Picture credit....Bethany Halford
GLPG 1690
2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]-methylamino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile
5- ​Thiazolecarbonitrile​, 2-​[[2-​ethyl-​6-​[4-​[2-​(3-​hydroxy-​1-​azetidinyl)​-​2-​oxoethyl]​-​ 1-​piperazinyl]​-​8-​methylimidazo[1,​2-​a]​pyridin-​3-​yl]​methylamino]​-​4-​(4-​fluorophenyl)​-
CAS 1628260-79-6

$GLPG compound for treating idiopathic pulmonary fibrosis

Molecular Formula:	C30H33FN8O2S
Molecular Weight:	588.698823 g/mol

Galapagos Nv

http://files.glpg.com/docs/website_1/Poster_ERS_2015_final.pdf
http://www.glpg.com/docs/view/56b360a81f6b2-en
Phase I Idiopathic pulmonary fibrosis

Description	Selective autotaxin (ENPP2; ATX) inhibitor
Molecular Target	Autotaxin (ENPP2) (ATX)

• Originator Galapagos NV
• Class Anti-inflammatories; Small molecules
• Mechanism of Action ENPP2 protein inhibitors

• 23 Sep 2015 Pharmacodynamics data from a preclinical trial in Indiopathic pulmonary fibrosis released by Galapagos
• 22 Sep 2015 Pharmacokinetics data from a phase I trial in healthy volunteers released by Galapagos
• 22 Sep 2015 Updated adverse events data from a phase I trial in healthy volunteers released by Galapagos

GLPG1690

GLPG1690 is a selective autotaxin inhibitor discovered by Galapagos, with potential application in idiopathic pulmonary disease (IPF). In a Phase 1 study in healthy human volunteers, GLPG1690 demonstrated favorable safety and tolerability, as well as a strong pharmacodynamic signal implying target engagement. Galapagos is currently preparing a Phase 2 study in IPF, to be filed for approval before the end of 2015. GLPG1690 is fully proprietary to Galapagos.

March 17, 2015 02:37 ET | Source: Galapagos NV

 

• Fully owned and proprietary clinical asset for pulmonary fibrosis
• GLPG1690 acts on autotaxin target
• Novel mode of action, originating from Galapagos target discovery engine
• Filing for Phase 2 clinical trial in 2015

MECHELEN, Belgium, March 16, 2015 (GLOBE NEWSWIRE) -- Galapagos NV (Euronext: GLPG) announced that Janssen Pharmaceutica NV and Galapagos have mutually agreed to terminate the inflammation alliance and option agreements between the companies.  Galapagos views the molecules emerging from the alliance as strong additions to its growing proprietary pipeline.  Among others, all rights to candidate drug GLPG1690, a selective autotaxin inhibitor, return to Galapagos.  Galapagos has successfully completed a First-in-Human Phase 1 trial for GLPG1690 and is preparing a Phase 2 clinical trial in idiopathic pulmonary fibrosis (IPF).

"We are pleased to regain the rights to GLPG1690 to pursue the most suitable clinical application of autotaxin inhibition.  There is a large unmet medical need in IPF, and our pre-clinical data with GLPG1690 supports its potential as a competitive and novel approach in this disease area," said Dr Piet Wigerinck, Chief Scientific Officer of Galapagos.  "The alliance with Janssen has been underway since October 2007 and has generated three clinical molecules, two of which are now proprietary Phase 2 assets of Galapagos: GLPG1205 and GLPG1690.  This program is a valuable component of our development portfolio, and regaining the rights is a next step in our transformation into a mature biotech company with a proprietary product pipeline."

Galapagos identified autotaxin as playing a key role in inflammation, using an inflammation assay in its unique target discovery platform.  Pharmacology and translational studies published by other parties in the literature since then suggest autotaxin may play a key role in metabolic disease, arthritic pain, oncology, and lung disease.

GLPG1690 is a potent and selective inhibitor of autotaxin.  In a Phase 1 study in healthy human volunteers, GLPG1690 demonstrated favorable safety and tolerability, as well as a strong pharmacodynamic signal implying target engagement.  Galapagos is currently preparing a Phase 2 study in IPF, to be filed for approval before the end of 2015.

About IPF
Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function.  Pulmonary fibrosis involves scarring of lung tissue and is the cause of shortness of breath.  Fibrosis is usually associated with a poor prognosis.  The term "idiopathic" is used because the cause of pulmonary fibrosis is still unknown.  Estimated incidence of IPF is up to 16.3 per 100,000 persons in the US and 7.4 per 100,000 persons in Europe, with approximately 30,000-35,000 new patients diagnosed with IPF worldwide each year.  The goals of treatment in IPF are essentially to reduce the symptoms, slow down disease progression, reduce acute exacerbations, and prolong survival.  Approved treatments thus far have improved the overall survival of IPF patients, but unwanted side effects with these treatments are common, presenting an unmet need for effective treatments with safer side effect profiles.

September 22, 2015 01:37 ET | Source: Galapagos NV

 

MECHELEN, Belgium, Sept. 22, 2015 (GLOBE NEWSWIRE) -- Galapagos NV (Euronext & NASDAQ: GLPG) presents pre-clinical and Phase 1 results for autotaxin inhibitor GLPG1690 at the European Respiratory Society Annual Meeting in Amsterdam, Netherlands.  Galapagos expects to file an exploratory Phase 2 study in idiopathic pulmonary fibrosis before year end.  GLPG1690 has potential application in other pulmonary diseases such as chronic obstructive pulmonary disease (COPD), as supported by the presentation on pre-clinical findings at ERS this year:
"Pharmacological profile and efficacy of GLPG1690, a novel ATX inhibitor for COPD treatment," poster PA2129 in Poster Discussion Session: "New targets and modalities for the treatment of asthma and COPD" (September 28, 2015; Room D201-202, 10:45 AM - 12:45 PM)

Galapagos is the first to show efficacy of an autotaxin inhibitor in pre-clinical models for COPD and IPF, pointing to novel therapeutic areas for autotaxin inhibition. The poster shows how GLPG1690 acts as a potent inhibitor of mouse and human autotaxin (IC₅₀: 100 -500 nM range).  Furthermore, GLPG1690 reduces inflammation in a mouse steroid-resistant tobacco smoke model to a similar extent as a standard therapy for COPD.

Galapagos also presents the topline results with GLPG1690 in Phase 1 in healthy human volunteers:  "Favorable human safety, pharmacokinetics and pharmacodynamics of the autotaxin inhibitor GLPG1690, a potential new treatment in COPD," oral presentation OA484 in session "Advances in the future treatment of COPD" (September 27, 2015; Room 2.1, 10:45 AM - 12:45 PM)

GLPG1690 was safe and well tolerated up to a single oral dose of 1500 mg and up to 1000 mg twice daily for 14 days, with no significant adverse effects on ECGs, vital signs or laboratory parameters.  The compound also showed good oral bioavailability with a half-life of 5 hours and a dose-proportional increase in exposure.  GLPG1690 showed concentration-dependent reduction of a relevant biomarker (plasma LPA18:2 levels) with a maximum of approximately 90%.  At steady state, continuous reduction of this biomarker levels of >60% was observed from 0 to 24 hours.  The presentation will also include relevant pre-clinical model data for COPD and IPF with GLPG1690.

Both the presentation and the posters will be made available on the Galapagos website after the conference.

About Galapagos

Galapagos (Euronext & NASDAQ: GLPG) is a clinical-stage biotechnology company specialized in the discovery and development of small molecule medicines with novel modes of action, with a pipeline comprising three Phase 2 programs, two Phase 1 trials, five pre-clinical studies, and 20 discovery small-molecule and antibody programs in cystic fibrosis, inflammation, and other indications.  In the field of inflammation, AbbVie and Galapagos signed a collaboration agreement for the development and commercialization of filgotinib.  Filgotinib is an orally-available, selective inhibitor of JAK1 for the treatment of rheumatoid arthritis and potentially other inflammatory diseases, currently in Phase 2B studies in RA and in Phase 2 in Crohn's disease. Galapagos reported good activity and a favorable safety profile in both the DARWIN 1 and 2 trials in RA.  AbbVie and Galapagos also signed a collaboration agreement in cystic fibrosis to develop and commercialize molecules that address mutations in the CFTR gene.  Potentiator GLPG1837 is currently in a Phase 1 trial, and corrector GLPG2222 is at the pre-clinical candidate stage.  GLPG1205, a first-in-class inhibitor of GPR84 and fully-owned by Galapagos, is currently being tested in a Phase 2 proof-of-concept trial in ulcerative colitis patients.  GLPG1690, a fully proprietary, first-in-class inhibitor of autotaxin, has shown favorable safety in a Phase 1 trial and is expected to enter Phase 2 in idiopathic pulmonary fibrosis.  The Galapagos Group, including fee-for-service subsidiary Fidelta, has approximately 400 employees, operating from its Mechelen, Belgium headquarters and facilities in The Netherlands, France, and Croatia.  More info at www.glpg.com

CONTACT

Galapagos NV
Elizabeth Goodwin, Head of Corporate Communications & IR
Tel: +31 6 2291 6240
ir@glpg.com

MECHELEN, Belgium, Feb. 16, 2015 (GLOBE NEWSWIRE) -- Galapagos NV (Euronext: GLPG) announced today that GLPG1690, a first-in-class molecule for pulmonary disease, has demonstrated target engagement, a good safety profile, and favorable drug properties in a Phase 1 study.  Galapagos is developing GLPG1690 within its alliance with Janssen Pharmaceutica NV.
The aim of the Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral single and multiple ascending doses of GLPG1690.  The randomized, double-blind, placebo-controlled, single center study was conducted in 40 healthy volunteers in Belgium.  In the first part of the study, single ascending doses were evaluated.  In the second part, the new compound was administered daily for 14 days.
GLPG1690 proved to be safe and well-tolerated over a wide dose range in healthy volunteers.  Engagement of the thus far undisclosed novel target was confirmed using a relevant biomarker. GLPG1690 displayed a favorable pharmacokinetic and pharmacodynamic profile.  The data shown in Phase 1 encourage Galapagos to explore a Phase 2 study design in pulmonary disease.
"GLPG1690 is the first molecule against this target ever to be evaluated clinically, and we are pleased with the outcome of the Phase 1 study," said Dr Piet Wigerinck, CSO of Galapagos.  "Galapagos continues to deliver novel therapeutics from its unique target and drug discovery engine."
In 2007, Galapagos announced an alliance agreement with Janssen Pharmaceutica NV providing the option to worldwide, commercial licenses to certain Galapagos internal inflammatory disease programs.  These programs are based on novel targets for inflammatory disorders that were identified and validated by Galapagos using its proprietary target discovery engine.  Subsequent Galapagos research led to the discovery of GLPG1690, a first-in-class molecule that entered the clinic for inflammatory disorders.  Galapagos is responsible for execution of Phase 1 and Phase 2A studies with GLPG1690.
SYNTHESIS


INTRODUCTION
relates to compounds that are inhibitors of autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), that is involved in fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases. The present invention also provides methods for the production of a compound of the invention, pharmaceutical compositions comprising a compound of the invention, methods for the prophylaxis and/or treatment of diseases involving fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering a compound
STAGE 1

STAGE2

STAGE 3

STAGE4

STAGE 5

FINAL

PATENT
US2014303140
http://www.google.com/patents/US20140303140


1.2.4.4. Illustrative Synthesis of Intermediate Gen-3-e: N-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-N-methylformamide

• 
•  
  To a suspension of formamide Gen-2-d (720 g, 2.55 mol, 1 eq.) in 5 L of acetone were added potassium carbonate (1 kg, 7.66 mol, 3 eq.) and methyl iodide (700 g, 4.93 mol, 1.9 eq.). The reaction mixture was heated to 40° C. overnight. Additional methyl iodide (25 g, 0.18 mol, 0.07 eq.) was then introduced and stirring continued for 1 h at 40° C. The reaction mixture was filtered and washed with acetone (2×300 mL) and DCM (2×300 mL). The filtrate was concentrated in vacuo and the residue was partitioned between DCM (3 L) and water (1 L). The aqueous layer was further extracted with DCM. The combined organic layers were then washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The solid was triturated with Et₂O (1 L) at r.t. for 1 h, filtered off and dried to afford Intermediate Gen-3-e.
•  
  Rotamer A (Major): ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.19 (1H, s), 7.78 (1H, s), 7.15 (1H, s), 3.24 (3H, s), 2.72 (2H, q), 2.59 (3H, s), 1.31 (3H, t)
•  
  Rotamer B (Minor): ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.49 (1H, s), 7.65 (1H, s), 7.08 (1H, s), 3.36 (3H, s), 2.72 (2H, q), 2.59 (3H, s), 1.31 (3H, t)
•  
  LC-MS: MW (calcd): 295 (⁷⁹Br), 297 (⁸¹Br); m/z MW (obsd): 296 (⁷⁹Br M+1), 298 (⁸¹Br M+1)

1.2.5.2. Illustrative Synthesis of Intermediate Gen-4-d: (6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine

•  
  
•  
  Intermediate Gen-3-e (80 g, 270 mmol, 1 eq.) was dissolved in a 1.25 M HCl solution in MeOH (540 mL, 2.5 eq.) and the resulting mixture was refluxed overnight. 270 mL of 1.25 M HCl solution in MeOH were added and heating continued overnight. After 48 h, additional 70 mL of the 1.25 M HCl solution in MeOH were introduced in the reaction mixture. Heating was maintained overnight until conversion was complete. The crude mixture was then concentrated in vacuo and the residue was partitioned between EtOAc (300 mL) and water (700 mL). A saturated NaHCO₃ solution was added until pH reached 8-9. The aqueous layer was extracted twice with EtOAc (2×300 mL). The combined organic layers were then washed with brine (200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give Intermediate Gen-4-d (6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine) as a free base.
•  
  ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.05 (1H, s), 7.04 (1H, s), 2.84-2.78 (5H, m), 2.60 (3H, s), 1.35 (3H, t)
•  
  LC-MS: MW (calcd): 267 (⁷⁹Br), 269 (⁸¹Br); m/z MW (obsd): 268 (⁷⁹Br M+1), 270 (⁸¹Br M+1)

1.2.6.4. Illustrative Synthesis of Intermediate Gen-5-t: 2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

• 
• To a solution of amine Gen-4-d (4.4 g, 16.6 mmol, 1 eq.) in THF (44 mL) under argon was slowly added NaH (60% in oil suspension, 2.0 g, 50.0 mmol, 3 eq.). The reaction mixture was heated at 90° C. for 30 min then cooled to 40° C. before adding the chlorothiazole Gen-12-a (4.74 g, 19.9 mmol, 1.2 eq.). The reaction mixture was stirred at 90° C. overnight. After cooling to r.t. the mixture was slowly quenched by addition of water and then diluted with EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic layers were then washed with water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was triturated in Et₂O, filtered and washed with Et₂O and MeCN. Recrystallization was performed in MeCN (180 mL) to afford Intermediate Gen-5-t (2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile).
•  
  ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.15 (2H, dd), 7.80 (1H, s), 7.22-7.14 (3H, m), 3.62 (3H, s), 2.77 (2H, q), 2.64 (3H, s), 1.35 (3H, t)
•  
  LC-MS: MW (calcd): 469 (⁷⁹Br), 471 (⁸¹Br); m/z MW (obsd): 470 (⁷⁹Br M+1), 472 (⁸¹Br M+1)

1.2.7.1.4. Illustrative Synthesis of 4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester

•  
  
•  
  To a solution of Intermediate Gen-5-t (24.2 g, 51.5 mmol, 1 eq.) in toluene under argon were successively added N-Boc piperazine (14.4 g, 77.3 mmol, 1.5 eq.), sodium tert-butoxide (9.9 g, 103 mmol, 2 eq.), JohnPhos (1.54 g, 5.15 mmol, 0.1 eq.) and Pd₂(dba)₃ (2.36 g, 2.58 mmol, 0.05 eq.). The reaction mixture was heated at 115° C. for 1 h. After cooling to r.t., the crude product was filtered on Celpure® P65 and the residue dissolved in EtOAc and washed with water. The organic layer was further washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (elution with heptane/EtOAc:90/10 to 20/80) to afford the expected product.
•  
  ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.16 (2H, dd), 7.17 (2H, app t), 6.99 (2H, bs), 3.62-3.53 (4H, m), 3.60 (3H, s), 3.04-2.93 (4H, m), 2.74 (2H, q), 2.62 (3H, s), 1.47 (9H, s), 1.33 (3H, t).
•  
  LC-MS: MW (calcd): 575; m/z MW (obsd): 576 (M+1)

1.2.7.8.4. Illustrative Synthesis of Compound 1: 2-[(2-Ethyl-8-methyl-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

•  
  
•  
  4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from intermediate Gen-5-t using Boc-piperazine and method Flb.
•  
  To a solution of 4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (24.4 g, 42 mmol, 1 eq.) in MeOH (100 mL) was added a 2 M HCl solution in Et₂O (127 mL, 254 mmol, 6 eq.). The reaction mixture was stirred at r.t. for 3.5 h then concentrated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. A 2 M NaOH solution was added to the aqueous layer until pH reached 8-9 and further extraction with EtOAc was performed. The combined organic layers were then washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The solid was triturated with heptane (100 mL) at r.t. overnight, filtered off, washed with heptane and Et₂O, and dried to afford the expected compound.
•  
  ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.17 (2H, dd), 7.18 (2H, app t), 6.99 (2H, bs), 3.61 (3H, s), 3.09-2.98 (8H, m), 2.75 (2H, q), 2.61 (3H, s), 1.34 (3H, t).
•  
  LC-MS: MW (calcd): 475; m/z MW (obsd): 476 (M+1)

 

1.2.7.14. Illustrative Synthesis of Compound 2: 2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

•  
  
•  
  To a solution of amine compound 1 (12.6 g, 27 mmol, 1 eq.) in 100 mL of MeCN were added potassium carbonate (7.3 g, 53 mmol, 2 eq.) and Gen13-a (5.2 g, 34 mmol, 1.3 eq.). The reaction mixture was refluxed for 5.5 h then cooled to r.t. and stirred for 40 h. The crude product was filtered and washed with MeCN. The collected precipitate was then suspended in 300 mL of water, stirred for 1 h, filtered, and finally washed with water and MeCN. The solid obtained was dried in vacuo for 48 h to afford Compound 2.
•  
  ¹H NMR (400 MHz, CDCl₃) δ ppm 8.20-8.12 (2H, m), 7.22-7.13 (2H, m), 6.99 (2H, s), 4.68 (1H, m), 4.43 (1H, dd), 4.26 (1H, dd), 4.14-4.05 (1H, m), 3.88 (1H, dd), 3.61 (3H, s), 3.58-3.52 (1H, m), 3.14-3.02 (6H, m), 2.74 (2H, q), 2.70-2.62 (4H, m), 2.59 (3H, s), 1.33 (3H, t)
•  
  LC-MS: MW (calcd): 588; m/z MW (obsd): 589 (M+1)

 

US9249141

Dec 17, 2014

Feb 2, 2016

Galapagos Nv

Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

1 to 2 of 2

Patent ID	Date	Patent Title
US2015111872	2015-04-23	NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
US2014303140	2014-10-09	NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS

////////////GLPG 1690, idiopathic pulmonary fibrosis, PHASE 1, GALAPAGOS, 1628260-79-6
n12c(c(nc1c(cc(c2)N3CCN(CC3)CC(=O)N4CC(C4)O)C)CC)N(C)c5nc(c(s5)C#N)c6ccc(cc6)F
CCC1=C(N2C=C(C=C(C2=N1)C)N3CCN(CC3)CC(=O)N4CC(C4)O)N(C)C5=NC(=C(S5)C#N)C6=CC=C(C=C6)F
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GDC 0853

.
Picture credit....Bethany Halford
GDC 0853
GDC-0853; RG 7845

Molecular Formula:	C37H44N8O4
Molecular Weight:	664.79646 g/mol

2-[3-(hydroxymethyl)-4-[1-methyl-5-[(7-methyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1-one
3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one
3-[3-(hydroxymethyl)-4-[5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-1H-pyridin-3-yl]-2-pyridyl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one
2H-​Cyclopenta[4,​5]​pyrrolo[1,​2-​a]​pyrazin-​1(6H)​-​one, 2-​[1,​6-​dihydro-​3'-​(hydroxymethyl)​-​1-​methyl-​5-​[[5-​[(2S) ​-​2-​methyl-​4-​(3-​oxetanyl)​-​1-​piperazinyl]​-​2-​pyridinyl]​amino]​ -​6-​oxo[3,​4'-​bipyridin]​-​2'-​yl]​-​3,​4,​7,​8-​tetrahydro-​7,​7-​ dimethyl-
s ISoMER 1434048-34-6 desired
r iSoMER 1434048-57-3 undesired


Phase 1
Patients with Patients with Resistant B-Cell Lymphoma or Chronic Lymphocytic Leukemia..
@genentech's Btk inhibitor
https://clinicaltrials.gov/ct2/show/NCT01991184
Bruton tyrosine kinase inhibitor

Genentech, Inc.

• 01 Sep 2015 Phase-I clinical trials in Autoimmune disorders (In volunteers) in USA (PO, Capsule and Tablet) (NCT02699710)
• 16 Oct 2014 Discontinued - Phase-I for Non-Hodgkin's lymphoma (Second-line therapy or greater) in USA (unspecified route)
• 16 Oct 2014 Discontinued - Phase-I for Chronic lymphocytic leukaemia (Second-line therapy or greater) in USA (unspecified route)

BTK inhibitor GDC-0853 An orally available inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, GDC-0853 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival.
Patent
WO 2013067274
https://www.google.co.in/patents/WO2013067274A1?cl=en
part
Example 271a (S)-tert-Butyl 4-(6-(5-Chloro-2-methoxypyridin-3-ylamino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate 271a

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), (S)-tert-butyl 4-(6-amino pyridin-3-yl)-3-methylpiperazine-1-carboxylate 101h (2.04 g, 7.0 mmol), 3-bromo-5-chloro-2-methoxypyridine (2.8 g, 12.6 mmol), Pd₂(dba)₃ (640 mg, 0.70 mmol), XantPhos (404.6 mg, 0.70 mmol), and cesium carbonate (4.56 g, 14.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100 °C for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 271a (1.7 g, 57%) as a yellow solid. MS-ESI: [M+H]⁺ 434.2

Example 271btert-Butyl (3S)-4-(6-{[5-(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl}-3-(hydroxymethyl)pyridin-4-yl)-2-methoxypyridin-3-yl] amino}pyridin-3-yl)-3-methylpiperazine-1-carboxylate 271b

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 271a (650 mg, 1.50 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (1.79 g, 4.5 mmol), Pd₂(dba)₃ (137.2 mg, 0.15 mmol), P(cy)₃(167.4 mg, 0.60 mmol), Cs₂CO₃ (978 mg, 3.0 mmol), dioxane (20 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110°C for 16 h. After this time the reaction was cooled to room temperature. Lithium hydroxide monohydrate (1.89 g, 45 mmol) and water (2.0 mL) were added. The resulting mixture was stirred at 45°C for 4 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 271b (290 mg, 27%) as a yellow solid. MS-ESI: [M+H]⁺ 709.3

Example 271c 10-[3-(Hydroxymethyl)-4-[5-({5-[(2S)-2-methylpiperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-9-one 271c

A solution of 271b (286.6 mg, 0.40 mmol) in dioxane/HCl (30 mL) was stirred at 50 °C for 2 h. It was evaporated under reduced pressure to afford 271c (450 mg, crude) as a black solid. MS-ESI: [M+H]⁺ 595.3

Example 271 3-[3-(hydroxymethyl)-4-[5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-1H-pyridin-3-yl]-2-pyridyl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one 271

To a solution of 271c (450 mg, 0.75 mmol) in methanol (10 mL) was added oxetan-3-one (162 mg, 2.25 mmol), NaBH₃CN (141.8 mg, 2.25 mmol), and ZnCl₂ (306 mg, 2.25 mmol). The reaction was stirred at room temperature for 3 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with dichloromethane (3 X 10 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 271 (23.0 mg, 8.8%, over two steps) as a yellow solid. MS-ESI: [M+H]⁺651.3. ¹H NMR (500 MHz, CDCl₃) δ 9.76 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.41 (d, J = 4.5 Hz, 1H), 7.35 (dd, J = 2.5 Hz, 8.5 Hz, 1H), 6.87 (s, 1H), 6.85 (d, J = 9.0 Hz, 1H), 5.16-5.13 (m, 1H), 4.72-4.69 (m, 5H), 4.54-4.53 (m, 1H), 4.36-4.35 (m, 1H), 4.19-4.17 (m, 2H), 3.89-3.87 (m, 1H), 3.56-3.49 (m, 2H), 3.11-3.09 (m, 2H), 2.60-2.48 (m, overlap, 7H), 2.24-2.21 (m, 1H), 1.29 (s, 6H), 1.02 (d, J = 6.0 Hz, 3H)

271
.............................
syn of 191 j
is intermediatenot product, is acid
To a mixture of 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (500 mg, 1.46 mmol), tert-butyl alcohol (20 mL), and dichloromethane (5 mL) was added 2-methyl-2-butene (3066 mg, 43.8 mmol). An aqueous solution (8 mL) of NaClO₂ (263 mg, 2.92 mmol) and NaH₂PO₄·2water (683 mg, 4.38 mmol) was added dropwise at -10°C and the reaction mixture was stirred at -10 °C for overnight. It was concentrated under reduced pressure and the residue was extracted with ethyl acetate (4 × 20 mL). The combined organic extract was dried over MgSO₄ and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 210a (315 mg, 60%) as a pale yellow solid. MS-ESI: [M+H]⁺ 360.1
Example 210b 2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-10-yl} -4-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-3-carboxylic Acid 210b

A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 210a (400 mg, 1.1 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (536 mg, 1.1 mmol), PdCl₂(dppf) (81 mg, 0.11 mmol), K₃PO₄ (466 mg, 2.2 mmol), sodium acetate (216 mg, 2.2 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100°C for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 210b as a yellow solid (306 mg, 41%). MS-ESI: [M+H]⁺ 679.3

construction, use your discretion
Example 130a (3S)-tert- utyl 3-methyl-4-(6-nitropyridin-3-yl)piperazine-l-carboxylate 130a

130a
Following the procedures as described for compound lOlg, reaction of 5-bromo-2-nitropyridine (10.5 g, 50 mmol), and (JS)-tert-butyl-3 -methylpiperazine- 1 -carboxylate (10.0 g, 50 mmol) afforded 130a as a yellow solid (8.05 g, 50%). LCMS: [M+H]⁺ 323
Example 130b (3 S)-tert-butyl-4-(6-aminopyridin-3 -yl)-3 -methylpiperazine- 1 -carboxylate 130b

130b
Following the procedures as described for compound lOlh, hydrogenation of 130a (5.8 g) afforded 130bas a brown solid (4.9 g, 96%). LCMS: [M+H]⁺ 293
Example 130c (3 S)-tert-Butyl-4-(6-(5 -bromo- 1 -methyl -2 -oxo- 1,2-dihydropyridin-3 -yl amino) pyridine-3 -yl)-3 -methylpiperazine- 1 -carboxylate 130c
N

Following the procedures as described for compound lOli, reaction of 130b (4.0 g) and 3,5-dibromo-l-methylpyridin-2(lH)-one (5.5 g) afforded 130c as a yellow solid (5.4 g, 83%). LCMS: [M+H]⁺ 478
Example 130d (3 S)-5 -Bromo- 1 -methyl-3 -(5 -(2-methylpiperazin- 1 -yl)pyridin- 2-ylamino)pyridine-2(lH)-one 130d

Following the procedures as described for compound lOlj, acidic hydrolysis of the Boc group of 130c (3.1 g) afforded 130d as a yellow solid (2.3 g, 95%). LCMS: [M+H]⁺ 380.
Example 130e (3 S)-5 -Bromo- 1 -methyl-3 -(5 -(2 -methyl-4-(ox etan-3-yl)piperazin-l-yl) pyridine -2-ylamino)pyridin-2(lH)-one 130e

Following the procedures as described for compound 101k, reductive amination of 130d (2.35 g) with oxetan-3-one (0.4 mL) afforded 130e as a yellow solid (2.6 g, 98%). LCMS: [M+H]⁺ 434.
Example 13 Of (3S)-l-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-l-yl)pyridin-2-ylamino) -5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one 130f
check pyridine ring position
A 100 mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 130e (1.0 g, 1.0 eq., 2.3 mmol), Pin₂B₂ (1.46 g, 2.50 eq., 5.75 mmol), Pd₂(dba)₃ (105 mg, 0.05 eq., 0.125 mmol), X-Phos (93 mg, 0.1 eq., 0.23 mmol), AcOK (676 mg, 3.0 eq., 6.9 mmol), and dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90 °C for 4 hrs, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with 3: 1 PE/EA (80 mL) to afford 130f as yellow solid (1.0 g, 90%). MS: [M+H]⁺ 482.
check pyridine ring position, use your discretion
Example 191h ( 3S)-5 -Bromo- 1 -methyl-3 -(5 -(2-methylpiperazin- 1 -yl)pyridin- -ylamino)pyridine-2(lH)-one 191h

Following the procedure described for compound lOlj and starting with (3S)-tert-butyl 4-(6-(5 -bromo- 1 -methyl-2-oxo- 1 ,2-dihydropyridin-3 -ylamino)pyridine-3 -yl)-3 -methyl-piperazine-l-carboxylate 191g (3.1 g, 6.5 mmol) afforded 191h as a yellow solid (2.3 g, 94%). MS-ESI: [M+H]⁺ 378.
Example 1 1 i (S)-5 -Bromo- 1 -methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin- 1 -yl)pyridin-2-ylamino)pyridin-2(lH)-one 191i
A mixture of (5)-5-bromo-l-methyl-3-(5-(2-methylpiperazin-l-yl)pyridin-2-ylamino)pyridin-2(lH)-one 191h (40.0 g, 106 mmol), oxetan-3-one (1 1.4 g, 159 mmol), NaBH₃CN (10.0 g, 159 mmol), and zinc chloride (21.3 g, 159 mmol) in methanol (700 mL) was stirred at 50°C for 5 hours. The mixture was added to water (100 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (200 mL x 3). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40: 1 dichloromethane /methanol to afford 191i (35 g, 73%). MS: [M+H]⁺ 434.
Example 191j (J5)-l-Methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-l-yl)-pyridin- -ylamino) -5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one 191j

191 i 191j
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (5)-tert-butyl-4-(6-(5-bromo-l-methyl-2-oxo-l ,2-dihydropyridin-3-ylamino)pyridine-3-yl)-3-methylpiperazine-l-carboxylate 191i (1.0 g, 1.0 eq., 2.3 mmol), Pin₂B₂ (1.46 g, 2.50 eq., 5.75 mmol), Pd₂(dba)₃ (105 mg, 0.05 eq., 0.125 mmol), X-Phos (93 mg, 0.1 eq., 0.23 mmol), potassium acetate (676 mg, 3.0 eq., 6.9 mmol), and dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90°C for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with 3 : 1 petroleum ether/ethyl acetate (80 mL) to afford 191j as yellow solid (1.0 g, 90%). MS: [M+H]⁺ 482.
pipeline
http://www.gene.com/medical-professionals/pipeline

Pictrelisib, GDC-0941, RG7321 and GNE0941

Patent ID	Date	Patent Title
US8921353	2014-12-30	Heteroaryl pyridone and aza-pyridone compounds
US2014378432	2014-12-25	HETEROARYL PYRIDONE AND AZA-PYRIDONE COMPOUNDS
US8716274	2014-05-06	Heteroaryl pyridone and aza-pyridone compounds

//////GDC 0853, genentech,  Btk inhibitor, phase 1, Patients with Resistant B-Cell Lymphoma,  Chronic Lymphocytic Leukemia, Bruton tyrosine kinase inhibitor,  GDC-0853,  RG 7845, 1434048-34-6
N1(CCN(CC1C)C2COC2)c3cnc(cc3)NC=4C(N(\C=C(/C=4)c5c(c(ncc5)N6CCn7c(C6=O)cc8CC(Cc78)(C)C)CO)C)=O
CC1CN(CCN1C2=CN=C(C=C2)NC3=CC(=CN(C3=O)C)C4=C(C(=NC=C4)N5CCN6C7=C(CC(C7)(C)C)C=C6C5=O)CO)C8COC8
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PF 06650808

.
Picture credit....Bethany Halford
PF 06650808

Phase 1

$PFE compound inspired by auristatins
https://clinicaltrials.gov/ct2/show/NCT02129205
http://www.pfizer.com/sites/default/files/product-pipeline/8_7_2014_Pipeline_Update.pdf
ALL DATA COMING.........
Notch-3 receptor antagonists
Neoplasms
Breast

Pfizer

Cancer
PF-06650808, is currently being examined in a Ph1 clinical trial (Protocol B7501001).
Notch3
Researchers are also exploring the use of Notch3 targeting. “The Notch pathway plays an important role in the growth of several solid tumours, including breast and ovarian cancer and melanoma,” explained Joerger. “In particular, Notch3 alterations such as gene amplification and upregulation are associated with poor patient survival. Research using Notch3 targeting as an innovative approach to treat solid malignancies included 27 patients unselected for Notch3 who received increasing doses of the anti-Notch3 antibody-drug conjugate PF-06650808. Responses were seen in two breast cancer patients (LBA 30). While preliminary, targeting Notch3 may become a new treatment approach in patients with selected solid tumours.”
The anti-Notch3 antibody-drug conjugate PF-06650808 is being developed by Pfizer.

• 31 Jul 2014 Phase-I clinical trials in Solid tumours (Late-stage disease) in USA (Parenteral)
• 30 Apr 2014 Preclinical trials in Solid tumours in USA (Parenteral)
• 30 Apr 2014 Pfizer plans a phase I trial for Solid tumours (late-stage disease, second-line therapy or greater) in USA (NCT02129205)

251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 262

/////////PF 06650808, PF-06650808, PF-6650808, monoclonal antibody, pfizer, phase 1, Solid tumours , Notch-3 receptor antagonists 
 

C1(C(N(C(C1)=O)CCCCCC(=O)NC([C@H](C)C)C(=O)NC(C(=O)Nc2ccc(cc2)COC(=O)NC(C)(C)C(=O)N[C@@H](C(C)C)C(=O)[N@](C)C(C(CC)C)[C@@H](OC)CC(=O)N3CCC[C@H]3C(OO)C(C)C(=O)N[C@H](c4nccs4)CC)CCCNC(=O)N)=O)SC
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I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP