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Piflufolastat F 18 injection, Dcfpyl F-18

June 11, 2021 1:41 am / Leave a comment

ChemSpider 2D Image | N-{[(1S)-1-Carboxy-5-({[6-(~18~F)fluoro-3-pyridinyl]carbonyl}amino)pentyl]carbamoyl}-L-glutamic acid | C18H2318FN4O8

Piflufolastat F 18 injection

Dcfpyl F-18

CAS 207181-29-0

PLAIN F 1423758-00-2 WITHOUT RADIO LABELC₁₈ H₂₃ F N₄ O_8, 441.4L-Glutamic acid, N-[[[(1S)-1-carboxy-5-[[[6-(fluoro-¹⁸F)-3-pyridinyl]carbonyl]amino]pentyl]amino]carbonyl]-2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl) amino]-pentyl}ureido)-pentanedioic acid

Other Names

N-[[[(1S)-1-Carboxy-5-[[[6-(fluoro-¹⁸F)-3-pyridinyl]carbonyl]amino]pentyl]amino]carbonyl]-L-glutamic acid
[¹⁸F]DCFPyl

Dcfpyl F-18

(18F)Dcfpyl

UNII-3934EF02T7

18F-DCFPyL

3934EF02T7

Progenics Pharmaceuticals, Inc.

APPROVED 5/26/2021 fda, Pylarify

For positron emission tomography imaging of prostate-specific membrane antigen-positive lesions in men with prostate cancer

For positron emission tomography (PET) of prostatespecific membrane antigen (PSMA) positive lesions in men with prostate cancer: • with suspected metastasis who are candidates for initial definitive therapy. • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

Originator Johns Hopkins University School of Medicine
Developer Curium Pharma; Progenics Pharmaceuticals
Class Amides; Carboxylic acids; Fluorinated hydrocarbons; Imaging agents; Pyridines; Radiopharmaceutical diagnostics; Radiopharmaceuticals; Small molecules; Urea compounds
Mechanism of ActionPositron-emission tomography enhancers
Orphan Drug StatusNo
MarketedProstate cancer

28 May 2021Registered for Prostate cancer (Diagnosis) in USA (IV) – First global approval
28 May 2021Adverse events data from phase III CONDOR and phase II/III OSPREY trials in prostate cancer released by Lantheus Holdings
27 May 2021Lantheus Holdings intends to launch Fluorine-18 DCFPyL in USA at end of 2021

PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl) amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is:

The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S). PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 µg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0. PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/µmol at the time of administration.

PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is:

PYLARIFY® (piflufolastat F 18) Structural Formula - Illustration

The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S).

PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 μg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0.

PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/μmol at the time of administration.

Physical Characteristics

PYLARIFY is radiolabeled with fluorine 18 (F 18), a cyclotron produced radionuclide that decays by positron emission to stable oxygen 18 with a half-life of 109.8 minutes. The principal photons useful for diagnostic imaging are the coincident pair of 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (Table 3).

Table 3: Principal Radiation Produced from Decay of Fluorine 18

	Radiation Energy (keV)	Abundance (%)
Positron	249.8	96.9
Gamma	511	193.5

FDA

Label (PDF)

Approval Letter(s) (PDF)
Printed Labeling (PDF)
Product Quality Review(s) (PDF)
Multi-Discipline Review (PDF)
Proprietary Name Review(s) (PDF)
Officer/Employee List (PDF)
Other Review(s) (PDF)
Risk Assessment and Risk Mitigation Review(s) (PDF)
Administrative and Correspondence Documents (PDF)

PATENT

WO 2016030329

WO 2017072200

PAPER

Journal of Labelled Compounds and Radiopharmaceuticals (2016), 59(11), 439-450

CLIP

https://ejnmmires.springeropen.com/articles/10.1186/s13550-016-0195-6

Automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models

Radiosynthesis of [ 18 F]DCFPyL

Structure of ¹⁸F-labeled small-molecule PSMA inhibitors

/////////piflufolastat F 18, injection, Orphan Drug , Prostate cancer, [18F]DCFPyL, 18F-DCFPYL, DCFPYL F-18, fda 2021, approvals 2021

Product Quality Review(s) (PDF)
Multi-Discipline Review (PDF)
Proprietary Name Review(s) (PDF)
Officer/Employee List (PDF)
Other Review(s) (PDF)
Risk Assessment and Risk Mitigation Review(s) (PDF)
Administrative and Correspondence Documents (PDF)
Label (PDF)

C1=CC(=NC=C1C(=O)NCCCCC(C(=O)O)NC(=O)NC(CCC(=O)O)C(=O)O)F

NEW DRUG APPROVALS

one time

$10.00

Sotorasib

June 9, 2021 4:40 am / Leave a comment

4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.png

Sotorasib

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

AMG 510
AMG-510
AMG510

Formula	C30H30F2N6O3
CAS	2296729-00-3
Mol weight	560.5944

FDA APPROVED, 2021/5/28 Lumakras

Antineoplastic, Non-small cell lung cancer (KRAS G12C-mutated)

ソトラシブ (JAN);

2296729-00-3 (racemate)

4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

Sotorasib [INN]

6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-((2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl)pyrido(2,3-d)pyrimidin-2-one

Sotorasib

(1M)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one

C₃₀H₃₀F₂N₆O₃ : 560.59
[2296729-00-3]

Sotorasib is an inhibitor of the RAS GTPase family. The molecular formula is C₃₀H₃₀F₂N₆O₃, and the molecular weight is 560.6 g/mol. The chemical name of sotorasib is 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2enoyl) piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one. The chemical structure of sotorasib is shown below:

LUMAKRAS™ (sotorasib) Structural Formula Illustration

Sotorasib has pKa values of 8.06 and 4.56. The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.

LUMAKRAS is supplied as film-coated tablets for oral use containing 120 mg of sotorasib. Inactive ingredients in the tablet core are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The film coating material consists of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow.

FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc

On May 28, 2021, the Food and Drug Administration granted accelerated approval to sotorasib (Lumakras™, Amgen, Inc.), a RAS GTPase family inhibitor, for adult patients with KRAS G12C ‑mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA ‑approved test, who have received at least one prior systemic therapy.

FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for Lumakras. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Approval was based on CodeBreaK 100, a multicenter, single-arm, open label clinical trial (NCT03600883) which included patients with locally advanced or metastatic NSCLC with KRAS G12C mutations. Efficacy was evaluated in 124 patients whose disease had progressed on or after at least one prior systemic therapy. Patients received sotorasib 960 mg orally daily until disease progression or unacceptable toxicity.

The main efficacy outcome measures were objective response rate (ORR) according to RECIST 1.1, as evaluated by blinded independent central review and response duration. The ORR was 36% (95% CI: 28%, 45%) with a median response duration of 10 months (range 1.3+, 11.1).

The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

The recommended sotorasib dose is 960 mg orally once daily with or without food.

The approved 960 mg dose is based on available clinical data, as well as pharmacokinetic and pharmacodynamic modeling that support the approved dose. As part of the evaluation for this accelerated approval, FDA is requiring a postmarketing trial to investigate whether a lower dose will have a similar clinical effect.

View full prescribing information for Lumakras.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, the Assessment Aid, and the Product Quality Assessment Aid (PQAA), voluntary submissions from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 10 weeks ahead of the FDA goal date.

This application was granted priority review, fast-track, breakthrough therapy and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Sotorasib, sold under the brand name Lumakras is an anti-cancer medication used to treat non-small-cell lung cancer (NSCLC).^[1]^[2] It targets a specific mutation, G12C, in the protein KRAS which is responsible for various forms of cancer.^[3]^[4]

The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough.^[1]^[2]

Sotorasib is an inhibitor of the RAS GTPase family.^[1]

Sotorasib is the first approved targeted therapy for tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancers.^[2] KRAS G12C mutations represent about 13% of mutations in non-small cell lung cancers.^[2] Sotorasib was approved for medical use in the United States in May 2021.^[2]^[5]

Sotorasib is an experimental KRAS inhibitor being investigated for the treatment of KRAS G12C mutant non small cell lung cancer, colorectal cancer, and appendix cancer.

Sotorasib, also known as AMG-510, is an acrylamide derived KRAS inhibitor developed by Amgen.^1,3 It is indicated in the treatment of adult patients with KRAS G12C mutant non small cell lung cancer.⁶ This mutation makes up >50% of all KRAS mutations.² Mutant KRAS discovered in 1982 but was not considered a druggable target until the mid-2010s.⁵ It is the first experimental KRAS inhibitor.¹

The drug MRTX849 is also currently being developed and has the same target.¹

Sotorasib was granted FDA approval on 28 May 2021.⁶

Medical uses

Sotorasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.^[1]^[2]

Clinical development

Sotorasib is being developed by Amgen. Phase I clinical trials were completed in 2020.^[6]^[7]^[8] In December 2019, it was approved to begin Phase II clinical trials.^[9]

Because the G12C KRAS mutation is relatively common in some cancer types, 14% of non-small-cell lung cancer adenocarcinoma patients and 5% of colorectal cancer patients,^[10] and sotorasib is the first drug candidate to target this mutation, there have been high expectations for the drug.^[10]^[11]^[12] The Food and Drug Administration has granted a fast track designation to sotorasib for the treatment of metastatic non-small-cell lung carcinoma with the G12C KRAS mutation.^[13]

Chemistry and pharmacology

Sotorasib can exist in either of two atropisomeric forms and one is more active than the other.^[10] It selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the mutated form of KRAS, but not in the normal form.^[10]

History

Researchers evaluated the efficacy of sotorasib in a study of 124 participants with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy.^[2] The major outcomes measured were objective response rate (proportion of participants whose tumor is destroyed or reduced) and duration of response.^[2] The objective response rate was 36% and 58% of those participants had a duration of response of six months or longer.^[2]

The U.S. Food and Drug Administration (FDA) granted the application for sotorasib orphan drug, fast track, priority review, and breakthrough therapy designations.^[2] The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA).^[2] The application reviews are ongoing at the other regulatory agencies.^[2]

The FDA granted approval of Lumakras to Amgen Inc.^[2]

Society and culture

Economics

Sotorasib costs US$17,900 per month.^[5]

Names

Sotorasib is the recommended international nonproprietary name (INN).^[14]

PAPER

Nature (London, United Kingdom) (2019), 575(7781), 217-223

https://www.nature.com/articles/s41586-019-1694-1

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours^1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity^3,4,5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS^G12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS^G12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

Paper

Scientific Reports (2020), 10(1), 11992

PAPER

European journal of medicinal chemistry (2021), 213, 113082.

https://www.sciencedirect.com/science/article/abs/pii/S0223523420310540

KRAS is the most commonly altered oncogene of the RAS family, especially the G12C mutant (KRAS^G12C), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRAS^G12C inhibitor AMG510, a scaffold hopping strategy was conducted including a F–OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.87 μM against KRAS^G12C and cell growth inhibition of 0.79 μM in MIA PaCa-2 pancreatic cancer cells. Treatment of 26a with NCI–H358 cells resulted in down-regulation of KRAS-GTP levels and reduction of phosphorylation of downstream ERK and AKT dose-dependently. Molecular docking suggested that the fluorophenol moiety of 26a occupies a hydrophobic pocket region thus forming hydrogen bonding to Arg68. These results will be useful to guide further structural modification.

PAPER

Journal of Medicinal Chemistry (2020), 63(1), 52-65.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01180

KRAS^G12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS^G12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS^G12C inhibitor currently in phase I clinical trials (NCT03600883).

AMG 510 [(R)-38]. (1R)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one

………… concentrated in vacuo. Chromatographic purification of the residue (silica gel; 0–100% 3:1 EtOAc–EtOH/heptane) followed by chiral supercritical fluid chromatography (Chiralpak IC, 30 mm × 250 mm, 5 μm, 55% MeOH/CO₂, 120 mL/min, 102 bar) provided (1R)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one (AMG 510; (R)-38; 2.25 g, 43% yield) as the first-eluting peak. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.20 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.9 Hz, 0.5H), 8.27 (d, J = 8.7 Hz, 0.5H), 7.27 (q, J = 8.4 Hz, 1H), 7.18 (d, J = 4.9 Hz, 1H), 6.87 (dd, J = 16.2, 10.8 Hz, 0.5H), 6.84 (dd, J = 16.2, 10.7 Hz, 0.5H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 16.2 Hz, 0.5H), 6.20 (d, J = 16.2 Hz, 0.5H), 5.76 (d, J = 10.8 Hz, 0.5H), 5.76 (d, J = 10.7 Hz, 0.5H), 4.91 (m, 1H), 4.41 (d, J = 12.2 Hz, 0.5H), 4.33 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.2 Hz, 0.5H), 4.14 (d, J = 12.2 Hz, 0.5H), 4.02 (d, J = 13.6 Hz, 0.5H), 3.69 (m, 1H), 3.65 (d, J = 13.6 Hz, 0.5H), 3.52 (t, J = 12.2 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.15 (t, J = 12.2 Hz, 0.5H), 2.72 (m, 1H), 1.90 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H).
¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.6 (d, J = 5.2 Hz, 1 F), −128.6 (br s, 1 F).
¹³C NMR (151 MHz, DMSO-d₆) δ ppm 165.0 (1C), 163.4 (1C), 162.5 (1C), 160.1 (1C), 156.8 (1C), 153.7 (1C), 151.9 (1C), 149.5 (1C), 148.3 (1C), 145.2 (1C), 144.3 (1C), 131.6 (1C), 130.8 (1C), 127.9 (0.5C), 127.9 (0.5C), 127.8 (0.5C), 127.7 (0.5C), 123.2 (1C), 122.8 (1C), 111.7 (1C), 109.7 (1C), 105.7 (1C), 105.3 (1C), 51.4 (0.5C), 51.0 (0.5C), 48.9 (0.5C), 45.4 (0.5C), 44.6 (0.5C), 43.7 (0.5C), 43.5 (0.5C), 41.6 (0.5C), 29.8 (1C), 21.9 (1C), 21.7 (1C), 17.0 (1C), 15.5 (0.5C), 14.8 (0.5C).
FTMS (ESI) m/z: [M + H]⁺ calcd for C₃₀H₃₀F₂N₆O₃ 561.24202. Found 561.24150.

d (1R)-6-Fluoro7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1- piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one ((R)-38; AMG 510; 2.25 g, 43% yield) as the first-eluting peak.1 H NMR (600 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.9 Hz, 0.5H), 8.27 (d, J = 8.7 Hz, 0.5H), 7.27 (q, J = 8.4 Hz, 1H), 7.18 (d, J = 4.9 Hz, 1H), 6.87 (dd, J = 16.2, 10.8 Hz, 0.5H), 6.84 (dd, J = 16.2, 10.7 Hz, 0.5H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 16.2 Hz, 0.5H), 6.20 (d, J = 16.2 Hz, 0.5H), 5.76 (d, J = 10.8 Hz, 0.5H), 5.76 (d, J = 10.7 Hz, 0.5H), 4.91 (m, 1H), 4.41 (d, J = 12.2 Hz, 0.5H), 4.33 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.2 Hz, 0.5H), 4.14 (d, J = 12.2 Hz, 0.5H), 4.02 (d, J = 13.6 Hz, 0.5H), 3.69 (m, 1H), 3.65 (d, J = 13.6 Hz, 0.5H), 3.52 (t, J = 12.2 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.15 (t, J = 12.2 Hz, 0.5H), 2.72 (m, 1H), 1.90 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H).
19F NMR (376 MHz, DMSO-d6) δ –115.6 (d, J = 5.2 Hz, 1 F), –128.6 (br. s., 1 F).
13C NMR (151 MHz, DMSO-d6) δ ppm 165.0 (1C), 163.4 (1C), 162.5 (1C), 160.1 (1C), 156.8 (1C), 153.7 (1C), 151.9 (1C), 149.5 (1C), 148.3 (1C), 145.2 (1C), 144.3 (1C), 131.6 (1C), 130.8 (1C), 127.9 (0.5C), 127.9 (0.5C), 127.8 (0.5C), 127.7 (0.5C), 123.2 (1C), 122.8 (1C), 111.7 (1C), 109.7 (1C), 105.7 (1C), 105.3 (1C), 51.4 (0.5C), 51.0 (0.5C), 48.9 (0.5C), 45.4 (0.5C), 44.6 (0.5C), 43.7 (0.5C), 43.5 (0.5C), 41.6 (0.5C), 29.8 (1C), 21.9 (1C), 21.7 (1C), 17.0 (1C), 15.5 (0.5C), 14.8 (0.5C).
FTMS (ESI) m/z: [M+H]+ Calcd for C30H30F2N6O3 561.24202; Found 561.24150. Atropisomer configuration (R vs. S) assigned crystallographically.The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01180.

PATENT

WO 2021097212

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021097212&tab=PCTDESCRIPTION&_cid=P22-KPOYIB-17931-1

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound of Formula 6A, having the structure,

useful for the synthesis of compounds for the treatment of KRAS G12C mutated cancers.

BACKGROUND

[0003] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in about 25% of patients with NSCLC, and some studies have indicated that KRAS mutations are a negative prognostic factor in patients with NSCLC. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR) targeted therapies in colorectal cancer; accordingly, the mutational status of KRAS can provide important information prior to the prescription of TKI therapy. Taken together, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those who have been diagnosed to have such cancers characterized by a KRAS mutation, and including those who have progressed after chemotherapy.

Related Synthetic Processes

[0126] The following intermediate compounds of 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one are representative examples of the disclosure and are not intended to be construed as limiting the scope of the present invention.

[0127] A synthesis of Compound 9 and the relevant intermediates is described in U.S. Serial No.15/984,855, filed May 21, 2018 (U.S. Publication No.2018/0334454, November 22, 2018) which claims priority to and the benefit claims the benefit of U.S. Provisional Application No.62/509,629, filed on May 22, 2017, both of which are incorporated herein by reference in their entireties for all purposes. 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using the following process, in which the isomers of the final product were isolated via chiral chromatography.

[0128] Step 1: 2,6-Dichloro-5-fluoronicotinamide (Intermediate S). To a mixture of 2,6-dichloro-5-fluoro-nicotinic acid (4.0 g, 19.1 mmol, AstaTech Inc., Bristol, PA) in dichloromethane (48 mL) was added oxalyl chloride (2M solution in DCM, 11.9 mL, 23.8 mmol), followed by a catalytic amount of DMF (0.05 mL). The reaction was stirred at room temperature overnight and then was concentrated. The residue was dissolved in 1,4-dioxane (48 mL) and cooled to 0 °C. Ammonium hydroxide solution (28.0-30% NH3 basis, 3.6 mL, 28.6 mmol) was added slowly via syringe. The resulting mixture was stirred at 0 °C for 30 min and then was concentrated. The residue was diluted with a 1:1 mixture of EtOAc/Heptane and agitated for 5 min, then was filtered. The filtered solids were discarded, and the remaining mother liquor was partially concentrated to half volume and filtered. The filtered solids were washed with heptane and dried in a reduced-pressure oven (45 °C) overnight to provide 2,6-dichloro-5-fluoronicotinamide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.23 (d, J = 7.9 Hz, 1 H) 8.09 (br s, 1 H) 7.93 (br s, 1 H). m/z (ESI, +ve ion): 210.9 (M+H)⁺.

[0129] Step 2: 2,6-Dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. To an ice-cooled slurry of 2,6-dichloro-5-fluoronicotinamide (Intermediate S, 5.0 g, 23.9 mmol) in THF (20 mL) was added oxalyl chloride (2 M solution in DCM, 14.4 mL, 28.8 mmol) slowly via syringe. The resulting mixture was heated at 75 °C for 1 h, then heating was stopped, and the reaction was concentrated to half volume. After cooling to 0 °C, THF (20 mL) was added, followed by a solution of 2-isopropyl-4-methylpyridin-3-amine (Intermediate R, 3.59 g, 23.92 mmol) in THF (10 mL), dropwise via cannula. The resulting mixture was stirred at 0 °C for 1 h and then was quenched with a 1:1 mixture of brine and saturated aqueous ammonium chloride. The mixture was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. This material was used without further purification in the following step. m/z (ESI, +ve ion): 385.1(M+H)⁺.

[0130] Step 3: 7-Chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. To an ice-cooled solution of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (9.2 g, 24.0 mmol) in THF (40 mL) was added KHMDS (1 M solution in THF, 50.2 mL, 50.2 mmol) slowly via syringe. The ice bath was removed and the resulting mixture was stirred for 40 min at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% 3:1 EtOAc-EtOH/heptane) to provide 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (br s, 1H), 8.48-8.55 (m, 2 H), 7.29 (d, J = 4.8 Hz, 1 H), 2.87 (quin, J = 6.6 Hz, 1 H), 1.99-2.06 (m, 3 H), 1.09 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H).¹⁹F NMR (376 MHz, DMSO-d₆) δ: -126.90 (s, 1 F). m/z (ESI, +ve ion): 349.1 (M+H)⁺.

[0131] Step 4: 4,7-Dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one. To a solution of 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.7 g, 13.5 mmol) and DIPEA (3.5 mL, 20.2 mmol) in acetonitrile (20 mL) was added phosphorus oxychloride (1.63 mL, 17.5 mmol), dropwise via syringe. The resulting mixture was heated at 80 °C for 1 h, and then was cooled to room temperature and concentrated to provide 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one. This material was used without further purification in the following step. m/z (ESI, +ve ion): 367.1 (M+H)⁺.

[0132] Step 5: (S)-tert-Butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. To an ice-cooled solution of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (13.5 mmol) in acetonitrile (20 mL) was added DIPEA (7.1 mL, 40.3 mmol), followed by (S)-4-N-Boc-2-methyl piperazine (3.23 g, 16.1 mmol, Combi-Blocks, Inc., San Diego, CA, USA). The resulting mixture was warmed to room temperature and stirred for 1 h, then was diluted with cold saturated aqueous sodium bicarbonate solution (200 mL) and EtOAc (300 mL). The mixture was stirred for an additional 5 min, the layers were separated, and the aqueous layer was extracted with more EtOAc (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% EtOAc/heptane) to provide (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. m/z (ESI, +ve ion): 531.2 (M+H)⁺.

[0133] Step 6: (3S)-tert-Butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. A mixture of (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (4.3 g, 8.1 mmol), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (Intermediate Q, 2.9 g, 10.5 mmol), potassium acetate (3.2 g, 32.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (661 mg, 0.81 mmol) in 1,4-dioxane (80 mL) was degassed with nitrogen for 1 min. De-oxygenated water (14 mL) was added, and the resulting mixture was heated at 90 °C for 1 h. The reaction was allowed to cool to room temperature, quenched with half-saturated aqueous sodium bicarbonate, and extracted with EtOAc (2x) and DCM (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-60% 3:1 EtOAc-EtOH/heptane) to provide (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (br s, 1 H), 8.38 (d, J = 5.0 Hz, 1 H), 8.26 (dd, J = 12.5, 9.2 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.18 (d, J = 5.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.68 (t, J = 8.9 Hz, 1 H), 4.77-4.98 (m, 1 H), 4.24 (br t, J = 14.2 Hz, 1 H), 3.93-4.08 (m, 1 H), 3.84 (br d, J=12.9 Hz, 1 H), 3.52-3.75 (m, 1 H), 3.07-3.28 (m, 1 H), 2.62-2.74 (m, 1 H), 1.86-1.93 (m, 3 H), 1.43-1.48 (m, 9 H), 1.35 (dd, J = 10.8, 6.8 Hz, 3 H), 1.26-1.32 (m, 1 H), 1.07 (dd, J = 6.6, 1.7 Hz, 3 H), 0.93 (dd, J = 6.6, 2.1 Hz, 3 H).¹⁹F NMR (376 MHz, DMSO-d6) δ: -115.65 (s, 1 F), -128.62 (s, 1 F). m/z (ESI, +ve ion): 607.3 (M+H)⁺.

[0134] Step 7: 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one. Trifluoroacetic acid (25 mL, 324 mmol) was added to a solution of (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (6.3 g, 10.4 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 1 h and then was concentrated. The residue was dissolved in DCM (30 mL), cooled to 0 °C, and sequentially treated with DIPEA (7.3 mL, 41.7 mmol) and a solution of acryloyl chloride (0.849 mL, 10.4 mmol) in DCM (3 mL; added dropwise via syringe). The reaction was stirred at 0 °C for 10 min, then was quenched with half-saturated aqueous sodium bicarbonate and extracted with DCM (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-100% 3:1 EtOAc-EtOH/heptane) to provide 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1 H), 8.39 (d, J = 4.8 Hz, 1 H), 8.24-8.34 (m, 1 H), 7.23-7.32 (m, 1 H), 7.19 (d, J = 5.0 Hz, 1 H), 6.87 (td, J = 16.3, 11.0 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.69 (t, J = 8.6 Hz, 1 H), 6.21 (br d, J = 16.2 Hz, 1 H), 5.74-5.80 (m, 1 H), 4.91 (br s, 1 H), 4.23-4.45 (m, 2 H), 3.97-4.21 (m, 1 H), 3.44-3.79 (m, 2 H), 3.11-3.31 (m, 1 H), 2.67-2.77 (m, 1 H), 1.91 (s, 3 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H).¹⁹F NMR (376 MHz, DMSO-d6) δ ppm -115.64 (s, 1 F), -128.63 (s, 1 F). m/z (ESI, +ve ion): 561.2 (M+H)⁺.

[0135] Another synthesis of Compound 9 and the relevant intermediates was described in a U.S. provisional patent application filed November 16, 2018, which is incorporated herein by reference in its entirety for all purposes.

Representative Synthetic Processes

[0136] The present disclosure comprises the following steps wherein the synthesis and utilization of the boroxine intermediate is a novel and inventive step in the manufacture of AMG 510 (Compound 9):

Raw Materials

Step la

[0137] To a solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (25kg; 119. lmol) in dichloromethane (167kg) and DMF (592g) was added Oxalyl chloride (18.9kg; 148.9mol) while maintaining an internal temp between 15-20 °C. Additional dichloromethane (33kg) was added as a rinse and the reaction mixture stirred for 2h. The reaction mixture is cooled then quenched with ammonium hydroxide (40.2L; 595.5mol) while maintaining internal temperature 0 ± 10°C. The resulting slurry was stirred for 90min then the product collected by filtration. The filtered solids were washed with DI water (3X 87L) and dried to provide 2,6-dichloro-5-fluoronicotinamide (Compound 1).

Step 1b

[0138] In reactor A, a solution of 2,6-dichloro-5-fluoronicotinamide (Compound 1) (16.27kg; 77.8mol) in dichloromethane (359.5kg) was added oxalyl chloride (11.9kg;

93.8mol) while maintaining temp ≤ 25°C for 75min. The resulting solution was then headed to 40°C ± 3°C and aged for 3h. Using vacuum, the solution was distilled to remove dichloromethane until the solution was below the agitator. Dichloromethane (300 kg) was then added and the mixture cooled to 0 ± 5°C. To a clean, dry reactor (reactor B) was added,2-isopropyl-4-methylpyridin-3-amine (ANILINE Compound 2A) (12.9kg; 85.9mol) followed by dichloromethane (102.6 kg). The ANILINE solution was azeodried via vacuum distillation while maintaining an internal temperature between 20-25 °), replacing with additional dichloromethane until the solution was dry by KF analysis (limit ≤ 0.05%). The solution volume was adjusted to approx. 23L volume with dichloromethane. The dried ANILINE solution was then added to reactor A while maintaining an internal temperature of 0 ± 5°C throughout the addition. The mixture was then heated to 23 °C and aged for 1h. the solution was polish filtered into a clean reactor to afford 2,6-dichloro-5-fluoro-N-((2- isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound 3) as a solution in DCM and used directly in the next step.

Step 2

[0139] A dichloromethane solution of 2,6-dichloro-5-fluoro-N-{[4-methyl-2-(propan-2- yl)pyridin-3-yl]carbamoyl}pyridine-3-carboxamide (UREA (Compound 3)) (15kg contained; 38.9mol) was solvent exchanged into 2-MeTHF using vacuum distillation while maintaining internal temperature of 20-25 °C. The reactor volume was adjusted to 40L and then

additional 2-MeTHF was charged (105.4 kg). Sodium t-butoxide was added (9.4 kg;

97.8mol) while maintaining 5-10 °C. The contents where warmed to 23 °C and stirred for 3h. The contents where then cooled to 0-5C and ammonium chloride added (23.0kg; 430mol) as a solution in 60L of DI water. The mixture was warmed to 20 C and DI water added (15L) and further aged for 30min. Agitation was stopped and the layers separated. The aqueous layer was removed and to the organic layer was added DI water(81.7L). A mixture of conc HCl (1.5kg) and water (9L) was prepared then added to the reactor slowly until pH measured between 4-5. The layers were separated, and the aqueous layer back extracted using 2-MeTHF (42.2kg). The two organic layers combined and washed with a 10% citric acid solution (75kg) followed by a mixture of water (81.7L) and saturated NaCl (19.8 kg). The organic layer was then washed with saturated sodium bicarbonate (75kg) repeating if necessary to achieve a target pH of ≥ 7.0 of the aqueous. The organic layer was washed again with brine (54.7kg) and then dried over magnesium sulfate (5kg). The mixture was filtered to remove magnesium sulfate rinsing the filtered bed with 2-MeTHF (49.2 kg). The combined filtrate and washes where distilled using vacuum to 40L volume. The concentrated solution was heated to 55 °C and heptane (10-12kg) slowly added until cloud point. The solution was cooled to 23 °C over 2h then heptane (27.3 kg) was added over 2h. The product slurry was aged for 3h at 20-25 °C then filtered and washed with a mixture of 2-MeTHF (2.8kg) and heptane (9kg). The product was dried using nitrogen and vacuum to afford solid 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (rac-DIONE (Compound 4)).

Step 3

[0140] To a vessel, an agitated suspension of Compound 4, (1.0 eq.) in 2- methylterahydrofuran (7.0 L/kg) was added (+)-2,3-dibenzoyl-D-tartaric acid (2.0 eq.) under an atmosphere of nitrogen. 2-MeTHF is chiral, but it is used as a racemic mixture. The different enantiomers of 2-MeTHF are incorporated randomly into the co-crystal. The resulting suspension was warmed to 75°C and aged at 75°C until full dissolution was observed (< 30 mins.). The resulting solution was polish filtered at 75°C into a secondary vessel. To the polish filtered solution was charged n-Heptane (2.0 L/kg) at a rate that maintained the internal temperature above 65°C. The solution was then cooled to 60°C, seeded with crystals (0.01 kg/kg) and allowed to age for 30 minutes. The resulting suspension was cooled to 20°C over 4 hours and then sampled for chiral purity analysis by HPLC. To the suspension, n-Heptane (3.0 L/kg) was charged and then aged for 4 hours at 20°C under an atmosphere of nitrogen. The suspension was filtered, and the isolated solids were washed two times with (2:1) n-Heptane:2-methyltetrahydrofuran (3.0 L/kg). The material was dried with nitrogen and vacuum to afford M-Dione:DBTA: Me-THF complex (Compound 4a).

Step 4

[0141] To vessel A, a suspension of disodium hydrogen phosphate (21.1 kg, 2.0 equiv) in DI water (296.8 L, 6.3 L/kg) was agitated until dissolution was observed (≥ 30 min.). To vessel B, a suspension of the M-Dione:DBTA: Me-THF complex (Composition 4a)[46.9 kg (25.9 kg corrected for M-dione, 1.0 equiv.)] in methyl tert-butyl ether (517.8 L, 11.0 L/kg) was agitated for 15 to 30 minutes. The resulting solution from vessel A was added to vessel B, and then the mixture was agitated for more than 3 hours. The agitation was stopped, and the biphasic mixture was left to separate for more than 30 minutes. The lower aqueous phase was removed and then back extracted with methyl tert-butyl ether (77.7 L, 1.7 L/kg). The organic phases were combined in vessel B and dried with magnesium sulfate (24.8 kg, 0.529 kg/kg). The resulting suspension from vessel B was agitated for more than three hours and then filtered into vessel C. To vessel B, a methyl tert-butyl ether (46.9 L, 1.0 L/kg) rinse was charged and then filtered into vessel C. The contents of vessel C were cooled to 10 °C and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until 320-350 kg (6.8-7.5 kg/kg) of methyl tert-butyl ether was collected. After cooling the contents of vessel C to 20°C, n-Heptane (278.7 L, 5.9 L/kg) was charged over one hour and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until a 190-200 kg (4.1-4.3 kg/kg) mixture of methyl tert-butyl ether and n-Heptane was collected. After cooling the contents of vessel C to 20°C, n-Heptane (278.7 L, 5.9 L/kg) was charged a second time over one hour and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until a 190-200 kg (4.1-4.3 kg/kg) mixture of methyl tert-butyl ether and n-Heptane was collected. After cooling the contents of vessel C to 20°C, n-Heptane (195.9 L, 4.2 L/kg) was charged a third time over one hour and then sampled for solvent composition by GC analysis. The vessel C suspension continued to agitate for more than one hour. The suspension was filtered, and then washed with a n-Heptane (68.6 L, 1.5 L/kg) rinse from vessel C. The isolated solids were dried at 50°C, and a sample was submitted for stock suitability. Afforded 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-DIONE) Compound 5M.

[0142] The first-generation process highlighted above has been successfully scaled on 200+ kg of rac-dione starting material (Compound 4). In this process, seeding the crystallization with the thermodynamically-stable rac-dione crystal form (which exhibits low solubility) would cause a batch failure. Based on our subsequent studies, we found that increasing the DBTA equivalents and lowering the seed temperature by adjusting heptane

charge schedule improves robustness of the process. The improved process is resistant to the presence of the thermodynamically-stable rac-dione crystal form and promotes successful separation of atropisomers. Subsequent batches will incorporate the improved process for large scale manufacture.

Step 5

Note: All L/kg amounts are relative to M-Dione input; All equiv. amounts are relative to M-Dione input after adjusted by potency.

[0143] M-Dione (Compound 5M, 1.0 equiv.) and Toluene-1 (10.0 L/kg) was charged to Vessel A. The resulting solution was dried by azeotropic distillation under vacuum at 45 °C until 5.0 L/kg of solvents has been removed. The contents of Vessel A were then cooled to 20 °C.

[0144] Vessel C was charged with Toluene-3 (4.5 L/kg), Phosphoryl chloride (1.5 equiv.) and N,N-Diisopropylethylamine-1 (2.0 equiv.) while maintaining the internal temperature below 20 ± 5 °C.

Upon finishing charging, Vessel C was warmed to 30 ± 5 °C. The contents of Vessel A were then transferred to Vessel C over 4 hours while maintaining the internal temperature at 30 ± 5°C. Vessel A was rinsed with Toluene-2 (0.5 L/kg) and transferred to Vessel C. The contents of Vessel C were agitated at 30°C for an additional 3 hours. The contents of Vessel C were cooled to 20 ± 5 °C. A solution of (s)-1-boc-3-methylpiperazine (1.2 equiv.), N,N-Diisopropylethylamine-2 (1.2 equiv.) in isopropyl acetate-1 (1.0 L/kg) was prepared in Vessel D. The solution of Vessel D was charged to vessel C while maintaining a batch temperature of 20 ± 5 °C (Note: Exotherm is observed). Upon the end of transfer, Vessel D was rinsed with additional dichloromethane (1.0 L/kg) and transferred to Vessel C. The contents of Vessel C were agitated for an additional 60 minutes at 20 °C. A solution of sodium bicarbonate [water-1 (15.0 L/kg + Sodium bicarbonate (4.5 equiv.)] was then charged into Vessel C over an hour while maintaining an internal temperature at 20 ± 5 °C throughout the addition. The contents of Vessel C were agitated for at least 12 hours at which point the Pipazoline (Compound 6) product was isolated by filtration in an agitated filter dryer. The cake was washed with water-2 and -3 (5.0 L/kg x 2 times, agitating each wash for 15 minutes) and isopropyl acetate-2 and 3 (5.0 L/kg x 2 times, agitating each wash for 15 min). The cake as dried under nitrogen for 12 hours.

Acetone Re-slurry (Optional):

[0145] Pipazoline (Compound 6) and acetone (10.0 L/kg) were charged to Vessel E. The suspension was heated to 50 °C for 2 hours. Water-4 (10.0 L/kg) was charged into Vessel E over 1 hour. Upon completion of water addition, the mixture was cooled to 20 °C over 1 hour. The contents of Vessel E were filtered to isolate the product, washing the cake with 1:1 acetone/water mixture (5.0 L/kg). The cake was dried under nitrogen for 12 hours.

Step 6

General Note: All equivalents and volumes are reported in reference to Pipazoline input

Note: All L/kg and kg/kg amounts are relative to Pipazoline input

[0146] Reactor A is charged with Pipazoline (Compound 6, 1.0 equiv), degassed 2- MeTHF (9.0 L/kg) and a solution of potassium acetate (2.0 equiv) in degassed water (6.5 L/kg). The resulting mixture is warmed to 75 ± 5 °C and then, charge a slurry of

Pd(dpePhos)Cl2 (0.003 equiv) in 2-MeTHF (0.5 L/kg). Within 2 h of catalyst charge, a solution of freshly prepared Boroxine (Compound 6A, 0.5 equiv) in wet degassed 2-MeTHF (4.0 L/kg, KF > 4.0%) is charged over the course of >1 hour, but < 2 hours, rinsing with an additional portion of wet 2-MeTHF (0.5 L/kg) after addition is complete. After reaction completion ( <0.15 area % Pipazoline remaining, typically <1 h after boroxine addition is complete), 0.2 wt% (0.002 kg/kg) of Biaryl seed is added as a slurry in 0.02 L/kg wet 2- MeTHF, and the resulting seed bed is aged for > 60 min. Heptane (5.0 L/kg) is added over 2 hours at 75 ± 5 °C. The batch is then cooled to 20 ± 5 °C over 2 hours and aged for an additional 2 h. The slurry is then filtered and cake washed with 1 x 5.0L/kg water, 1 x 5.0L/kg 1:1 iPrOH:water followed by 1 x 5.0 L/kg 1:1 iPrOH:heptane (resuspension wash: the cake is resuspended by agitator and allow to set before filtering) . The cake (Biaryl, Compound 7) is then dried under vacuum with a nitrogen sweep.

Note: If the reaction stalls, an additional charge of catalyst and boroxine is required

Step 7 Charcoal Filtration for Pd removal

General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to crude Biaryl input

[0147] In a clean Vessel A, charge crude Biaryl (1 equiv) and charge DCM (10 L/kg). Agitate content for > 60 minutes at 22 ± 5 °C, observing dissolution. Pass crude Biaryl from Vessel A, through a bag filter and carbon filters at a flux ≤ 3 L²/min/m and collect filtrate in clean Vessel B. Charge DCM rinse (1 L/kg) to Vessel A, and through carbon filters to collect in vessel B.

[0148] From filtrate in Vessel B, pull a solution sample for IPC Pd content. Sample is concentrated to solid and analyzed by ICP-MS. IPC: Pd ≤ 25 ppm with respect to Biaryl. a. If Pd content is greater than 25 ppm with respect to Biaryl on first or second IPC sample, pass solution through carbon filter a second time at ≤ 3 L²/min/m², rinsing with 1 L/kg DCM; sample filtrate for IPC.

b. If Pd content remains greater than 25 ppm after third IPC, install and condition fresh carbon discs. Pass Biaryl filtrate through refreshed carbon filter, washing with 1 L/kg DCM. Sample for IPC.

[0149] Distill and refill to appropriate concentration. Prepare for distillation of recovered filtrate by concentrating to ≤ 4 L/kg DCM, and recharge to reach 5.25 ± 0.25 L/kg DCM prior to moving into Step 7 Boc-deprotection reaction.

Step 7

General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to Biaryl input

[0150] To Reactor A was added: tert-butyl (3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate (Biaryl) (1.0 equiv), dichloromethane (5.0 L/kg), and the TFA (15.0 equiv, 1.9 L/kg) is charged slowly to maintain the internal temperature at 20 ± 5 °C. The reaction was stirred for 4 h at 20 ± 5 °C.

[0151] To Reactor B was added: potassium carbonate (18.0 equiv), water (20.0 L/kg), and NMP (1.0) to form a homogenous solution. While agitating at the maximum acceptable rate for the equipment, the reaction mixture in A was transferred into the potassium carbonate solution in B over 30 minutes (~ 0.24 L/kg/min rate). The mixture was stirred at 20 ± 5 °C for an additional 12 h.

[0152] The resulting slurry was filtered and rinsed with water (2 x 10 L/kg). The wet cake was dried for 24 h to give 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin- 1-yl]-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one (Des- Boc, Compound 8).

Step 8

Note: All L/kg and kg/kg amounts are relative to Des-Boc input

[0153] Des-Boc (Compound 8, 1.0 equiv) and NMP (4.2 L/kg) are charged to Vessel A under nitrogen, charge the TFA (1.0 equiv.) slowly to maintain the Tr <25 °C. The mixture is aged at 25 °C until full dissolution is observed (about 0.5 hour). The solution is then polish filtered through a 0.45 micron filter into Vessel B, washing with a NMP (0.8 L/kg). The filtrate and wash are combined, and then cooled to 0 °C. To the resulting solution, Acryloyl Chloride (1.3 equiv.) is added while maintaining temperature < 10 C. The reaction mixture is then aged at 5 ±5°C until completed by IPC (ca.1.5 hrs).

Preparation of Aqueous Disodium Phosphate Quench:

[0154] Disodium Phosphate (3.0 equiv) and Water (15.0 L/kg) are charged to Vessel C. The mixture is aged at 25 °C until full dissolution is observed. The solution is warmed to 45 ±5°C. A seed slurry of AMG 510 (0.005 equiv.) in Water (0.4 L/kg) is prepared and added to Vessel C while maintaining temperature at 45 ±5°C.

[0155] The reaction mixture in Vessel B is transferred to Vessel C (quench solution) while maintaining temperature at 45 ±5°C (ca.1 hrs). Vessel B is washed with a portion of NMP (0.5 L/kg). The product slurry is aged for 2 hrs at 45 ±5°C, cooled to 20 °C over 3 hrs, aged at 20 °C for a minimum of 12 hrs, filtered and washed with Water (2 x 10.0 L/kg). The product is dried using nitrogen and vacuum to afford Crude AMG 510 (Compound 9A).

Step 9

General Note: All equivalents and volumes are reported in reference to crude AMG 510 input

Note: All L/kg and kg/kg amounts are relative to Crude AMG 510 input

[0156] Reactor A was charged with 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4- methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1- yl]pyrido[2,3-d]pyrimidin-2(1H)-one (Crude AMG 510) (1.0 equiv), ethanol (7.5 L/kg), and water (1.9 L/kg). The mixture heated to 75 °C and polish filtered into a clean Reactor B. The solution was cool to 45 °C and seeded with authentic milled AMG 510 seed (0.015 േ 0.005

¹ Seed performs best when reduced in particle size via milling or with other type of mechanical grinding if mill is not available (mortar/ pestle). Actual seed utilized will be based on seed availability. 1.0- 2.0% is seed is target amount.

kg/kg); the resulting slurry was aged for 30 min. Water (15.0 L/kg) was added over 5h while maintaining an internal temperature > 40 °C; the mixture was aged for an additional 2h.

[0157] The mixture was cooled to 20 °C over 3 hours and aged for 8h, after which the solid was collected by filtration and washed using a mixture of ethanol (2.5 L/kg) and water (5.0 L/kg). The solid was dried using vacuum and nitrogen to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one (AMG 510, Compound 9).

Compound 6A Boroxine Synthesis:

Lithiation/borylation

[0158] Reactor A was charged with THF (6 vol), a secondary amine base, Diisopropylamine (1.4 equiv), and a catalyst, such as triethylamine hydrochloride (0.01 equiv.). The resulting solution was cooled to -70 °C and a first base, n-BuLi (2.5 M in hexane, 1.5 equiv) was slowly added. After addition is complete, a solution of 3-fluoroanisole (1.0 equiv) in THF (6 vol) was added slowly and kept at -70 °C for 5 min. Concurrently or subsequently, a reagent, B(EtO)3 (2.0 equiv), was added slowly and kept at -70 °C for 10 min. The reaction mixture was quenched with an acid, 2N HCl. The quenched reaction mixture was extracted with MTBE (3 x 4 vol). The combined organic phases were concentrated to 1.5-3 total volumes. Heptane (7-9 vol) was added drop-wise and the mixture was cooled to 0-10 °C and stirred for 3 h. The mixture was filtrated and rinsed with heptane (1.5 vol). The solid was dried under nitrogen at < 30 °C to afford (2-fluoro-6-methoxyphenyl)boronic acid.

Demethylation:

Note: All L/kg and kg/kg amounts are relative to (2-fluoro-6-methoxyphenyl)boronic acid input

[0159] To a reactor, charge dichloromethane (solvent, 4.0 L/kg) and an acid, BBr3 (1.2 equiv), and cool to -20 °C. To this solution, a suspension of (2-fluoro-6-methoxyphenyl)boronic acid (1.0 equiv) in dichloromethane (4.0 L/kg) was added into the BBr₃/DCM mixture while keeping temperature -15 to -25 °C. The reaction was allowed to proceed for approximately 2 hours while monitored by HPLC [≤1% (2-fluoro-6-methoxyphenyl)boronic acid] before reverse quenching into water (3.0 L/kg). The precipitated solid was then isolated by filtration and slurried with water (3.0 L/kg) on the filter prior to deliquoring. The filtrates were adjusted to pH 4-6 by the addition of sodium bicarbonate. The bottom organic phase was separated and the resulting aqueous layer was washed with dichloromethane (solvent, 5.0 Vol) and adjusted to pH = 1 by addition of concentrated hydrochloric acid. The resulting solids were isolated by filtration, washing the cake with water (2 x 5.0 L/kg)

Purification via Reslurry (required)

[0160] The combined crude solids were charged into a reactor and slurried with 5% EtOH/water (5.0 L/kg) at 20 °C for >1 h. The purified product was then isolated by filtration and rinsed with water (2 x 3 L/kg) before drying on the filter at < 30 °C to with nitrogen/vacuum to afford 2,2′,2”-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(3-fluorophenol) (Boroxine, Compound 6A).

PATENT

WO 2020102730

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020102730

PATENT

US 20180334454

References

^ Jump up to:^a ^b ^c ^d ^e “Lumakras- sotorasib tablet, coated”. DailyMed. Retrieved 6 June 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy”. U.S. Food and Drug Administration (FDA). 28 May 2021. Retrieved 28 May 2021. This article incorporates text from this source, which is in the public domain.
^ “KRAS mutant-targeting AMG 510”. NCI Drug Dictionary. National Cancer Institute. 2 February 2011. Retrieved 16 November2019.
^ Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. (November 2019). “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity”. Nature. 575 (7781): 217–23. Bibcode:2019Natur.575..217C. doi:10.1038/s41586-019-1694-1. PMID 31666701.
^ Jump up to:^a ^b “FDA approves Amgen drug for lung cancer with specific mutation”. CNBC. 28 May 2021. Retrieved 28 May 2021.
^ Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. (2020). “KRAS^G12C inhibition with sotorasib in advanced solid tumors”. N Engl J Med. doi:10.1056/NEJMoa1917239. PMC 7571518.
^ Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation ” at ClinicalTrials.gov
^ “The Discovery Of Amgen’s Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature” (Press release). Amgen. 30 October 2019. Retrieved 16 November 2019.
^ Irving M (24 December 2019). “Drug targeting common cancer cause enters phase 2 clinical trials”. New Atlas. Retrieved 24 December 2019.
^ Jump up to:^a ^b ^c ^d Halford B (3 April 2019). “Amgen unveils its KRas inhibitor in human clinical trials: AMG 510 shuts down a mutant version of the cancer target via covalent interaction”. Chemical & Engineering News. 97 (4). Retrieved 16 November 2019.
^ Al Idrus A (9 September 2019). “Amgen’s KRAS drug continues to deliver but faces ‘curse’ of high expectations”. fiercebiotech.com. Retrieved 16 November 2019.
^ Kaiser J (30 October 2019). “Two new drugs finally hit ‘undruggable’ cancer target, providing hope for treatments”. Science Magazine. AAAS. Retrieved 16 November 2019.
^ Astor L (9 September 2019). “FDA Grants AMG 510 Fast Track Designation for KRAS G12C+ NSCLC”. targetedonc.com. Retrieved 16 November 2019.
^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85” (PDF). WHO Drug Information. 35 (1).

External links

“Sotorasib”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)” at ClinicalTrials.gov

Clinical data

Trade names	Lumakras
Other names	AMG 510
License data	US DailyMed: Sotorasib
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
show IUPAC name
CAS Number	2252403-56-6
PubChem CID	137278711
DrugBank	DB15569
ChemSpider	72380148
UNII	2B2VM6UC8G
KEGG	D12055
Chemical and physical data
Formula	C₃₀H₃₀F₂N₆O₃
Molar mass	560.606 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

////////Sotorasib, ソトラシブ , FDA 2021, APPROVALS 2021, Lumakras, CANCER, ANTINEOPLASTIC, AMG 510, AMG-510, AMG510, AMGEN, priority review, fast-track, breakthrough therapy, orphan drug

CC1CN(CCN1C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CN=C5C(C)C)C)C(=O)C=C

Sotorasib

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

AMG 510
AMG-510
AMG510

Formula	C30H30F2N6O3
CAS	2296729-00-3
Mol weight	560.5944

FDA APPROVED, 2021/5/28 Lumakras

Antineoplastic, Non-small cell lung cancer (KRAS G12C-mutated)

ソトラシブ (JAN);

2296729-00-3 (racemate)

4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

Sotorasib [INN]

6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-((2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl)pyrido(2,3-d)pyrimidin-2-one

Sotorasib

(1M)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one

C₃₀H₃₀F₂N₆O₃ : 560.59
[2296729-00-3]

Sotorasib has pKa values of 8.06 and 4.56. The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.

FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc

The recommended sotorasib dose is 960 mg orally once daily with or without food.

View full prescribing information for Lumakras.

The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough.^[1]^[2]

Sotorasib is an inhibitor of the RAS GTPase family.^[1]

Sotorasib is an experimental KRAS inhibitor being investigated for the treatment of KRAS G12C mutant non small cell lung cancer, colorectal cancer, and appendix cancer.

The drug MRTX849 is also currently being developed and has the same target.¹

Sotorasib was granted FDA approval on 28 May 2021.⁶

Medical uses

Clinical development

Sotorasib is being developed by Amgen. Phase I clinical trials were completed in 2020.^[6]^[7]^[8] In December 2019, it was approved to begin Phase II clinical trials.^[9]

Chemistry and pharmacology

History

The FDA granted approval of Lumakras to Amgen Inc.^[2]

Society and culture

Economics

Sotorasib costs US$17,900 per month.^[5]

Names

Sotorasib is the recommended international nonproprietary name (INN).^[14]

PAPER

Nature (London, United Kingdom) (2019), 575(7781), 217-223

https://www.nature.com/articles/s41586-019-1694-1

Paper

Scientific Reports (2020), 10(1), 11992

PAPER

European journal of medicinal chemistry (2021), 213, 113082.

https://www.sciencedirect.com/science/article/abs/pii/S0223523420310540

PAPER

Journal of Medicinal Chemistry (2020), 63(1), 52-65.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01180

AMG 510 [(R)-38]. (1R)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one

PATENT

WO 2021097212

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021097212&tab=PCTDESCRIPTION&_cid=P22-KPOYIB-17931-1

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound of Formula 6A, having the structure,

useful for the synthesis of compounds for the treatment of KRAS G12C mutated cancers.

BACKGROUND

Related Synthetic Processes

Representative Synthetic Processes

Raw Materials

Step la

Step 1b

[0138] In reactor A, a solution of 2,6-dichloro-5-fluoronicotinamide (Compound 1) (16.27kg; 77.8mol) in dichloromethane (359.5kg) was added oxalyl chloride (11.9kg;

Step 2

additional 2-MeTHF was charged (105.4 kg). Sodium t-butoxide was added (9.4 kg;

Step 3

Step 4

Step 5

Note: All L/kg amounts are relative to M-Dione input; All equiv. amounts are relative to M-Dione input after adjusted by potency.

[0144] Vessel C was charged with Toluene-3 (4.5 L/kg), Phosphoryl chloride (1.5 equiv.) and N,N-Diisopropylethylamine-1 (2.0 equiv.) while maintaining the internal temperature below 20 ± 5 °C.

Acetone Re-slurry (Optional):

Step 6

General Note: All equivalents and volumes are reported in reference to Pipazoline input

Note: All L/kg and kg/kg amounts are relative to Pipazoline input

Note: If the reaction stalls, an additional charge of catalyst and boroxine is required

Step 7 Charcoal Filtration for Pd removal

General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to crude Biaryl input

b. If Pd content remains greater than 25 ppm after third IPC, install and condition fresh carbon discs. Pass Biaryl filtrate through refreshed carbon filter, washing with 1 L/kg DCM. Sample for IPC.

Step 7

General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to Biaryl input

Step 8

Note: All L/kg and kg/kg amounts are relative to Des-Boc input

Preparation of Aqueous Disodium Phosphate Quench:

Step 9

General Note: All equivalents and volumes are reported in reference to crude AMG 510 input

Note: All L/kg and kg/kg amounts are relative to Crude AMG 510 input

kg/kg); the resulting slurry was aged for 30 min. Water (15.0 L/kg) was added over 5h while maintaining an internal temperature > 40 °C; the mixture was aged for an additional 2h.

Compound 6A Boroxine Synthesis:

Lithiation/borylation

Demethylation:

Note: All L/kg and kg/kg amounts are relative to (2-fluoro-6-methoxyphenyl)boronic acid input

Purification via Reslurry (required)

PATENT

WO 2020102730

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020102730

PATENT

US 20180334454

References

^ Jump up to:^a ^b ^c ^d ^e “Lumakras- sotorasib tablet, coated”. DailyMed. Retrieved 6 June 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy”. U.S. Food and Drug Administration (FDA). 28 May 2021. Retrieved 28 May 2021. This article incorporates text from this source, which is in the public domain.
^ “KRAS mutant-targeting AMG 510”. NCI Drug Dictionary. National Cancer Institute. 2 February 2011. Retrieved 16 November2019.
^ Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. (November 2019). “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity”. Nature. 575 (7781): 217–23. Bibcode:2019Natur.575..217C. doi:10.1038/s41586-019-1694-1. PMID 31666701.
^ Jump up to:^a ^b “FDA approves Amgen drug for lung cancer with specific mutation”. CNBC. 28 May 2021. Retrieved 28 May 2021.
^ Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. (2020). “KRAS^G12C inhibition with sotorasib in advanced solid tumors”. N Engl J Med. doi:10.1056/NEJMoa1917239. PMC 7571518.
^ Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation ” at ClinicalTrials.gov
^ “The Discovery Of Amgen’s Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature” (Press release). Amgen. 30 October 2019. Retrieved 16 November 2019.
^ Irving M (24 December 2019). “Drug targeting common cancer cause enters phase 2 clinical trials”. New Atlas. Retrieved 24 December 2019.
^ Jump up to:^a ^b ^c ^d Halford B (3 April 2019). “Amgen unveils its KRas inhibitor in human clinical trials: AMG 510 shuts down a mutant version of the cancer target via covalent interaction”. Chemical & Engineering News. 97 (4). Retrieved 16 November 2019.
^ Al Idrus A (9 September 2019). “Amgen’s KRAS drug continues to deliver but faces ‘curse’ of high expectations”. fiercebiotech.com. Retrieved 16 November 2019.
^ Kaiser J (30 October 2019). “Two new drugs finally hit ‘undruggable’ cancer target, providing hope for treatments”. Science Magazine. AAAS. Retrieved 16 November 2019.
^ Astor L (9 September 2019). “FDA Grants AMG 510 Fast Track Designation for KRAS G12C+ NSCLC”. targetedonc.com. Retrieved 16 November 2019.
^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85” (PDF). WHO Drug Information. 35 (1).

External links

“Sotorasib”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)” at ClinicalTrials.gov

Clinical data

Trade names	Lumakras
Other names	AMG 510
License data	US DailyMed: Sotorasib
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
show IUPAC name
CAS Number	2252403-56-6
PubChem CID	137278711
DrugBank	DB15569
ChemSpider	72380148
UNII	2B2VM6UC8G
KEGG	D12055
Chemical and physical data
Formula	C₃₀H₃₀F₂N₆O₃
Molar mass	560.606 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

////////Sotorasib, ソトラシブ , FDA 2021, APPROVALS 2021, Lumakras, CANCER, ANTINEOPLASTIC, AMG 510, AMG-510, AMG510, AMGEN, priority review, fast-track, breakthrough therapy, orphan drug

CC1CN(CCN1C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CN=C5C(C)C)C)C(=O)C=C

NEW DRUG APPROVALS

ONE TIME

$10.00

Loncastuximab tesirine

May 18, 2021 5:48 am / Leave a comment

Loncastuximab tesirine

ZYNLONTA FDA APPROVED 2021/4/23

Formula	C6544H10048N1718O2064S52
Exact mass	147387.9585
CAS	1879918-31-6
Efficacy	Antineoplasitc, Anti-CD19 antibody
Disease	Diffuse large B-cell lymphoma not otherwise specified [DS:H02434]
Comment	Antibody-drug conjugate Treatment of hematological cancers

ロンカスツキシマブテシリン; ADCT-402, ADCX 19

Immunoglobulin G1, anti-(human CD19 antigen) (human-Mus musculus monoclonal RB4v1.2 γ1-chain), disulfide with human-Mus musculus monoclonal RB4v1.2 κ-chain, dimer, bis(thioether) with N-[31-(3-mercapt-2,5-dioxo-1-pyrrolidinyl)-1,29-dioxo-4,7,10,13,16,19,22,25-octaoxa-28-azahentriacont-1-yl]-L-valyl-N-[4-[[[[(11S,11aS)-8-[[5-[[(11aS)-5,11a-dihydro-7-methoxy-2-methyl-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy]pentyl]oxy]-11,11a-dihydro-11-hydroxy-7-methoxy-2-methyl-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-10(5H)-yl]carbonyl]oxy]methyl]phenyl]-L-alaninamide

NEW DRUG APPROVALS

ONETIME

$10.00

Monoclonal antibody
Type	Whole antibody
Source	Humanized
Target	CD19
Clinical data
Trade names	Zynlonta
Other names	ADCT-402, loncastuximab tesirine-lpyl
License data	US DailyMed: Loncastuximab_tesirine
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
CAS Number	1879918-31-6
DrugBank	DB16222
ChemSpider	none
UNII	7K5O7P6QIU
KEGG	D11338
Chemical and physical data
Formula	C₆₅₄₄H₁₀₀₄₈N₁₇₁₈O₂₀₆₄S₅₂
Molar mass	147481.45 g·mol⁻¹

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Zynlonta	Injection, powder, lyophilized, for solution	5 mg/1mL	Intravenous	ADC Therapeutics America, Inc.	2021-04-30	Not applicable

Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate, consisting of a humanized IgG1 kappa monoclonal antibody conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent, through a protease-cleavable valine–alanine linker. SG3199 attached to the linker is designated as SG3249, also known as tesirine.

Loncastuximab tesirine-lpyl has an approximate molecular weight of 151 kDa. An average of 2.3 molecules of SG3249 are attached to each antibody molecule. Loncastuximab tesirine-lpyl is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

ZYNLONTA (loncastuximab tesirine-lpyl) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder, which has a cake-like appearance, for intravenous infusion after reconstitution and dilution. Each single-dose vial delivers 10 mg of loncastuximab tesirine-lpyl, L-histidine (2.8 mg), L-histidine monohydrochloride (4.6 mg), polysorbate 20 (0.4 mg), and sucrose (119.8 mg). After reconstitution with 2.2 mL Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 6.0.

Loncastuximab tesirine , sold under the brand name Zynlonta, is used for the treatment of large B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19, which is expressed in a wide range of B cell hematological tumors.^[2] The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL).

On April 23, 2021, the Food and Drug Administration granted accelerated approval to loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics SA), a CD19-directed antibody and alkylating agent conjugate, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

Approval was based on LOTIS-2 (NCT03589469), an open-label, single-arm trial in 145 adult patients with relapsed or refractory DLBCL or high-grade B-cell lymphoma after at least two prior systemic regimens. Patients received loncastuximab tesirine-lpyl 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Patients received treatment until progressive disease or unacceptable toxicity.

The main efficacy outcome measure was overall response rate (ORR), as assessed by an independent review committee using Lugano 2014 criteria. The ORR was 48.3% (95% CI: 39.9, 56.7) with a complete response rate of 24.1% (95% CI: 17.4, 31.9). After a median follow-up of 7.3 months, median response duration was 10.3 months (95% CI: 6.9, NE). Of the 70 patients who achieved objective responses, 36% were censored for response duration prior to 3 months.

Most common (≥20%) adverse reactions in patients receiving loncastuximab tesirine-lpyl, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

The prescribing information provides warnings and precautions for adverse reactions including edema and effusions, myelosuppression, infections, and cutaneous reactions.

The recommended loncastuximab tesirine-lpyl dosage is 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles, by intravenous infusion over 30 minutes on day 1 of each cycle (every 3 weeks). Patients should be premedicated with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before loncastuximab tesirine-lpyl.

Technology

The humanized monoclonal antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors^[3] including certain forms of lymphomas and leukemias. After binding to the tumor cells the antibody is internalized, the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. PBD dimers work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.^[4]

Clinical trials

Two phase I trials are evaluating the drug in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma and relapsed or refractory B-cell acute lymphoblastic leukemia.^[5] At the 14th International Conference on Malignant Lymphoma interim results from a Phase I, open-label, dose-escalating study designed to evaluate the treatment of loncastuximab tesirine in relapsed or refractory non-Hodgkin’s lymphoma were presented.^[6] Among the patients enrolled at the time of the data cutoff the overall response rate was 61% in the total patient population (42% complete response and 19% partial response) and in patients with relapsing or refractory diffuse large B-cell lymphoma (DLBCL) the overall response rate was 57% (43% complete response and 14% partial response).^[7]^[8]

Orphan drug designation

Loncastuximab tesirine was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma and mantle cell lymphoma.^[9]

References

^ https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761196s000lbl.pdf
^ WHO Drug Information: International Nonproprietary Names for Pharmaceutical Substances
^ Wang K, Wei G, Liu D (November 2012). “CD19: a biomarker for B cell development, lymphoma diagnosis and therapy”. Experimental Hematology & Oncology. 1 (1): 36. doi:10.1186/2162-3619-1-36. PMC 3520838. PMID 23210908.
^ “Pyrrolobenzodiazepine”. ADC Review.
^ Clinical trial number NCT02669017 for “ADCT-402 in B-NHL” at ClinicalTrials.gov
^ Kahl B, Hamadani M, Caimi PF, Reid EG, Havenith K, He S, Feingold JM, O’Connor O (June 2017). “First clinical results of ADCT‐402, a novel pyrrolobenzodiazepine-based antibody drug conjugate (ADC), in relapsed/refractory B‐cell linage NHL” (PDF). Hematol Oncol. 35 (S2): 49–51. doi:10.1002/hon.2437_33.
^ “First clinical results of ADCT-402”. ADC Review.
^ Bainbridge K. “Grandfather fighting deadly cancer reveals scans of tumors after testing new drug”. Mirror.
^ “ADCT-402 Orphan Drug Designation” (PDF). ADC Therapeutics press release.

External links

“Loncastuximab tesirine”. Drug Information Portal. U.S. National Library of Medicine.

https://www.fda.gov/drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma

/////////Loncastuximab tesirine, FDA 2021, APPROVALS 2021, ZYNLONTA, ロンカスツキシマブテシリン, ORPHAN DRUG, ADCT-402, priority review, ADCX 19

Dostarlimab

May 12, 2021 3:42 am / Leave a comment

(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS
LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS QEEMTKNQVS
LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS
CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK

>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-(programmed cell death protein 1 (PDCD1)) (humanized clone ABT1 γ4-chain), disulfide with humanized clone ABT1 κ-chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

GSK-4057190
GSK4057190
TSR 042
TSR-042
WBP-285
ANB 011

Formula	C6420H9832N1680O2014S44
CAS	2022215-59-2
Mol weight	144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.^[1]^[2]^[3]^[4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.^[1]^[2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.^[1]^[2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.^[1]^[2]

Dostarlimab was approved for medical use in the United States in April 2021.^[1]^[2]^[5]

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Jemperli	Injection	50 mg/1mL	Intravenous	GlaxoSmithKline LLC	2021-04-22	Not applicable

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.^[1]^[2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having durations ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.^[1]^[2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.^[1]^[2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.^[6]^[7]^[8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.^[6]^[9]^[10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.^[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.^[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).^[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.^[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.^[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.^[13]

References[

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”. U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Jemperli- dostarlimab injection”. DailyMed. Retrieved 28 April 2021.
^ Statement On A Nonproprietary Name Adopted By The USAN Council – Dostarlimab, American Medical Association.
^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information. 32 (2).
^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
^ Jump up to:^a ^b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”. Tesaro (Press release). Retrieved 1 January 2020.
^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”. Targeted Oncology. Retrieved 1 January 2020.
^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”. Drugs.com. Retrieved 29 April 2020.
^ “FDA Approves New Immunotherapy for Endometrial Cancer”. Medscape. Retrieved 23 April 2021.
^ Jump up to:^a ^b “Jemperli: Pending EC decision”. European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

“Dostarlimab”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov

Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Monoclonal antibody
Type	Whole antibody
Source	Humanized
Target	PCDP1
Clinical data
Trade names	Jemperli
Other names	TSR-042, WBP-285, dostarlimab-gxly
License data	US DailyMed: Dostarlimab
Routes of administration	Intravenous
Drug class	Antineoplastic
ATC code	L01XC40 (WHO)
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
CAS Number	2022215-59-2
PubChem SID	384585344
DrugBank	DB15627
UNII	P0GVQ9A4S5
KEGG	D11366
Chemical and physical data
Formula	C₆₄₂₀H₉₈₃₂N₁₆₉₀O₂₀₁₄S₄₄
Molar mass	144325.73 g·mol⁻¹

/////////Dostarlimab, PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

Sacituzumab govitecan-hziy

April 9, 2021 11:59 am / 1 Comment on Sacituzumab govitecan-hziy

Sacituzumab Govitecan for Metastatic Triple-Negative Breast Cancer - National Cancer Institute

Sacituzumab govitecan-hziy

1601.8 g/mol

C₇₆H₁₀₄N₁₂O₂₄S

(2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)-6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0^2,11.0^4,9.0^15,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid

Trodelvy

hRS 7SN38
hRS7-SN38
IMMU 132
IMMU-132

CAS: 1491917-83-9

M9BYU8XDQ6

EX-A4354

UNII-DA64T2C2IO component ULRUOUDIQPERIJ-PQURJYPBSA-N

UNII-SZB83O1W42 component ULRUOUDIQPERIJ-PQURJYPBSA-N

Efficacy	Antineoplastic, Topoisomerase I inhibitor
Disease	Breast cancer (triple negative)

sacituzumab govitecan-hziy Archives | Access Market Intelligence

Sacituzumab Govitecan is an antibody drug conjugate containing the humanized monoclonal antibody, hRS7, against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) and linked to the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), with potential antineoplastic activity. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis. TROP2, also known as epithelial glycoprotein-1 (EGP-1), is a transmembrane calcium signal transducer that is overexpressed by a variety of human epithelial carcinomas; this antigen is involved in the regulation of cell-cell adhesion and its expression is associated with increased cancer growth, aggressiveness and metastasis.

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https://www.businesswire.com/news/home/20210407006027/en/FDA-Approves-Trodelvy%C2%AE-the-First-Treatment-for-Metastatic-Triple-Negative-Breast-Cancer-Shown-to-Improve-Progression-Free-Survival-and-Overall-Survival?fbclid=IwAR16bUSCbkK98d8j01NNKVnJ-7r8nHSvCOGE4ogCp_Aex79mNh8AOwQFIQc

FDA Approves Trodelvy^®, the First Treatment for Metastatic Triple-Negative Breast Cancer Shown to Improve Progression-Free Survival and Overall Survival

– Trodelvy Significantly Reduced the Risk of Death by 49% Compared with Single-Agent Chemotherapy in the Phase 3 ASCENT Study –

– Trodelvy is Under Regulatory Review in the EU and in the United Kingdom, Canada, Switzerland and Australia as Part of Project Orbis –April 07, 2021 07:53 PM Eastern Daylight Time

FOSTER CITY, Calif.–(BUSINESS WIRE)–Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has granted full approval to Trodelvy^® (sacituzumab govitecan-hziy) for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. The approval is supported by data from the Phase 3 ASCENT study, in which Trodelvy demonstrated a statistically significant and clinically meaningful 57% reduction in the risk of disease worsening or death (progression-free survival (PFS)), extending median PFS to 4.8 months from 1.7 months with chemotherapy (HR: 0.43; 95% CI: 0.35-0.54; p<0.0001). Trodelvy also extended median overall survival (OS) to 11.8 months vs. 6.9 months (HR: 0.51; 95% CI: 0.41-0.62; p<0.0001), representing a 49% reduction in the risk of death.

Trodelvy is directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including TNBC, where high expression is associated with poor survival and relapse. Prior to the FDA approval of Trodelvy, patients with previously treated metastatic TNBC had few treatment options in this high unmet-need setting. The FDA granted accelerated approval to Trodelvy in April 2020 based on objective response rate and duration of response results in a Phase 1/2 study. Today’s approval expands the previous Trodelvy indication to include treatment in adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

“Women with triple-negative breast cancer have historically had very few effective treatment options and faced a poor prognosis,” said Aditya Bardia, MD, MPH, Director of Breast Cancer Research Program, Mass General Cancer Center and Assistant Professor of Medicine at Harvard Medical School, and global principal investigator of the ASCENT study. “Today’s FDA approval reflects the statistically significant survival benefit seen in the landmark ASCENT study and positions sacituzumab govitecan-hziy as a potential standard of care for pre-treated TNBC.”

“A metastatic TNBC diagnosis is frightening. As an aggressive and difficult-to-treat disease, it’s a significant advance to have an FDA-approved treatment option with a proven survival benefit for patients with metastatic disease that continues to progress,” said Ricki Fairley, Founder and CEO of Touch, the Black Breast Cancer Alliance. “For far too long, people with metastatic TNBC had very few treatment options. Today’s news continues the progress of bringing more options to treat this devastating disease.”

Among all patients evaluable for safety in the ASCENT study (n=482), Trodelvy had a safety profile consistent with the previously approved FDA label. The most frequent Grade ≥3 adverse reactions for Trodelvy compared to single-agent chemotherapy were neutropenia (52% vs. 34%), diarrhea (11% vs. 1%), leukopenia (11% vs. 6%) and anemia (9% vs. 6%). Adverse reactions leading to treatment discontinuation occurred in 5% of patients receiving Trodelvy.

“Today’s approval is the culmination of a multi-year development program and validates the clinical benefit of this important treatment in metastatic TNBC,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “Building upon this milestone, we are committed to advancing Trodelvy with worldwide regulatory authorities so that, pending their decision, Trodelvy may become available to many more people around the world who are facing this difficult-to-treat cancer.”

Regulatory submissions for Trodelvy in metastatic TNBC have been filed in the United Kingdom, Canada, Switzerland and Australia as part of Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE) that provides a framework for concurrent submission and review of oncology products among international partners, as well as in Singapore through our partner Everest Medicines.The European Medicines Agency has also validated a Marketing Authorization Application for Trodelvy in the European Union. All filings are based on data from the Phase 3 ASCENT study.

Trodelvy Boxed Warning

The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer (TNBC), where high expression is associated with poor survival and relapse.

Trodelvy is also being developed as an investigational treatment for metastatic urothelial cancer, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER 2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER 2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer (TNBC) who had received two or more prior systemic therapies (including a taxane), at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients’ treating physicians. The primary efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS). More information about ASCENT is available at http://clinicaltrials.gov/show/NCT02574455.

Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe, life-threatening, or fatal neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patient with febrile neutropenia without delay.
Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤ Grade 1 and reduce subsequent doses.

CONTRAINDICATIONS

Severe hypersensitivity to TRODELVY

WARNINGS AND PRECAUTIONS

Neutropenia: Dose modifications may be required due to neutropenia. Neutropenia occurred in 62% of patients treated with TRODELVY, leading to permanent discontinuation in 0.5% of patients. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 6%.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3 diarrhea occurred in 12% of patients. Neutropenic colitis occurred in 0.5% of patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤ Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: TRODELVY can cause severe and life-threatening hypersensitivity and infusion-related reactions, including anaphylactic reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 1% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.4%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use.

Nausea and Vomiting: Nausea occurred in 67% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 5% of patients. Vomiting occurred in 40% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤ 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia in genotyped patients was 69% in patients homozygous for the UGT1A1*28, 48% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia in genotyped patients was 24% in patients homozygous for the UGT1A1*28 allele, 8% in patients heterozygous for the UGT1A1*28 allele, and 10% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced hemoglobin, lymphocytes, leukocytes, and neutrophils.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY

Please see full Prescribing Information, including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate indicated for the treatment of metastatic triple-negative breast cancer (mTNBC) in adult patients that have received at least two prior therapies.^[1]^[2]

The most common side effects are nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia (hair loss), constipation, decreased appetite, rash and abdominal pain.^[1]^[2] Sacituzumab govitecan has a boxed warning about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea.^[1]^[2] Sacituzumab govitecan may cause harm to a developing fetus or newborn baby.^[1] Women are advised not to breastfeed while on sacituzumab govitecan and 1 month after the last dose is administered.^[3]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[4]

Mechanism

Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.^[5] Each antibody having on average 7.6 molecules of SN-38 attached.^[6] SN-38 is too toxic to administer directly to patients, but linkage to an antibody allows the drug to specifically target cells containing Trop-2.

Sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells.^[1] Approximately two of every ten breast cancer diagnoses worldwide are triple-negative.^[1] Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein.^[1] Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.^[1]

Development

Immunomedics announced in 2013, that it had received fast track designation from the US Food and Drug Administration (FDA) for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer.^[7]^[8] In February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.^[9]^[10]

History

Sacituzumab govitecan was added to the proposed INN list in 2015,^[11] and to the recommended list in 2016.^[12]

Sacituzumab govitecan-hziy was approved for use in the United States in April 2020.^[1]^[13]^[14]^[2]

Sacituzumab govitecan-hziy was approved based on the results of IMMU-132-01, a multicenter, single-arm clinical trial (NCT01631552) of 108 subjects with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease.^[1]^[14]^[2] Of the 108 patients involved within the study, 107 were female and 1 was male.^[15] Subjects received sacituzumab govitecan-hziy at a dose of 10 milligrams per kilogram of body weight intravenously on days one and eight every 21 days.^[14]^[15] Treatment with sacituzumab govitecan-hziy was continued until disease progression or unacceptable toxicity.^[15] Tumor imaging was obtained every eight weeks.^[14]^[2] The efficacy of sacituzumab govitecan-hziy was based on the overall response rate (ORR) – which reflects the percentage of subjects that had a certain amount of tumor shrinkage.^[1]^[14] The ORR was 33.3% (95% confidence interval [CI], 24.6 to 43.1). ^[1]^[14]^[15] Additionally, with the 33.3% of study participants who achieved a response, 2.8% of patients experienced complete responses.^[15] The median time to response in patients was 2.0 months (range, 1.6 to 13.5), the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8), the median progression free survival was 5.5 months, and the median overall survival was 13.0 months.^[15] Of the subjects that achieved an objective response to sacituzumab govitecan-hziy, 55.6% maintained their response for six or more months and 16.7% maintained their response for twelve or more months.^[1]^[14]

Sacituzumab govitecan-hziy was granted accelerated approval along with priority review, breakthrough therapy, and fast track designations.^[1]^[14] The U.S. Food and Drug Administration (FDA) granted approval of Trodelvy to Immunomedics, Inc.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o “FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments”. U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 22 April 2020. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e ^f “Drug Trial Snapshot: Trodelvy”. U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 29 April 2020. This article incorporates text from this source, which is in the public domain.
^ (PDF)https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761115s000lbl.pdf. Missing or empty |title= (help)
^ “New Drug Therapy Approvals 2020”. U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January2021. This article incorporates text from this source, which is in the public domain.
^ Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. 2015
^ “Novel Agents are Targeting Drivers of TNBC”. http://www.medpagetoday.com. 28 June 2016.
^ “Sacituzumab govitecan Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
^ “Sacituzumab govitecan Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
^ “New Therapy Shows Early Promise, Continues to Progress in Triple-Negative Breast Cancer”. Cure Today.
^ “U.S. Food and Drug Administration (FDA) Grants Breakthrough Therapy Designation to Immunomedics for Sacituzumab Govitecan for the Treatment of Patients With Triple-Negative Breast Cancer”(Press release). Immunomedics. 5 February 2016. Retrieved 25 April 2020 – via GlobeNewswire.
^ World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 113”. WHO Drug Information. 29 (2): 260–1. hdl:10665/331080.
^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information. 30 (1): 151–3. hdl:10665/331046.
^ “Trodelvy: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 22 April 2020.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer”. U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 23 April 2020. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e ^f “Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer”. The New England Journal of Medicine.

External links

“Sacituzumab govitecan”. Drug Information Portal. U.S. National Library of Medicine.
“Sacituzumab govitecan”. ADC Review.
“Sacituzumab govitecan”. National Cancer Institute.
Clinical trial number NCT01631552 for “Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers” at ClinicalTrials.gov
Sacituzumab govitecan at the US National Library of Medicine Medical Subject Headings (MeSH)

Monoclonal antibody

Type	?
Source	Humanized (from mouse)
Target	Trop-2
Clinical data
Trade names	Trodelvy
Other names	IMMU-132, hRS7-SN-38, sacituzumab govitecan-hziy
AHFS/Drugs.com	Monograph
MedlinePlus	a620034
License data	US DailyMed: Sacituzumab_govitecan
Pregnancy category	Contraindicated
ATC code	None
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	1491917-83-9
PubChem CID	91668186
DrugBank	DB12893
ChemSpider	none
UNII	M9BYU8XDQ6
KEGG	D10985
Chemical and physical data
Formula	C₇₆H₁₀₄N₁₂O₂₄S
Molar mass	1601.79 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
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//////////sacituzumab govitecan-hziy, fda 2021, approvals 2021, Trodelvy , hRS 7SN38, hRS7-SN38, IMMU 132, IMMU-132, MONOCLONAL ANTIBODY, Sacituzumab govitecan, sacituzumab govitecan-hziy, CANCER, MONOCLONAL ANTIBODIES

#sacituzumab govitecan-hziy, #fda 2021, #approvals 2021, #Trodelvy , #hRS 7SN38, #hRS7-SN38, #IMMU 132, #IMMU-132, #MONOCLONAL ANTIBODY, #Sacituzumab govitecan, #sacituzumab govitecan-hziy, #CANCER, #MONOCLONAL ANTIBODIES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)C(CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SCC(C(=O)O)N)C2=NC9=C1C=C(C=C9)O

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CC-90010

February 11, 2020 8:52 am / Leave a comment

CC-90010

C₂₁ H₂₁ N O₄ S, 383.46

CAS 1706738-98-8

1(2H)-Isoquinolinone, 4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-

4-[2-(Cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-1(2H)-isoquinolinone
4-[2-(Cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one
4-[2-(Cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

Quanticel Pharmaceuticals Inc, Michael John Bennett Juan Manuel Betancort Amogh Boloor Stephen W. Kaldor Jeffrey Alan Stafford James Marvin Veal

Celgene (now a wholly owned subsidiary of Bristol-Myers Squibb ) , following its acquisition of Quanticel , is developing CC-90010, an oral inhibitor of BET (bromodomain and extraterminal) proteins, for the potential treatment of solid tumors and non-Hodgkin’s lymphoma. In August 2019, a phase I trial for diffuse astrocytoma, grade III anaplastic astrocytoma and recurrent glioblastoma was planned

PATENT

WO2018075796 claiming solid composition comprising a bromodomain inhibitor, preferably 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one in crystalline form A.

PATENT

WO2015058160 (compound 89, page 103).

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9B64008287A0D105A68DDF31141C7419.wapp1nA?docId=WO2015058160&tab=PCTDESCRIPTION

Example 89: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one

[00344] A suspension of 4-bromo-2-methylisoquinolin-l-one (100 mg, 0.42 mmol), bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl₂ (31 mg, 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 mL) under nitrogen was warmed up to 90 °C for 135 minutes. It was then cooled down to room temperature and diluted with ethyl acetate (8 mL). The mixture was washed with aqueous saturated solution of NaHC0₃ (8 mL) and brine (8 mL). The organic phase was separated, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purifed by normal phase column chromatography (10-90% EtOAc/Hexanes) to give the title compound (44 mg, 37%). 1H NMR (CDC1₃, 400 MHz) δ 8.43 (d, J = 7.9 Hz, 1 H), 8.40 (dd, J = 8.2 Hz, 0.9 Hz, 1 H), 7.68 (s, 1 H), 7.65 (ddd, J = 8.2, 8.2, 1.1 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS (M+H)⁺ 286. Step 2: 4-[2-(cyclopropylmethox -5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00345] The title compound was prepared in a manner similar to Example 18, step 3, substituting 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2 H), 0.29 (m, 1H), 0.35 (m, 1H),

0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.37 (d, J =

8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8,

2.4 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H). LCMS (M+H)⁺ 384.

[00346] Alternatively, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one can be prepared as described below.

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one

[00347] A mixture of 4-bromo-2-methylisoquinolin-l-one (8.0 g, 33.6 mmol),

bis(pinacolato)diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd₂(dba)3 (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrous dioxane (200 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE : EA = 15 : 1) to give the title compound (6.0 g, 62 %) as a solid.

Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00348] The title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K₃PO₄ (9.3 g, 43.9 mmol) and Pd(dppf)Cl₂ (1.4 g, 1.75 mmol) in a dioxane/water (100 mL / 10 mL) mixture were stirred at 60 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA : DCM = 1 : 4).

Appropriate fractions were combined and concentrated under reduce pressure. The resultant solid was recrystallized from DCM / MTBE (1 : 1, 50 mL) to give the title compound (4.0 g, 60 %) as a white solid. 1H NMR: (CDC1₃, 400 MHz) δ 8.51 (dd, Ji = 8.0 Hz, J₂ = 0.8 Hz, 1 H), 7.98 (dd, Ji = 8.4 Hz, J₂ = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.53 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.10 (m, 2 H), 3.88 (m, 2 H), 3.66 (s, 3 H), 3.09 (s, 3 H), 1.02-0.98 (m, 1 H), 0.44-0.38 (m, 2 H), 0.11-0.09 (m, 2 H). LCMS: 384.1 (M+H)⁺

Patent

WO-2020023438

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020023438&tab=PCTDESCRIPTION&_cid=P10-K6HCMJ-20465-1

A process for preparing bromodomain inhibitor, particularly 4-[2(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one (having HPLC purity of 99%; compound 1; (hereafter referred to as C-90010)) and its hydrates, solvates, prodrugs and salts comprising the reaction of a substituted 4-(methylsulfonyl)phenol compound with a quinoline derivative, followed by purification is claimed. Also claimed are novel intermediates of CC-90010 and their processes for preparation. Further claimed are novel crystalline form of CC-90010. CC-90010 is known and disclosed to be a bromodomain containing protein inhibitor, useful for treating cancer.

Scheme 10: Synthesis of Compound 1

[0090] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compound 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223g, l.OSmol). Agitation

was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum purged three times with nitrogen. The batch was heated to about 65 to about 75 °C (or any temperature in between and including these two values) and contents stirred for at least about 16 hours until reaction was complete by HPLC analysis. The batch was cooled to about 60 to about 70 °C (or any temperature in between and including these two values), agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at about 60 to about 70°C (or any temperature in between and including these two values). Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at about 60 to about 70°C (or any temperature in between and including these two values). After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at about 60 to about 70°C (or any temperature in between and including these two values). The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to about 60 to about 65°C (or any temperature in between and including these two values) and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at about 60 to about 65°C (or any temperature in between and including these two values). The slurry was cooled to about 15 to about 25°C (or any temperature in between and including these two values) over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at about 40°C with nitrogen purge. Yield: 139g of 1.

[0091] The above procedure for coupling Compound 3 and Compound 2 to produce

Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used.

The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy₃ 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);

Pd(PPh₃)2Cb (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

VI. Purification of Compound 1 fCC-900101 bv crystallization from formic acid and water

[0092] Described herein are methods of purifying Compound 1 by crystallization from formic acid and water. Also described are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1 and two metastable forms, Form 4

The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCh(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy₃ 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);

Pd(PPh3)2Cl2 (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

VI. Purification of Compound 1 (CC-90010! bv crystallization from formic acid and water

33 -a

and Form 5. Supporting data (XRPD, DSC, photomicroscopy) for all three forms is provided in the examples below.

[0093] The stmcture of Compound 1 (CC-90010) is shown below:

Example 1: Synthesis of Compound 1

[0217] Synthesis of compound 1 was accomplished according to Scheme 1 below. Referring to Scheme 1, synthesis commenced with bromination of starting material 4-(methylsulfonyl)phenol 4, to produce compound 5. Compound 5 was O-alkylated with (bromomethyl)cyclopropane to produce compound 6. Boronate Compound 2 was then formed by borylation of Compound 6 with Pd catalyst and bis(pinacolato)diboron to produce transient Compound 7, which was subsequenctly treated with diethanolamine (DBA) to afford cross-coupling partner Compound 2. Cross-coupling partner Compound 3 was formed in one pot starting from commercially available Compound 8. Compound 8 was N-methylated and brominated to afford Compound 3. Compounds 2 and 3 were cross-coupled (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)) to afford the target compound 1.

Scheme 1: Synthesis of compound 1

1.1: Bromination of 4

[0218] The bromination of Compound 4 to produce Compound 5 itself is simple, however stopping at the mono-brominated Compound 5 was challenging. The bis-brominated Compound 5-a (see Scheme 2 below) is a particularly pernicious impurity as it couples downstream to form a di ffi cult-to-purge impurity.

Scheme 2: Bromination of Compound 4

[0219] The key to high purity with reasonable yield was to exploit the solubility differences of the starting material Compound 4 (46 mg/ml at 20 °C) and the product Compound 5 (8 mg/ml) in CH₂CI2. These solubility differences are summarized in Table 3 below.

[0220] This solubility difference is exploited by performing the reaction at a high

concentration to drive Compound 5 out of solution once formed, thereby minimizing its ability to react further with the brominating reagent to form Compound 5-a diBr. The reaction is seeded with Compound 5 to initiate its crystallization.

[0221] In Fig. 22 (Conversion of Compound 4 to Compound 5: Effect of Sulfuric Acid) it can be seen that in the absence of acid the initial reaction to Compound 5 is rapid, however the conversion plateaus at about 30% Compound 5. The main side product was found to be the impurity Compound 5-a diBr (see Fig. 23: Conversion of Compound 5 and Compound 5-a diBr: No H2SO4). Addition of increasing amounts of sulfuric acid leads to a higher conversion to desired Compound 5.

[0222] Fig. 24 (Compound 4 to Compound 5 Reaction Profile: Portion-wise Addition of NBS, Seeding) depicts further reaction control. The portion-wise addition ofNBS after addition of catalytic sulfuric acid minimizes the temperature rise, and the addition of Compound 5 after an initial NBS charge promotes the reactive crystallization of Compound 5. After about 6 to 7 hours of reaction it can be seen that the major product is Compound 5, with only a small (<5%) of the di-brominated impurity formed. In contrast, in a reaction where Compound 4 and all of the NBS were charged followed by the addition of 4 volumes of methylene chloride, a rapid exotherm resulted and undesired Compound 5-a diBr was found to be the major product.

[0223] Thus, the reaction was run under a high concentration in CH₂CI2 with a portion-wise solid addition of NBS (to control both availability of the electrophile and the exotherm). An end of reaction slurry sample typically showed not more than 5% of the starting material Compound 4 remaining. After filtration the crude cake was washed with cold CH₂CI2 and the OkCk-washed filter cake contained not more than 0.5% by weight dibrominated Compound 5-a. It also contained a large amount of HPLC-silent succinimide.

[0224] The following procedure was carried out: Compound 4 (25g, 145mmol) followed by CH₂CI2 (lOOmL) were added to a reaction vessel and agitated. The batch was adjusted to 17 °C to 23 °C. Sulfuric acid was charged (2.7mL, Slmmol) to the batch maintaining 17 °C to 23°C. The batch was stirred at 17 °C to 23 °C for 10 minutes to 20 minutes. The first portion of A-bromosuccimide (NBS) was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The second portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The batch was seeded with

Compound 5 (0.02wt) and stirred for ca. 30 min at 17 °C to 23 °C to induce crystallization.

[0225] The third portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23 °C and stirred for at least 30 min. NBS (6.5g, 36.5 mmol) was charged to the batch at 17 °C to 23 °C and stirred for at least 30 min. Additional CH₂CI2 was charged (50mL) to the batch while maintaining 17 °C to 23 °C to aid in agitation and transfer for filtration. The batch was stirred at 17 °C to 23 °C until complete by HPLC analysis (~20 – 40 h). The product was collected by suction filtration. The filter cake was slurry washed with CH₂CI2 (3 x 50mL) at 17 °C to 23 °C (target 20 °C). The filter cake was slurry washed with purified water (3.0vol) at 65 °C to 75 °C for 2 to 3 hours. Then, the filter cake was slurry washed with purified water (3 x 1.0 vol, 3 x 1.0 wt) at 17 °C to 23°C. The wet cake was dried under vacuum with nitrogen bleed at 60 °C. Yield: 27g 5 (74% molar) >97% by weight. ¾ NMR (500 MHz, de-DMSO) 8.01 (1H, d, ⁴J = 2.1 Hz, RO-Ar meta- H ), 7.76 (1H, dd, J = 8.6 and ⁴J = 2.1 Hz, RO-Ar meta-H ), 7.14 (1H, d, J = 8.6 Hz, RO-Ar ortho- H), 3.38 (1H, br s, OH), 3.20 (3H, s,

CHJ); MS (ES-) calc. 249/251; found 249/251. Melting point (MP): (DSC) 188 °C.

[0226] The above procedure allowed for the following modifications. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as acetonitrile, tetrahydrofuran, or 2- methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from about 2X vol to about 20 X vol (with respect to Compound 4). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 1.9 equiv. Bromination reagent addition: The brominating reagent can be added all at once, portion wise in about 2 to about 20 portions, or continuously. The addition times can vary from about 0 to about 72 hours. Temperature: Reaction temperatures from about 0 °C to about 40 °C could be used. Acids: Different acids can be envisioned, including benzenesulfonic acid, para-toluenesulfonic acid, triflic acid, hydrobromic acid, and trifluoroacetic acid. Isolation: Instead of directly filtering the product and washing with methylene chloride and water, at the end of reaction an organic solvent capable of dissolving Compound 5 could be charged, followed by an aqueous workup to remove succinimide, and addition of an antisolvent or solvent exchange to an appropriate solvent to crystallize Compound 4. Drying: A temperature range of about 10 to about 60 °C could be used for drying.

[0227] An alternative process to Compound 5 has also been developed. This process is advantageous in that it does not use a chlorinated solvent, and provides additional controls over the formation of the Compound 5-a dibromo impurity. See Oberhauser, T. J Org. Chem 1997, 62, 4504-4506. The process is as follows. Compound 4 (10 g, 58 mmol) and acetonitrile (100 ml) were charged to the reactor and agitated. The batch was cooled to -20 °C. Triflic acid (CF3SO3H or TfOH, 5.5 mL, 62 mmol) was charged while maintaining a batch temperature of -10 to -25 °C. N-bromosuccinimide was charged (NBS, 11.4 g, 64 mmol), stirred at -10 to -25 °C for 30 minutes, then warmed to 20 °C over 3 to 4 hours. Agitation was continued at 15 °C to 25 °C until reaction completion. If the reaction conversion plateaued before completion, the reaction was cooled to -5 to -15 °C, and additional NBS was added, the amount based off of unreacted starting material, followed by warming to 15 °C to 25 °C and reacting until complete.

[0228] After reaction completion, the batch was warmed to 40 °C to 50 °C and concentrated under reduced pressure to 40 mL. The batch was cooled to -5 °C to -15 °C and the resulting product solids were filtered off. The solids were slurry washed three times, each with 20 mL water, for at least 15 minutes. The final cake was dried at 50 °C to 60 °C under reduced pressure to furnish 10 g of 5 containing less than 0.1% MeCN, 0.07% water, and 0.1% triflic acid (TfOH) by weight.

[0229] Alternatives to the above procedure employing MeCN and TfOH are as follows. Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination Reagent Stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 2 equiv. Drying: A temperature range of about 10 °C to about 60 °C could be used for drying.

[0230] The impurity 5-a is was prepared and characterized as follows. 10 g of Compound 4 and sulfuric acid (35 mol%) were dissolved in MeOH (10 vol). The mixture was set to stir at 20 °C to 25 °C for 5-10 min and 2.0 equivalents of NBS were charged in one portion. The resulting yellow mixture was stirred for three days at 20-25 °C. The batch was concentrated under reduced pressure and the resulting solid was slurried in water at 95-100 °C for 3 hours. After a second overnight slurry in CH₂CI2 at room temperature, the batch was filtered and dried to give a white solid 5-a (15.0 g, 78%). ¾ NMR (500 MHz, de-DMSO), 8.05 (2H, s, ArH), 3.40 (1H, br s, HO-Ar), 3.28 (3H, s, CH₃); MS (ES^‘) calc. 327/329/331; found

327/329/331; MP (DSC): 226 °C (onset 221 °C, 102 J/g); lit. 224-226 °C.

1.2: O-alkylation of 5 to produce 6

[0231] Compound 6 was prepared according to Scheme 7 below.

Scheme 7: O-alkylation of 5 to produce 6

[0232] Compound 5 (100 g, 398 mmol) and methyl ethyl ketone (MEK, 700 mL) were charged to the reaction vessel and agitated. Potassium carbonate (K2CO3, 325 mesh 82.56 g, 597 mmol) was then charged to the stirred reaction vessel at 15 °C to 25 °C.

Bromomethylcyclopropane (64.4 mL, 664 mmol) was charged to the reaction vessel over at least 1 hour, maintaining the temperature between 15 °C to 25 °C. MEK (200 mL) was added into the reactor and the reactor heated to 65 to 75 °C. The contents of the reaction vessel were stirred at 65 to 75°C for approximately 10 hours until reaction was complete by HPLC analysis. Water (3.0 vol, 3.0wt) was charged to the vessel maintaining the temperature at 65 to 75 °C. The batch was stirred at 65 to 75 °C. The phases were allowed to separate at 65°C to 75 °C and the lower aqueous phase was removed. Water (300 mL) was charged to the vessel maintaining the temperature at 65 °C to 75 °C. The batch was agitated for at least 10 minutes at 65 to 75 °C. The phases were allowed to separate at 65 °C to 75 °C and the lower aqueous phase was removed. The water wash was repeated once. The temperature was adjusted to 40 to 50°C. The mixture was concentrated to car. 500 mL under reduced pressure. The mixture was distilled under reduced pressure at up to 50 °C with MEK until the water content was <1.0% w/w. n-heptane (500mL) was charged to the vessel maintaining the temperature at 40 to 50 °C. The mixture was continuously distilled under vacuum with n-heptane (300mL), maintaining a 1L volume in the reaction vessel. Compound 6 seeds (0.0 lwt) were added at 40 to 50 °C. The mixture was continuously distilled under reduced pressure at up to 50 °C with n-heptane (300mL) while maintaining 1L volume in the reactor. The batch was cooled to 15 to 25 °C and aged for 2 hours. The product was collected by suction filtration. The filter cake was washed with a solution of 10% MEK in n-heptane (5vol) at 15 to 25°C. The filter cake was dried under reduced pressure at up to 40 °C under vacuum with nitrogen flow to afford 95g of 6. ¹H NMR (500 MHz, de-DMSO) 8.07 (1H, d, ⁴J = 2.2 Hz, ArH), 7.86 (1H, d, J = 8.7 Hz, meta-ArH), 7.29 (1H, d, J = 8.8 Hz, ortho-AiK),

4.04 (2H, d, J = 6.9 Hz, OCH₂CH), 3.21 (3H, s, CH₃), 1.31-1.24 (1H, m, OCH), 0.62- 0.58 (2H, m, 2 x CHCHaHb), 0.40-0.37 (2H, m, 2 x CHC¾Hb); MS (ES⁺) calc. 305/307; found 305/307; MP: (DSC) 93 °C.

[0233] The following modifications of the above reaction, synthesis of 6 from 5, may be employed as well. Solvent: Different solvents could be used, for example acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, or 2-methyl tetrahydrofuran. Reaction volume: Reaction volumes of 3 to 30 volumes with respect to 3 could be used. Base: Different inorganic bases, such as cesium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Also, organic bases, such as trimethylamine or diisopropyldiimide could be used. Base particle size: Different particle sizes of potassium carbonate from 325 mesh could be used. Reaction temperature: A lower temperature, such

as 50 °C could be used. A higher temperature, such as about 100 °C could be used. Any temperature above the boiling point of the solvent could be run in a pressure vessel.

Isolation: Different solvent ratios of MEK to n-heptane could be used. Different amounts of residual water can be left. Different amounts of seeds, from 0 to 50% could be used.

Seeding could take place later in the process and/or at a lower temperature. An un-seeded crystallization can be employed. A different isolation temperature, from 0 °C to 50 °C could be used. A different wash could be used, for example a different ratio of MEK to n-heptane. A different antisolvent from n-heptane could be used, such as hexane, pentane, or methyl tert-butyl ether. Alternatively, the batch could be solvent exchanged into a solvent where Compound 3 has a solubility of less than 100 mg/ml and isolated from this system. Drying: A temperature range of 10 to 60 °C could be used for drying.

[0234] Compound 10, shown below may also be formed as a result of O-alkylation of unreacted 4 present in product 5, or alternatively from or via a palladium mediated proteodesbromination or proteodesborylation in subsequent chemistry discussed in Example 1.3 below.

[0235] Preparation of methylsulfonylphenyl(cyclopropylmethyl) ether 10: Compound 4 (0.86 g, 5.0 mmol) and K2CO3 (1.04 g, 7.5 mmol) were slurried in acetone (17 mL, 20 vols). Cyclopropylmethyl bromide (0.73 mL, 7.5 mmol) was added in several small portions over ~1 minute and the reaction mixture heated to 50 °C for 48 hours, then cooled to 25 °C. Water (5.0 mL) was added with stirring and the acetone was evaporated on a rotary evaporator from which a fine white solid formed which was filtered off and returned to a vessel as a damp paste. A 1 : 1 mixture of MeOH/ water (8 mL) was added and heated to 40 °C with stirring. After 1 hour, the white solid was filtered off. Some residual solid was washed out with fresh water that was also rinsed through the cake, which was then isolated and left to air dry over the two days to give a dense white solid 10 (1.00 g, 88%). ¾ NMR (500 MHz, CDCb) 7.85

(2H, d, J = 8.8 Hz, RO-Ar ortho-H), 7.00 (2H, d, J = 8.8 Hz, RO-Ar meta- H), 3.87 (2H, d, J = 7.0 Hz, OCH₂CH), 3.02 (3H, s, CHs), 1.34-1.23 (1H, m, OCH₂CH), 0.72-0.60 (2H, m, 2 x CHCH_flHb), 0.42-0.31 (2H, m, 2 x CHCH^.

1.3: Synthesis and Isolation Coupling Partner Boronic Ester 2

[0236] The final bond forming step to Compound 1 is a Suzuki-Miyaura coupling between Compounds 2 and 3, as shown in Scheme 3 below (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)). Early studies demonstrated that the boronic ester of the isoquinolinone Compound 3-a had poor physical attributes and solid phase stability (Kaila, N. et al., J. Med Chem., 57: 1299-1322 (2014)). The pinacolatoboronate of the O-alkyl phenol, Compound 7, had acceptable solid phase stability and could be isolated via crystallization.

Scheme 3: Suzuki-Miyaura coupling between 2 and 3

[0237] Process robustness studies for the isolation of Compound 7, however, indicated that Compound 7 has poor solution stability, decomposing primarily to the proteodeborylated compound 10, as shown in Scheme 4 below. This was particularly problematic as the isolation process involved a solvent exchange from 2-MeTHF (2-methyl tetrahydrofuran) to iPrOAc (isopropyl acetate), which is not a fast unit operation on scale.

Scheme 4: Modification of 7

[0238] A search for a more stable boronic ester was undertaken. Early attempts targeted making N-methyliminodiacetic acid (MID A) boronate Compound 2-a (E. Gilis and M. Burke,“Multi step Synthesis of Complex Boronic Acids from Simple MIDA Boronates,” J Am. Chem. Soc., 750(43): 14084-14085 (2008)), however, all attempts resulted in product decomposition. Applicant then turned to a relatively obscure boronate formed by the addition of diethanolamine to Compound 7 (Bonin et al., Tetrahedron Lett., 52: 1132-1135 (2011)). Addition of diethanolamine to a solution of Compound 7 led to rapid ester formation and concomitant crystallization of Compound 2.

[0239] The discovery of boronic ester Compound 2 allowed for a simple, fast, high-yielding, high-purity process comprising the following procedure. Tetrahydrofuran (THF, 1500mL) was charged to a flask containing Compound 6 (100g, 328 mmol), bis(pinacolato)diboron (90.7g, 357 mmol) and cesium acetate (CsOAc, 158g, 822 mmol). The system was vacuum purged three times with nitrogen. Pd(PPh3)2Cl2 (13.8g, 20 mmol) was charged to the reaction and the system was vacuum purged three times with nitrogen. The reaction was then heated to 55 to 65°C.

[0240] The batch was stirred for approximately 8 hours until reaction was complete by HPLC analysis. The batch was cooled to 15 to 25 °C (target 20 °C ) and charged with silica gel (20g) and Ecosorb C-941 (20g). After lh, the mixture was filtered to remove solid. The residual solids were washed twice, each with THF (300mL). The filtrate and washes were combined. In a separate vessel, diethanolamine (34.5mL, 360 mmol) was dissolved in THF (250 mL). The diethanolamine solution in THF (25mL) was then charged to the batch. After 10 minutes, the batch was seeded with 2 (1 g) and aged for 1 to 2 hours. The remaining of the diethanolamine solution in THF was charged to the batch over at least 2 hours and the slurry was stirred for at least 2 hours. The product 2 was collected by suction filtration. The wet cake was washed thrice with THF (200mL). The material was dried under vacuum at 40 °C with nitrogen purge yielding 94.6g of 2.

[0241] The reaction to synthesize Compound 2 from Compound 6 described above may be modified as follows. Solvent: Different solvents from THF could be used, such as 1,4 dioxane or 2-methyltetrahydrofuran. Reaction volume: The reaction volume can be varied from 4 to 50 volumes with respect to compound 2. Catalyst and base: Different palladium catalyst and bases can be used for the borylation. Examples can be found in Chow et al., RSC Adv., 3 : 12518-12539 (2013). Borylation reaction temperature: Reaction temperatures from room temperature (20 °C) to solvent reflux can be used. Carbon/ Silica treatment:

The treatment can be performed without silica gel. The process can be performed without a carbon treatment. Different carbon sources from Ecosorb C-941 can be used. Different amounts of silica, from 0.01X to IX weight equivalents, can be used. Different amounts of Ecosorb C-941, from 0.01X to IX weight equivalents, can be used. Crystallization: A different addition rate of diethanolamine can be used. Different amounts of diethanolamine, from 1.0 to 3.0 molar equivalents can be used. A different cake wash with more or less THF can be used. Different amount of seeds from 0.0001X wt to 50X wt can be used.

Alternatively, the process can be unseeded. Drying: A temperature range of 10 °C to 60 °C could be used for drying.

[0242] The subsequent Suzuki-Miyaura coupling between Compounds 2 and 3 also proceeded well, providing over 20 kg of crude compound 1 with an average molar yield of 80% and LCAP of 99.7%.

1.4: Synthesis of Coupling Partner 3

[0243] Cross-coupling partner 3 was prepared by two different processes corresponding to Schemes 8 and 9 shown below.

Scheme 8: Process A for preparation of 3

[0244] According to Process A, Compound 9 (100g, 628 mmol) was dissolved in acetonitrile (450 mL) at room temperature. In a separate vessel, N-bromosuccinimide (NBS, 112g, 628 mmol) was suspended in acetonitrile (1 L). Compound 9 in acetonitrile was charged to the NBS slurry over at least 45 minutes. The contents of the reaction vessel were warmed to 45 °C to 55 °C and the batch stirred until the reaction was complete by HPLC analysis. The batch was cooled to 35 °C to 45 °C and ensured dissolution. Norit SX plus carbon (lOg) was charged to the mixture and the reaction mixture adjusted to 55 °C to 60 °C. The mixture was stirred at 55 °C to 60 °C for about lh and the mixture filtered at 55 °C to 60 °C to remove solids. The solids were washed with acetonitrile (500mL) at 55 °C to 60 °C. The volume of the combined filtrate was reduced to 900 mL by distilling off acetonitrile under reduced pressure. The batch with Compound 3 (lg) and stirred at 35 °C to 45 °C for at least 60 minutes. The contents of the reaction vessel were cooled to 15 °C to 25 °C over at least 1 hour. Water (2000 mL) was charged to the reaction vessel over at least 90 minutes and the slurry aged for at least 60 minutes. The product was collected by suction filtration. The cake was washed with a premixed 5% solution of acetonitrile in water (300mL). The wet cake was dried under vacuum at 40 °C with nitrogen purge. Yield: 120g of 3.

[0245] The above procedure, Process A for this synthesis of 3, may be practiced with alternative reagents and conditions as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 9). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent Stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 °C to 60 °C could be used for drying.

Scheme 9: Process B for preparation of 3

[0246] According to Process B, Compound 3 can be formed starting from 8 via non-isolated compound 9 as follows. Compound 8 (80 g, 55 mmol), cesium carbonate (CS2CO3, 215 g, 66 mmol), and acetonitrile (800 mL) were charged to the reactor. The temperature was adjusted from 15 to 25 °C and iodomethane charged to the reactor (Mel, 86 g, 0.61 mol) while maintaining a batch temperature below 25 °C. The batch was heated to 40 °C and agitated for 10 hours to form Compound 9. The batch was cooled to 25 °C, filtered into a fresh reactor to remove solids, and the solids washed twice with acetonitrile. The combined organic layers were concentrated via atmospheric distillation to about 320 mL.

[0247] In a separate reactor N-bromosuccinimide (NBS, 98.1 g, 0.55 mol) was charged to acetonitrile (800 mL) and agitated. The batch containing Compound 9 was transferred to the NBS solution while maintaining a batch temperature of 15 to 25 °C. The batch was heated to 45 to 55 °C and agitated for at least 4 hours to allow for reaction completion to Compound 3. Upon reaction completion, Norit SX Plus activated carbon (8 g) was charged, and agitated at 45 to 55 °C for one hour. The batch was filtered into a fresh vessel, the Norit SX plus cake was washed with 400 ml of 45 to 55 °C acetonitrile. The acetonitrile layers were combined, cooled to 35 to 45 °C, and distilled under reduced pressure to 720 mL. The batch was adjusted to a temperature of 40 °C, charged with Compound 3 seeds (0.8 g), agitated for one hour, cooled to 15 to 25 °C over at least on hour, then charged with water (1600 mL) over at least two hours. The mixture was agitated for an additional one to two hours, filtered, the cake washed with a premixed 5% solution of acetonitrile in water (240 mL). The wet cake was dried under vacuum at 40°C with nitrogen purge. Yield: 52 g of 3.

[0248] Process B to synthesize Compound 3, described above, may be modified as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 8).

Alkylating reagent: Alternative methylating reagents to methyl iodide can be used such as dimethylsulfate. Alkylating reagent stoichiometry: 1 to 10 molar equivalents of methyl iodide may be used. Base: Different inorganic bases, such as potassium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Brominating agents:

Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. Seeding levels from 0.0001% to 50% can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying.

1.5: Cross-coupling of 2 and 3 to Produce Target Compound 1

[0249] 1 is synthesized by Suzuki cross-coupling of 3 and 2 according to Scheme 10 and as described below.

Scheme 10: Synthesis of 1

[0250] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compovmd 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223 g, l.OSmol). Agitation was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum

purged three times with nitrogen. The batch was heated to 65 to 75°C and contents stirred for at least 16 hours until reaction was complete by HPLC analysis. The batch was cooled to 60 to 70°C, agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at 60 to 70°C. Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at 60 to 70°C. After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at 60 to 70°C. The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to 60 to 65°C and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at 60 to 65°C. The slurry was cooled to 15 to 25°C over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at 40°C with nitrogen purge. Yield: 139g of 1.

[0251] The above procedure for coupling Compound 3 and Compound 2 to produce

Compound 1 may be modified in any of the ways that follow. Reaction solvents: Different reaction solvents from acetonitrile can be used, including tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, and isopropanol. Boronic ester: Different boronic esters from Compound 2 can be used, including pinacolato ester compound 7, and the free boronic acid of Compound 2. Examples of boronic esters can be found in Lennox, Alister, J.J., Lloyd-Jones, Guy C. Chem. Soc. Rev., 2014, 43, 412. Carbon treatment: Different carbon treatments from Ecosorb C-941 could be used. Different amounts of carbon, from 0.01 to 0.5X weight can be used. The carbon can be eliminated. Different amounts of Celite, from 0.01 to 0.5X weight can be used. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1);

cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy₃ 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5); Pd(PPh₃)2Cl2 (Cas# 13965-03-2). Examples of

catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

1.6: Crystallization of 1

[0252] The final isolation of Compound 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH

Harmonized Guideline“Impurities: Guideline for Residual Solvents Q3C(R6)” October 20, 2016). A reasonable solubility was obtained in a warm MeCN-water mix, but this is not an optimal system (requires a heated filtration, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/ml) include N-methyl-2- pyrrolidone (NMP) and dimethylacetamide (DMAc); but the development of isolations from these solvents required large volumes and raised residual solvent limit concerns (530 ppm or less for NMT and 1090 ppm or less for DMAc).

catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

1.6: Crystallization of 1

[0252] The final isolation of Compoxmd 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH

[0253] Formic acid is one ICH Class 3 solvent in which Compound 1 is highly soluble, having a solubility greater than 250 mg/ml at 20 °C. The solubility curve of Compound 1 in formic acid-Water is quite steep (see Figure 7), which enables a volumetrically efficient process.

[0254] Initial attempts to recrystallize crude Compound 1 involved dissolving in formic acid, polish filtering, and charging polish filtered water to about 20% supersaturation, followed by seeding with the thermodynamically most stable form (Form 1), followed by slow addition of water to the final solvent ratio, filtration, washing, and drying. Applicant observed that during the initial water charge, if the batch self-seeded it formed a thick slurry. X-ray diffraction (XRD), differential scanning calorimetry (DSC), and photomicroscopy demonstrated that a metastable form was produced. Once seeded with Form 1, the batch converted to the desired form (Form 1) prior to the addition of the remaining water. This process worked well during multiple lab runs, consistently delivering the desired form and purity with about 85% yield.

[0255] Unfortunately, upon scale-up, the batch did not convert to Form 1 after seeding. Additional water was charged and the batch began to convert to the desired form (mix of Form 1 and the metastable form by X-ray powder diffraction (XRPD)). When additional water was charged, the XRPD indicated only the metastable form. After a few hours with no change, Applicant continued the water charge to the final solvent ratio, during which time the batch eventually converted to Form 1. This process is summarized in Figure 8.

[0256] It was subsequently found by closer analysis of the plant and laboratory retains that a new metastable form was formed during scale up, with a similar, but different XRPD pattern. This form (metastable B) could be reproduced in the laboratory, but only when the batch has a high formic acid:water ratio and is seeded with Form 1. Without Form 1 seeds, metastable A is the kinetic form. Both metastable forms converted to Form 1 with additional water and/or upon drying, leading Applicant to believe that the metastable forms are formic acid solvates. These findings are summarized in Figure 9.

[0257] While there is little risk in not being able to control the final form, there is a risk of forming a difficult-to-stir slurry which can lead to processing issues. The crystallization procedure was therefore modified to keep a constant formic acid-water ratio. This was performed by charging 2.4X wt. formic acid and 1.75X wt. water (final solvent composition)

to the crystallizer with 0.03X wt. Form 1 seeds, and performing a simultaneous addition of Compound 1 in 6. IX wt. formic acid and 4.4X wt. water. The batch filtered easily and was washed with formic acid/water, then water, and dried under reduced pressure to yield 8.9 kg of Compound 1 (92% yield) with 99.85% LCAP and N.D. formic acid.

Example 2: Exemplary high throughput experimentation reaction

[0258] The following procedure is an exemplary high throughput experimentation reaction.

[0259] An overview of the reaction is shown below in Scheme 5:

Scheme 5: Reaction conditions tested for cross-coupling reaction of 2 and 3

[0260] Pd catalysts were dosed into the 24-well reactor vial as solutions (100 pL of 0.01 M solution in tetrahydrofuran (THF) or dichloroethane (DCE) depending upon the solubility of the ligand). Plates of these ligands are typically dosed in advance of the reaction, the solvent is removed by evacuation in an evaporative centrifuge and plates are stored in the glovebox. The catalysts screened in the coupling are the following: XPhos, SPhos, CataCXium A, APhos, P(Cy)3, PEPPSI-IPent. For the first five ligands, these were initially screened as the Buchwald Pd G2/G3 precatalysts.

[0261] To the plates was then added a stock solution of Compound 3 (10 pmol) and Compound 2 (12 pmol) dissolved in the following solvents: dimethylformamide (DMF),

tetrahydrofuran (THF), butanol (/r-BuOH), and toluene. The base was then added as a stock solution (30 mmol) in 20 mL of water.

[0262] A heatmap summarizing catalyst performance is shown in Figs. 10A and 10B. High performance liquid chromatography (HPLC) yields for this screening span from <5% up to -85%. Larger circles indicate higher yield. Lighter circles indicate higher cleanliness.

[0263] A similarly designed screening of base and solvent also indicate that a range of alcoholic solvents (methanol, ethanol, propanol, 2-butanol, 2-propanol, and /-amyl alcohol) are also all viable in this coupling chemistry. Bases such as potassium phosphate, potassium carbonate, potassium acetate, and potassium hydroxide were all successful in achieving the coupling. Fig. 10B shows a heatmap with HPLC yields ranging from -50 – 95%. Larger, darker circles indicate higher yield.

[0264] This chemistry from microvial screening has been scaled to a laboratory process. To a 3 -necked jacketed 250 mL flask equipped with overhead stirring, nitrogen inlet, and thermocouple was added Compound 3 (1.0 eq, 4.00 grams), Compound 2 (1.2 eq, 1.71 x wt), potassium carbonate (3.0 eq, 1.74 x wt). The reactor was inerted three times and then degassed 2-propanol (24 x vol.) followed by degassed water (6 x vol) was then added.

Stirring was then initiated at 300 rpms. The reactor was then stirred and blanketed with nitrogen for 1 hour. The catalyst was then added (0.01 eq, 0.028 x wt) and stirring continued (300 rpms) and the reactor was heated into the Tj = 65 °C.

[0265] After 2 hours, with full conversion confirmed analytically, trioctylphosphine (0.1 eq, 0.16 x wt) dosed, and reaction mixture allowed to cool slowly to room temperature hours.

The reaction mixture was then filtered, washed with 2-propanol (4 x vol), 2-propanol: water (4: 1, 4 x vol), and then with water (4 x vol). Note: If 2 is dimer present in cake, an additional ethyl acetate (EtOAc) wash (4 x vol) can be added for purging. The cake was then transferred to a vacuum oven to dry overnight at 40 °C, -40 cm Hg, under nitrogen flow. After transfer to a bottle, 6.03 grams of 1 were isolated, 98.6% assay, 91% overall yield.

Scheme 6: Alternative reagents and solvents for cross-coupling

[0266] Based on the previously delineated results, it was expected that a variety of monodentate (PPI13 [triphenylphosphine], PBu3 [tributylphosphine], etc) and bidentate phosphines (dppf [1,1 ‘-bis(diphenylphosphino)ferrocene], BINAP [2,2 -bis(diphenylphosphino)- 1 , 1 -binaphthyl], Xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], dppe [l,2-bis(diphenylphosphino)ethane], etc) ligated to any number of Pd sources (Pd halides, Pd(H) precatalyts, Pd(0) sources) could reasonably be employed to arrive at the Compound 1 crude material. A range of organic solvents ranging from non-polar (heptane, benzene), protic (alcohols), polar aprotic (dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile) as well as a variety of esters and ketones (acetone, 2-butanone, ethylacetate) should also serve as effective solvents for this reactivity. Finally, inorganic bases of varying strength (phosphates, carbonates, acetates, etc) along with organic variants such as triethylamine, l,8-diazabicyclo(5.4.0)undec-7-ene, and others in a wide pKa range are viable as stoichiometric basic additives.

Example 3: Exemplary Compound 5 process

[0267] The purpose of this example was to describe an exemplary process for making Compound 5.

[0268] Charge 4 (lOg, 58mmol) and acetonitrile (lOOmL) to a reaction vessel and start the stirrer. Adjust the batch to -18 °C to -22 °C (target -20 °C). Charge triflic acid (5.5mL, 62mmol) to the batch maintaining -10 °C to -25 °C (target -20 °C). Stir the batch at -10 °C to -25 °C (target -20 °C) for 10 to 20 minutes. Charge NBS (11.38g, 64mmol) to the batch at -10 °C to -25 °C (target -20 °C) and stir for ca. 30 min at -10 °C to -25 °C (target -20 °C). Warm the batch to 20 °C over 3-4 hours (reaction will occur when internal temp is between 5 °C and 15 °C). Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and sample for reaction completion.

[0269] If Compound 4 relative to Compound 5 is more than 5%:

[0270] Cool the bath to -5 °C to -15 °C (target -10 °C) (cooling below 0 °C to ensure selectivity). Charge NBS to the batch according to the follow formula: Mass of NBS = (% Compound 4 x lOg). Warm the batch to 20 °C over 1-2 hours. Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and check reaction for completion. Proceed to next line.

[0271] If Compound 4 relative to Compound 5 is less than 5%:

[0272] Warm the batch to 40 °C to 50 °C (target 48 °C). Concentrate the batch under reduced pressure to a final volume of ~40mL. Cool the batch to -15 °C to -5 °C (target -10 °C) and stir for ca. lh. Filter the batch by suction filtration. Slurry wash the filter cake with purified water (3 x 20mL) at 15 °C to 25 °C (target 20 °C) for 10 to 15 minutes each wash. Remove a sample of the filter cake for analysis by ¾ NMR. Continue washing cake until the residual succimide is below 1.0%mol% relative to 5. Dry the filter cake at up to 60°C under vacuum and nitrogen purge. Analyse the 5 by HPLC analysis (97%w/w to 99%w/w). Expected yield: 60-85% theory (90-110% w/w).

Example 4: Purification of Compound 1 (CC-90010) by crystallization from formic acid and water.

[0273] This example describes a method for the purification of Compound 1 by

crystallization from formic acid and water. Also detailed are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1.

[0274] Figure 11 shows ^XH NMR of Compound 1 (CC-90010). Solvent: d6DMSO; and Figure 12 shows microscopy of Compound 1 (CC-90010) Form I. Figure 13 shows XRPD of Compound 1 (CC-90010) Form I, with peak information detailed in Table 6:

PATENT

US 20190008852

WO 2018081475

US 20180042914

WO 2016172618

WO 2015058160

/////////CC-90010, solid tumors , non-Hodgkin’s lymphoma, PHASE 1, CANCER, QUANTICEL

CS(=O)(=O)c4cc(C1=CN(C)C(=O)c2ccccc12)c(OCC3CC3)cc4

Zanubrutinib, ザヌブルチニブ , занубрутиниб , زانوبروتينيب ,

January 27, 2020 9:40 am / Leave a comment

Zanubrutinib (USAN/INN).png

ChemSpider 2D Image | zanubrutinib | C27H29N5O3

Zanubrutinib, BGB-3111

Formula	C27H29N5O3
CAS	1691249-45-2
Mol weight	471.5509

FDA , 2019/11/14, Brukinsa

ザヌブルチニブ ,

занубрутиниб [Russian]

زانوبروتينيب [Arabic]

(7S)-7-(1-Acryloyl-4-piperidinyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Pyrazolo[1,5-a]pyrimidine-3-carboxamide, 4,5,6,7-tetrahydro-7-[1-(1-oxo-2-propen-1-yl)-4-piperidinyl]-2-(4-phenoxyphenyl)-, (7S)-

Antineoplastic, Bruton’s tyrosine kinase inhibitor, Mantle cell lymphoma

Zanubrutinib, sold under the brand name Brukinsa, is for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.^[3]

It was approved for medical use in the United States in November 2019.^[4]^[3]^[5]^[6]

Zanubrutinib is classified as a Bruton’s tyrosine kinase (BTK) inhibitor. It is administered orally.

History

Efficacy was evaluated in BGB-3111-206 (NCT03206970), a phase II open-label, multicenter, single-arm trial of 86 patients with mantle cell lymphoma (MCL) who received at least one prior therapy.^[5] Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity.^[5] Efficacy was also assessed in BGB-3111-AU-003 (NCT 02343120), a phase I/II, open-label, dose-escalation, global, multicenter, single-arm trial of B‑cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib administered orally at 160 mg twice daily or 320 mg once daily.^[5]^[6]

The primary efficacy outcome measure in both trials was overall response rate (ORR), as assessed by an independent review committee.^[5] In trial BGB-3111-206, FDG-PET scans were required and the ORR was 84% (95% CI: 74, 91), with a complete response rate of 59% (95% CI 48, 70) and a median response duration of 19.5 months (95% CI: 16.6, not estimable).^[5] In trial BGB-3111-AU-003, FDG-PET scans were not required and the ORR was 84% (95% CI: 67, 95), with a complete response rate of 22% (95% CI: 9, 40) and a median response duration of 18.5 months (95% CI: 12.6, not estimable).^[5] Trial 1 was conducted at 13 sites in China, and Trial 2 was conducted at 25 sites in the United States, United Kingdom, Australia, New Zealand, Italy, and South Korea.^[6]

The U.S. Food and Drug Administration (FDA) granted zanubrutinib priority review, accelerated approval, breakthrough therapydesignation, and orphan drug designation.^[3]^[5]^[7]

The FDA approved zanubrutinib in November 2019, and granted the application for Brukinsa to BeiGene USA Inc.^[3]^[5]^[8]

PAPER

https://www.x-mol.com/paper/5799457

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase Journal of Medicinal Chemistry ( IF 6.054 ) Pub Date: 2019-08-19 , DOI: 10.1021 / acs.jmedchem.9b00687

Yunhang Guo, Ye Liu, Nan Hu, Desheng Yu, Changyou Zhou, Gongyin Shi, Bo Zhang, Min Wei, Junhua Liu, Lusong Luo, Zhiyu Tang, Huipeng Song, Yin Guo, Xuesong Liu, Dan Su, Shuo Zhang, Xiaomin Song , Xing Zhou, Yuan Hong, Shuaishuai Chen, Zhenzhen Cheng, Steve Young, Qiang Wei, Haisheng Wang, Qiuwen Wang, Lei Lv, Fan Wang, Haipeng Xu, Hanzi Sun, Haimei Xing, Na Li, Wei Zhang, Zhongbo Wang, Guodong Liu, Zhijian Sun, Dongping Zhou, Wei Li, Libin Liu, Lai Wang, Zhiwei Wang

Aberrant activation of Bruton’s tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.

PATENT

WO 2014173289

WO 2018033135

PATENT

WO 2018033853

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018033853&tab=PCTDESCRIPTION

Bruton’s tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361: 226-233, 1993; Bradshaw, Cell Signal. 22: 1175-84, 2010). Btk is primarily expressed in most hematopoietic cells such as B cells, mast cells and macrophages (Smith et al., J. Immunol. 152: 557-565, 1994) and is localized in bone marrow, spleen and lymph node tissue. Btk plays important roles in B-cell receptor (BCR) and FcR signaling pathways, which involve in B-cell development, differentiation (Khan, Immunol. Res. 23: 147, 2001). Btk is activated by upstream Src-family kinases. Once activated, Btk in turn phosphorylates PLC gamma, leading to effects on B-cell function and survival (Humphries et al., J. Biol.Chem. 279: 37651, 2004).

[0003] These signaling pathways must be precisely regulated. Mutations in the gene encoding Btk cause an inherited B-cell specific immunodeficiency disease in humans, known as X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). Aberrant BCR-mediated signaling may result in dysregulated B-cell activation leading to a number of autoimmune and inflammatory diseases. Preclinical studies show that Btk deficient mice are resistant to developing collagen- induced arthritis. Moreover, clinical studies of Rituxan, a CD20 antibody to deplete mature B-cells, reveal the key role of B-cells in a number of inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis (Gurcan et al, Int. Immunopharmacol. 9: 10-25, 2009). Therefore, Btk inhibitors can be used to treat autoimmune and/or inflammatory diseases.

[0004] In addition, aberrant activation of Btk plays an important role in pathogenesis of B-cell lymphomas indicating that inhibition of Btk is useful in the treatment of hematological malignancies (Davis et al, Nature 463: 88-92, 2010). Preliminary clinical trial results showed that the Btk inhibitor PCI-32765 was effective in treatment of several types of B-cell lymphoma (for example, 54thAmerican Society of Hematology (ASH) annual meeting abstract, Dec. 2012: 686 The Bruton’s Tyrosine Kinase (Btk) Inhibitor, Ibrutinib (PCI- 32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results of a Multic enter, Open-Label, Phase I Study). Because Btk plays a central role as a mediator in multiple signal transduction pathways, inhibitors of Btk are of great interest as anti-inflammatory and/or anti-cancer agents {Mohamed et al., Immunol. Rev. 228: 58-73, 2009; Pan, Drug News perspect 21: 357-362, 200%; Rokosz et al., Expert Opin. Ther. Targets 12: 883-903, 2008; Uckun et al., Anti-cancer Agents Med. Chem. 7: 624-632, 2007; Lou et al, J. Med. Chem. 55(10): 4539-4550, 2012).

[0005] International application WO2014173289A disclosed a series of fused heterocyclic compounds as Btk inhibitors. In particular, WO2014173289A disclosed

(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[l,5-a]pyrimi dine-3-carboxamide (hereinafter C

Compound 1

[0006] Compound 1 is a potent, specific and irreversible BTK kinase inhibitor. The data generated in preclinical studies using biochemical, cell based and animal studies suggested that Compound 1 could offer significant benefit in inhibiting tumor growth in B-cell malignancies. As Compound 1 was shown to be more selective than ibrutinib for inhibition of BTK vs. EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC, it is expected to give rise to less side-effects than ibrutinib in clinic. In addition, Compound 1 showed significantly less inhibition of rituximab-induced antigen-dependent cell-mediated cytotoxicity (ADCC) than ibrutinib due to weaker ITK inhibition, and therefore may provide better efficacy when combined with rituximab or other ADCC-dependent antibody in treating B-cell malignancies.

[0007] Preclinical safety evaluation has demonstrated that Compound 1 was safer than ibrutinib in terms of the overall tolerance and severe toxicities in both rat and dog single and repeat dose toxicity studies up to 28 days. Additionally, Compound 1 had better bioavailability without accumulation issues observed for ibrutinib. These unique characteristics warrant further evaluation of Compound 1 in clinical studies.

[0008] However, Compound 1 was found to be an amorphous form according to the preparation method for Compound 27 in WO 2014173289A, which was further confirmed by the X-Ray Powder Diffraction pattern of FIG. 7A. The amorphous form was shown to have a low glass transition temperature as shown in FIG. 7B, indicating some difficulties in the drug formulation with the amorphous form, such as low stability and hard to purify. Therefore, it’s necessary to develop a new form of Compound 1 which possesses characteristics such as high melting point and better stability, suitable for drug formulation.

Scheme 1: Preparation of Compound 1 and deuterium-labeled Compound 1

Deuterium-Labeled Compound 1

Step 15: Synthesis of

(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolori,5-a1pyrimi dine-3-carboxamide (Compound 1

[0105] Under N₂ atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHC0₃ (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and

stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.

[0106] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.

Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)

-4,5,6,7-tetrahydropyrazolori,5-a1pyrimidine-3-carboxamide (Compound 1, alternative method)

[0107] A mixture of CHsCN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH3CN (residue volume: NMT 5.0 v). CH3CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCCb (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH3CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3%> w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.

Step 16: Preparation of Crystalline Form A of Compound 1

[0108] The above cake of Compound 1 was dissolved in 7.0 volumes of DCM, and then swapped to solvent EA. After recrystallization from EA/MTBE, the cakes was collected by centrifugation, and was dried under vacuum. This gave 4.44 Kg product (Yield: 70.2%).

[0109] The product was then characterized by X-ray powder diffraction (XRPD) pattern method, which was generated on a PANalytical Empyrean X-ray powder diffractometer with the XRPD parameters as follows: X-Ray wavelength (Cu, ka, Kal (A): 1.540598, Ka2(A): 1.544426; Ka2/Kal intensity ratio: 0.50); X-Ray tube setting (45 Kv, 40mA); divergence slit (automatic); scan mode (Continuous); scan range (°2TH) (3°-40); step size (°2TH) (0.0131); scan speed (°/min) (about 10). The XRPD result found the resultant product as a crystalline shown in FIG. 1.

[0110] The differential scanning calorimetry (DSC) curves shown as in FIG. 2 was generated on a TA Q2000 DSC from TA Instruments. The DSC parameters used includes: temperature (25°C-desired temperature); heating rate (10°C/min) ; method (ramp); sample pan (aluminum, crimped); purge gas (N₂). DSC result showed a sharp melting point at 139.4°C (onset temperature).

[0111] The thermo-gravimetric analysis (TGA) curves shown as in FIG. 3 was generated on a TA Q5000 TGA from TA Instruments. The TGA parameters used includes: temperature

(RT-desired temperature); heating rate (10°C/min); method (ramp); sample pan (platinum, open); purge gas (N₂). TGA result showed is anhydrous with no weight loss even up to 110 °C.

[0112] The proton nuclear magnetic resonance ^H-NMR) shown as in FIG. 4 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. ¾-NMR (DMSO-de) δ 7.50 (d, J= 8.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.08 (d, J= 7.6 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.85-6.72 (m, 1H), 6.67 (s, 1H), 6.07 (dd, J= 16.8, 2.2 Hz, 1H), 5.64 (dd, J= 10.4 Hz, 2.2 Hz, 1H), 4.55-4.38 (m, 1H), 4.17-3.94 (m, 2H), 3.33-3.22 (m, 2H), 3.08-2.88 (m, 1H), 2.67-2.51 (m, 1H), 2.36-2.15 (m, 1H), 2.12-1.82 (m, 2H), 1.79-1.65 (m, 1H), 1.63-1.49 (m, 1H), 1.38-1.08 (m, 2H).

[0113] The carbon nuclear magnetic resonance (¹³C-NMR) shown as in FIG. 5 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. ¹³C-NMR spectra for Crystalline Form A of Compound 1.

PATENT

WO 2019108795

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019108795&tab=PCTDESCRIPTION

Step 15: Synthesis of (S)-7-(1-acrvlovlpiperidin-4-vl)-2-(4-phenoxvphenyl)-4.5.6.7-tetrahvdropvrazolo[1.5-a1pvrimidine-3-carboxamide (Compound 1)

[0119] Under N₂ atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHCO₃ (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.

[0120] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.

Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl) -4.5.6.7-tetrahvdropvrazolori.5-a1pvrimidine-3-carboxamide (Compound 1. alternative method)

[0121] A mixture of CH₃CN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH₃CN (residue volume: NMT 5.0 v). CH₃CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCO₃ (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH₃CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3% w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.

References

^ “Zanubrutinib (Brukinsa) Use During Pregnancy”. Drugs.com. 3 January 2020. Retrieved 26 January 2020.
^ “Zanubrutinib”. DrugBank. Retrieved 15 November 2019.
^ Jump up to:^a ^b ^c ^d “FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage”. U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Retrieved 15 November 2019. This article incorporates text from this source, which is in the public domain.
^ “Brukinsa (zanubrutinib) FDA Approval History”. Drugs.com. 14 November 2019. Archived from the original on 15 November 2019. Retrieved 15 November 2019.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma”. U.S. Food and Drug Administration (FDA)(Press release). 15 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c “Drug Trials Snapshots Brukinsa”. U.S. Food and Drug Administration (FDA). 14 November 2019. Retrieved 26 January 2020. This article incorporates text from this source, which is in the public domain.
^ “Zanubrutinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). 28 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
^ “Drug Approval Package: Brukinsa”. U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.

External links

“Zanubrutinib”. Drug Information Portal. U.S. National Library of Medicine.

Zanubrutinib
Clinical data

Trade names	Brukinsa
Other names	BGB-3111
AHFS/Drugs.com	Monograph
License data	US DailyMed: Zanubrutinib US FDA: Brukinsa
Pregnancy category	US: N (Not classified yet) ^[1]
Routes of administration	By mouth
Drug class	Bruton’s tyrosine kinase(BTK) inhibitor
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	1691249-45-2
PubChem CID	135565884
PubChem SID	384585399
DrugBank	DB15035
ChemSpider	64835237
UNII	AG9MHG098Z
KEGG	D11422
ChEMBL	ChEMBL3936761
Chemical and physical data
Formula	C₂₇H₂₉N₅O₃
Molar mass	471.5509 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] NC(=O)C1=C2NCC[C@@H](C3CCN(CC3)C(=O)C=C)N2N=C1C1=CC=C(OC2=CC=CC=C2)C=C1
InChI

/////////////////Zanubrutinib, FDA 2019, ザヌブルチニブ , занубрутиниб , زانوبروتينيب , BGB-3111

CK-101

August 30, 2019 2:30 pm / Leave a comment

N-[3-[2-[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]anilino]quinazolin-8-yl]phenyl]prop-2-enamide.png

CK-101, RX-518

CAS 1660963-42-7

MF C₂₉ H₂₈ F₂ N₆ O₂

MW 530.57

2-Propenamide, N-[3-[2-[[2,3-difluoro-4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-8-quinazolinyl]phenyl]-

N-[3-[2-[[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]amino]quinazolin-8-yl]phenyl]acrylamide

N-(3-(2-((2,3-Difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide

EGFR-IN-3

UNII-708TLB8J3Y

708TLB8J3Y

AK543910

Suzhou NeuPharma (Originator)
Checkpoint Therapeutics

Non-Small Cell Lung Cancer Therapy
Solid Tumors Therapy

PHASE 2 Checkpoint Therapeutics, Cancer, lung (non-small cell) (NSCLC), solid tumour

RX518(CK-101) is an orally available third-generation and selective inhibitor of certain epidermal growth factor receptor (EGFR) activating mutations, including the resistance mutation T790M, and the L858R and exon 19 deletion (del 19) mutations, with potential antineoplastic activity.

In August 2019, Suzhou Neupharma and its licensee Checkpoint Therapeutics are developing CK-101 (phase II clinical trial), a novel third-generation, covalent, EGFR inhibitor, as a capsule formulation, for the treatment of cancers including NSCLC and other advanced solid tumors. In September 2017, the FDA granted Orphan Drug designation to this compound, for the treatment of EGFR mutation-positive NSCLC; in January 2018, the capsule was being developed as a class 1 chemical drug in China.

CK-101 (RX-518), a small-molecule inhibitor of epidermal growth factor receptor (EGFR), is in early clinical development at Checkpoint Therapeutics and Suzhou NeuPharma for the potential treatment of EGFR-mutated non-small cell lung cancer (NSCLC) and other advanced solid malignancies.

In 2015, Suzhou NeuPharma granted a global development and commercialization license to its EGFR inhibitor program, excluding certain Asian countries, to Coronado Biosciences (now Fortress Biotech). Subsequently, Coronado assigned the newly acquired program to its subsidiary Checkpoint Therapeutics.

In 2017, the product was granted orphan drug designation in the U.S. for the treatment of EGFR mutation-positive NSCLC.

There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.

[0003] The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.

[0004] The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial.

[0005] While such compounds are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance, such as a kinase inhibitor, can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties

can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers. For example, polymorphism has been evaluated in many multi-million dollar and even multi-billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and/or efficacy of a drug product, such as a kinase inhibitor. Thus, there still remains a need for polymorphs of kinase inhibitors. The present disclosure addresses this need and provides related advantages as well.

PATENT

WO2015027222

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027222

PATENT

WO-2019157225

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019157225&tab=PCTDESCRIPTION&_cid=P10-JZNKMN-12945-1

Crystalline form II-VIII of the compound presumed to be CK-101 (first disclosed in WO2015027222 ), for treating a disorder mediated by epidermal growth factor receptor (EGFR) eg cancer.

SCHEME A

Scheme B

General Procedures

Example 1: Preparation of the compound of Formula I (N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide)

[0253] To a solution of l,2,3-trifluoro-4-nitrobenzene (2.5 g, 14 mmol, 1.0 eq.) in DMF (20 mL) was added K₂C0₃ (3.8 g, 28 mmol, 2.0 eq.) followed by 2-(piperazin-l-yl)ethanol (1.8 g, 14 mmol, 1.0 eq.) at 0 °C and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water (200 mL), filtered and dried in vacuo to afford 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 67.5%).

[0254] To a solution of 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 9.0 mmol) in MeOH (30 mL) was added Pd/C (270 mg) and the resulting mixture was stirred at r.t.

overnight. The Pd/C was removed by filtration and the filtrate was concentrated to afford 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (2.39 g, 99% yield) as off-white solid.

[0255] To a solution of 8-bromo-2-chloroquinazoline (15.4 g, 63.6 mmol, 1 eq. ) and (3-aminophenyl)boronic acid (8.7 g, 63.6 mmol, 1 eq.) in dioxane/H₂0 (200 mL/20 mL) was added Na₂C0₃ (13.5 g, 127.2 mmol, 2 eq.), followed by Pd(dppf)Cl₂ (2.6 g, 3.2 mmol, 0.05 eq.) under N₂, then the mixture was stirred at 80 °C for 12 h. Then the solution was cooled to r.t.,

concentrated and the residue was purified via column chromatography (PE/EA=3 :2, v/v) to afford 3-(2-chloroquinazolin-8-yl)aniline as yellow solid (8.7 g, 53.7% yield).

[0256] To a solution of 3-(2-chloroquinazolin-8-yl)aniline (8.7 g, 34 mmol, 1 eq.) in DCM ( 200 mL ) cooled in ice-bath was added TEA (9.5 mL, 68 mmol, 2 eq. ), followed by acryloyl chloride (4.1 mL, 51 mmol, 1.5 eq.) dropwise. The resulting mixture was stirred at r.t. for 1 h, then washed with brine, dried over anhydrous N₂S0₄ concentrated and the residue was purified via column chromatography (PE/EA=l : 1, v:v) to afford N-(3-(2-chloroquinazolin-8-yl)phenyl)acryl amide as yellow solid(6.6 g, 65% yield).

[0257] To a suspension of 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (83 mg,

0.32 mmol, 1 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.32 mmol, 1 eq.) in n-BuOH (5 mL) was added TFA (68 mg, 0.64 mmol, 2 eq.) and the resulting mixture was stirred at 90 °C overnight. The mixture was concentrated, diluted with DCM (20 mL) , washed with Na₂C0₃ solution (20 mL), dried over anhydrous Na₂S0₄, concentrated and the residue was purified via column chromatography (MeOH/DCM=l/30, v:v) to afford N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide as a yellow solid(l6.3 mg, 9.5% yield). LRMS (M+H⁺) m/z calculated 531.2, found 531.2. 1H NMR

(CD₃OD, 400 MHz) d 9.21 (s, 1 H), 7.19-8.01 (m, 10 H), 8.90 (s, 1 H), 6.41-6.49 (m, 3 H), 5.86 (m, 1 H), 3.98-4.01 (m, 3 H), 3.70-3.76 (m, 3 H), 3.40-3.49 (m, 2 H), 3.37-3.39 (m, 4 H), 3.18 (m, 2H).

Example 2. Preparation of Form I of the compound of Formula I

[0258] Crude compound of Formula I (~30 g, 75% of weight based assay) was dissolved in ethyl acetate (3 L) at 55-65 °C under nitrogen. The resulting solution was filtered via silica gel pad and washed with ethyl acetate (3 L><2) at 55-65 °C. The filtrate was concentrated via vacuum at 30-40 °C to ~2.4 L. The mixture was heated up to 75-85 °C and maintained about 1 hour.

Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and the mixture was then cooled down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with ethyl acetate (60 mL><2). The wet cake was dried via vacuum at 30-40 °C to get (about 16 g) of the purified Form I of the compound of Formula I.

Example 3. Preparation of Form III of the compound of Formula I

[0259] The compound of Formula I (2 g) was dissolved in EtOH (40 mL) at 75-85 °C under nitrogen. n-Heptane (40 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 75-85 °C for 1 hour. Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with EtOH/n-Heptane (1/1, 5 mL><2). The wet cake was dried via vacuum at 30-40 °C to get the purified Form III of the compound of Formula I (1.7 g).

Example 4. Preparation of Form IV of the compound of Formula I The crude compound of Formula I (15 g) was dissolved in ethyl acetate (600 mL) at 75-85 °C under nitrogen and treated with anhydrous Na₂S0₄, activated carbon, silica metal scavenger for 1 hour. The resulting mixture was filtered via neutral Al₂0₃ and washed with ethyl acetate (300 mL><2) at 75-85 °C. The filtrate was concentrated under vacuum at 30-40 °C and swapped with DCM (150 mL). n-Heptane (75 mL) was added into this DCM solution at 35-45 °C, and then the mixture was cooled down to 20-30 °C slowly. The resulting mixture was filtered and washed with DCM/n-Heptane (2/1, 10 mL><3). The wet cake was dried via vacuum at 35-40 °C to get the purified Form IV of the compound of Formula I (9.6 g).

Example 5. Preparation of Form V of the compound of Formula I

[0260] Polymorph Form III of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form V.

Example 6. Preparation of Form VI of the compound of Formula I

[0261] The compound of Formula I (1 g) was dissolved in IPA (20 mL) at 75-85 °C under nitrogen. n-Heptane (20 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 45-55 °C for 16 hours. Then heated up to 75-85 °C and maintained about 0.5 hour.

Then cooled down to 45-55 °C for 0.5 hour and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. Filtered and washed with IPA/n-Heptane (1/1, 3 mL><2). The wet cake was dried via vacuum at 75-80 °C for 2 hours to get the purified Form VI of the compound of Formula I.

Example 7. Preparation of Form VIII of the compound of Formula I

[0262] The polymorph Form VI of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form VIII.

Example 8. X-ray powder diffraction (XRD)

[0263] X-ray powder diffraction (XRD) patterns were obtained on a Bruker D8 Advance. A CuK source (=1.54056 angstrom) operating minimally at 40 kV and 40 mA scans each sample between 4 and 40 degrees 2-theta. The step size is 0.05°C and scan speed is 0.5 second per step.

Example 9. Thermogravimetric Analyses (TGA)

[0264] Thermogravimetric analyses were carried out on a TA Instrument TGA unit (Model TGA 500). Samples were heated in platinum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 60mL/min (sample purge) and 40mL/min (balance purge). The TGA temperature was calibrated with nickel standard, MP=354.4 °C. The weight calibration was performed with manufacturer-supplied standards and verified against sodium citrate dihydrate desolvation.

Example 10. Differential scanning calorimetry (DSC)

[0265] Differential scanning calorimetry analyses were carried out on a TA Instrument DSC unit (Model DSC 1000 or 2000). Samples were heated in non-hermetic aluminum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 50mL/min. The DSC temperature was calibrated with indium standard, onset of l56-l58°C, enthalpy of 25-29J/g.

Example 11. Hygroscopicity (DVS)

[0266] The moisture sorption profile was generated at 25°C using a DVS Moisture Balance Flow System (Model Advantage) with the following conditions: sample size approximately 5 to 10 mg, drying 25°C for 60 minutes, adsorption range 0% to 95% RH, desorption range 95% to 0% RH, and step interval 5%. The equilibrium criterion was <0.01% weight change in 5 minutes for a maximum of 120 minutes.

Example 12: Microscopy

[0267] Microscopy was performed using a Leica DMLP polarized light microscope equipped with 2.5X, 10X and 20X objectives and a digital camera to capture images showing particle shape, size, and crystallinity. Crossed polars were used to show birefringence and crystal habit for the samples dispersed in immersion oil.

Example 13: HPLC

[0256] HPLCs were preformed using the following instrument and/or conditions.

///////////////CK-101 , CK 101 , CK101 , phase II , Suzhou Neupharma, Checkpoint Therapeutics , Orphan Drug designation, EGFR mutation-positive NSCLC, NSCLC, CANCER, SOLID TUMOUR, China, RX-518, AK543910

OCCN1CCN(CC1)c5ccc(Nc2nc3c(cccc3cn2)c4cccc(NC(=O)C=C)c4)c(F)c5F

FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor

August 20, 2019 10:25 am / Leave a comment

FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor

FDA also approves drug for second indication in a type of lung cancer

The U.S. Food and Drug Administration today granted accelerated approval to Rozlytrek (entrectinib), a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” said FDA Acting Commissioner Ned Sharpless, M.D. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released in 2018. The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

The ability of Rozlytrek to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for nine months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.

Rozlytrek was also approved today for the treatment of adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic). Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

Rozlytrek’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects of Rozlytrek are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing fetus or newborn baby.

Rozlytrek was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. Rozlytrek also received Priority Review, Breakthrough Therapy and Orphan Drug designation. The approval of Rozlytrek was granted to Genentech, Inc.

link http://s2027422842.t.en25.com/e/es?s=2027422842&e=244904&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=46563b1749694ceb96d9f79a6d5cd8a7&elqaid=9150&elqat=1

///////////////Rozlytrek, entrectinib, accelerated approval, priority Review, Breakthrough Therapy, Orphan Drug designation, fda 2019, Genentech, cancer

BQ-788

July 26, 2019 10:04 am / Leave a comment

ChemSpider 2D Image | BQ-788 | C34H50N5NaO7

Image result for bq-788

BQ-788

Molecular FormulaC₃₄H₅₀N₅NaO₇
Average mass663.780 Da

SP ROT +3.8 ° Conc: 1.032 g/100mL; methanol; Wavlenght: 589.3 nm, Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues
Peptides (New York, NY, United States) (2005), 26, (8), 1441-1453., https://doi.org/10.1016/j.peptides.2005.03.022

FOR FREE FORM +19.6 °, Conc: 0.998 g/100mL; : N,N-dimethylformamide; 589.3 nm

CAS 156161-89-6 [RN]

CAS 173326-37-9 FREE ACID

2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle

BQ 788 sodium salt

BQ788

D-Norleucine, N-(((2R,6S)-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt

D-Norleucine, N-((cis-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt

D-Norleucine, N-[[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, sodium salt (1:1)

MFCD00797882

N-[N-[N-[(2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine sodium salt

Sodium N-{[(2R,6S)-2,6-dimethylpiperidin-1-yl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide

2,6-Dimethylpiperidinecarbonyl-Î³-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle

BQ-788 is a selective ET_B antagonist.^[1]

presumed to be under license from Banyu , was investigating BQ-788, a selective endothelin receptor B (ETRB) antagonist, for treating metastatic melanoma. By December 2009, the drug was in validation.

Also claimed is their use as an ETBR antagonist and for treating cancers, such as brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma and squamous cell carcinoma. Represent a first filing from ENB Therapeutics Inc and the inventors on these deuterated forms of BQ-788. Melcure SarL ,

SYN

By Brosseau, Jean-Philippe et alFrom Peptides (New York, NY, United States), 26(8), 1441-1453; 2005

CONTD…………

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo00130a028

N-(cw-2,6-Dimethylpiperidinocarbonyl)-y-methylleucylD-l-(methoxycarbonyl)tryptophanyl-D-norleucine Sodium Salt (1, BQ-788). To a solution of 15 (3.5 g, 5.5 mmol) in methanol (50 mL) was slowly added 5% aqueous NaHCOs (300 mL) over a period of 30 min. The solution was stirred until clarity was achieved (30 min, 23 °C). The solution was diluted with water (200 mL), and the resulting solution was passed through a C18 (60 mL) cartridge preequilbrated in water. BQ-788 (1) was eluted with methanol (2 x 50 mL), concentrated under reduced pressure, resuspended in water (50 mL), and lyophilized to quantitatively yield compound 1 as a white powder:

HPLC £r = 16.4 (gradient A, > 99%);

NMR (400 MHz, DMSO-d6) ó 0.80 (s, 9H), 0.74-0.85 (m, 3H), 1.00 (d, 3H), 1.02 (d, 3H), 1.10-1.25 (m, 6H), 1.30-1.55 (m, 6H), 1.60-1.75 (m, 2H), 2.92 (dd, 1H), 3.12 (dd, 1H), 3.78 (m, 1H), 3.95 (s, 3H), 4.08 (m, 1H), 4.13 (m, 1H), 4.29 (m, 1H), 4.50 (m, 1H), 5.98 (d, 1H), 7.22 (t, 1H), 7.32 (t, 1H), 7.50 (s, 1H), 7.58 (br d, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.15 (br d, 1H) ESMS m/z 640.6 (M).

PATENT

WO-2019140324

Novel deuterated analogs of a substituted heterocyclic compound, particularly BQ-788 , processes for their preparation and compositions and combinations comprising them are claimed.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019140324&tab=PCTDESCRIPTION&_cid=P22-JYJK98-13819-1

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0196978105001415

Image result for bq-788

PAPER

By He, John X.; Cody, Wayne L.; Doherty, Annette M., From Journal of Organic Chemistry (1995), 60(25), 8262-6

Journal of medicinal chemistry (1996), 39(12), 2313-30.

References

^ Okada, M; Nishikibe, M (Winter 2002). “BQ-788, a selective endothelin ET(B) receptor antagonist”. Cardiovascular drug reviews. 20 (1): 53–66. PMID 12070534.

BQ-788
Names

Systematic IUPAC name Sodium N-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
Identifiers
CAS Number	156161-89-6
3D model (JSmol)	Interactive image
ChemSpider	4470569
PubChem CID	5311031
CompTox Dashboard (EPA)	DTXSID40166053
InChI [show]
SMILES [show]
Properties
Chemical formula	C₃₄H₅₀N₅NaO₇
Molar mass	663.792 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////BQ-788, BQ 788, BQ788, ETBR antagonist, cancers, brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma, squamous cell carcinoma, PEPTIDE

CCCC[C@H](C(=O)O)NC(=O)[C@@H](Cc1cn(c2c1cccc2)C(=O)OC)NC(=O)[C@H](CC(C)(C)C)NC(=O)N3[C@@H](CCC[C@@H]3C)C

	DR ANTHONY MELVIN CR… on Pegylated Interferon alpha-2b,…
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Physical Characteristics

Radiosynthesis of [ 18 F]DCFPyL

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FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC

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AMG 510 [(R)-38]. (1R)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one

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FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC

Clinical development

Chemistry and pharmacology

History

Society and culture

Economics

Names

AMG 510 [(R)-38]. (1R)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one

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