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HS-10340

CAS 2156639-66-4

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CAS 2307670-65-9

Jiangsu Hansoh Pharmaceutical Group Co Ltd

Being investigated by Jiangsu Hansoh, Shanghai Hansoh Biomedical and Changzhou Hengbang Pharmaceutical ; in June 2018, the product was being developed as a class 1 chemical drug in China.

Useful for treating liver cancer, gastric cancer and prostate cancer.

Use for treating cancers, liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma and rhabdomyosarcoma

At present, some FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia. Such as target related side effects. Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition. Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.

SYN

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PATENT

WO2017198149

where it is claimed to be an FGFR-4 inhibitor for treating liver and prostate cancers, assigned to Jiangsu Hansoh Pharmaceutical Group Co Ltd and Shanghai Hansoh Biomedical Co Ltd .

PATENT

WO2019085860

[0003]

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https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019085860

Example 1: Preparation of a compound of formula (I)

[0048]

First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol

[0049]

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[0050]

2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) _{. 3} (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH ₂ CI ₂ was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .

[0051]

^{. 1} H NMR (400 MHz, CDCl3 _{. 3} ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);

[0052]

MS m/z (ESI): 310.2 [M+H] ⁺ .

[0053]

The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone

[0054]

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[0055]

4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH ₂ Cl ₂ (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).

[0056]

MS m/z (ESI): 336.2 [M+H] ⁺ .

[0057]

The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate

[0058]

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[0059]

3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N ₂ in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH ₄ Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .

[0060]

^{. 1} H NMR (400 MHz, CDCl3 _{. 3} ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);

[0061]

MS m/z (ESI): 456.2 [M+H] ⁺ .

[0062]

The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis

[0063]

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[0064]

(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N ₂atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH ₄ Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).

[0065]

1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);

[0066]

MS m/z (ESI): 568.3 [M+H] ⁺ .

[0067]

Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

[0068]

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[0069]

(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 _{. 3} solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).

[0070]

^{. 1} H NMR (400 MHz, CDCl3 _{. 3} ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);

[0071]

MS m/z (ESI): 522.2 [M+H] ⁺ .

PATENT

WO-2019085927

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019085927&tab=FULLTEXT

Novel crystalline salt (such as hydrochloride, sulfate, methane sulfonate, mesylate, besylate, ethanesulfonate, oxalate, maleate, p-toluenesulfonate) forms of FGFR4 inhibitor, particularly N-[5-cyano-4-[[(1R)-2-methoxy-1-methyl-ethyl]amino]-2-pyridyl]-7-formyl-6-[(2-oxo-1,3-oxazepan-3-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide (designated as Forms I- IX), compositions comprising them and their use as an FGFR4 inhibitor for the treatment of cancer such as liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and glioma or rhabdomyosarcoma are claimed.

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///////////HS-10340 , HS 10340 , HS10340, CANCER, Jiangsu Hansoh, Shanghai Hansoh Biomedical,  Changzhou Hengbang, CHINA,  liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma,  rhabdomyosarcoma

C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

CCS(=O)(=O)O.C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

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SYN-01, SYN-510

Synthena AG

Preclinical

Synthena , presumed to be under license from  University of Bern , is investigating (presumably SYN-01 ), a lead from the tricyclo(tc)-DNA based antisense oligonucleotides (AON) developed using its proprietary tricyclo-DNA technology platform, for the treatment of Duchenne muscular dystrophy. In January 2017, the drug was listed as being in preclinical development.

Patent

WO-2019142135

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019142135&tab=PCTDESCRIPTION&_cid=P22-JYQVON-19722-1

Process for preparing tricyclo-deoxyribonucleic acid (tc-DNA) which may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Antisense technology is an effective means for reducing the expression of specific gene products and can therefore be useful in therapeutic, diagnostic, and research applications.

Generally, the principle behind antisense technology is that an antisense oligomeric compound (a sequence of nucleotides or analogues thereof) hybridizes to a target nucleic acid and modulates gene expression activities or function, such as transcription and/or translation.

[003] Antisense oligomeric compounds may be prepared from chemically-modified antisense oligonucleotides, which may include a variety of different structural variations depending upon the therapeutic strategy. For example, tricyclo-deoxyribonucleic acids (tc-DNA) are conformationally constrained DNA analogs.

[004] There is a need in the field for processes that allow for the bulk preparation of tc-DNA nucleoside precursors that may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Example 4 – Cvclopropanation of Compound 17 with Carbenoid Prepared from CH2I2 and Et₂Zn in the Absence of Additives

[00127] According to the following scheme, compound 17 was converted to tc-DNA Nucleoside Precursor 18 using the cyclopropanation conditions set forth in Examples 4 to 7 :

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[00128] 1.07 g purified a-anomer (3.736 mmol) 17 was dissolved in 37 ml of dry CH₂C1₂ and cooled to 0 °C (ice). Subsequently, 22.3 ml (22.3 mmol, 6 eq.) Et₂Zn 1.0 M in hexane (Aldrich) were added dropwise and stirred under Ar for 30 min at 0 °C. Then, 3.02 ml (37.2 mmol, 10 eq.) of CH₂I₂ were added dropwise over 15 min at the same temperature and stirred for further 2 h at 0 °C. Afterwards the cooling bath was removed and the mixture was stirred for additional 21 h at ambient temperature. TLC showed substantial amount of unreacted a- 17. It was diluted by addition of EtOAc and quenched with 50 mL of sat. aqueous NH₄Cl. Extractive work-up provided 1.79 g of crude which was purified by chromatography on silica-gel giving 0.43 g (39%) of 18 and 0.49 g of mixture of compound 17 and 18 (approximately 20:80).

PATENT

WO2018193428

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018193428

claiming a composition comprising an oligomeric compound having tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and a lipid moiety.

EXAMPLE 1

Inventive compositions for the treatment of Duchenne muscular dystrophy

Evaluation of efficacy

[00464] Adult mdx mice were treated weekly over 4 weeks with intravenous injections of different 13-mer AONs targeting the donor splice site of exon 23 of the dystrophin pre-mRNA (M23D: +2-11), namely with either SY-0308, SY-0210 and the inventive SY-0299, SY-0343, SY-0442 and SY-0455. SY-0308 (also named “tcDNA-PO M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: l, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorodiester linkage groups, and p being a phosphate moiety at the 5′ end. SY-0210 (also named “tcDNA-PS M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: 1, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorothioate linkage groups, and p being a phosphate moiety at the 5′ end. The inventive composition SY-0343 is herein interchangeably referred to as “Palm-2PS-tcDNA-PO M23D” which is depicted in the following:

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[00465] The inventive composition SY-0442 is herein interchangeably referred to as “Palm-lPS-tcDNA-PO M23D” which is depicted in the following:

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[00466] The inventive composition SY-0299 is herein interchangeably referred to as “Palm-2PO-tcDNA-PO M23D” which is depicted in the following:

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//////////////////SYN-01, SYN 01, SYN01, preclinical , Duchenne muscular dystrophy, University of Bern,

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SK1-I , BML 258

Sphingosine kinase 1 (SphK1) inhibitor; antiproliferative

• (1E)-1,2,4-Trideoxy-4-(methylamino)-1-(4-pentylphenyl)-D-erythro-pent-1-enitol
• (E,2R,3S)-2-(Methylamino)-5-(4-pentylphenyl)pent-4-ene-1,3-diol
• D-erythro-Pent-1-enitol, 1,2,4-trideoxy-4-(methylamino)-1-(4-pentylphenyl)-, (1E)-

• Originator Enzo Biochem; Virginia Commonwealth University
• Developer Enzo Biochem
• Class Antineoplastics; Small molecules
• Mechanism of Action Sphingosine kinase inhibitors

• Preclinical Autoimmune hepatitis; Haematological malignancies; Liver cancer; Solid tumours

• 07 May 2019 Preclinical trials in Liver cancer in USA (unspecified route)
• 03 Dec 2018 SK1 I is available for licensing as of 03 Dec 2018. http://www.enzo.com/
• 03 Dec 2018 Enzo Biochem has patent pending for SK1 I worldwide

SK1 I, a small molecule that specifically inhibits sphingosine kinase 1, is being developed by Enzo Biochem for the treatment of cancer and autoimmune diseases. Preclinical development is underway for the treatment of solid tumours, liver cancer, haematological malignancies and autoimmune hepatitis in the US.

As at December 2018, Enzo Biochem seeks partners for the development of SK1

SK1-I is a sphingosine analog and a sphingosine competitive inhibitor specific for sphingosine kinase 1 (SK1), with k_i~10µM and excellent water solubility. It is not to be confused with SKI-I, 5-naphthalen-2-yl-2H-pyrazole-3-carboxylic acid (2-hydroxy-naphthalen-1-ylmethylene)-hydrazide, CAS 306301-68-8, a noncompetitive inhibitor of both SK1 and SK2 with poor water solubility (K.J. French, et al., 2006; N.J. Pyne and S. Pyne, 2010). SK1-I does not inhibit SK2, PKCα, PKCδ, PKA, AKT1, ERK1, EGFR, CDK2, IKKβ or CamK2β. Not only does it decrease sphingosine-1-phosphate levels, it also causes an accumulation of its proapoptotic precursor ceremide. Inhibits tumor cell growth in vitro and in vivo.

PATENTS

US 20100035959

WO 2010127093

US 20100278741

WO 2011025545

Patent

US-10364211

https://patentscope.wipo.int/search/en/detail.jsf?docId=US249091462&tab=PCTDESCRIPTION&_cid=P10-JZ0Q22-89420-1

This patent was granted in July 30, 2019 and set to expire on October 24, 2038. Claims methods for synthesizing the compound (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol (also known as SK1-I and BML-258 (as HCl salt)) and its intermediates.

(2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, also known as SK1-I and BML-258 (as HCl salt), is a pharmaceutical inhibitor of sphingosine kinase 1 initially described in Paugh et al., Blood. 2008 Aug. 15; 112(4): 1382-1391. An existing method for synthesizing SK1-I is disclosed in U.S. Pat. No. 8,314,151.

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N-Boc-(D)-Serine Methyl Ester

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Protection of N-Boc-(D)-Serine Methyl Ester

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(R)—Garner Aldehyde

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Addition of 4-Pentylphenyl Acetylene to the Above Aldehyde

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Deprotection of the Above Oxazolidine

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Reduction of the Above Alcohol

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Deprotection to SK1-I (BML-258)

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PATENT

WO2018237379 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018237379

claiming sphingosine pathway modulating compounds for the treatment of cancers, assigned to Enzo Biochem Inc , naming different team

Sphingosine- 1 -phosphate (SIP) was discovered to be a bioactive signaling molecule over 20 years ago. Studies have since identified two related kinases, sphingosine kinase 1 and 2 (a/k/a sphingosine kinase “type I” and “type II” respectively, and SphKl and SphK2 respectively), which catalyze the phosphorylation of sphingosine to SIP. Extracellular SIP can bind to and activate each of five S IP-specific, G protein-coupled receptors (designated S IPR1-5) to regulate cellular and physiological processes in an autocrine or paracrine manner. Selective inhibitors of each of sphingosine kinase 1 and 2, as well as both nonselective and selective agonists of SlPRs, have been developed and are known in the art.

Product Literature References

General Literature References

/////////SK1-I , SK1I , SK1 I , BML 258, Enzo Biochem,  Virginia Commonwealth, Preclinical, solid tumours, liver cancer, haematological malignancies, autoimmune hepatitis, 

CCCCCC1=CC=C(/C=C/[C@H](O)[C@H](NC)CO)C=C1.Cl

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ADX-103

CAS 916056-81-0

Preclinical, Antiinflammatory Ophthalmic Agents, Diabetic Retinopathy,

Agents for Ophthalmic Drugs
MF C₁₆ H₁₆ N₂ O₂

5-Amino-α,α-dimethyl-2-phenyl-6-benzoxazolemethanol

Aldeyra Therapeutics Inc
ADX-103 , an aldehyde trap being investigated by Aldeyra for the treatment of dry eye syndrome; in May 2018, preclinical data were presented at 2018 ARVO Meeting in Honolulu, HI. Aldeyra, in collaboration with an undisclosed company, is also investigating an anti-inflammatory agent for treating ocular inflammation.

PATENT

WO-2020033344

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020033344&tab=PCTDESCRIPTION&_cid=P21-K6SRJF-10276-1

Novel crystalline forms of a specific benzoxazole and it’s salts, process for their preparation, and compositions comprising them are claimed, useful for treating dry eye, inflammation and diabetes, through action as an aldehyde scavenger.

It has now been found that compounds of the present invention, and compositions thereof, are useful for treating, preventing, and/or reducing a risk of a disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis. In general, salt forms or freebase forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of diseases or disorders as described in detail herein. Such compounds are represented by the chemical structure below, denoted as compound A:

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or a pharmaceutically acceptable salt thereof.

[0008] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with toxic aldehydes. Such diseases, disorders, or conditions include those described herein.

[0009] Compounds provided by this invention are also useful for the study of certain aldehydes in biology and pathological phenomena.

Scheme 1 – Synthesis of Compound A

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Step 1: Synthesis of Compound A2

[00549] A 30L jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with methanol (10L). Compound A1 (2.0kg) was added, followed by further methanol to rinse (9L). The reaction mixture was warmed to Tjacket=40°C. Once temperature had stabilized, sulfuric acid (220 mL, 0.4eq.) was slowly added. Once addition was complete, agitation was maintained for 30 mins then the vessel was heated to Tjmt=62°C. Reaction progress was

monitored by LC-MS analysis of reaction mixture. The reaction does not go to completion but is deemed complete when no change is apparent in ratio of starting material : product.

[00550] The vessel contents were cooled to Tjmt=24°C and stirred 60 minutes before filtration under vacuum. The filter cake was air dried for 2 hours and the contents then dissolved in ethyl acetate (18L) which was then washed sequentially with saturated sodium bicarbonate (8L), water (8L) and brine (8L) before drying over sodium sulfate, filtration and evaporation in vacuo. Compound A2 (1.5kg, 68.1%) was obtained as a bright orange powder.

Step 2: Synthesis of Compound A3

[00551] A 30L jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with /V,/V-dimethylformamide (16L). Compound A2 (1.5kg) was added and the brown reaction mixture set to cool to Tint<20^oC. Once temperature had stabilized, A-bromosucci ni mi de (l.5kg, 1.1 eq.) was added portion wise, maintaining Tint<27°C. Once addition was complete, the reaction was allowed to stir until starting material content was <1% AUC (250nm) by LCMS analysis.

[00552] A secondary jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with ethyl acetate (16L) and deionized water (22L). The reaction mixture was vacuum transferred into this vessel and held at high agitation for not less than 30 minutes. The aqueous layer was discharged and the organic layer washed with saturated sodium chloride (2 x 8L) then dried over sodium sulfate before evaporation in vacuo to Compound A3 as a deep brown oil (2.lkg, 100.8%), suitable for use in following step without purification.

Step 3: Synthesis of Compound A4

[00553] A 30L jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with dichloromethane (9L). Compound A3 (2.lkg) was added and the reaction mixture cooled to Tmt<l°C. A solution of Di-/er/-butyl dicarbonate (3.6kg, 2.2 eq.) in dichloromethane (0.5L) was added followed by a solution of A, A-di methyl ami nopyri di ne (92g, 0.1 eq.) in dichloromethane (0.5L). The resultant clear brown solution was stirred for 30 minutes whereupon pyridine (1.3L, 1.7 eq.) was dropwise added, maintaining Tint<5°C. Upon complete addition internal temperature was ramped from Tint=l°C to Tint=20°C over 18 hours.

[00554] The reaction mixture was sequentially washed with saturated sodium chloride (3 x 4.5L), 10 % ^w/_v aqueous citric acid (2 x 4L), saturated sodium bicarbonate (4L), aqueous hydrochloric acid (1M, 4L), saturated sodium bicarbonate (4L) and saturated sodium chloride (4L) then dried over sodium sulfate and evaporated in vacuo with one azeotropic distillation with toluene (2L) to a very dark, heavy tar (3.4kg).

[00555] The isolated tar was mixed with absolute ethanol (3.1L) for 2 days whereupon it was filtered providing light cream colored, granular solids and a black mother liquor. The solids were washed with ice-cold ethanol (3 x 1L) and dried to constant mass. Compound A4 was obtained as off- white granules (1.7 kg, 50.2%).

Step 4: Synthesis of Compound AS

[00556] A 30L jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with reagent alcohol (6.1 L) and Compound A4 (0.8kg), Tm_t<20°C. Iron powder (0.5kg, 5.0 eq.) was added and the suspension stirred vigorously for 30 minutes. Acetic acid (glacial, 1.6L, 15.7 eq.) was added, maintaining Tint<30C.

[00557] Once LCMS confirmed complete consumption of starting material, ethyl acetate (10.2L) and water (10.2L) were added. Sodium bicarbonate (2.3kg, 15.9 eq.) was added portion wise and the layers separated once gas evolution had ceased. The aqueous layer was washed with ethyl acetate until LCMS indicated no further product was being extracted (8 x 2L) and the combined organic layers were sequentially washed with deionized water (6L) then saturated sodium chloride (6L) before drying over magnesium sulfate and evaporation in vacuo. Compound A5 was obtained as a light orange solid (0.7kg, 91.5%).

Step 5: Synthesis of Compound A6

[00558] A 30L jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with dichloromethane (9L), Compound A5 (0.7kg), and the reaction mixture cooled to Tint 20°C. Benzoyl chloride (0.3L, 1.5 eq.) was added and the reaction stirred 15 minutes. N,N-dimethylaminopyridine (7g, 0.04 eq.) in dichloromethane (0.1L) was added and the reaction stirred 15 minutes. Pyridine (0.5L, 2.5 eq.) was dropwise added, maintaining Tint<20°C. Upon complete addition the reaction was stirred until LCMS indicated consumption of starting material.

[00559] The reaction mixture was washed with deionized water (11L) and the organic layer extracted sequentially with aqueous hydrochloric acid (1M, 3 x 5L), saturated aqueous sodium bicarbonate (11 L), saturated sodium chloride (11 L), dried over magnesium sulfate and evaporated in vacuo. Compound A6 was obtained as a cream colored solid, suitable for use without further purification (0.9kg, 100.7%).

Step 6: Synthesis of Compound A 7

[00560] A 30L jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with l,2-dimethoxy ethane (16L) and temperature set to Tint=2l°C. Compound A6 (0.9kg) was added and stirred to dissolution. Copper iodide (0.3kg, 1.0 eq.) was added and the mixture stirred 15 minutes. l, lO-phenanthroline (0.3kg, 1.2 eq.) was added and the mixture stirred 15 minutes. Cesium carbonate (l .5kg, 3.0 eq.) was added and the reaction was stirred for 15 minutes. The reaction temperature was ramped to Tint=80-85^oC and maintained for 23 hours whereupon it was cooled to Tmt=20°C.

[00561] The reaction mixture was filtered through a celite pad, washing sequentially with deionized water (8L) and ethyl acetate (8L). The organic layer was extracted sequentially with deionized water (2 x 5L), saturated sodium chloride (4L), dried over sodium sulfate and evaporated in vacuo. Compound A7 was obtained as a brown solid, suitable for use without further purification (0.8kg, 104.1%).

Step 7: Synthesis of Compound A8

[00562] A 12L 3 -neck round bottom flask with nitrogen bleed and mechanical stirring was charged with a solution of Compound A7 (0.8kg) in dichloromethane (3.6L) and cooled to Tmt<5°C in an ice bath. Hydrochloric acid in dioxane (4M, 1 2L, 3.1 eq.) was added dropwise with vigorous stirring, maintaining Tmt<25°C. Once addition was complete, the reaction mixture was allowed to stir for 18 hours at Tint=20-25^oC.

[00563] The reaction mixture was filtered and the filter cake washed with dichloromethane (2 x 1L) and dried to constant mass. The hydrochloride salt of Compound A8 was isolated as an off-white solid (0.5kg, 88.7%).

Step 8: Synthesis of Compound A

[00564] A 12L 3 -neck round bottom flask with nitrogen bleed and mechanical stirring was charged with a solution of Compound A8 (0.5kg) in tetrahydrofuran (4.8L) and cooled to Tint<-30°C in a dry-ice / acetone bath. Methylmagnesium bromide (3.4M in 2-methyltetrahydrofuran, 2.4L, 5.0eq.) was added slowly, maintaining Tmt<-lO°C. Once addition was complete, the reaction was allowed to warm to room temperature overnight.

[00565] Saturated aqueous ammonium chloride (2L) and ethyl acetate (2L) were added and the reaction mixture stirred for 30 minutes. The aqueous layer was extracted with further ethyl acetate (2 x 2L) and the combined organic layers washed with saturated sodium chloride (2L), dried over sodium sulfate and evaporated in vacuo to a dark heavy oil. The heavy oil was purified by column chromatography on silica gel, eluting with ethyl acetate : heptane 1 : 19 to 1 : 1. Pure Compound A was obtained after evaporation and drying as a brown powder (99.8 g, 23.0%).

Example 1 – Preparation of Free Base Forms A, B and C of Compound A

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Compound A

Primary Polymorph Screen

[00566] Based on solubility screen results, a primary polymorph screen using an initial set of 24 solvents, as shown in Table 18, was performed as follows: A) To 24 x 20 mL vials, approximately 50 mg of the received ADX-103 was added; B) The solids were then slurried in 2 mL of the solvents and left placed in an incubator/shaker to temperature cycle between ambient and 40 °C in 4 hour cycles; C) After 72 hours temperature cycling, the mother liquors were removed from the vials and split evenly between 4 x 2 mL vials. The vials were then split between evaporation, crash cooling to 2 °C and -18 °C and anti-solvent addition; and D) Any solids

recovered were analysed by XRPD, any new patterns identified were also analysed by TG/DTA and PLM.

Table 18. Solvents Selected for Initial Primary Polymorph Screen

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PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018039197&tab=PCTDESCRIPTION&_cid=P21-K6SRNE-12791-1

WO2018039197 , as compound I-8.

PATENT

WO 2006127945

WO 2011072141

WO 2014116593

US 20150344447

WO 2020028820

////////////ADX-103, Preclinical, Antiinflammatory,  Ophthalmic Agents, Diabetic Retinopathy, Aldeyra Therapeutics Inc,

CC(C)(O)c1cc2oc(nc2cc1N)c3ccccc3

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GST-HG-121

mw 431.4

C23 H29 N07

Fujian Cosunter Pharmaceutical Co Ltd

Preclinical for the treatment of hepatitis B virus infection

This compound was originally claimed in WO2018214875 , and may provide the structure of GST-HG-121 , an HBsAg inhibitor which is being investigated by Fujian Cosunter for the treatment of hepatitis B virus infection; in June 2019, an IND application was planned in the US and clinical trials of the combination therapies were expected in 2020. Fujian Cosunter is also investigating GST-HG-131 , another HBsAg secretion inhibitor, although this appears to be being developed only as a part of drug combination.

WO2017013046A1

PATENT

WO2018214875

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214875&_cid=P21-KB0QYA-12917-1

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PATENT

WO-2020103924

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020103924&tab=FULLTEXT&_cid=P21-KB0QP8-09832-1

Novel crystalline forms of 11-oxo-7,11-dihydro-6H-benzo[f]pyrido[1,2-d][1,4]azepine, a hepatitis B surface antigen and HBV replication inhibitor, useful for treating HBV infection.

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[0060]

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Step H: Compound 9 (15.80 g, 35.95 mmol) was dissolved in dichloromethane (150.00 mL), and trifluoroacetic acid (43.91 mL, 593.12 mmol) was added. The reaction solution was stirred at 10 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure and spin-dried, sodium bicarbonate aqueous solution (100.00 mL) was added, and dichloromethane (100.00 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 10.

Step J: Compound 12 (875.00 mg, 1.90 mmol) was dissolved in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), and tetrachlorobenzoquinone (1.40 g, 5.69 mmol) was added. The reaction solution was stirred at 120 degrees Celsius for 12 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium carbonate solution (50.00 ml) and ethyl acetate (60.00 ml) were added. The mixed solution was stirred at 10-15 degrees Celsius for 20 minutes, and the liquid was separated to obtain an organic phase. Add 2.00 mol/L aqueous hydrochloric acid solution (60.00 mL) to the organic phase, stir at 10-15 degrees Celsius for 20 minutes, and separate the liquid. Wash the organic phase with 2 mol/L aqueous hydrochloric acid solution (60.00 mL×2), separate the liquid, and separate the water phase A 2 mol/L aqueous sodium hydroxide solution (200.00 ml) and dichloromethane (200.00 ml) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 13.

Step K: Compound 13 (600.00 mg, 1.31 mmol) was dissolved in methanol (6.00 mL), and 4.00 mol/L aqueous sodium hydroxide solution (2.00 mL, 6.39 equiv) was added. The reaction solution was stirred at 15 degrees Celsius for 0.25 hours. The reaction solution was adjusted to pH=3-4 with a 1.00 mol/L hydrochloric acid aqueous solution, and then extracted with dichloromethane (50.00 mL×3). The organic phases were combined, washed with saturated brine (50.00 mL), and dried over anhydrous sodium sulfate , Filtered and concentrated under reduced pressure to obtain the compound of formula (I). ee value (enantiomeric excess): 100%.

////////////GST-HG-121, Fujian Cosunter,  Preclinical ,  hepatitis B,  virus infection

O=C(O)C1=CN2C(=CC1=O)c3cc(OC)c(OCCCOC)cc3OC[C@H]2C(C)(C)C

O=C(O)C1=CN2C(=CC1=O)c3cc(OC)c(OCCCOC)cc3OC[C@H]2C(C)(C)C

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EXAMPLE

O=C(OC)/C=C/c1ccc(CNC2CC2c2ccc(F)cc2)cc1

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EXAMPLE ONLY NOT CONFIRMED

JBI-802

• Myeloid Leukemia Therapy
• Solid Tumors Therapy

Epigenetic Modifier Modulators

• Histone Deacetylase 6 (HDAC6) Inhibitors
• Lysine-Specific Histone Demethylase 1A (KDM1A; LSD1) Inhibitors

Jubilant Therapeutics Announces Successful Completion of Pre-IND Meeting with FDA for its Novel Dual LSD1 and HDAC6 Inhibitor JB1-802

https://markets.businessinsider.com/news/stocks/jubilant-therapeutics-announces-successful-completion-of-pre-ind-meeting-with-fda-for-its-novel-dual-lsd1-and-hdac6-inhibitor-jb1-802-1030834551
PRESS RELEASE PR Newswire

Sep. 30, 2021, 10:23 AM

BEDMINSTER, NJ, Sept. 30, 2021 /PRNewswire/ — Jubilant Therapeutics Inc., a biopharmaceutical company advancing small molecule precision therapeutics to address unmet medical needs in oncology and autoimmune diseases, today announced the successful completion of a pre-IND (Investigational New Drug) meeting with the U.S. Food and Drug Administration (FDA) regarding the development plan, clinical study design and dosing strategy for the Phase I/II trial of JB1-802, a dual inhibitor of LSD1 and HDAC6, for the treatment of small cell lung cancer, treatment-induced neuro-endocrine prostate cancer and other mutation-defined neuroendocrine tumors.

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Clik here to view.A pre-IND meeting provides the drug development sponsor an opportunity for an open communication with the FDA to discuss the IND development plan and to obtain the agency’s guidance regarding planned clinical evaluation of the sponsor’s new drug candidate. After reviewing the preclinical data provided, plans for additional data generation and the Phase I/II clinical trial protocol, the FDA addressed Jubilant Therapeutics’ questions, provided guidance and aligned with the sponsor on the proposed development plan for JBI-802.

“We appreciate the FDA’s guidance as we endeavor to find an innovative new treatment for high unmet-need tumors with devastatingly low survival rates,” said Hari S Bhartia, Chairman, Jubilant Therapeutics Inc.

“We are pleased with the outcome of the pre-IND meeting with the FDA and plan to submit the IND application by the end of 2021,” said Syed Kazmi, Chief Executive Officer, Jubilant Therapeutics Inc.

About Jubilant TherapeuticsJubilant Therapeutics Inc. is a patient-centric biopharmaceutical company advancing potent and selective small molecule modulators to address unmet medical needs in oncology and autoimmune diseases. Its advanced discovery engine integrates structure-based design and computational algorithms to discover and develop novel, precision therapeutics against both first-in-class and validated but intractable targets in genetically defined patient populations. The Company plans to file an IND later this year for the first in class dual inhibitor of LSD1/HDAC6, followed by two additional INDs in 2022 with novel modulators of PRMT5 and PAD4 in oncology and inflammatory indications. Jubilant Therapeutics is headquartered in Bedminster NJ and guided by globally renowned key opinion leaders and scientific advisory board members. For more information, please visit www.jubilanttx.com or follow us on Twitter @JubilantTx and LinkedIn.

View original content:https://www.prnewswire.com/news-releases/jubilant-therapeutics-announces-successful-completion-of-pre-ind-meeting-with-fda-for-its-novel-dual-lsd1-and-hdac6-inhibitor-jb1-802-301388983.html

SOURCE Jubilant Therapeutics Inc.

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Mohd Zainuddin

Director at Jubilant Therapeutics Inc

PATENT

IN 201641016129

PATENT

US20200308110 – CYCLOPROPYL-AMIDE COMPOUNDS AS DUAL LSD1/HDAC INHIBITORS

https://patentscope.wipo.int/search/en/detail.jsf?docId=US306969204&tab=NATIONALBIBLIO&_cid=P21-KUANET-85789-2ApplicantsJubilant Epicore LLC
Inventors

Sridharan RAJAGOPAL
Mahanandeesha S. HALLUR
Purushottam DEWANG
Kannan MURUGAN
Durga Prasanna KUMAR C.H.
Pravin IYER
Chandrika MULAKALA
Dhanalakshmi SIVANANDHAN
Sreekala NAIR
Mohd ZAINUDDIN
Subramanyam Janardhan TANTRY
Chandru GAJENDRAN
Sriram RAJAGOPAL
Priority Data201641016129 09.05.2016 IN

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Sridharan Rajagopal

Vice President-Head of Medicinal Chemistry at Jubilant Therapeutics Inc

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Dhanalakshmi Sivanandhan

Vice President at Jubilant Therapeutics Inc

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Mahanandeesha Hallur

Associate Director at Jubilant Biosys

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Sreekala Nair

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Chandrika Mulakala

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Pravin Iyer

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Purushottam (M.) Dewang

ERRORS CALL ME , +919321316780

AND TO ADD TOO

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 EXAMPLE

CAS 2152635-16-8

C₂₀ H₂₀ F N O₂2-​Propenoic acid, 3-​[4-​[[[2-​(4-​fluorophenyl)​cyclopropyl]​amino]​methyl]​phenyl]​-​, methyl ester, (2E)​-Molecular Weight, 325.38

Patent

WO2017195216

I-3methyl (E)-3-(4-(((tert-butoxycarbonyl)(2-(4-((4-fluorobenzyl)oxy)phenyl) cyclopropyl)amino)methyl)phenyl)acrylate

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The compound was synthesized using amine B6 and (E)-3-(4-Formyl-phenyl)-acrylic acid methyl esterfoUowing the procedure for the synthesis of 1-2. LC-MS m/z calcd for C₃₂H₃₄FN0₅, 531.2; found 532.2 [M+H]⁺.

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join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

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Anthony Melvin Crasto Dr. | Facebook

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Anthony Melvin Crasto Dr. | twitter

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EMAIL. amcrasto@gmail.com

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Step 2: (E)-3-[4-({tert-Butoxycarbonyl-[2-(4-fluoro-phenyl)-cyclopropyl]-amino}-methyl)-phenyl]-acrylic acid methyl ester (I-2)

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REFJBI-802, novel dual inhibitor of LSD1-HDAC6 for treatment of cancerSivanandhan, D.; Rajagopal, S.; Nair, S.; et al.Annu Meet Am Assoc Cancer Res (AACR) · 2020-06-22 / 2020-06-24 · Virtual, N/A · Abst 1756Synthesis and optimization of a novel series of LSD1-HDAC dual inhibitors led to the discovery of JBI-802 as the lead compound, with IC50 of 0.05 mcM against LSD1 and isoform selective HDAC6/8 activity, with IC50 of 0.011 and 0.098 mcM for HDAC6 and HDAC8, respectively. The candidate also showed excellent selectivity against other HDACs, with approximately 77-fold selectivity for HDAC6. In vitro, JBI-802 showed strong antiproliferative activity on selected cell lines, including acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma and certain solid tumors, such as small cell lung cancer and sarcoma. In vivo, JBI-802 demonstrated strong efficacy in erythroleukemia xenograft model, leading to prolonged survival of mice bearing HEL92.1.7 tumors. The candidate showed excellent dose-response and superior efficacy compared to single agents in this model, with ED50 of approximately 6.25 mg/kg twice-daily by oral administration. When evaluated in CT-26 syngeneic model, JBI-802 showed promising activity as single agent and in the combination of JBI-802 plus anti-programmed cell death protein 1 (PD-1) monoclonal antibody (MAb), with approximately 80% tumor growth inhibition observed for the combination. Exploratory toxicology studies showed that JBI-802 was well tolerated at efficacious doses. Further preclinical IND-enabling studies are currently underway for this molecule, which is to be developed as a clinical candidate for the treatment of acute myeloid leukemia and other tumor types. 

REFNovel dual inhibitor of LSD1-HDAC6/8 for treatment of cancerDhanalakshmi, S.; Rajagopal, S.; Sadhu, N.; et al.62nd Annu Meet Am Soc Hematol · 2020-12-05 / 2020-12-08 · Virtual, N/A · Abst 3378 Blood 2020, 136(Suppl. 1) 


REFJubilant Therapeutics Presents Preclinical Data at the American Association for Cancer Research, Reveals Unique Dual-Action Anti-Cancer Mechanism Underscoring First-in-Class Pipeline Asset in Hematological Tumors 
Jubilant Therapeutics Press Release 2020, June 22

////////////////JB1-802, JUBILANT, CANCER,  PRECLINICAL

EXTRAS…………

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PATENTWO2021062327 – FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOFhttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021062327&_cid=P21-KUAMRR-83330-1PCT/US2020/052953

Priority Data

Inventors

• VENKATESHAPPA, Chandregowda
• SIVANANDHAN, Dhanalakshmi
• RAJAGOPAL, Sridharan
• ROTH, Bruce
• PANDEY, Anjali
• SAXTON, Tracy
• HALLUR, Gurulingappa
• MADHYASTHA, Naveena
• SADHU M, Naveen

Lung cancer accounts for the greatest number of cancer deaths, and approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). The development of targeted therapies for lung cancer has primarily focused on tumors displaying specific oncogenic drivers, namely mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Three generations of tyrosine kinase inhibitors (TKIs) have been developed for cancers with the most frequently observed EGFR mutations, however, other oncogenic drivers in the EGFR family of receptor tyrosine kinases have received less research and development focus and several oncogenic drivers, including insertions in the exon 20 gene of EGFR, have no currently approved therapeutics to treat their cancers.

[0003] The mutation, amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2), another member of the human epidermal growth factor receptor family of receptor tyrosine kinases, has been implicated in the oncogenesis of several cancers, including lung, breast, ovarian, and gastric cancers. Although targeted therapies such as trastuzumab and lapatinib have shown clinical efficacy especially in breast tumors, their utility in lung cancer has been limited. It is likely that this variation is due to tissue-specific factors, including the low potency of kinase inhibitors like lapatinib for the mutagenic alterations in HER2 that are observed in the lung cancer patient population, including insertions in the exon 20 gene of HER2.

[0004] Given that many patients with mutations in EGFR and HER2 do not derive clinical benefit from currently available therapies against these targets, there remains a significant unmet need for the development of novel therapies for the treatment of cancers associated with EGFR and HER2 mutations.

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Compound 49: (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide

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Step 1: Synthesis of (E)-4-(dimethylamino)but-2-enoyl chloride

[0280] To a stirred mixture of acetonitrile (2 mL) and DMF (2 drop) under N2 atmosphere was added N,N-dimethylamino crotonic acid hydrochloride (0.1 g, 0.77 mmol). After 10 min, this solution was cooled to 0-5 °C. Oxalyl chloride (0.122 g, 0.968 mmol) was added and the reaction mixture was maintained at 0-5 °C for 30 min. It was allowed to warm to RT and stirring was continued for 2 h. It was then heated to 40 °C for 5 min and again brought to RT and stirred for 10 min. Formation of product was confirmed by TLC and the reaction mass was used as such to the next step without any workup.

Step-2: Synthesis of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 49)

[0281] 1-(3-Aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.11g, 0.7 mmol) in DMP (2 mL) was cooled to -15 °C and then (E)-4-(dimethylamino)but-2-enoylchloride was added. The reaction mixture was stirred for 1 h at -15 °C to RT. After the completion of reaction, the reaction mass was quenched with ice water, sodium bicarbonate solution and extracted with DCM (100 mL x 2). The combined organic layer was washed with cold water (3 x 50 mL), brine solution (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by prep HPLC to get pure product (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 49, 0.022 g, 16 % yield) as white solid.¹H NMR (400 MHz, DMSO-d₆): δ 10.21 (s, 1H), 9.32 (s, 1H), 8.06 (s, 1H), 7.76 (bs, 1H) 7.65 (s, 1H), 7.48 (bs, 1H), 7.39-7.29 (m, 5H), 7.03 (d, J = 7.2 Hz, 2H), 6.74-6.68 (m, 1H), 6.62 (s, 1H), 6.25 (d, J = 15.2 Hz, 1H), 4.62 (s, 2H), 4.37 (s, 2H), 3.47 (s, 3H), 3.03 (d, J = 5.6 Hz, 2H), 2.15 (s, 6H); LCMS Calcd for [M+H] ⁺ 538.2, found 538.5

Compound 50: (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-3-chloroacrylamide

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Step-1: Synthesis of (Z)-3-chloroacrylic acid

[0282] To a stirred solution propiolic acid (2 g, 28.5 mmol) in DMF (15 mL) under N2 atmosphere was added thionyl chloride (4.07 g, 34.2 moles) slowly and the reaction mixture was maintained at 25 °C for 1 h. The reaction was monitored by TLC, after the completion of reaction, the residue was poured into ice and the resulting aqueous solution was extracted with ether (3 x100 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified to get pure product (Z)-3-chloroacrylic acid (1.9 g, 62.9 % yield). LCMS Calcd for [M-H] ⁺, 104.98, found 105.1

Step-2: Synthesis of (Z)-3-chloroacryloyl chloride

[0283] To a stirred solution of acetonitrile (3 mL) and DMF (3 drop) under N₂ atmosphere was added of (Z)-3-chloroacrylic acid (0.2 g, 1.87 mmol). After 10 min this solution was cooled 0-5 °C. Oxalyl chloride (0.122 g, 0.968 mmol) was added and the reaction mixture was maintained at 0-5 °C for 30 min. It was allowed to warm to RT and stirring was continued for 2 h to get (Z)-3-chloroacryloyl chloride. Formation of product was confirmed by TLC and the reaction mass was used as such to the next step without any workup.

Step-3: Synthesis of (E)-3-((3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)amino)acryloyl chloride (Compound 50)

[0284] A solution of 1-(3-Aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.11 g, 0.7 mmol) in DMP (2 mL) was cooled to -15 °C and then (Z)-3-chloroacryloyl chloride was added. The reaction mixture was stirred for 1 h at -15 °C to RT. The reaction was monitored by TLC. After the completion of reaction, reaction mass was quenched with ice water and sodium bicarbonate solution. The aqueous layer was e 0.028 g, 22% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 9.32 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.41-7.35 (m, 5H), 7.30-7.29 (m, 1H), 7.08-7.02 (m, 2H), 6.62-6.58 (m, 2H), 4.62 (s, 2H), 4.37 (s, 2H), 3.47 (s, 3H); LCMS Calcd for [M+H] ⁺ 515.1, LCMS found 515.2

Compound 51: (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide

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Step-1: Synthesis of 2,4-dichloro-5-(chloromethyl)pyrimidine

[0285] Title compound was prepared in a similar manner to general procedure I.5-(hydroxymethyl)pyrimidine-2,4-diol (15 g, 106 mmol) gave 2,4-dichloro-5-(chloromethyl)pyrimidine (11.50 g, 55% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 8.66 (s, 1H), 4.65 (s, 2H).

Step-2: Synthesis of 2,4-dichloro-5-(iodomethyl)pyrimidine

[0286] Title compound was prepared in a similar manner to general procedure J.2,4-dichloro-5-(chloromethyl)pyrimidine (11.50 g, 58.20 mmol) on treatment with NaI (10.50 g, 69.0 mmol) in acetone (100 mL) resulted in 2,4-dichloro-5-(iodomethyl)pyrimidine (15.20 g, 91% yield). The solid was immediately taken up in toluene and stored under refrigeration.¹H NMR (400 MHz, CDCl₃): δ 8.60 (s, 1H), 4.39 (s, 2H).

Step-3: Synthesis of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline

[0287] A solution of iodo compound (18, 7.0 g, 24.20 mmol) in toluene (50 mL) was cooled to 0 °C and aniline (2.20 g, 24.20 mmol) was added. The reaction mixture was stirred for 30 min at 0 °C. Then a solution of sodium hydroxide (1.30 g, 32.50 mmol) in water (5 ml) was added and reaction mixture was stirred for 16 h at RT. The reaction was monitored by TLC. After completion of the reaction, water (25 mL) was added and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude residue. The crude compound was purified by silica gel column chromatography to afford the title compound as a white solid (10 g, 81% yield). LCMS Calcd for [M+H] ⁺ 254.11, found 254.09

Step-4: Synthesis of tert-butyl (3-((2-chloro-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate

[0288] To a stirred solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (4.0 g, 15.08 mmol) in IPA (30 mL), tert-butyl (3-aminophenyl)carbamate (4.90 g, 23.0 mmol) and DIPEA (8.20 mL, 47 mmol) were added. The reaction mixture was heated at 100 °C for 16 h in a sealed tube. Solvent was then evaporated and the crude thus obtained was purified by flash column chromatography to afford the title compound as off white solid (2.50 g, 37% yield). LCMS Calcd for [M+H] ⁺ 425.92, found 426.35

Step-5: Synthesis of tert-butyl (3-(7-chloro-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate

[0289] To a solution of tert-butyl (3-((2-chloro-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (1.50 g, 3.50 mmol) in THF (35 mL) was added DIPEA (2.40 mL, 14.10 mmol) and thiophosgene (0.27 g, 3.50 mmol) at 0 °C. The reaction mixture was stirred at RT for 24 h with TLC monitoring. After completion of the reaction, sodium bicarbonate solution was added. The reaction mixture was partitioned between DCM (2 x 100 mL) and water (50 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography to afford the title compound as a yellow solid (1.36 g, 82% yield). LCMS Calcd for [M+H] ⁺ 467.97, found 468.27

Step-6: Synthesis of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate

[0290] To a solution of tert-butyl (3-(7-chloro-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (1.30 g, 2.78 mmol) in IPA (15 mL) was added 3-

chloro-1-methyl-1H-pyrazol-4-amine (0.44 g, 3.34 mmol) and TFA (1 mL). The reaction mixture was heated for 16 h at 110 °C. Reaction was monitored by TLC. After the completion of reaction, the reaction mixture was concentrated, water (10 mL) and saturated sodium bicarbonate (20 mL) solution were added to the residue and extracted with DCM (3 x 200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound (1.30 g) that was used as such for the next step without further purification. LCMS Calcd for [M+H] ⁺ 563.08, found 562.90

Step-7: Synthesis of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione

[0291] To an ice-cold solution of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (1.30 g, 2.30 mmol) in DCM (20 mL) and MeOH (10 mL) was added 4N HCl in dioxane (5 mL). The reaction mixture was stirred for 16 h at RT. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated followed by addition of water (10 mL) and saturated sodium bicarbonate (20 mL) solution and extraction with DCM (3 x 200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography to afford the title compound as a brown solid (0.20 g). LCMS Calcd for [M+H] ⁺ 462.96, found 463.0. Purity: 68%

Step-8: Synthesis of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 51)

[0292] To an ice-cold solution of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione (0.18 g, 0.39 mmol) and trans-N,N-dimethylaminocrotonic acid hydrochloride (0.077 g, 0.47 mmol) in dichloromethane (10 mL) was added triethyl amine (1.2 mmol) followed by drop wise addition of propylphosphonic anhydride (T3P) (0.26 g, 0.97 mmol). The mixture was stirred at RT for 6 h. Completion of the reaction was monitored by TLC. The reaction mixture was portioned between 5% methanol in dichloromethane and saturated bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude obtained was purified by silica gel chromatography to afford the title compound as off white solid (Compound 51, 0.010 g, 5% yield).¹H NMR (400 MHz, DMSO-d₆): δ 10.36 (bs, 1H), 8.97 (bs, 1H), 8.25 (s, 1H), 7.72 (bs, 2H), 7.48-7.42 (m, 5H), 7.36-7.32 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.76-6.60 (m, 2H), 6.30 (d, J = 14.8 Hz, 1H), 4.95 (s, 2H), 3.50 (s, 3H), 3.12 (bs, 2H), 2.21 (s, 6H); LCMS Calcd for [M+H] ⁺ 574.10, found 574.41

Scheme 28: Preparation of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 52):

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Clik here to view. Step 1: Preparation of ethyl 4-((3-((tert-butoxycarbonyl) amino) phenyl) amino)-2-(methylthio) pyrimidine-5-carboxylate (106):

[0293] Title compound (106) was prepared as off-white solid (142 g; Yield: 74%) in a manner substantially similar to procedure mentioned in General procedure O.¹H-NMR (400 MHz, CDCl3): ^ 10.36 (s, 1H), 8.77 (d, 1H), 7.89 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.51 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.51 (s, 9H), 1.42-1.38 (m, 3H). LCMS: [M+H]⁺ 405.21, 89.28%.

Step 2: Preparation of tert-butyl (3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (107):

[0294] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure P. The crude was triturated with dichloromethane afforded 107 as off white solid (40.0 g; Yield: 31%).¹H-NMR (400 MHz, CDCl3): ^ 8.09 (s, 1H), 7.86 (m, 2H),

7.36 (d, J = 8.0 Hz, 1H), 7.25-7.15 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 4.59 (s, 2H), 2.50 (s, 3H), 1.51 (s, 9H). LCMS: [M+H]⁺ 363.05, 91.24%.

Step 3: Preparation of tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (108):

[0295] Title compound (108) was prepared as a pale yellow solid (31.0 g; Yield: 78%) in a manner substantially similar to procedure mentioned in General procedure Q.¹H-NMR (400 MHz, CDCl3): ^ 10.59 (s, 1H), 9.75 (s, 1H), 8.42 (s, 1H), 7.97 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 3.48 (s, 1H), 2.58 (s, 3H), 1.52 (s, 9H). LCMS: [M+H]⁺ 361.30, 97.51%.

Step 4: Preparation of tert-butyl (E)-(3-((5-((benzylimino)methyl)-2(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (110):

[0296] Title compound (110) was prepared as a yellow solid (28 g; Yield: 72%) in a manner substantially similar to procedure mentioned in General procedure R.¹H-NMR (400 MHz, CDCl₃): ^ 12.15 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.41 (m, 4H), 7.35-7.33 (m, 1H), 7.32-7.29 (m, 1H), 7.26-7.22 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 4.84 (s, 2H), 2.59 (s, 3H), 1.52 (s, 9H). LCMS: [M+H]⁺ 450.38; 99.66%.

Step 5: Preparation of tert-butyl (3-((5-((benzylamino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (111):

[0297] Title compound (111) was prepared as a pale yellow solid (40 g; Yield: 80%) in a manner substantially similar to procedure mentioned in General procedure S. LCMS: [M+H]⁺ 452.44; 83.57%

Step 6: Preparation of tert-butyl (3-(3-benzyl-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (112):

[0298] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure T. The crude was triturated with diethyl ether afforded 112 as off white solid (12 g; Yield: 28%).¹H-NMR (400 MHz, CDCl3): ^ 8.03 (s, 1H), 7.50 (s, 1H), 7.37 (m, 6H), 7.26 (m, 1H), 6.96 (m, 1H), 6.59 (s, 1H), 4.69 (s, 2H), 4.34 (s, 2H), 2.16 (s, 3H), 1.50 (s, 9H). LCMS: [M+H]⁺ 478.16; 95.62%.

Step 7: Preparation of tert-butyl (3-(3-benzyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido [4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (113):

[0299] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure U. The crude was triturated with diethyl ether afforded 113 as an off white solid (8.0 g; Yield: 76%).¹H-NMR (400 MHz, CDCl₃): ^ 8.39 (s, 1H), 7.63 (s, 1H), 7.40 (m, 6H), 7.17 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 4.71 (s, 2H), 4.48 (s, 2H), 2.97 (s, 3H), 1.49 (s, 9H). LCMS: [M+H]⁺ 510.31, 93.69%.

Step 8: Preparation of tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114):

[0300] Title compound was prepared in a manner substantially similar to General procedure V, tert-butyl (3-(3-benzyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (113) and 1-methyl-1H-pyrazol-3-amine (41) gave (tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114) as a brown solid (Yield: 77%), which was used directly for the next step without any further purification. MS: [M+H]⁺ 527.46.

Step 9: Preparation of 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115):

[0301] Title compound was prepared in a manner substantially similar to General procedure W, tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114) gave 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115) as a brown solid (Yield: 93%), which was used directly for the next step. MS: [M+H]⁺ 427.44.

Step 10: Preparation of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 52):

[0302] Title compound was prepared in a manner substantially similar General procedure X, 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115) and trans-N,N-dimethylaminocrotonic acid hydrochloride gave (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide Compound 52, as a white solid (48 mg; Yield: 13%), after prep-HPLC purification.¹H-NMR (400 MHz, CDCl₃): δ 10.17 (s, 1H), 9.51 (s, 1H), 8.08 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.43-7.35 (m, 5H), 7.33-7.29 (m, 1H), 7.10 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.75-6.69 (m, 1H), 6.27 (d, J = 15.3 Hz, 1H), 5.51 (s, 1H), 4.62 (s, 2H), 4.39 (s, 2H), 3.59 (s, 3H), 3.06 (d, J = 4.8 Hz, 2H), 2.17 (s, 6H). MS: [M+H]⁺ 538.32.

Scheme 30: Alternative Preparation of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4- (dimethylamino)but-2-enamide (Compound 35):

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Step 1: Preparation of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (119):

[0308] An ice-cold solution of pyrimidine-2,4(1H,3H)-dione (118) (10 g, 89.21 mmol) and paraformaldehyde (9.63 g, 107.05 mmol) in aqueous potassium hydroxide (132 mL, 0.5 M,

66.74 mmol) was heated at 55 °C for 14 hours. After completion of starting material (TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 6 with 12N hydrochloric acid, the resulting white precipitate was filtered through sintered funnel and washed with diethyl ether afforded 119 as a white solid (6.3 g, Yield: 50%) which was used directly for the next step.¹H-NMR (400 MHz, DMSO-d6): ^ 10.98 (bs, 1H), 10.64 (bs, 1H), 7.24 (s, 1H), 4.78 (m, 1H), 4.12 (d, J = 12.8 Hz, 2H). LCMS: [M+H]⁺ 143.04 (99.92% purity).

Step 2: Preparation of 2,4-dichloro-5-(chloromethyl)pyrimidine (120):

[0309] To an ice-cold solution of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (119) (10 g, 70.36 mmol) in toluene (25 mL) was added phosphoryl chloride (14 mL, 140.72 mmol) then N,N-diisopropylethylamine (37 mL, 211 mmol). The reaction mixture was heated at 120 °C for 16 hours. After the complete disappearance of starting material on TLC, the reaction mixture was quenched slowly with sodium bicarbonate solution and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure afforded 120 as a brown solid (12 g, Yield: 86%) which was used directly for the next step.¹H NMR (400 MHz, CDCl₃): ^ 8.66 (s, 1H), 4.64 (s, 2H). MS: [M+H]⁺ 197.0

Step 3: Preparation of 2,4-dichloro-5-(iodomethyl)pyrimidine (121):

[0310] To a solution of 2,4-dichloro-5-(chloromethyl)pyrimidine (120) (8.0 g, 40.51 mmol in acetone (40 mL) was added sodium iodide (9.71 g, 64.82 mmol). The reaction mixture was stirred at room temperature for 30 min and heated to reflux for 2 hours. After completion of reaction (TLC monitoring), the reaction mixture cooled to room temperature. The resulting white precipitate was filtered through sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure afforded 121 as a brown solid (10 g, Yield: 85%) which was used directly for the next step.¹H-NMR (400 MHz, CDCl3): ^ 8.60 (s, 1H), 4.39 (s, 2H). Step 4: Preparation of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (122):

[0311] To an ice-cold solution of 2, 4-dichloro-5-(iodomethyl)pyrimidine (121) (5.0 g, 17.30 mmol) in acetone (50 mL) was added potassium carbonate (5.26 g, 38.06 mmol) and aniline (1.93 g, 20.76 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion the reaction (as per TLC monitoring), the resulting white precipitate was filtered through sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure and crude was purified by column chromatography on silica gel (100-200 mesh) using 15% ethyl acetate-hexane as an eluent afforded 122 as a brown solid (2.5 g, Yield: 57%).¹H-NMR (400 MHz, CDCl3): ^ 8.61 (s, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.58 (m, 3H), 6.30 (bs, 1H), 4.33 (m, 2H). LCMS: [M+H]⁺ 254.03 (99.01% purity).

Step 5: Preparation of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (123):

[0312] To an ice-cold solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (122) (500 mg, 1.96 mmol), in isopropanol (5 mL) was added N,N-diisopropylethylamine (1.47 mL, 8.42 mmol) and tert-butyl (3-aminophenyl)carbamate (105) (409 mg, 1.96 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours in a sealed tube. After completion of reaction (TLC monitoring), the solvent was then evaporated under reduced pressure and resulting crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate-hexane as an eluent afforded 123 as a brown solid (500 mg, Yield: 60%).¹H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.96 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.25 (m, 2H), 7.12 (m, 3H), 6.61 (m, 3H), 6.14 (t, J = 7.2 Hz, 1H), 4.26 (m, 2H) and 1.53 (s, 9H). LCMS: [M+H]⁺ 426.14 (93% purity).

Step 6: Preparation of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (124):

[0313] To an ice-cold solution of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (123) (500 mg, 1.17 mmol) in tetrahydrofuran (6 mL) was added N,N-diisopropylethylamine (0.81 ml, 4.68 mmol) and triphosgene (139 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (TLC monitoring), aqueous triethylamine solution was added and extracted with dichloromethane (3 times). The combined organic layer was washed with brine and dried over sodium sulfate and evaporated under reduced pressure to obtain the crude residue. The crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate-hexane as an eluent afforded 124 as a brown solid (450 mg, Yield: 85%).¹H-NMR (400 MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.43 (s, 1H), 7.58 (s, 1H), 7.44 (m, 4H), 7.29 (t, J = 7.2 Hz, 3H), 6.94 (s, 1H), 5.0 (s, 2H) and 1.47 (s, 9H). LCMS: [M+H]⁺ 452.27 (99% purity).

Step 7: Preparation of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125):

[0314] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure V, (tert-butyl(3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (124) and 3-chloro-1-methyl-1H-pyrazol-4-amine (44) gave tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125) as a brown solid in 70% yield, which was used directly for the next step. MS: [M+H]⁺ 547.17.

Step 8: Preparation of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126):

[0315] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure W, tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125) gave 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126) as a brown solid (800 mg, Yield: 82%) which was used directly for the next step. MS: [M+H]⁺ 447.08.

Step 9: Preparation of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 35):

[0316] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure X, 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126) and trans-N,N-dimethylaminocrotonic acid hydrochloride gave the titled compound, which was purified by prep-HPLC purification to afforded the title compound Compound 35 as a white solid (285 mg, Yield: 23%).¹H-NMR (400 MHz, DMSO-d6): δ 10.27 (bs, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 7.73 (s, 2H), 7.51-7.40 (m, 5H), 7.30-7.25 (m, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.76-6.70 (m, 2H), 6.29 (d, J = 15.4 Hz, 1H), 4.88 (s, 2H), 3.50 (s, 3H), 3.05 (d, J = 4.8 Hz, 2H) and 2.16 (s, 6H). MS:

[M+H]⁺ 558.16.

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LINZAGOLIX

CAS 935283-04-8

C22H15F3N2O7S

• Hormone Antagonists

3-[5-[(2,3-difluoro-6-methoxyphenyl)methoxy]-2-fluoro-4-methoxyphenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid

• WHO 10711
• Treatment of Endometriosis Pain and Uterine Myoma-Associated Heavy Menstrual Bleeding

• OriginatorKissei Pharmaceutical
• DeveloperKissei Pharmaceutical; ObsEva
• Class2 ring heterocyclic compounds; Antihormones; Antineoplastics; Carboxylic acids; Fluorinated hydrocarbons; Ketones; Pyrimidines; Small molecules; Thiophenes
• Mechanism of ActionLHRH receptor antagonists

• PreregistrationUterine leiomyoma
• Phase IIIEndometriosis
• Phase IIAdenomyosis

• 22 Nov 2021FDA assigns PDUFA action date of (13/09/2022) for linzagolix for Uterine leiomyoma
• 22 Nov 2021The US FDA accepts NDA for linzagolix for Uterine leiomyoma for review
• 20 Oct 2021Efficacy and adverse events data from a phase II trial in Adenomyosis presented at the American Society for Reproductive Medicine (ASRM) 2021 Scientific Congress & Expo

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Linzagolix choline
CAS#: 1321816-57-2 (choline)
Chemical Formula: C27H28F3N3O8S
Exact Mass: 611.1549
Molecular Weight: 611.58

Linzagolix is an orally bioavailable gonadotropin-releasing hormone (GnRH or LHRH) receptor antagonist, with potential hormone production inhibitory activity. Upon oral administration of linzagolix, this agent competes with GnRH for receptor binding and inhibits GnRH receptor signaling in the anterior pituitary gland, thereby inhibiting the secretion and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). In males, the inhibition of LH secretion prevents the release of testosterone. As a result, this may relieve symptoms associated with hormonally dependent disease states such as hormone-dependent prostate cancer. In women, this prevents the production of estrogen by the ovaries and may relieve symptoms from sex-hormone dependent diseases, such as pain associated with endometriosis, heavy menstrual bleeding or uterine fibroids.

Linzagolix (INN; developmental code names KLH-2109, OBE-2109; tentative brand name Yselty) is a small-molecule, non-peptide, orally active gonadotropin-releasing hormone antagonist (GnRH antagonist) which is under development by Kissei Pharmaceutical and ObsEva for the treatment of uterine fibroids, endometriosis, and adenomyosis.^[1][3][2] As of December 2020, it is under review for approval for uterine fibroids, is in phase III clinical trials for endometriosis, and is in phase II clinical studies for adenomyosis.^[1]

Estrogen-dependent disorders represent a challenging class of diseases that have a high incidence in the general population and are often associated with particularly severe symptomology. Uterine fibroids, for example, also referred to as leiomyomata, are among the most common benign tumors in women. Symptoms associated with uterine fibroids commonly include heavy or prolonged menstrual bleeding, pelvic pressure and pelvic organ compression, back pain, and adverse reproductive outcomes. Heavy menstrual bleeding may lead to iron deficiency anemia, a key symptom of uterine fibroids and the leading cause of surgical interventions that may include hysterectomy. Endometriosis is another estrogen-dependent gynecological condition, characterized by the presence of endometrial-like tissue outside the uterus.

Additional examples of estrogen-dependent diseases include adenomyosis and rectovaginal endometriosis, which are particularly severe endometrial growth disorders characterized by the invasion of endometrial tissue into the uterine myometrium and rectovaginal zones, respectively. The term adenomyosis or uterine adenomyosis is used to describe the presence of both endometrial glands and stroma deep within the myometrium. This condition is associated with hypertrophy and hyperplasia of the subjacent muscle cells, which may ultimately result in an altered size and globulous morphology of the uterus. Due to the severity of this disorder, one of the key symptoms is strong menstrual and even non-menstrual pelvic pain with abnormal uterine bleeding. Like adenomyosis, rectovaginal endometriosis patients present with a variety of pain symptoms including dysmenorrhea, dyspareunia, chronic pelvic pain, dysuria, and dyschezia. Treatment options for rectovaginal endometriosis are limited. Since medical therapies are either ineffective or have considerable side effects, rectovaginal endometriosis patients often undergo surgical procedures to reduce the endometrial node, and may even be subject to resection of the bowel if the node infiltrates the rectal or sigmoidal wall.

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Obseva Announces U.S. FDA Acceptance of New Drug Application for Linzagolix

November 22, 2021 01:05 ET | Source: ObsEva SA………. https://www.globenewswire.com/news-release/2021/11/22/2338610/0/en/Obseva-Announces-U-S-FDA-Acceptance-of-New-Drug-Application-for-Linzagolix.html

FDA Accepts NDA for Linzagolix for the Management of Heavy Menstrual Bleeding Associated with Uterine Fibroids

GENEVA, Switzerland November 22, 2021 – Obseva SA (NASDAQ: OBSV; SIX: OBSN), a biopharmaceutical company developing and commercializing novel therapies to improve women’s reproductive health, today announced that the New Drug Application (NDA) for linzagolix for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women has been accepted for review by the United States Food and Drug Administration (FDA). The submission is based on data from the two Phase 3 PRIMROSE trials. Linzagolix has a differentiated profile and if approved, would be the first and only GnRH receptor antagonist with flexible dosing options for uterine fibroids, including a low dose option to address the needs of women who cannot or do not want to take hormones.^1,4 The FDA set a target action date of September 13, 2022 for this NDA under the Prescription Drug User Fee Act (PDUFA).

“Today marks an important milestone not only in the linzagolix clinical development process, but for Obseva as a company, and most importantly, the millions of women living with uterine fibroids throughout the US. Linzagolix is a significant innovation in the field of women’s health – an area that is consistently underinvested in – and we are incredibly excited about the potential of bringing this important treatment to market” said Brian O’Callaghan, CEO of Obseva. “We are encouraged by our positive Phase 3 PRIMROSE results. If approved, we believe linzagolix will address a significant unmet need in offering a more individualized treatment option for a broader range of women.”

The Phase 3 PRIMROSE trials of linzagolix (PRIMROSE 1: US; n=574 and PRIMROSE 2: Europe and US; n=535) investigated the efficacy and safety of two dosing regimens, 100mg once daily and 200mg once daily, alone or in combination with hormonal ABT (1 mg estradiol and 0.5 mg norethisterone acetate) for the treatment of heavy menstrual bleeding associated with uterine fibroids. The NDA submission comprises positive 24-week treatment results from both studies, as well as supportive results from Week 52 and the 76-week post-treatment follow-up.

“Uterine fibroids can have a devastating impact on women’s day-to-day life. With its unique dosing options, linzagolix has the potential to significantly advance medical options for women,” stated Elizabeth Garner, MD, MPH, Chief Medical Officer of Obseva. “A dosing option without hormonal ABT would be welcomed by the significant number of women who either have contraindications to or a personal preference to avoid the use of estrogen-based therapies, while also providing a dosing option for women in whom hormonal ABT is indicated.”

The linzagolix marketing authorization application (MAA) was validated by the European Medicine Agency (EMA) with an approval recommendation from the Committee for Medicinal Products for Human Use (CHMP) expected in Q4 2021. Obseva announced previously that the company has entered into a partnership with Syneos Health to support commercialization of linzagolix in the US and EU.

About Linzagolix
Linzagolix is a novel, once daily, oral GnRH receptor antagonist with a potentially best-in-class profile^1,2,3. Linzagolix is the subject of submitted marketing authorization applications for the treatment of heavy menstrual bleeding associated with uterine fibroids and is currently in late-stage clinical development for the treatment of pain associated with endometriosis. Obseva licensed linzagolix from Kissei in late 2015 and retains worldwide commercial rights, excluding Asia, for the product. Linzagolix is not currently approved anywhere in the world.

About the Phase 3 PRIMROSE Program in Uterine Fibroids
PRIMROSE 1 & 2 were prospective, randomized, parallel group, double-blind, placebo-controlled Phase 3 studies that investigated the efficacy and safety of two dosing regimens of linzagolix, 100 mg and 200 mg once daily, alone and in combination with hormonal ABT (1 mg estradiol and 0.5 mg norethisterone acetate) for the treatment of heavy menstrual bleeding associated with uterine fibroids. PRIMROSE 1 was conducted in the United States and enrolled 574 women. PRIMROSE 2 was conducted in Europe and the United States and enrolled 535 women. Both trials comprised a 52-week treatment period followed by a 6-month post treatment follow-up period. Additional information can be found here.

About Uterine Fibroids
Uterine fibroids are common benign tumors of the muscular tissue of the uterus which affect women of childbearing age and can vary in size from undetectable to large bulky masses. Few long-term medical treatments are available, and as a result, approximately 300,000 hysterectomies are performed for uterine fibroids every year in the US.

The symptoms of uterine fibroids are wide-ranging and include heavy menstrual bleeding, anemia, pelvic pressure and bloating, urinary frequency and pain that can be extremely debilitating with a significant impact on quality of life. These symptoms can also have an impact on mental health, creating the additional burden of anxiety and distress.

About Obseva
Obseva is a biopharmaceutical company built to address some of the most challenging unmet needs in women’s health – an under-researched, under-invested field of medicine. With deep expertise in clinical development, Obseva is passionate about the pursuit of advances that benefit women and their health and the importance of delivering truly meaningful innovation in this space. Through strategic in-licensing and disciplined drug development, Obseva has established a late-stage clinical pipeline with development programs focused on new therapies for the treatment of uterine fibroids, endometriosis, and preterm labor. Obseva is listed on the Nasdaq Global Select Market and is traded under the ticker symbol “OBSV” and on the SIX Swiss Exchange where it is traded under the ticker symbol “OBSN”. For more information, please visit http://www.ObsEva.com.

About Kissei
Kissei is a Japanese pharmaceutical company with approximately 70 years of history, specialized in the field of urology, kidney-dialysis and unmet medical needs. Silodosin is a Kissei product for the treatment of the signs and symptoms of benign prostatic hyperplasia which is sold worldwide through its licensees. KLH-2109/OBE2109 is a new chemical entity discovered by Kissei R&D.

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PATENT

WO 2007046392

https://patents.google.com/patent/WO2007046392A1/en

PATENT

 WO 2014042176

https://patents.google.com/patent/WO2014042176A1/en

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(Process 1)
Compound (D) can be produced by reacting compound (B) or a salt thereof with compound (C) in the presence of a base in a solvent. Examples of the solvent include halogen solvents such as dichloromethane, cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, amide solvents such as N, N-dimethylformamide, aromatic hydrocarbon solvents such as toluene, A nitrile solvent such as acetonitrile, an ester solvent such as ethyl acetate, or a mixed solvent thereof and a mixed solvent thereof and water are preferable, and a mixed solvent of tetrahydrofuran and water is preferable. Examples of the base include organic bases such as triethylamine and pyridine, and inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium carbonate, and potassium carbonate, preferably triethylamine, sodium hydrogen carbonate, or potassium carbonate Is mentioned. The equivalent of the base may be an equivalent amount capable of neutralizing the salt and neutralizing the acid generated by the reaction. The equivalent of (C) can be used in an amount of 0.8 to 1.1 equivalents relative to (B), preferably 1.0 equivalent. The reaction temperature is usually 0 to 30 ° C., and the reaction time is usually 0.5 to 3 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. Examples of the salt of the compound (B) include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene And salts with sulfonic acid and the like. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Among these salts, salts with hydrochloric acid and methanesulfonic acid are preferable. Compound (C) used in Scheme 1 may be a commercially available product, or can be produced according to a known method or a method analogous thereto. Compound (D) may be isolated before the next step, but it can also be used in the next step without isolation.(Process 2)
Compound (F) can be produced by reacting compound (D) with compound (E) or a salt thereof in a solvent in the presence or absence of a base. Examples of the solvent include cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, amide solvents such as N, N-dimethylformamide, aromatic hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, An ester solvent such as ethyl acetate or a mixed solvent thereof and a mixed solvent thereof with water, and the like are preferable, and a mixed solvent of tetrahydrofuran and water is preferable. Examples of the base include organic bases such as N, N-dimethylaminopyridine, triethylamine, N-methylpyrrolidine, N-methylmorpholine, diisopropylethylamine, and preferably N, N-dimethylaminopyridine, triethylamine and the like. . The equivalent of the base can be used in an amount of 0.1 to 2.0 equivalents relative to the compound (E), preferably 0.1 to 0.5 equivalents (provided that when a salt of the compound (E) is used, Further base necessary for neutralization is required). The reaction temperature is from room temperature to 60 ° C., and the reaction time is usually from 1 to 24 hours, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like. Examples of the salt of compound (E) include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene And salts with sulfonic acid and the like. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Compound (F) may be isolated before the next step, but it can also be used in the next step without isolation.(Process 3)
The intramolecular cyclization and hydrolysis reaction in this step can be performed simultaneously or separately.
(Step 3-1)
Compound (A) can be produced by subjecting compound (F) to intramolecular cyclization and hydrolysis in the presence of a base in a solvent. Examples of the solvent include cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran, lower alcohols such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, and nitriles such as acetonitrile. Examples thereof include a solvent and the like or a mixed solvent of a mixed solvent thereof and water, and a mixed solvent of tetrahydrofuran / methanol / water is preferable. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium hydride, and metal alkoxides such as sodium methoxide and potassium tert-butoxide, preferably lithium hydroxide and sodium And methoxide. The base can be used in an amount of 3.0 to 6.0 equivalents, preferably 4.0 to 4.5 equivalents, relative to compound (F). The reaction temperature is usually from 0 to 20 ° C., and the reaction time is usually from 1 to 10 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
(Step 3-2)
When isolating compound (G), compound (G) can be produced by subjecting compound (F) to an intramolecular cyclization reaction in a solvent in the presence of a base. Examples of the solvent include cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran, lower alcohols such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, and nitriles such as acetonitrile. Examples thereof include a solvent and the like or a mixed solvent thereof, and a mixed solvent of tetrahydrofuran / methanol is preferable. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide or sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, and lithium hydroxide, sodium methoxide and the like. preferable. The base can be used in an amount of 0.1 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents, relative to compound (F). The reaction temperature is usually from 0 to 20 ° C., and the reaction time is usually from 1 to 10 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
(Step 3-3)
The hydrolysis reaction in this step can be performed by the same method as in step 3-1 or a method analogous thereto.(Process 4)
Compound (A) can be converted to a salt thereof by a conventional method. Examples of such salts include inorganic salts such as sodium salt, potassium salt, calcium salt, magnesium salt, triethylamine, diisopropylamine, N, N′-dibenzylethylenediamine, ethanolamine, (2-hydroxyethyl) trimethylammonium. (Hereinafter referred to as choline), addition salts with organic bases such as N-methylglucamine, arginine, lysine and the like, and choline salts are preferred. Examples of the reagent used for conversion to the choline salt include choline hydroxide, choline bicarbonate, choline chloride and choline acetate.Here, the compound (B) and the salt thereof used in the above-mentioned scheme 1 are commercially available, or manufactured by the method described in a) to c), the method described in the reference examples, or a method analogous thereto. Can do.
a) JP-A 64-29373
b) Synthetic Communications, 32, 2565 (2002)
c) Synthesis, 200 (1977)Further, the compound (E) or a salt thereof used in the scheme 1 can be produced by the method described in Patent Document 1, the method described in Reference Examples, or a method analogous thereto.The compound obtained in the production process in the present specification includes hydrates or solvates thereof, and any of them can be used. Furthermore, the compound obtained in the production process in the present specification may have tautomers and / or geometric isomers, any of which can be used, and also a mixture thereof. be able to.By the production method of the present invention, the compound (A) useful as a pharmaceutical product or a salt thereof can be obtained in high yield and high purity through the compound (D) which is a production intermediate.The content of the present invention will be described in more detail by the following examples, but the present invention is not limited to the content.Reference example 1
Dimethyl 4-oxothiolane-2,3-dicarboxylate methylthioglycolate (15.0 g), tetrahydrofuran (45 g), piperidine (0.361 g) in a reaction mixture at room temperature with dimethyl maleate (21.4 g) in tetrahydrofuran (30 g) The solution was added. To the reaction mixture was added 20% sodium methoxide in methanol (43 g) at 55 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at reflux for 3 hours. Diisopropyl ether (105 g) and acetic acid (0.85 g) were added to the reaction mixture at 45-50 ° C., and then cooled. The suspension was filtered to obtain wet crystals (43.3 g) of sodium salt of dimethyl 4-oxothiolane-2,3-dicarboxylate. The wet crystals were added to a mixture of 85% phosphoric acid (9.8 g), water (20 g) and ethyl acetate (150 g) at room temperature, and the aqueous layer was removed. The obtained organic layer was washed with 10% brine and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (22.7 g).Reference example 2
Dimethyl 4- (hydroxyimino) thiolane-2,3-dicarboxylate Dimethyl 4-oxothiolane-2,3-dicarboxylate (10.0 g), pyridine (5.44 g), hydroxylamine hydrochloride (3.34 g) Was stirred at 50 ° C. for 1 hour. Ethyl acetate and 7% aqueous phosphoric acid solution were added to the reaction mixture at room temperature, and the aqueous layer was removed. The obtained organic layer was washed with 5% sodium bicarbonate water and 10% brine. The organic layer was dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (10.4 g).Reference example 3
4-Aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride 4- (hydroxyimino) thiolane-2,3-dicarboxylate (10.4 g) in acetic acid (32 g) solution in 4N-hydrogen chloride / ethyl acetate solution ( 120 g) was added at room temperature. The reaction mixture was stirred at room temperature for 8 hours. After filtering the suspension, the obtained solid was dried to obtain the title compound (9.42 g).Reference example 4
4-Aminothiophene-2,3-dicarboxylic acid dimethyl methanesulfonate To a solution of methanesulfonic acid (80.0 g) in ethyl acetate (900 g), dimethyl 4- (hydroxyimino) thiolane-2,3-dicarboxylate (97. 1 g) of ethyl acetate (500 g) was added at 65-75 ° C. The reaction mixture was stirred at the same temperature for 2 hours. Methyl isobutyl ketone (100 g) was added at 45-50 ° C. and cooled to room temperature. After filtering the suspension, the obtained solid was dried to obtain the title compound (102 g).Reference Example 5
1,2-difluoro-3-[(4-fluoro-2-methoxyphenoxy) methyl] -4-methoxybenzene sodium borohydride in a solution of 2,3-difluoro-6-methoxybenzaldehyde (150 g) in toluene (900 g) (13.2 g) of 0.1N sodium hydroxide aqueous solution (180 g) was added at 35 to 39 ° C. The reaction mixture was stirred at the same temperature for 5 hours. After cooling the reaction mixture to room temperature, the aqueous layer was removed. The obtained organic layer was washed with 20% brine to obtain a toluene solution of 2,3-difluoro-6-methoxybenzyl alcohol. To this solution was added concentrated hydrochloric acid (610 g) at room temperature. The reaction mixture was stirred at 38-43 ° C. for 5 hours. After cooling the reaction mixture to room temperature, the aqueous layer was removed. The obtained organic layer was washed with water and 20% brine to obtain a toluene solution of 3- (chloromethyl) -1,2-difluoro-4-methoxybenzene. To this solution, 4-fluoro-2-methoxyphenol (125 g) and tetrabutylammonium bromide (56.2 g) were added at room temperature. A 25% aqueous sodium hydroxide solution (170 g) was added to the reaction mixture at 60 to 63 ° C., and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture and the aqueous layer was removed. The obtained organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in 2-propanol and water was added. After filtering the suspension, the obtained solid was dried to obtain the title compound (232 g).Reference Example 6
1,2-difluoro-3-[(4-fluoro-2-methoxy-5-nitrophenoxy) methyl] -4-methoxybenzene 1,2-difluoro-3-[(4-fluoro-2-methoxyphenoxy) methyl ] To a solution of 4-methoxybenzene (158 g) in acetic acid (1200 g) was added 60% nitric acid (72.2 g) at 59-62 ° C., and the mixture was stirred at the same temperature for 2 hours. Water (1200 g) was added to the suspension at 15 to 19 ° C., and the mixture was stirred at the same temperature for 1 hour. After filtering the suspension, the obtained solid was washed with water to obtain wet crystals of the title compound (190 g, Net amount 168 g).Reference Example 7
2-Fluoro-5-[(2,3-difluoro-6-methoxyphenyl) methoxy] -4-methoxyaniline Raney nickel (2.5 g), ethyl acetate (180 g), 1,2-difluoro-3-[(4 -Fluoro-2-methoxy-5-nitrophenoxy) methyl] -4-methoxybenzene wet crystal (10.9 g, Net amount 10.0 g) was stirred at room temperature under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved with methanol and water was added. After filtering the suspension, the obtained solid was dried to obtain the title compound (7.97 g).Example 1
4- (phenoxycarbonylamino) thiophene-2,3-dicarboxylic acid dimethyl potassium carbonate (17.1 g), water (90 g), tetrahydrofuran (150 g) and 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (30 0.06) was added phenyl chloroformate (18.6 g) at 6-13 ° C. The reaction mixture was stirred at 12-13 ° C. for 30 minutes, and then the aqueous layer was removed. To the obtained organic layer, tert-butyl methyl ether was added and washed with 20% brine. The obtained organic layer was concentrated under reduced pressure. The residue was dissolved with diisopropyl ether and n-hexane was added. After filtering the suspension, the obtained solid was dried to obtain the title compound (37.0 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.82 (3H, s), 3.82 (3H, s), 7.13-7.30 (3H, m), 7.40-7.46 (2H, m), 7.80 (1H, s ), 10.24 (1H, s)Example 2
4- {3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} dimethyl thiophene-2,3-dicarboxylate 2-fluoro-5-[( 2,3-difluoro-6-methoxyphenyl) methoxy] -4-methoxyaniline (7.70 g), dimethyl 4- (phenoxycarbonylamino) thiophene-2,3-dicarboxylate (8.65 g), triethylamine (0. 37 g) and tetrahydrofuran (80 mL) were stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and methanol were added to the residue. After filtering the suspension, the obtained solid was dried to obtain the title compound (12.0 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.71 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 3.89 (3H, s), 5.00 (2H, d, J = 1.6 Hz), 6.87-6.93 (1H, m), 7.00 (1H, d, J = 12.8Hz), 7.41-7.50 (1H, m), 7.75 (1H, d, J = 8.0Hz), 7.94 (1H, s ), 8.82 (1H, s), 8.95 (1H, s)Example 3
3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] methyl pyrimidine-5-carboxylate 4- {3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} thiophene-2,3-dicarboxylic acid A methanol solution (3.48 g) of 28% sodium methoxide was added to a suspension of dimethyl (10.0 g) in tetrahydrofuran (40 g), stirred at room temperature for 3 hours, and acetic acid (1.30 g) was added. The reaction mixture was concentrated under reduced pressure. Methanol was added to the residue, and water was further added. After filtering the suspension, the obtained solid was dried to obtain the title compound (8.58 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.79 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 4.95 (2H, s), 6.88-6.94 (1H, m), 7.08 (1H, d, J = 11.6Hz), 7.19-7.23 (2H, m), 7.44-7.53 (1H, m), 11.62 (1H, s)Example 4
4- (phenoxycarbonylamino) thiophene-2,3-dicarboxylate potassium carbonate (9.38 kg), water (49 kg), tetrahydrofuran (82 kg), dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride (16 4 kg) of the reaction mixture was stirred for 40 minutes, and then phenyl chloroformate (10.1 kg) was added at 11-21 ° C. The reaction mixture was stirred for 30 minutes, and then the aqueous layer was removed to obtain a tetrahydrofuran solution of the title compound.Example 5
4- {3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} dimethyl thiophene-2,3-dicarboxylate 4-obtained in Example 4 To a tetrahydrofuran solution of dimethyl (phenoxycarbonylamino) thiophene-2,3-dicarboxylate, 2-fluoro-5-[(2,3-difluoro-6-methoxyphenyl) methoxy] -4-methoxyaniline (17.0 kg), Tetrahydrofuran (8.5 kg) and triethylamine (1.1 kg) were added, and the mixture was stirred at 50 ° C. for 3.5 hours to obtain a tetrahydrofuran solution of the title compound.Example 6
3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] pyrimidine-5-carboxylic acid tetrahydrofuranate 4- {3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} obtained in Example 5 Methanol (41 kg) and water (47 kg) are added to a tetrahydrofuran solution of dimethyl thiophene-2,3-dicarboxylate, a 7.3% lithium hydroxide aqueous solution (80.1 kg) is added at 11 to 13 ° C., and 90 ° C. at 11 ° C. Stir for minutes. Acetic acid (11.4 kg) was added to the reaction mixture at 9 to 16 ° C., and acetic acid (13.0 kg) was further added at 29 to 31 ° C. Seed crystals were added to the reaction mixture, and the mixture was stirred at the same temperature for 30 minutes. Water (34 kg) was added to the suspension and stirred at 30 ° C. for 40 minutes. The suspension was stirred at 4-9 ° C. for 90 minutes. After the suspension was filtered, the obtained solid was washed with a mixed solution of methanol (54 kg) and water (68 kg) to give wet crystals of the title compound (31.64 kg, Net amount (compound (A) free form equivalent)) 26 0.7 kg) was obtained.
A part of the wet crystals of the title compound was dried under reduced pressure at an external temperature of 60 ° C., and ¹ H-NMR, HPLC and powder X-ray diffraction were measured on the obtained dried crystals of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.68-1.82 (3H, m), 3.53-3.65 (3H, m), 3.80 (3H, s), 3.81 (3H, s), 4.94-4.98 (2H , m), 6.87-6.94 (1H, m), 7.13 (1H, d, J = 11.2Hz), 7.25 (1H, d, J = 7.2Hz), 7.39 (1H, s), 7.43-7.52 (1H, m), 11,99 (1H, s), 14.53 (1H, s)

PATENT

WO 2020089190

https://patents.google.com/patent/WO2020089190A2/enFor example, the GnRH antagonist may be 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4- methoxyphenyl]-2,4-dioxo-1 ,2,3,4- tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid, or a pharmaceutically acceptable salt thereof. The salt may be, for instance, the choline salt thereof, represented by formula (Via), below.

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Compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof (compound (Via)), can be synthesized, for example, using the methodology described in WO 2014/042176, the disclosure of which is incorporated herein by reference in its entirety. An exemplary synthetic scheme that may be used for the preparation of compound (VI) and the choline salt thereof is shown in Scheme 1 , below.Scheme 1 . Exemplary preparation of compound (VI) and the choline salt thereof

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wherein Ri and R are each independently C alkoxy groups; LG is a nucleofugal leaving group, such as chlorine or bromine, among others; R represents an optional substituent, such as halogen, acyl group, C alkyl group, or a nitro substituent; DMAP denotes A/-dimethylaminopyridine; and TEA denotes trimethylamine.Crystalline compound (Via) has been characterized spectroscopically, for instance, in US Patent No. 9,169,266, the disclosure of which is incorporated herein by reference in its entirety. The foregoing crystalline form has been shown to exhibit characteristic X-ray powder diffraction peaks at about 7.1⁰ 2Q, about 11 .5° 2Q, about 19.4° 2Q, about 21 .5° 2Q, about 22.0° 2Q, about 22.6° 2Q, about 23.5° 2Q, and about 26.2° 2Q. Additionally, this crystalline form exhibits ¹³C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 1 1 1 .6 ppm, about 113.7 ppm, about 1 18.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm. This crystalline form further exhibits ¹⁹F solid-state NMR peaks centered at about -151.8 ppm, -145.2 ppm, and -131 .6 ppm.Compound (VI), as well as pharmaceutically acceptable salts thereof, such as the choline salt thereof, exhibit a high affinity for human GnRH receptor (27.4 nM). Using the compositions and methods described herein, a patient that is presenting with or has been diagnosed as having, adenomyosis or rectovaginal endometriosis may be administered a compound of formula (VI), or a pharmaceutically acceptable salt thereof, such as the choline salt thereof, to treat the disease or ameliorate one or more symptoms of the disease. Exemplary doses of compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof, include doses of from 25 mg to 500 mg daily, such as doses of 100 mg per day and 200 mg per day. Additional dosing information is provided below.3-Aminoalkyl pyrimidine-2, 4(1 H,3H)-dionesAdditional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted 3-aminoalkyl pyrimidine-2, 4(1 H,3H)-dione derivatives, such as compounds represented by formula (VII)

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PATENTWO 2021023876https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021023876&_cid=P11-KWFRM2-91270-1

In some embodiments, the compound is the choline salt of the compound represented by formula (VI), choline 3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) 4-methoxyphenyI] -2,4- dioxo-1,2,3,4-

tetrahydrothieno [3,4d] pyrimidine-5-carboxylate. It is to be understood that references herein to a compound represented by formula (VI) specifically include the choline salt of compound (VI), which is represented by formula (VIa), below.

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In some embodiments, the choline 3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) 4-methoxyphenyI] -2,4-dioxo-1,2,3,4- tetrahydrothieno [3,4d ] pyrimidine-5-carboxylate is in a crystalline state.

PATENT

WO 2021023877

References

1. ^ Jump up to:^a b c “Linzagolix – Kissei Pharmaceutical/ObsEva – AdisInsight”.
2. ^ Jump up to:^a b Ezzati M, Carr BR (2015). “Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain”. Womens Health (Lond). 11 (1): 19–28. doi:10.2217/whe.14.68. PMID 25581052.
3. ^ Chodankar, Rohan; Allison, Jennifer (2018). “New Horizons in Fibroid Management”. Current Obstetrics and Gynecology Reports. 7 (2): 106–115. doi:10.1007/s13669-018-0242-6. ISSN 2161-3303.

External links

• Linzagolix – AdisInsight

////////LINZAGOLIX, Hormone Antagonists, WHO 10711, KLH-2109, KLH 2109, OBE-2109, OBE 2109

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