.42 mol) were then charged to the reactor, and the jacket temperature was increased to 50 °C. Once the reactor contents were close to 50 °C, methyl methacrylate (1.854 kg, 18.52 mol) was added slowly over 100 minutes. The reaction temperature was maintained at or close to 50 °C for 21 hours. The reaction mixture was concentrated in vacuo then transferred back to the reactor and diluted with methyl fert-butyl ether (MTBE) (14 L). 2 M HC1 (7.5 L) was added, and this mixture was stirred for 5 minutes then allowed to settle. Two clear layers were visible – a lower yellow aqueous phase and an upper green organic phase. The aqueous layer was removed, and the organic layer was stirred again with 2 M HC1 (3 L). After separation, the HC1 washes were recombined and stirred with MTBE (3 L) for 5 minutes. The aqueous layer was removed, and all of the organic layers were combined in the reactor and stirred with water (3 L) for 5 minutes. After separation, the organic layers were concentrated in vacuo to afford a cloudy green oil. This was dried with MgS04 and filtered to afford methyl-2,4-dimethyl-4-nitro-pentanoate as a clear green oil (3.16 kg, 99% yield). ¾ MR (400 MHz, Chloroform-i ) δ 3.68 (s, 3H), 2.56 – 2.35 (m, 2H), 2.11 – 2.00 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.19 (d, J= 6.8 Hz, 3H).

Step 2: Synthesis of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate

[00382] A reactor was charged with purified water (2090 L; 10 vol) and then potassium phosphate monobasic (27 kg, 198.4 moles; 13 g/L for water charge). The pH of the reactor contents was adjusted to pH 6.5 (± 0.2) with 20% (w/v) potassium carbonate solution. The reactor was charged with racemic methyl-2,4-dimethyl-4-nitro-pentanoate (209 kg; 1104.6 moles), and Palatase 20000L lipase (13 L, 15.8 kg; 0.06 vol).

[00383] The reaction mixture was adjusted to 32 ± 2 °C and stirred for 15-21 hours, and pH 6.5 was maintained using a pH stat with the automatic addition of 20% potassium carbonate solution. When the racemic starting material was converted to >98% ee of the S-enantiomer, as determined by chiral GC, external heating was

switched off. The reactor was then charged with MTBE (35 L; 5 vol), and the aqueous layer was extracted with MTBE (3 times, 400-1000L). The combined organic extracts were washed with aqueous Na2CCb (4 times, 522 L, 18 % w/w 2.5 vol), water (523 L; 2.5 vol), and 10% aqueous NaCl (314 L, 1.5 vol). The organic layer was concentrated in vacuo to afford methyl (2,S)-2,4-dimethyl-4-nitro-pentanoate as a mobile yellow oil (>98% ee, 94.4 kg; 45 % yield).

Step 3: Synthesis of (3S)-3,5,5-trimethylpyrrolidin-2-one

[00384] A 20 L reactor was purged with N2. The vessel was charged sequentially with DI water-rinsed, damp Raney® Ni (2800 grade, 250 g), methyl (2S)-2,4-dimethyl-4-nitro-pentanoate (1741g, 9.2 mol), and ethanol (13.9 L, 8 vol). The reaction was stirred at 900 rpm, and the reactor was flushed with H2 and maintained at -2.5 bar. The reaction mixture was then warmed to 60 °C for 5 hours. The reaction mixture was cooled and filtered to remove Raney nickel, and the solid cake was rinsed with ethanol (3.5 L, 2 vol). The ethanolic solution of the product was combined with a second equal sized batch and concentrated in vacuo to reduce to a minimum volume of ethanol (-1.5 volumes). Heptane (2.5 L) was added, and the suspension was concentrated again to -1.5 volumes. This was repeated 3 times; the resulting suspension was cooled to 0-5 °C, filtered under suction, and washed with heptane (2.5 L). The product was dried under vacuum for 20 minutes then transferred to drying trays and dried in a vacuum oven at 40 °C overnight to afford (3S)-3,5,5-trimethylpyrrolidin-2-one as a white crystalline solid (2.042 kg, 16.1 mol, 87 %). ¾ MR (400 MHz, Chloroform-i ) δ 6.39 (s, 1H), 2.62 (ddq, J = 9.9, 8.6, 7.1 Hz, 1H), 2.17 (dd, J = 12.4, 8.6 Hz, 1H), 1.56 (dd, J = 12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H).

Step 4: Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride

[00385] A glass lined 120 L reactor was charged with lithium aluminium hydride pellets (2.5 kg, 66 mol) and dry THF (60 L) and warmed to 30 °C. The resulting suspension was charged with (¾)-3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over 2 hours while maintaining the reaction temperature at 30 to 40 °C. After complete addition, the reaction temperature was increased to 60 – 63 °C and maintained overnight. The reaction mixture was cooled to 22 °C, then cautiously quenched with the addition of ethyl acetate (EtOAc) (1.0 L, 10 moles), followed by a mixture of THF (3.4 L) and water (2.5 kg, 2.0 eq), and then a mixture of water (1.75 kg) with 50 % aqueous sodium hydroxide (750 g, 2 equiv water with 1.4 equiv sodium hydroxide relative to aluminum), followed by 7.5 L water. After the addition was complete, the reaction mixture was cooled to room temperature, and the solid was removed by filtration and washed with THF (3 x 25 L). The filtrate and washings were combined and treated with 5.0 L (58 moles) of aqueous 37% HC1 (1.05 equiv.) while maintaining the temperature below 30°C. The resultant solution was concentrated by vacuum distillation to a slurry. Isopropanol (8 L) was added and the solution was concentrated to near dryness by vacuum distillation. Isopropanol (4 L) was added, and the product was slurried by warming to about 50 °C. MTBE (6 L) was added, and the slurry was cooled to 2-5 °C. The product was collected by filtration and rinsed with 12 L MTBE and dried in a vacuum oven (55 °C/300 torr/N2 bleed) to afford (4S)-2,2,4-trimethylpyrrolidine»HCl as a white, crystalline solid (6.21 kg, 75% yield). ¾ NMR (400 MHz, DMSO-^6) δ 9.34 (br d, 2H), 3.33 (dd, J= 11.4, 8.4 Hz, 1H), 2.75 (dd, J = 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, J= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, J= 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J= 6.6 Hz, 3H).

Part B: Synthesis of N-(benzenesulfonyl)-6-[3-[2-[l- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-l-yl]pyridine-3-carboxamide

HO CF,

Synthesis of starting materials:

Synthesis of terf-Butyl 2,6-dichloropyridine-3-carboxylate

[00386] A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol) in THF (210 mL) was treated successively with di-tert-butyl dicarbonate (17 g, 77.89 mmol) and 4-(dimethylamino)pyridine (3.2 g, 26.19 mmol) and stirred overnight at room temperature. At this point, HCI IN (400 mL) was added, and the mixture was stirred vigorously for about 10 minutes. The product was extracted with ethyl acetate (2x300mL), and the combined organic layers were washed with water (300 mL) and brine (150 mL) and dried over sodium sulfate and concentrated under reduced pressure to give 12.94 g (96% yield) of tert-butyl 2,6-dichloropyridine-3-carboxylate as a colorless oil. ESI-MS m/z calc. 247.02, found 248.1 (M+1) +; Retention time: 2.27 minutes. ¾ NMR (300 MHz, CDCh) ppm 1.60 (s, 9H), 7.30 (d, J=7.9 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H).

Synthesis of terf-Butyl 3-oxo-2,3-dihydro-lH-pyrazole-l-carboxylate

[00387] A 50L reactor was started, and the jacket was set to 20 °C, with stirring at 150 rpm, reflux condenser (10 °C) and nitrogen purge. MeOH (2.860 L) and methyl (E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added, and the reactor was capped. The reaction was heated to an internal temperature of 40 °C, and the system was set to hold jacket temperature at 40 °C. Hydrazine hydrate (1300 g of 55 %w/w, 22.31 mol) was added portion wise via addition funnel over 30 min. The reaction was heated to 60 °C for 1 h. The reaction mixture was cooled to 20 °C and triethyamine (2.483 kg, 3.420 L, 24.54 mol) was added portion-wise, maintaining reaction

temperature <30 °C. A solution of Boc anhydride (di-tert-butyl dicarbonate) (4.967 kg, 5.228 L, 22.76 mol) in MeOH (2.860 L) was added portion-wise maintaining temperature <45 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction solution was partially concentrated to remove MeOH, resulting in a clear, light amber oil. The resulting oil was transferred to the 50L reactor, stirred and water (7.150 L) and heptane (7.150 L) were added. The additions caused a small amount of the product to precipitate. The aqueous layer was drained into a clean container, and the interface and heptane layer were filtered to separate the solid (product). The aqueous layer was transferred back to the reactor, and the collected solid was placed back into the reactor and mixed with the aqueous layer. A dropping funnel was added to the reactor and loaded with acetic acid (1.474 kg, 1.396 L, 24.54 mol) and added dropwise. The jacket was set to 0 °C to absorb the quench exotherm. After the addition was complete (pH=5), the reaction mixture was stirred for 1 h. The solid was collected by filtration and washed with water (7.150 L) and washed a second time with water (3.575 L). The crystalline solid was transferred into a 20L rotovap bulb, and heptane (7.150 L) was added. The mixture was slurried at 45 °C for 30 mins, and 1-2 volumes of solvent were distilled off. The slurry in the rotovap flask was filtered, and the solids were washed with heptane (3.575 L). The solid was further dried in vacuo (50 °C, 15 mbar) to give tert-butyl 5-oxo-lH-pyrazole-2-carboxylate (2921 g, 71%) as a coarse, crystalline solid. ¾ MR

(400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.98 (d, J= 2.9 Hz, 1H), 5.90 (d, J

1H), 1.54 (s, 9H).

Synthesis of 2-[l-(trifluoromethyl)cyclopropyl]ethanol

[00388] To a solution of lithium aluminum hydride (293 mg, 7.732 mmol) in THF (10.00 mL) in an ice-bath, 2-[l-(trifluoromethyl)cyclopropyl]acetic acid (1.002 g, 5.948 mmol) in THF (3.0 mL) was added dropwise over a period of 30 minutes keeping the reaction temperature below 20 0 C. The mixture was allowed to gradually warm to ambient temperature and was stirred for 18 h. The mixture was cooled with an ice-bath and sequentially quenched with water (294 mg, 295 μΐ., 16.36 mmol), NaOH (297 μΐ. of 6 M, 1.784 mmol), and then water (884.0 μΐ., 49.07 mmol) to afford a granular solid in the mixture. The solid was filtered off using celite, and the precipitate was washed with ether. The filtrate was further dried with MgS04 and filtered and concentrated in vacuo to afford the product with residual THF and ether. The mixture was taken directly into the next step without further purification.

Step 1: tert-Butyl 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate

[00389] tert-Butyl 5-oxo-lH-pyrazole-2-carboxylate (1.043 g, 5.660 mmol), 2-[l-(trifluoromethyl)cyclopropyl]ethanol (916 mg, 5.943 mmol), and triphenyl phosphine (1.637 g, 6.243 mmol) were combined in THF (10.48 mL) and the reaction was cooled in an ice-bath. Diisopropyl azodicarboxylate (1.288 g, 1.254 mL, 6.368 mmol) was added dropwise to the reaction mixture, and the reaction was allowed to warm to room temperature for 16 hours. The mixture was evaporated, and the resulting material was partitioned between ethyl acetate (30 mL) and IN sodium hydroxide (30 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0- 30%) to give tert-butyl 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-l-carboxylate (1.03 g, 57%). ESI-MS m/z calc. 320.13, found 321.1 (M+1) +; Retention time: 0.72 minutes.

Step 2: 3-[2-[l-(Trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole

[00390] tert-Butyl-3 -[2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazole- 1 -carboxylate (1.03 g, 3.216 mmol) was dissolved in dichloromethane (10.30 mL) with trifluoroacetic acid (2.478 mL, 32.16 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was evaporated, and the resulting oil was partitioned between ethyl acetate (10 mL) and a saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated to give 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (612 mg, 86%). ESI-MS m/z calc. 220.08, found 221.0 (M+1) +; Retention time: 0.5 minutes. ¾ MR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.50 (t, J= 2.1 Hz, 1H), 5.63 (t, J= 2.3 Hz, 1H), 4.14 (t, J= 7.1 Hz, 2H), 2.01 (t, J= 7.1 Hz, 2H), 0.96 – 0.88 (m, 2H), 0.88 -0.81 (m, 2H).

Step 3: tert-Butyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridine-3-carboxylate

[00391] tert-Butyl 2,6-dichloropyridine-3-carboxylate (687 mg, 2.770 mmol), 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (610 mg, 2.770 mmol), and freshly ground potassium carbonate (459 mg, 3.324 mmol) were combined in anhydrous DMSO (13.75 mL). l,4-diazabicyclo[2.2.2]octane (DAB CO (1,4-diazabicyclo[2.2.2]octane), 62 mg, 0.5540 mmol) was added, and the mixture was

stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (20 mL) and stirred for 15 minutes. The resulting solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and concentrated to give tert-butyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (1.01 g, 84%). ESI-MS m/z calc. 431.12, found 432.1 (M+l) +; Retention time: 0.88 minutes.

Step 4: 2-Chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid

[00392] tert-Butyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (1.01 g, 2.339 mmol) and trifluoroacetic acid (1.8 mL, 23.39 mmol) were combined in dichloromethane (10 mL) and heated at 40 °C for 3 h. The reaction was concentrated. Hexanes were added, and the mixture was concentrated again to give 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (873 mg, 99%) ESI-MS m/z calc. 375.06, found 376.1 (M+l)+; Retention time: 0.69 minutes.

Step 5: N-(Benzenesulfonyl)-2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridine-3-carboxamide

[00393] A solution of 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]

ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (0.15 g, 0.3992 mmol) and carbonyl diimidazole (77 mg, 0.4790 mmol) in THF (2.0 mL) was stirred for one hour, and

benzenesulfonamide (81 mg, 0.5190 mmol) and DBU (72 μΐ^, 0.4790 mmol) were added. The reaction was stirred for 16 hours, acidified with 1 M aqueous citric acid, and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-5%) to give N-(benzenesulfonyl)-2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxamide (160 mg, 78%). ESI-MS m/z calc. 514.07, found 515.1 (M+l)+; Retention time: 0.74 minutes.

Step 6: N-(Benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide

[00394] A mixture of N-(benzenesulfonyl)-2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridine-3-carboxamide (160 mg, 0.3107 mmol), (4S)-2,2,4-trimethylpyrrolidine hydrochloride salt (139 mg, 0.9321 mmol), and potassium carbonate (258 mg, 1.864 mmol) in DMSO (1.5 mL) was stirred at 130 °C for 17 hours. The reaction mixture was acidified with 1 M aqueous citric acid and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to yield a crude product that was purified by reverse-phase HPLC utilizing a gradient of 10-99%) acetonitrile in 5 mM aqueous HC1 to yield N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide (87 mg, 47%). ESI-MS m/z calc. 591.21, found 592.3 (M+l) +; Retention time: 2.21 minutes. 1H MR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.19 (d, J= 2.8 Hz, 1H), 8.04 – 7.96 (m, 2H), 7.81 (d, J= 8.2 Hz, 1H), 7.77 – 7.70 (m, 1H), 7.70 – 7.62 (m, 2H), 6.92 (d, J= 8.2 Hz, 1H), 6.10 (d, J= 2.8 Hz, 1H), 4.31 (t, J= 7.0 Hz, 2H), 2.42 (t, J= 10.5 Hz, 1H), 2.28 (dd, J = 10.2, 7.0 Hz, 1H), 2.17 – 2.01 (m, 3H), 1.82 (dd, J= 11.9, 5.5 Hz, 1H), 1.52 (d, J = 9.4 Hz, 6H), 1.36 (t, J= 12.1 Hz, 1H), 1.01 – 0.92 (m, 2H), 0.92 – 0.85 (m, 2H), 0.65 (d, J = 6.3 Hz, 3H). pKa: 4.95±0.06.

Synthesis of sodium salt of N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide (sodium salt of Compound I)

[00395] N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide (1000 mg, 1.679 mmol) was dissolved in ethanol (19.87 ml) under warming, filtered clear through a syringe filter (0.2 μπι), washed with warm ethanol (10 ml) and the warm solution was treated with 1M NaOH (1.679 ml, 1.679 mmol). The solution was evaporated at 30-35 °C, co-evaporated 3 times with ethanol (-20 ml), to give a solid, which was dried overnight under vacuum in a drying cabinet at 45 °C with a nitrogen bleed to give 951 mg of a cream colored solid. The solid was further dried under vacuum in a drying cabinet at 45 °C with a nitrogen bleed over the weekend. 930 mg (89%) of the sodium salt of N-(benzenesulfonyl)-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide was obtained as an off-white amorphous solid. ¾ NMR (400 MHz, DMSO-d) δ 8.15 (d, J= 2.7 Hz, 1H), 7.81 (dd, J= 6.7, 3.1 Hz, 2H), 7.61 (d, J= 7.9 Hz, 1H), 7.39 (dd, J= 4.9, 2.0 Hz, 3H), 6.74 (d, J= 7.9 Hz, 1H), 6.01 (d, J= 2.6 Hz, 1H), 4.29 (t, J= 7.0 Hz, 2H), 2.93 – 2.78 (m, 2H), 2.07 (t, J= 7.1 Hz, 3H), 1.78 (dd, J= 11.8, 5.6 Hz, 1H), 1.52 (d, J= 13.6 Hz, 6H), 1.33 (t, J= 12.0 Hz, 1H), 1.00 – 0.92 (m, 2H), 0.89 (q, J= 5.3, 4.6 Hz, 2H), 0.71 (d, J= 6.3 Hz, 3H). EST-MS m/z calc. 591.2127, found 592.0 (M+l)+; Retention time: 3.28 minutes. XRPD (see FIG. 16).

Alternate synthesis of 2-Chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy] pyrazol-l-yl] pyridine-3-carboxylic acid

Step 1: ethyl 3-hydroxy-lH-pyrazole-4-carboxylate

[00396] A mixture of EtOH (20.00 L, 10 vol) and diethyl 2-(ethoxymethylene) propanedioate (2000 g, 9.249 mol, 1.0 equiv) was added under nitrogen purge a to a 50 L reactor equipped with a reflux condenser (10 °C) and the jacket set to 40 °C. The mixture was stirred, and then hydrazine hydrate (538.9 g of 55 %w/w, 523.7 mL of 55 %w/w, 9.249 mol, 1.00 equiv) was added in portions via an addition funnel. Once the addition was complete, the reaction was heated to 75 °C for 22 h to afford a solution of ethyl 3-hydroxy-lH-pyrazole-4-carboxylate that was used directly in the next step.

Step 2: l-(tert-butyl) 4-ethyl 3-hydroxy-lH-pyrazole-l,4-dicarboxylate

[00397] The solution of ethyl 3 -hydroxy- lH-pyrazole-4-carboxylate was cooled from 75 °C to 40 °C, then triethylamine (TEA) (46.80 g, 64.46 mL, 462.5 mmol, 0.05 eq.) was added. A solution of Boc anhydride (2.119 kg, 9.711 moll .05 equiv) in EtOH (2.000 L, 1 equiv) was added to the reactor over 35 min. The mixture was stirred for 4 hours to complete the reaction; then water (10.00 L, 5.0 vol) was added over 15 mins. The resulting mixture was cooled to 20 °C to complete crystallization of the product. The crystals were allowed to age for 1 hour, then the mixture was filtered. The solid was washed with a mixture of EtOH (4.000 L, 2.0 vol) and water (2.000 L, 1.0 vol). The solid was then dried in vacuo to afford l-(tert-butyl)-4-ethyl-3-hydroxy-lH-pyrazole-1,4-dicarboxylate (1530 g, 65%) as colorless, fine needle, crystalline solid. ¾ NMR (400 MHz, DMSO-de) δ 11.61 (s, 1H), 8.40 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.56 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).

Step 3: l-(tert-butyl) 4-ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-ΙΗ-pyr azole- 1 ,4-dicarboxylate

[00398] A 5L reactor was started with the jacket set to 40 °C, stirring at 450 rpm, reflux condenser at room temperature and nitrogen purge. The vessel was charged with toluene (1.0L, 10.0 vol), 2-[l-(trifluoromethyl)cyclopropyl]ethanol (lOO.Og, 648.8 mmol, 1.0 equiv), and l-(tert-butyl) 4-ethyl 3-hydroxy-lH-pyrazole-l,4-dicarboxylate (166.3 g, 648.8 mmol), and the mixture was stirred. The reaction mixture was charged with triphenyl phosphine (195.7 g, 746.1 mmol, 1.15 equiv), then the reactor was set to maintain an internal temperature of 40 °C. Diisopropyl azoldicarboxylate (150.9 g, 746.1 mmol, 1.15 equiv) was added into an addition funnel and was added to the reaction while maintaining the reaction temperature between 40 and 50 °C (addition was exothermic, exotherm addition controlled), and stirred for a total of 2.5 hours. Once the reaction was deemed complete by HPLC, heptane was added (400 mL, 4 vol), the solution was cooled to 20 °C over 60 minutes, and the bulk of triphenylphosphine oxide-DIAD complex (TPPO-DIAD) crystallized out. Once at room temp, the mixture was filtered, and the solid was washed with heptane (400 mL, 4.0 vol) and pulled dry. The filtrate was used in the next step as a solution in toluene-heptane without further purification.

Step 4: ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylate

[00399] A 500mL reactor was started with the jacket set to 40 °C, stirring at 450 rpm, reflux condenser at room temp, and nitrogen purge. The vessel was charged with a toluene solution consisting of approximately 160 mmol, 65.0 g of l-(tert-butyl) 4-ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-l,4-dicarboxylate in 3 vol of toluene (prepared by concentrating a 25% portion of filtrate from previous reaction down to 4 volumes in a rotovap). The reaction was set to maintain an internal temperature at 40 °C and KOH (33.1 g, 1.5 eq. of aqueous 45 % KOH solution) was added in one portion, resulting in a mild exothermic addition, while CO2 was generated upon removal of the protecting group. The reaction proceeded for 1.5 hr, monitored by HPLC, with the product partially crystallizing during the reaction. Heptane (160 mL, 2.5 vol) was added to the reaction mixture and the reaction was cooled to room temperature over 30 minutes. The resulting mixture was filtered, and the solid was

washed with heptane (80.00 mL, 1.25 vol), pulled dry, then dried in vacuo (55 °C, vacuum). 52.3 g of ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylate was obtained as a crude, colorless solid that was used without further purification.

Step 5: 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylic acid

[00400] A 500mL reactor was started with the jacket set to 40 °C, stirring at 450 rpm, reflux condenser at room temp, and nitrogen purge. The vessel was charged with methanol (150.0 mL, 3.0 vol), a solution of ethyl 3-(2-(l-(trifluoromethyl)cyclopropyl) ethoxy)-lH-pyrazole-4-carboxylate (50.0 g, 171.1 mmol, 1.0 equiv), and the reaction was stirred to suspend the solids. The reactor was set to maintain internal temperature at 40 °C. To the mixture was added KOH (96 g of aqueous 45 % KOH, 1.71 mol, 10.0 equiv) in portions maintaining the internal temperature <50 °C. Once addition was complete, the reaction was set to maintain temperature at 50 °C, and the reaction proceeded for 23 hours, monitored by HPLC. Once complete the reaction was cooled to 10 °C then partially concentrated on a rotary evaporator to remove most of the MeOH. The resulting solution was diluted with water (250 mL, 5.0 vol) and 2-Me-THF (150 mL, 3.0 vol), and transferred to the reactor, stirred at room temp, then stopped, and layers were allowed to separate. The layers were tested, with remaining TPPO-DIAD complex in the organic layer and product in the aqueous layer. The aqueous layer was washed again with 2-Me-THF (100 mL, 2.0 vol), the layers separated, and the aqueous layer returned to the reactor vessel. The stirrer was started and set to 450 rpm, and the reactor jacket was set to 0 °C. The pH was adjusted to pH acidic by addition of 6M aqueous HC1 (427mL, 15 equiv) portion wise, maintaining the internal temperature between 10 and 30 °C. The product began to crystallize close to pH neutral and was accompanied with strong off-gassing, and so the acid was added slowly, and then further added to reach pH 1 once the off-gassing had ended. To the resulting suspension was added 2-Me-THF (400 mL, 8.0 vol), and the product was allowed to dissolve into

the organic layer. Stirring was stopped, the layers were separated, and the aqueous layer was returned to the reactor, stirred and re-extracted with 2-Me-THF (100 mL, 2.0 vol). The organic layers were combined in the reactor and stirred at room temperature, washed with brine (lOOmL, 2 vols), dried over Na2S04, filtered through celite, and the solid was washed with 2-Me-THF (50 mL, 1.0 vol). The filtrate was transferred to a clean rotovap flask, stirred, warmed to 50 °C and heptane (200 mL, 4.0 vol) added, and then partially concentrated with the addition of heptane (300 mL, 6.0 vol) and then seeded with 50mg of 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylic acid), and the product crystallized during solvent removal. The distillation was stopped when the bulk of the 2-Me-THF had distilled off. The bath heater was turned off, the vacuum removed, and the mixture was allowed to stir and cool to room temperature. The mixture was filtered (slow speed) and the solid was washed with heptane (100 mL, 2.0 vol), and the solid was collected and dried in vacuo (50 °C, rotovap). 22.47 g of 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole-4-carboxylic acid was obtained as an off-white solid. ¾ MR (400 MHz, DMSO-de) δ

12.45 (s, 2H), 8.01 (s, 1H), 4.26 (t, J= 7.0 Hz, 2H), 2.05 (t, J= 7.0 Hz, 2H), 0.92 (m,

4H).

Step 6: 3-(2-(l-(trifluoromethyl)cyclopropyl)ethoxy)-lH-pyrazole

[00401] A mixture of toluene (490.0 mL), 3-(2-(l-(trifluoromethyl)cyclopropyl) ethoxy)-lH-pyrazole-4-carboxylic acid (70.0 g, 264.9 mmol), and DMSO (70.00 mL) was placed in a reactor and heated to 100 °C with stirring. DBU (approximately 20.16 g, 19.80 mL, 132.4 mmol) was added to the reactor over 15 min. The mixture was stirred for 20 h to complete the reaction and then cooled to 20 °C. The mixture was washed with water (350.0 mL), then 0.5N aq HC1 (280.0 mL), then water (2 x 140.0 mL), and lastly with brine (210.0 mL). The organic layer was dried with Na2S04, and then activated charcoal (5 g, Darco 100 mesh) was added to the stirred slurry. The dried mixture was filtered through celite, and the solid was washed with toluene (140.0 mL) and then pulled dry. The filtrate was concentrated in a rotovap (50 °C, vac) to afford 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (30.89 g, 53%) as an amber oil. 1H MR (400 MHz, DMSO-d) δ 11.87 (s, 1H), 7.50 (d, J= 2.4 Hz, 1H), 5.63 (d, J = 2.4 Hz, 1H), 4.23 – 4.06 (m, 2H), 2.01 (t, J= 7.1 Hz, 2H), 1.00 – 0.77 (m, 4H).

Step 7: ethyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy] pyrazol-l-yl]pyridine-3-carboxylate

[00402] A mixture of DMF (180.0 mL), ethyl 2,6-dichloropyridine-3-carboxylate (approximately 29.97 g, 136.2 mmol), 3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]-lH-pyrazole (30.0 g, 136.2 mmol), and K2CO3, (325 mesh, approximately 24.48 g, 177.1 mmol) was added to a stirred reactor at 20 °C. DABCO (approximately 2.292 g, 20.43 mmol) was then added to the reactor, and the mixture was stirred at 20 °C for 1 hour, and then the temperature was increased to 30 °C, and the mixture stirred for 24 hours to complete the reaction. The mixture was cooled to 20 °C; then water (360 mL) was added slowly. The mixture was then drained from the reactor and the solid was isolated by filtration. The solid was then washed with water (2 x 150 mL), and then the solid was dried under vacuum at 55 °C to afford ethyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (51.37 g, 93%) as a fine, beige colored solid. ¾ MR (400 MHz, DMSO-^e) δ 8.44 (d, J= 2.9 Hz, 1H), 8.41 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 8.5 Hz, 1H), 6.21 (d, J= 2.9 Hz, 1H), 4.34 (m, 4H), 2.09 (t, J= 7.1 Hz, 2H), 1.34 (t, J= 7.1 Hz, 3H), 1.00 – 0.84 (m, 4H).

Step 8: 2-Chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid

[00403] A solution of ethyl 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-l-yl]pyridine-3-carboxylate (50.0 g, 123.8 mmol) in THF (300.0 mL) was prepared in a reactor at 20 °C. EtOH (150.0 mL) was added, followed by aqueous NaOH (approximately 59.44 g of 10 %w/w, 148.6 mmol). The mixture was stirred for 1 hour to complete the reaction; then aq IN HC1 (750.0 mL) was slowly added. The resulting suspension was stirred for 30 min at 10 °C, and then the solid was isolated by filtration. The solid was washed with water (150 mL then 2 x 100 mL) and then pulled dry by vacuum. The solid was then further dried under vacuum with heating to afford 2-chloro-6-[3-[2-[l-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (42.29 g, 91%). ¾ NMR (400 MHz, DMSO-i¾) δ 13.63 (s, 1H), 8.48 -8.35 (m, 2H), 7.73 (d, J= 8.4 Hz, 1H), 6.20 (d, J= 2.9 Hz, 1H), 4.35 (t, J= 7.1 Hz, 2H), 2.09 (t, J= 7.1 Hz, 2H), 1.01 – 0.82 (m, 4H).

Example 2: Preparation of a Spray Dried Dispersion (SDD) of Compound I

[00404] A spray dried dispersion of Compound I (free form) was prepared using Buchi Mini Spray Dryer B290. HPMCAS-HG (6.0 grams) was dissolved in 200 mL of MeOH/DCM (1/1), and Compound I (6.0 grams) was added and stirred for 30 minutes forming a clear solution. The resulting solution was spray dried under the following conditions resulting in a 50 wt% Compound 1/50 wt% HPMCAS- HG spray dried dispersion (Yield: 80%, Solid load: 6%). FIG. 14 shows the XRPD spectrum of a SDD of 50% Compound I in HPMCAS-HG. FIG. 15 is spectrum showing modulated differential scanning calorimetry (MDSC) spectrum of a spray dried dispersion (SDD) of 50% Compound I in HPMCAS-HG.

Table 64 SDD of Compound I

Example 3: Synthesis of Compound II: (R)-l-(2,2-Difluorobenzo[d][l,3]dioxol-5- yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- -2-yl)-lH-indol-5-yl)cyclopropanecarboxamide

Step 1: (R)-Benzyl 2-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate and ((S)-2,2-Dimethyl-l,3-dioxolan-4-yl)methyl 2-(l-(((R)-2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate

[00405] Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of benzyl 2-(6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate (3.0 g, 8.4 mmol) and (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (7.23 g, 25.3 mmol) in DMF (N,N-dimethylformamide) (17 mL). The reaction was stirred at 80 °C for 46 hours under a nitrogen atmosphere. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgS04, filtered and concentrated. The crude product, a viscous brown oil which contains both of the products shown above, was taken directly to the next step without further purification. (R)-Benzyl 2-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate, ESI-MS m/z calc. 470.2, found 471.5 (M+l)+. Retention time 2.20 minutes. ((S)-2,2-Dimethyl-l,3-dioxolan-4-yl)methyl 2-(l-(((R)-2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate, ESI-MS m/z calc. 494.5, found 495.7 (M+l)+. Retention time 2.01 minutes.

Step 2: (R)-2-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropan-l-ol

[00406] The crude reaction mixture obtained in step (A) was dissolved in THF (tetrahydrofuran) (42 mL) and cooled in an ice-water bath. LiAlH4 (16.8 mL of 1 M solution, 16.8 mmol) was added drop-wise. After the addition was complete, the

mixture was stirred for an additional 5 minutes. The reaction was quenched by adding water (1 mL), 15% NaOH solution (1 mL) and then water (3 mL). The mixture was filtered over Celite, and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate-hexanes) to obtain (R)-2-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropan-l-ol as a brown oil (2.68g, 87 % over 2 steps). ESI-MS m/z calc. 366.4, found 367.3 (M+l)+. Retention time 1.68 minutes. 1H MR (400 MHz, DMSO-^6) δ 8.34 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 13.4 Hz, 1H), 6.57 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.64 – 4.60 (m, 1H), 4.52 – 4.42(m, 2H), 4.16 – 4.14 (m, 1H), 3.76 – 3.74 (m, 1H), 3.63 – 3.53 (m, 2H), 1.42 (s, 3H), 1.38 – 1.36 (m, 6H) and 1.19 (s, 3H) ppm. (DMSO is dimethylsulfoxide).

Step 3: (R)-2-(5-amino-l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-lH-indol-2-yl)-2-methylpropan-l-ol

[00407] (R)-2-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropan-l-ol (2.5 g, 6.82 mmol) was dissolved in ethanol (70 mL) and the reaction was flushed with N2. Then Pd-C (250 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 2.5 hours only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was re-subjected to the conditions above. After 2 hours LCMS indicated complete conversion to product. The reaction mixture was filtered through Celite. The filtrate was concentrated to yield the product (1.82 g, 79 %). ESI-MS m/z calc. 336.2, found 337.5 (M+l)+. Retention time 0.86 minutes. ¾ NMR (400 MHz, DMSO-^6) δ 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.03 (s, 1H), 4.79 – 4.76 (m, 1H), 4.46 (s, 2H), 4.37 – 4.31 (m, 3H),4.06 (dd, J = 6.1, 8.3 Hz, 1H), 3.70 – 3.67 (m, 1H), 3.55 – 3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.

Step 4: (R)-l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide

[00408] DMF (3 drops) was added to a stirring mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The

solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5 -amino- 1-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-lH-indol-2-yl)-2-methylpropan-l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with IN HC1 solution, saturated NaHCCb solution and brine, dried over MgSCb and concentrated to yield the product (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. ¾ NMR (400 MHz, DMSO-^6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 – 7.40 (m, 2H), 7.34 – 7.30 (m, 3H), 6.24 (s, 1H), 4.51 – 4.48 (m, 1H), 4.39 – 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 – 3.51 (m, 2H), 1.48 – 1.45 (m, 2H), 1.39 (s, 3H), 1.34 – 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 -1.12 (m, 2H) ppm

Step 5: (R)-l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide

[00409] (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-2-(l -hydroxy -2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) was added followed by p-TsOH.H20 (p-toluenesulfonic acid hydrate) (204 mg, 1.1 mmol). The reaction was heated at 80 °C for 45 minutes. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCCb solution. The ethyl acetate layer was dried over MgS04 and concentrated. The residue was purified by column chromatography (50-100 % ethyl acetate – hexanes) to yield the product. (1.3 g, 47 %, ee >98% by SFC). ESI-MS m/z calc. 520.5, found 521.7 (M+l)+. Retention time 1.69 minutes. ¾ NMR (400 MHz, DMSC 6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 – 7.38 (m, 2H), 7.33 – 7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.40 (dd, J = 2.6, 15.1 Hz, 1H), 4.10 (dd, J = 8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65 – 3.54 (m, 2H), 3.48 – 3.33 (m, 2H), 1.48 -1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 – 1.11 (m, 2H) ppm.

Example 4: Synthesis of Compound III: N-(2,4-di-terf-butyl-5-hydroxyphi oxo-l,4-dihydroquinoline-3-carboxamide

Part A: Synthesis of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid

Step 1: 2-Phenylaminomethylene-malonic acid diethyl ester

[00410] A mixture of aniline (25.6 g, 0.275 mol) and diethyl 2-(ethoxymethylene)malonate (62.4 g, 0.288 mol) was heated at 140-150 °C for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. ¾ MR (OMSO-de) δ 1 1.00 (d, 1H), 8.54 (d, J = 13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).

Step 2: 4-Hydroxyquinoline-3-carboxylic acid ethyl ester

[00411] A I L three-necked flask fitted with a mechanical stirrer was charged with 2-phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.100 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to 70 °C and stirred for 4 h. The mixture was cooled to room temperature and filtered. The residue was treated with aqueous Na2CCb solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a pale brown solid (15.2 g, 70%). The crude product was used in next step without further purification.

Step 3: 4-Oxo-l,4-dihydroquinoline-3-carboxylic acid

[00412] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). ¾ MR (DMSO-^e) δ 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).

Part B: Synthesis of N-(2,4-di-terf-butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide

Step 1: Carbonic acid 2,4-di-ferf-butyl-phenyl ester methyl ester

[00413] Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-fert-butyl-phenol (103.2 g, 500 mmol), Et3N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled in an ice-water bath to 0 °C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approx. 1L) using 10% ethyl acetate – hexanes (~ 4 L) as the eluent. The combined filtrates were concentrated to yield carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.). ¾ MR (400 MHz, DMSO-i¾) δ 7.35 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.5, 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).

Step 2: Carbonic acid 2,4-di-ferf-butyl-5-nitro-phenyl ester methyl ester and Carbonic acid 2,4-di-terf-butyl-6-nitro-phenyl ester methyl ester

[00414] To a stirring mixture of carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester (4.76 g, 180 mmol) in cone, sulfuric acid (2 mL), cooled in an ice-water bath, was added a cooled mixture of sulfuric acid (2 mL) and nitric acid (2 mL). The addition was done slowly so that the reaction temperature did not exceed 50 °C. The reaction was allowed to stir for 2 h while warming to room temperature. The reaction mixture was then added to ice-water and extracted into diethyl ether. The ether layer was dried (MgS04), concentrated and purified by column chromatography (0 – 10% ethyl acetate – hexanes) to yield a mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester as a pale yellow solid (4.28 g), which was used directly in the next step.

Step 3: 2,4-Di-terf-butyl-5-nitro-phenol and 2,4-Di-terf-butyl-6-nitro-phenol

[00415] The mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester (4.2 g, 14.0 mmol) was dissolved in MeOH (65 mL) before KOH (2.0 g, 36 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then made acidic (pH 2-3) by adding cone. HC1 and partitioned between water and diethyl ether. The ether layer was dried (MgS04), concentrated and purified by column

chromatography (0 – 5 % ethyl acetate – hexanes) to provide 2,4-di-tert-butyl-5-nitro-phenol (1.31 g, 29% over 2 steps) and 2,4-di-tert-butyl-6-nitro-phenol. 2,4-Oi-tert-butyl-5-nitro-phenol: ¾ MR (400 MHz, DMSO-i¾) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H). 2,4-Di-tert-butyl-6-nitro-phenol: ¾ MR (400 MHz, CDCh) δ 11.48 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 1.47 (s, 9H), 1.34 (s, 9H).

Step 4: 5-Amino-2,4-di-terf-butyl-phenol

[00416] To a refluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g, 7.40 mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was added Pd-5% wt. on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature and filtered through Celite. The Celite was washed with methanol and the combined filtrates were concentrated to yield 5-amino-2,4-di-tert-butyl-phenol as a grey solid (1.66 g, quant.). ¾ MR (400 MHz, DMSO-^e) δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, H2), 1.27 (m, 18H); HPLC ret. time 2.72 min, 10-99 % CftCN, 5 min run; ESI-MS 222.4 m/z [M+H]+.

Step 5: N-(5-hydroxy-2,4-di-ieri-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide

[00417] To a suspension of 4-oxo-l,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 °C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et20

(diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 °C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CftCN, 5 min run; 1H MR (400 MHz, DMSO-i¾) δ 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m/z calc’d 392.21; found 393.3 [M+H]+.

PAPER

The New England journal of medicine (2018), 379(17), 1599-1611

https://www.nejm.org/doi/10.1056/NEJMoa1807119

////////////VX-659, VX 659,  VX659, PHASE 2,  CYSTIC FIBRIOSIS , VERTEX, Bamocaftor potassium

[K+].C[C@@H]1CN(c2nc(ccc2C(=O)[N-]S(=O)(=O)c3ccccc3)n4ccc(OCCC5(CC5)C(F)(F)F)n4)C(C)(C)C1

C[C@@H]1CN(c2nc(ccc2C(=O)NS(=O)(=O)c3ccccc3)n4ccc(OCCC5(CC5)C(F)(F)F)n4)C(C)(C)C1

First FDA-approved vaccine Dengvaxia for the prevention of dengue disease in endemic regions


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First FDA-approved vaccine for the prevention of dengue disease in endemic regions

May 01, 2019

The U.S. Food and Drug Administration announced today the approval of Dengvaxia, the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico and the U.S. Virgin Islands.

“Dengue disease is the most common mosquito-borne viral disease in the world and global incidence has increased in recent decades,” said Anna Abram, FDA deputy commissioner for policy, legislation, and international affairs. “The FDA is committed to working proactively with our partners at the U.S. Centers for Disease Control and Prevention, as well as international partners, including the World Health Organization, to combat public health threats, including through facilitating the development and availability of medical products to address emerging infectious diseases. While there is no cure for dengue disease, today’s approval is an important step toward helping to reduce the impact of this virus in endemic regions of the United States.”

The CDC estimates more than one-third of the world’s population is living in areas at risk for infection by dengue virus which causes dengue fever, a leading cause of illness among people living in the tropics and subtropics. The first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu or another viral infection. A subsequent infection can lead to severe dengue, including dengue hemorrhagic fever (DHF), a more severe form of the disease that can be fatal. Symptoms may include stomach pain, persistent vomiting, bleeding, confusion and difficulty breathing. Approximately 95 percent of all severe/hospitalized cases of dengue are associated with second dengue virus infection. Because there are no specific drugs approved for the treatment of dengue disease, care is limited to the management of symptoms.

Each year, an estimated 400 million dengue virus infections occur globally according to the CDC. Of these, approximately 500,000 cases develop into DHF, which contributes to about 20,000 deaths, primarily among children. Although dengue cases are rare in the continental U.S., the disease is regularly found in American Samoa, Puerto Rico, Guam, the U.S. Virgin Islands, as well as Latin America, Southeast Asia and the Pacific islands.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease, which may lead to hospitalization or even death,” said Peter Marks, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “As the second infection with dengue is often much more severe than the first, the FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease.”

The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region. The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease. Dengvaxia has already been approved in 19 countries and the European Union.

The most commonly reported side effects by those who received Dengvaxia were headache, muscle pain, joint pain, fatigue, injection site pain and low-grade fever. The frequency of side effects was similar across Dengvaxia and placebo recipients and tended to decrease after each subsequent dose of the vaccine.

Dengvaxia is not approved for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown. This is because in people who have not been infected with dengue virus, Dengvaxia appears to act like a first dengue infection – without actually infecting the person with wild-type dengue virus – such that a subsequent infection can result in severe dengue disease.Therefore, health care professionals should evaluate individuals for prior dengue infection to avoid vaccinating individuals who have not been previously infected by dengue virus. This can be assessed through a medical record of a previous laboratory-confirmed dengue infection or through serological testing (tests using blood samples from the patient) prior to vaccination.

Dengvaxia is a live, attenuated vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.

The FDA granted this application Priority Review and a Tropical Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of certain tropical diseases. The approval was granted to Sanofi Pasteur.

https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-dengue-disease-endemic-regions?utm_campaign=050119_PR_First%20FDA-approved%20vaccine%20for%20prevention%20of%20dengue%20in%20endemic%20areas&utm_medium=email&utm_source=Eloqua

//////////fda 2019, Priority Review, Tropical Disease Priority Review Voucher , Sanofi Pasteur,  Dengvaxia, vaccine, dengue

Erdafitinib, エルダフィチニブ ,Эрдафитиниб , إيردافيتينيب , 厄达替尼 ,


Erdafitinib.svg

Erdafitinib.png

Erdafitinib

エルダフィチニブ

JNJ-42756493

CAS 1346242-81-6

MF, C25H30N6O2, MW 446.54

UNII-890E37NHMV

890E37NHMV

2019/4/12, FDA APPROVED, BALVERSA (Janssen Products LP)

Balversa

Эрдафитиниб [Russian] [INN]

إيردافيتينيب [Arabic] [INN]
厄达替尼 [Chinese] [INN]

N‘-(3,5-dimethoxyphenyl)-N‘-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane-1,2-diamine

1,2-Ethanediamine, N1-(3,5-dimethoxyphenyl)-N2-(1-methylethyl)-N1-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]- [ACD/Index Name]
10147
1346242-81-6 [RN]
890E37NHMV
N-(3,5-dimethoxyphenyl)-N’-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine
5SF
MFCD28502040
N’-(3,5-dimethoxyphenyl)-N’-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane-1,2-diamine
N1-(3,5-dimethoxyphenyl)-N2-(1-methylethyl)-N1-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethanediamine

Image result for Erdafitinib

Erdafitinib is an orally bioavailable, pan fibroblast growth factor receptor (FGFR) inhibitor with potential antineoplastic activity. Upon oral administration, erdafitinib binds to and inhibits FGFR, which may result in the inhibition of FGFR-related signal transduction pathways and thus the inhibition of tumor cell proliferation and tumor cell death in FGFR-overexpressing tumor cells. FGFR, upregulated in many tumor cell types, is a receptor tyrosine kinase essential to tumor cell proliferation, differentiation and survival

Erdafitinib has been used in trials studying the basic science and treatment of Tumor or Lymphoma.

Erdafitinib[1] is a small molecule inhibitor of FGFR approved for treatment of cancer and marketed under the name Balversa. FGFRs are a subset of tyrosine kinases which are unregulated in some tumors and influence tumor cell differentiation, proliferation, angiogenesis, and cell survival.[2] Astex Pharmaceuticals discovered the drug and licensed it to Janssen Pharmaceuticals for further development.

Researchers have investigated erdafitinib for safety and efficacy in treatment of cholangiocarcinomagastric cancernon-small cell lung cancer, and esophageal cancer.[3]

In March 2018, erdafitinib was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration for treatment of urothelial cancer.[2],

In April 2019, erdafitinib was granted approval by the FDA for treatment of metastatic or locally advanced bladder cancer with an FGFR3 or FGFR2 alteration that has progressed beyond traditional platinum-based therapies, subject to a confirmatory trial.

PATENT

WO 2011135376

https://patents.google.com/patent/WO2011135376A1/ru

STR1-1

MORE……………

STR1-1

References

  1. ^ https://searchusan.ama-assn.org/usan/documentDownload?uri=%2Funstructured%2Fbinary%2Fusan%2Ferdafitinib.pdf
  2. Jump up to:a b “Janssen Announces U.S. FDA Breakthrough Therapy Designation for Erdafitinib in the Treatment of Metastatic Urothelial Cancer – Johnson & Johnson”http://www.jnj.com.
  3. ^ “Erdafitinib – Janssen Pharmaceutica – AdisInsight”adisinsight.springer.com.
Erdafitinib
Erdafitinib.svg
Clinical data
Synonyms JNJ-42756493
Identifiers
CAS Number
PubChem CID
UNII
KEGG
ECHA InfoCard 100.235.008 Edit this at Wikidata
Chemical and physical data
Formula C25H30N6O2
Molar mass 446.555 g·mol−1
3D model (JSmol)

Patent IDTitleSubmitted DateGranted Date

US2018186775QUINOXALINE DERIVATIVES USEFUL AS FGFR KINASE MODULATORS2017-12-28

US2018127397PYRAZOLYL QUINOXALINE KINASE INHIBITORS2017-11-13

US20172601682-ARYL- AND 2-HETEROARYL-SUBSTITUTED 2-PYRIDAZIN-3(2H)-ONE COMPOUNDS AS INHIBITORS OF FGFR TYROSINE KINASES2016-10-24

US2017267684A DEUTERATED TRIAZOLOPYRIDAZINE AS A KINASE MODULATOR2015-12-03

US9464071PYRAZOLYL QUINOXALINE KINASE INHIBITORS2014-10-022015-04-16

US8895601Pyrazolyl quinoxaline kinase inhibitors2011-04-282014-11-25

US2017100406COMBINATIONS OF AN FGFR INHIBITOR AND AN IGF1R INHIBITOR2015-03-26

US9850228PYRAZOLYL QUINOXALINE KINASE INHIBITORS2016-04-28

US9902714QUINOXALINE DERIVATIVES USEFUL AS FGFR KINASE MODULATORS2015-03-26

US2018296558COMBINATIONS2018-04-17

US2018021332PHARMACEUTICAL COMPOSITIONS COMPRISING N-(3,5-DIMETHOXYPHENYL)-N’-(1-METHYLETHYL)-N-[3-(1-METHYL-1H-PYRAZOL-4-YL)QUINOXALIN-6-YL]ETHANE-1,2-DIAMINE2016-02-09

US2017119763COMBINATIONS2015-03-26

US2016090633USE OF FGFR MUTANT GENE PANELS IN IDENTIFYING CANCER PATIENTS THAT WILL BE RESPONSIVE TO TREATMENT WITH AN FGFR INHIBITOR2015-09-182016-03-31

US2016287699FGFR/PD-1 COMBINATION THERAPY FOR THE TREATMENT OF CANCER2016-03-24

/////////Erdafitinib, FDA 2019, エルダフィチニブ, BALVERSA, Janssen Products LP, JNJ-42756493, Эрдафитиниб ,  إيردافيتينيب 厄达替尼 ,

CC(C)NCCN(C1=CC2=NC(=CN=C2C=C1)C3=CN(N=C3)C)C4=CC(=CC(=C4)OC)OC

 

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