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(2S)-2-hydroxy-3-[(3R)-12-{[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]oxy}-7-thia-9,11-diazatricyclo[6.4.0.0²,⁶]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanamide

S)-2-hydroxy-3-((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5-yl)propanamide

 CAS 1388896-07-8
C22 H30 N4 O4 S
5H-​Cyclopenta[4,​5]​thieno[2,​3-​d]​pyrimidine-​5-​propanamide, 6,​7-​dihydro-​α-​hydroxy-​4-​[[trans-​4-​(4-​morpholinyl)​cyclohexyl]​oxy]​-​, (αS,​5R)​-
Molecular Weight446.56

STR3

ND 2158

IRAK4, 446.2

C22H30N4O4S

Company Nimbus Therapeutics LLC
Description IL-1 receptor-associated kinase 4 (IRAK4) inhibitor
Molecular Target Interleukin-1 receptor-associated kinase 4 (IRAK4)
Mechanism of Action Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor
Therapeutic Modality Small molecule

ND-2158 is a potent and selective experimental inhibitor of IRAK4 described in patent WO2013106535 [2] and in a poster presented at the American College of Rheumatology meeting in 2012 (Abstract #1062 in Supplement: Abstracts of the American College of Rheumatology & Association of Rheumatology Health Professionals, Annual Scientific Meeting, November 9-4, 2012 Washington DC, Volume 64, Issue S10, Page S1-S1216).

PATENT

WO2013106535

http://www.google.com/patents/WO2013106535A1?cl=en

Figure imgf000085_0001

Figure imgf000086_0001

Scheme II

Example 88: (S)-l-((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7-dihydro- 5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)butan-2-ol (1-64) and Example 89: (R)-l- ((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-

Synthesis of compound 88.1. Note: For the preparation of the starting material compound 29.2, please see Example 29. A solution of

yl)cyclohexyl]oxy]-7-thia-9,l l-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,l l-tetraen-3- yl]ethan-l-ol (190 mg, 0.47 mmol, 1.00 equiv) in 10 mL of dichloromethane was added Dess- Martin periodinane at 0 °C in a water/ice bath under nitrogen. The resulting mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was then diluted with saturated aqueous sodium bicarbonate and extracted with 3 x 30 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5 to 1 : 1) to afford 2-[(3Λ)-12-[[4-^ο 1ιο1ϊη-4-γ1)ογο1ο1ιβχγ1]οχγ]-7-ωΕ-9,11- diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,l l-tetraen-3-yl]acetaldehyde (130 mg, 69%) as a colorless oil. MS (ES): m/z 402 [M+H]+.

Synthesis of Compound 1-64 and Compound 1-65. A solution of [(3i?)-12-[[4- (moφholin-4-yl)cyclohexyl]oxy]-7-thia-9,l l-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,l l- tetraen-3-yl]acetaldehyde (130 mg, 0.32 mmol, 1.00 equiv) in 5 mL of anhydrous THF was added bromo(ethyl)magnesium (1 M in THF, 0.62 mL, 2.0 equiv) dropwise at 0 °C under nitrogen. The resulting solution was stirred for 4 h at room temperature and then quenched by the addition of saturated aqueous NH4CI and extracted with 3 x 50 mL of DCM/i-PrOH (3:1). The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5um; mobile phase: water with 0.05% NH4CO3 and CH3CN (6.0% CH3CN up to 54.0% in 25 min); UV detection at 254/220 nm to afford (S)-l-((R)-4-(((lr,4R)-4-moφholinocyclohexyl)oxy)-6,7-dihydro-5H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)butan-2-ol (11.8 mg) and (R)-l-((R)-4-(((lr,4R)-4- mo holinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)butan- 2-ol (23.9 mg) as white solids.

Example 88 (1-64): MS: 432 (M+H)+. ¾ NMR (300 MHz, CDC13) S 8.47 (s, 2H), 5.24-5.20 (m, 1H), 3.75-3.58 (m, 5H), 3.06-2.93 (m, 2H), 2.70-2.61 (m, 4H), 2.28-1.98 (m, 3H), 1.59-1.41 (m, 10H), 1.28-1.23 (m, 2H),0.95-0.85 (m, 3H).

Example 89 (1-65): MS: 432 (M+H)+. ¾ NMR (300 MHz, CDC13) S 8.47 (s, 2H), 5.25 (m, 1H), 3.71-3.39 (m, 6H), 3.04-2.90 (m, 2H), 2.67-2.55 (m, 5H), 2.34-2.22 (m, 4H), 2.01- 1.81 (m, 3H), 1.64-1.39 (m, 7H), 0.94-0.92 (m, 3H).

WATCH OUT SYNTHESIS COMING…………

PATENT

WO 2014011906

https://www.google.co.in/patents/WO2014011906A2?cl=en

PATENT

WO-2014194242

https://www.google.com/patents/WO2014194242A2?cl=en

Example 49: Synthesis of Intermediate 49.1.

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step 1 step 2

35.1 49.1 49.2 Image loading...

step 3 49 3

] Intermediate 49.3 was prepared from 35.1 in a manner analogous to the synthesis of 36.3. Isolated 150 mg of a white solid in 57% overall yield. MS (ES): m/z 402 [M+H]+.

Example 50: Synthesis of Intermediate 50.4.

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49.3 50.1 50.2

Image loading...

50.3 50.4

Intermediate 50.4 was prepared from 49.3 in a manner analogous to the synthesis of 1-25, except that HCl/MeOH rather than TBAF/THF was used in the second step. Isolated 124 mg of a white solid in 48% overall yield. MS (ES): m/z 447 [M+H]+. 1H NMR (400 MHz, CDCls): δ 8.46 (s, 1H), 5.28-5.25 (m, 1H), 4.17-4.06 (m, 51H), 3.74-3.72 (m, 5H), 3.37-2.98 (m, 2H), 2.72-2.28 (m, 10H), 2.11-2.08 (m, 2H), 1.79-1.46 (m, 5H).

Example 51: Synthesis of (S)-2-hydroxy-3-((R)-4-(((lr,4R)-4- morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5- yl)propanamide (1-34) and Example 52: Synthesis of (R)-2-hydroxy-3-((R)-4-(((lr,4R)-4- morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5- yl)propanamide (1-44)

Image loading...

The racemic 50.4 (1.6 g, 96.5% purity) was separated by Chiral-HPLC with the following conditions (Gilson G x 281): column: Chiralpak AD-H, 2*25 cm Chiral-P(AD-H); mobile phase: phase A: hex (O. P/oDEA) (HPLC grade), phase B: IPA (HPLC grade), gradient: 30% B in 9 min; flow rate: 20 mL/min; UV detection at 220/254 nm. The former fractions (tR = 4.75 min) were collected and evaporated under reduced pressure and lyophilized overnight to afford 1-44 (520 mg) with 100% ee as a white solid. And the latter fractions (tR = 5.82 min) were handled as the former fractions to give the desired 1-34 (510 mg) with 99.6%> ee as a white solid. The ee values of the two isomers were determined by the chiral-HPLC with the following conditions (SHIMADZU-SPD-20A): column: Chiralpak AD-H, 0.46*25 cm, 5um (DAICEL); mobile phase: hex (0.1% TEA): IPA = 85:15; UV detection at 254 nm. Flow rate: 1.0 mL/min. tR (1-44) = 7.939 min and tR (1-34) = 11.918 min.

[00431] Analytical data for 1-44: MS: (ES, m/z) 447 [M+H]+. 1H NMR (400 MHz, CD3OD+CDCI3): δ 8.47 (s, 1H), 5.32-5.22 (m, 1H), 4.08 (dd, 1H), 4.89-4.62 (m, 5H), 3.20-3.10 (m, 1H), 3.05-2.95 (m, 1H), 2.75-2.55 (m, 5H), 2.44-2.38 (m, 2H), 2.34-2.28 (m, 3H), 2.10 (d, 2H), 1.82-1.62 (m, 3H), 1.58-1.40 (m, 2H).

Analytical data for 1-34: MS: (ES, m/z) 447 [M+H]+. 1H NMR (400 MHz, CDC13): δ 8.46 (s, 1H), 5.32-5.22 (m, 1H), 4.15 (t, 1H), 3.73 (t, 4H), 3.59 (td, 1H), 3.19-3.08 (m, 1H), 3.02- 2.92 (m, 1H), 2.78-2.70 (m, 1H), 2.69-2.60 (m, 4H), 2.58-2.20 (m, 5H), 2.10 (d, 2H), 1.75-1.63 (m, 3H), 1.53-1.40 (m, 2H).

Paper

http://pubs.acs.org/doi/abs/10.1021/jm5016044

Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders

Miniperspective

Nimbus Discovery, 25 First Street, Suite 404, Cambridge, Massachusetts 02141, United States
Schrödinger Inc., 120 West Forty-Fifth Street, New York, New York 10036, United States
J. Med. Chem., 2015, 58 (1), pp 96–110
DOI: 10.1021/jm5016044
Abstract Image

IRAK4, a serine/threonine kinase, plays a key role in both inflammation and oncology diseases. Herein, we summarize the compelling biology surrounding the IRAK4 signaling node in disease, review key structural features of IRAK4 including selectivity challenges, and describe efforts to discover clinically viable IRAK4 inhibitors. Finally, a view of knowledge gained and remaining challenges is provided.

STR3

  1. 78 Romero, D. L.; Robinson, S.; Wessel, M. D.; Greenwood, J. R. IRAK Inhibitors and Uses Thereof. WO201401902, January 16, 2014.

  2. 79.

    Harriman, G. C.; Romero, D. L.; Masse, C. E.; Robinson, S.; Wessel, M. D.; Greenwood, J. R. IRAK Inhibitors and Uses Thereof. WO2014011911A2, January 16, 2014.

  3. 80.

    Harriman, G. C.; Wester, R. T.; Romero, D. L.; Masse, C. E.; Robinson, R.; Greenwood, J. R. IRAK Inhibitors and Uses Thereof. WO2014011906A2, January 16, 2014
Patent ID Date Patent Title
US2013231328 2013-09-05 IRAK INHIBITORS AND USES THEREOF

PATENT

STR3

WO 2014194242

WO 2013106535

WO 2012097013

US20070155777 * Feb 21, 2007 Jul 5, 2007 Amgen, Inc. Antiinflammation agents
US20100041676 * Feb 18, 2010 Hirst Gavin C Kinase inhibitors
US20100143341 * Jun 21, 2006 Jun 10, 2010 Develogen Aktiengesellschaft Thienopyrimidines for pharmaceutical compositions
US20120015962 * Jan 19, 2012 Nidhi Arora PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
US20120283238 * Nov 8, 2012 Nimbus Iris, Inc. Irak inhibitors and uses thereof
References
1. Chaudhary D, Robinson S, Romero DL. (2015)
Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders.
J. Med. Chem.58 (1): 96-110. [PMID:25479567]
2. Harriman GC, Wester RT, Romero DL, Robinson S, Shelley M, Wessel MD, Greenwood JR, Masse CE, Kapeller-Libermann R. (2013)
Irak inhibitors and uses thereof.
Patent number: WO2013106535. Assignee: Nimbus Iris, Inc.. Priority date: 18/07/2013. Publication date: 10/01/2012.

http://nimbustx.com/sites/default/files/uploads/posters/irak4_nimbus_acr_poster_2012_small.pdf

///////ND 2158, IRAK4, ND-2158, NIMBUS, 1388896-07-8

NC(=O)C(CC1CCc2c1c1c(ncnc1s2)OC1CCC(CC1)N1CCOCC1)O

C1CC(CCC1N2CCOCC2)OC3=C4C5=C(CCC5CC(C(=O)N)O)SC4=NC=N3


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DR ANTHONY CRASTO

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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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