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INAXAPLIN

June 13, 2025 2:46 am / Leave a comment

INAXAPLIN

Gepirone

June 12, 2025 3:03 am / Leave a comment

Gepirone

CAS 83928-76-1

BMY 13805, MJ 13805, ORG 13011, Gepirona,
JW5Y7B8Z18

FDA 9/22/2023, Gepirone is indicated for the treatment of major depressive disorder (MDD) in adults

Exxua

Weight
Average: 359.474
Monoisotopic: 359.232125194
Chemical Formula
C₁₉H₂₉N₅O₂

4,4-dimethyl-1-{4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl}piperidine-2,6-dione

Ingredient	UNII	CAS	InChI Key
Gepirone Hydrochloride	80C9L8EP6V	83928-66-9	DGOCVISYYYQFEP-UHFFFAOYSA-N

Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder.^[1] It is taken orally.^[1]

Side effects of gepirone include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion).^[1] Gepirone acts as a partial agonist of the serotonin 5-HT_1A receptor.^[1]^[2] An active metabolite of gepirone, 1-(2-pyrimidinyl)piperazine, is an α₂-adrenergic receptor antagonist.^[1]^[3] Gepirone is a member of the azapirone group of compounds.^[2]

Gepirone was synthesized by Bristol-Myers Squibb in 1986 and was developed and marketed by Fabre-Kramer Pharmaceuticals.^[4] It was approved for the treatment of major depressive disorder in the United States in September 2023.^[4] This came after the drug had been rejected by the Food and Drug Administration (FDA) three times over two decades due to insufficient evidence of effectiveness.^[5]

History

Gepirone was developed by Bristol-Myers Squibb in 1986,^[5] but was out-licensed to Fabre-Kramer in 1993. The FDA rejected approval for gepirone in 2002 and 2004.^[5] It was submitted for the preregistration (NDA) phase again in May 2007 after adding additional information from clinical trials as the FDA required in 2009. However, in 2012 it once again failed to convince the FDA of its qualities for treating anxiety and depression.^[5] In December 2015, the FDA once again gave gepirone a negative review for depression due to concerns of efficacy.^[12] However, in March 2016, the FDA reversed its decision and gave gepirone ER a positive review.^[13] Gepirone ER was finally approved for the treatment of major depressive disorder in the United States in September 2023.^[5]

SYN

Synthesis

Ormaza, V. A.; 1986, ES 8606333.

SYN

https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/gepirone

Gepirone (Exxua)

Gepirone, a selective and affinitive 5-hydroxytryptamine 1A (5-HT_1A) agonist, received FDA approval on September 22, 2023, to treat major depressive disorder in adults [37]. Gepirone, an azapirone compound, is a pharmacological derivative of buspirone that exhibits specific activity on both pre- and post-synaptic 5-HT_1A receptors. Despite the promising results observed in previous clinical trials for Gepirone, the need for frequent administration is a requirement due to its formulation as an immediate-release tablet and its short half-lives. Gepirone did not become a potential candidate for a new antidepressant until an extended-release formulation of it was developed [38–40].

An efficient approach of Gepirone has been disclosed in Scheme 11 [41]. Substitution of 2-(piperazin-1-yl)pyrimidine (GEPI-001) with 1,4-dibromobutane (GEPI-002), followed by ring opening and addition, generated the final product Gepirone.

PATENT

https://patents.google.com/patent/WO2020148621A1/en

Gepirone (4,4-dimethyl-l-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-2,6- piperidindione) is an antidepressant and anxiolytic medicament belonging to the azapirone group, currently at the pre-registration stage in the USA. Like other azapirones, gepirone is a selective partial agonist of the 5-HT1A receptor.

The prior art includes some synthesis strategies for the preparation of gepirone (I); they are mainly multi-step reactions which present various drawbacks such as economic inefficiency, low yield and low industrial applicability.

The synthesis of gepirone (I) is described in J. Med. Chem. 1988, 31, 1967-1971; WO 2012/016569; EP 0680961; Dier Junyi Daxue Xuebao, 26(2), 223-224; 2005; Patentschrift (CH), 682564, 15 October 1993; Heterocycles, 36(7), 1463-9, 1993; and Bioorganic & Medicinal Chemistry Letters, 14(7), 1709-1712, 2004.

The scientific article published in J. Med. Chem. 1988, 31, 1967-1971 describes the synthesis of gepirone (I) from N-bromobutyl phthalimide (2) and l-(pyrimidin-2- yl)piperazine (3) in the presence of potassium carbonate to give the intermediate 2-(4-(4- (pyrimidin-2-yl)piperazin-l-yl)butyl)isoindoline-l,3-dione (4), from which the phthalimide protecting group is removed with hydrazine hydrate. The compound 4-(4-(pyrimidin-2-yl)piperazin- 1 -yl)butan- 1 -amine (5) thus synthesised is used in the reaction with 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (6) to obtain gepirone (I) (Scheme 1).

SCHEME 2

In WO 2012/016569, gepirone (I) is synthesised in four synthesis steps from 1- (pyrimidin-2-yl)pipetazine (3) and 4-((tert-butoxycarbonyl)amino)butanoic acid (7) with the use of condensing agents, such as HATU, and strong reducing agents such as lithium aluminium hydride. The use of condensing agents makes the process practically unusable on an industrial scale because of their high economic impact and the formation of countless by-products which are difficult to remove during the work-up step (Scheme 2).

A further approach for the synthesis of gepirone is described in the literature (Ί). This strategy, disclosed in EP 0680961, initially involves synthesising (i) a spiranic intermediate (8-(pyrimidin-2-yl)- 5 ,8-diazaspiro [4,5] decan- 5 -ium bromide) (11) from 1- (pyrimidin-2-yl)piperazine (3) and (ii) 1,4-dibromobutane (10), then opening the spiranic compound (11) with the use of potassium 4,4-dimethyl-2,6-dioxopiperidin-l-ide (13), a secondary amine characterised by a high level of nucleophilicity (Scheme 3)

A novel approach to the synthesis of gepirone (I) has now been found, which involves opening spiranic derivative (11) to give 4-(4-(pyrimidin-2-yl)piperazin-l- yl)butan- 1 -amine (5), using suitable nitrogen nucleophile precursors of a primary amino group having the following characteristics: moderate nucleophilicity, so as to prevent reaction by-products, and easy generation of a primary amino group by means of a mild work-up (Scheme 4).

synthesis of gepirone (I) from

8-(pyrimidin-2-yl)-5,8-diazaspiro[4,5]decan-5-ium bromide (11), which is commercially available or easily obtainable by well-known procedures, such as those described in US 4351939.

Spiranic derivative (11) initially undergoes selective opening by suitable nitrogen nucleophile precursors of a primary amino group, such as di-tert-butyl iminodicarboxylate (14) and 2,2,2-trifluoroacetamide (15), in the presence of an organic and/or inorganic base. The opening of spiranic ring (11), followed by a simple, mild acid- base work-up, produces, in a single high-yield synthesis step, the intermediate 4-(4-(pyrimidin-2-yl)piperazin- 1 -yl)butan- 1 -amine (5), which is converted to gepirone (I) by reaction with 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (6) (Scheme 5).

Example 1 – 4-(4-(pyrimidin-2-yl)piperazin- 1 -yl)butan- 1 -amine (5)

10.0 g of 8-(pyrimidin-2-yl)-5,8-diazaspiro[4,5]decan-5-ium bromide (11) (0.0334 moles), obtained according to US 4423049, is suspended in xylene (150 mL). 21.78 g of caesium carbonate (0.0668 moles) is then added. The resulting mixture is heated to 130°C and left under stirring for 60 minutes. 12.7 g of di-tert-butyl iminodicarboxylate (0.0584 moles) is then added and left under stirring until the reaction is complete. The mixture is cooled to about 80°C and filtered under vacuum, and the solid filtrate is washed with xylene (100 mL). 50 mL of 37% HC1 is added to the organic phase, and the resulting mixture is left under stirring for 10 min. The phases are then separated, and the organic phase is washed with a mixture of 50 mL of water and 5 mL of 37% HC1. 130 mL of dichloromethane is added to the aqueous acid phase and basified with 30% NaOH until pH = 13 is reached. The resulting mixture is left under stirring for 10 min., and the phases are separated. The aqueous phase is re-extracted with 200 mL of dichloromethane, and the combined organic phases are washed with 300 mL of water and 50 mL of brine, dried on sodium sulphate, filtered, and finally concentrated under vacuum to give 7.8 g of 4-(4-(pyrimidin-2-yl)piperazin-l-yl)butan-l-amine (5) (orange oil; yield 99%).

¹H NMR (400 MHz, chloroform-d) d 8,17 (d, J = 4,7 Hz, 2H), 6,34 (t, J = 4,7 Hz, 1H), 3,76 – 3,63 (m, 4H), 2,60 (t, J = 6,9 Hz, 2H), 2,46 – 2,32 (m, 4H), 2,32 – 2,21 (m, 2H), 1,53 – 1,24 (m, 6H).

¹³C NMR (101 MHz, chloroform-d) d 161,55, 157,55, 109,65, 58,48, 53,02, 43,57, 42,01, 31,63, 24,18.

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al ^am “EXXUA (gepirone) extended-release tablets, for oral use” (PDF). Mission Pharmacal Company. U.S. Food and Drug Administration. 2023. Archived from the original (PDF) on 28 September 2023. Retrieved 28 September 2023.
^ Jump up to:^a ^b ^c Kishi T, Meltzer HY, Matsuda Y, Iwata N (August 2014). “Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis” (PDF). Psychological Medicine. 44 (11): 2255–2269. doi:10.1017/S0033291713002857. PMID 24262766. S2CID 20830020. Archived from the original (PDF) on 18 February 2019.
^ Jump up to:^a ^b Halbreich U, Montgomery SA (1 November 2008). Pharmacotherapy for Mood, Anxiety, and Cognitive Disorders. American Psychiatric Pub. pp. 375–. ISBN 978-1-58562-821-6.
^ Jump up to:^a ^b ^c ^d ^e “Gepirone – Fabre-Kramer Pharmaceuticals”. AdisInsight. Springer Nature Switzerland AG. Archived from the original on 11 April 2023. Retrieved 28 September 2023.
^ Jump up to:^a ^b ^c ^d ^e Becker Z (28 September 2023). “Decades long regulatory odyssey ends with FDA nod for Fabre-Kramer’s depression med Exxua”. Fierce Pharma.
^ Firth S (30 November 2015). “Controversial Antidepressant Comes Up for FDA OK — Again”. MedPage Today.
^ Kirsch I (2014). “Antidepressants and the Placebo Effect”. Zeitschrift für Psychologie. 222 (3): 128–134. doi:10.1027/2151-2604/a000176. PMC 4172306. PMID 25279271.
^ “FDA Rules Favorably On Efficacy Of Travivo (Gepirone ER) For Treatment Of Major Depressive Disorder”. Fabre-Kramer Pharmaceuticals, Inc. Cision PR Newswire. 17 March 2016.
^ “Gepirone”. Drugs and Lactation Database. National Institute of Child Health and Human Development. 2006. PMID 37856644. Retrieved 11 December 2023.
^ Schatzberg AF, Nemeroff CB (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 494–. ISBN 978-1-58562-309-9.
^ Kaur Gill A, Bansal Y, Bhandari R, Kaur S, Kaur J, Singh R, et al. (July 2019). “Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties”. Drugs of Today. 55 (7): 423–437. doi:10.1358/dot.2019.55.7.2958474. PMID 31347611. S2CID 198911377.
^ “Gepirone ER”. Adis Insight. Archived from the original on 6 August 2016. Retrieved 13 January 2016.
^ “FDA Rules Favorably On Efficacy Of Travivo (Gepirone ER) For Treatment Of Major Depressive Disorder” (Press release). 17 March 2016. Archived from the original on 24 September 2017. Retrieved 23 January 2018.
^ Jump up to:^a ^b Fabre LF, Brown CS, Smith LC, Derogatis LR (May 2011). “Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women”. The Journal of Sexual Medicine. 8 (5): 1411–1419. doi:10.1111/j.1743-6109.2011.02216.x. PMID 21324094.
^ Jump up to:^a ^b Fabre LF, Clayton AH, Smith LC, Goldstein I, Derogatis LR (March 2012). “The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men”. The Journal of Sexual Medicine. 9 (3): 821–829. doi:10.1111/j.1743-6109.2011.02624.x. PMID 22240272.

Robinson DS, Sitsen JM, Gibertini M: A review of the efficacy and tolerability of immediate-release and extended-release formulations of gepirone. Clin Ther. 2003 Jun;25(6):1618-33. doi: 10.1016/s0149-2918(03)80159-5. [Article]
Jenkins SW, Robinson DS, Fabre LF Jr, Andary JJ, Messina ME, Reich LA: Gepirone in the treatment of major depression. J Clin Psychopharmacol. 1990 Jun;10(3 Suppl):77S-85S. doi: 10.1097/00004714-199006001-00014. [Article]
Yocca FD: Neurochemistry and neurophysiology of buspirone and gepirone: interactions at presynaptic and postsynaptic 5-HT1A receptors. J Clin Psychopharmacol. 1990 Jun;10(3 Suppl):6S-12S. [Article]
FDA Approved Drug Products: EXXUA (gepirone) extended-release tablets, for oral use [Link]
Gepirone US Patent Application Publication [Link]
Fabre-Kramer Pharmaceuticals Announces FDA Approval of EXXUA™, the First and Only Oral Selective 5HT1a Receptor Agonist for the Treatment of Major Depressive Disorder in Adults [Link]

Clinical data

Trade names	Exxua
Other names	BMY-13805; MJ-13805; ORG-13011
Routes of administration	By mouth^[1]
ATC code	N06AX19 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Pharmacokinetic data
Bioavailability	14–17%^[1]
Protein binding	72%^[1]
Metabolism	CYP3A4^[1]
Metabolites	3′-OH-gepirone; 1-(2-Pyrimidinyl)piperazine^[1]
Elimination half-life	IRTooltip Instant release: 2–3 hours ERTooltip Modified-release dosage: 5 hours^[1]
Excretion	Urine: 81%^[1] Feces: 13%^[1]
Identifiers
showIUPAC name
CAS Number	83928-76-183928-66-9
PubChem CID	55191
DrugBank	DB12184 DBSALT002148
ChemSpider	4983649835
UNII	JW5Y7B8Z18 80C9L8EP6V
KEGG	D04314
ChEBI	CHEBI:135990
ChEMBL	ChEMBL284092ChEMBL1204187
CompTox Dashboard (EPA)	DTXSID90232813
Chemical and physical data
Formula	C₁₉H₂₉N₅O₂
Molar mass	359.474 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

////////Gepirone, FDA 2023, APPROVALS 2023, Exxua, BMY 13805, MJ 13805, ORG 13011, BMY-13805, MJ-13805, ORG-13011, Gepirona, JW5Y7B8Z18

IGERMETOSTAT

June 11, 2025 2:36 am / Leave a comment

Igermetostat

HEXASODIUM PHYTATE

June 10, 2025 3:04 am / Leave a comment

HEXASODIUM PHYTATE

cas 34367-89-0

myo-Inositol, 1,2,3,4,5,6-hexakis(dihydrogen phosphate) sodium salt (1:6)

hexasodium;[2,3,4,5,6-pentakis[[hydroxy(oxido)phosphoryl]oxy]cyclohexyl] hydrogen phosphate

free form RN: 83-86-3

C₆H₁₂Na₆O₂₄P₆, 791.93

Inositol, hexakis(dihydrogen phosphate) hexasodium salt, myo– (8CI)
myo-Inositol, hexakis(dihydrogen phosphate), hexasodium salt (9CI)
Hexasodium fytate
Hexasodium phytate
SNF 472
UNII-ZBX50UG81V
CSL-525; Hexasodium phytate; Myo-inositol hexaphosphate; SNF-472

x Na salt

14306-25-3

C₆H₁₈O₂₄P₆.xNa

free form : 83-86-3

myo-Inositol, 1,2,3,4,5,6-hexakis(dihydrogen phosphate), sodium salt

(1R,2R,3S,4S,5R,6S)-CYCLOHEXANE-1,2,3,4,5,6-HEXAYL-HEXAKIS(DIHYDROGEN PHOSPHATE)

INOSITOL, HEXAKIS(DIHYDROGEN PHOSPHATE) HEXASODIUM SALT, MYO-

Inositol, hexakis(dihydrogen phosphate) sodium salt, myo– (8CI)
myo-Inositol, hexakis(dihydrogen phosphate), sodium salt (9CI)
Inositol hexaphosphate sodium salt
Phytic acid sodium salt
Sodium inositol hexaphosphate
Sodium phytate

OriginatorLaboratoris Sanifit
DeveloperCSL Vifor; Laboratoris Sanifit
ClassAntineoplastics; Calcium regulators; Cardiovascular therapies; Phosphates; Small molecules; Sodium compounds; Sugar alcohols
Mechanism of ActionUndefined mechanism
Orphan Drug StatusYes – Peripheral arterial disorders; Calciphylaxis
Phase IIICalciphylaxis; Peripheral arterial disorders
09 Nov 2022Phase-III clinical trials in Peripheral arterial disorders in USA (IV) (CSL Behring pipeline, November 2022)
24 Oct 2022Sanifit Therapeutics completes a phase III trial in Calciphylaxis in Belgium, Poland, United Kingdom, Germany, Spain, USA (IV) (NCT04195906)
28 Sep 2022Hexasodium fytate is still in phase III trials for Calciphylaxis in USA (IV) (NCT04195906)
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Hexasodium phytate (also known as SNF472) is a compound being developed as a potential treatment for calciphylaxis, a condition causing skin damage and tissue death in patients with end-stage renal disease. It works by inhibiting the formation and growth of hydroxyapatite crystals, which are implicated in calciphylaxis.

What it is:Hexasodium phytate is the hexasodium salt of myo-inositol hexaphosphate (IP6), a naturally occurring substance found in foods like beans and grains.

How it works:It binds to hydroxyapatite crystals, the main component of vascular calcification, and prevents their growth, potentially disrupting the calciphylaxis process.
Why it’s used:Hexasodium phytate is being investigated as a treatment for calciphylaxis, a serious complication of end-stage renal disease characterized by skin and tissue damage due to calcification of small blood vessels.
Mechanism:It is believed to work by inhibiting the formation and growth of calcium-phosphate crystals (hydroxyapatite) in the blood vessels, thus preventing the calcification that leads to calciphylaxis.
Clinical trials:Clinical trials have demonstrated the safety and potential efficacy of hexasodium phytate in reducing hydroxyapatite crystallization in patients undergoing hemodialysis, providing a basis for its use in treating calciphylaxis.
Intravenous administration:It is administered intravenously during dialysis sessions to achieve supra-physiological plasma concentrations, which are thought to be necessary for its therapeutic effect.
Benefits:It has shown promise in preclinical studies and clinical trials, potentially improving wound healing, pain, and health-related quality of life in patients with calciphylaxis.
Active development:It is currently in active development as a novel experimental drug for the treatment of calciphylaxis and other related conditions.

Phytic acid is a major phosphorus storage compound of most seeds and cereal grains. It has the strong ability to chelate multivalent metal ions, especially zinc, calcium, and iron. Phytic acid is also considered to be a natural antioxidant and is suggested to have potential functions of reducing lipid peroxidation and as a preservative in foods. Clathrin-associated adaprot complex AP-2 has it been suggested may act as one of the receptor sites for Phytic acid. Both in vivo and in vitro experiments have demonstrated striking anticancer (preventive as well as therapeutic) effects of Phytic acid.

SCHEME

contd………

References

WO2022129148

EP4015494

CN114874473

iScience (2022), 25(3), 103950

CN111718463

CN110483240

Uzbekskii Khimicheskii Zhurnal (1995), (5-6), 72-75 JP61056142

////////HEXASODIUM PHYTATE, Hexasodium fytate, Hexasodium phytate, SNF 472, calciphylaxis, UNII-ZBX50UG81V, CSL-525, Hexasodium phytate, Myo-inositol hexaphosphate, SNF-472, ORPHAN DRUG

Ibuzatrelvir

June 9, 2025 3:08 am / Leave a comment

Ibuzatrelvir

PF-07817883

CAS 2755812-39-4

Molecular Weight	489.49
Formula	C₂₁H₃₀F₃N₅O₅

Ibuzatrelvir
N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-[(1S)-1-cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl]-4-(trifluoromethyl)-L-prolinamide
PF 07817883
methyl N-[(2S)-1-[(2S,4R)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-4-(trifluoromethyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate
KZ2X7QH2VT

Ibuzatrelvir (development code PF-07817883) is an experimental antiviral drug being developed by Pfizer for the treatment of COVID-19.^[1] It is a second-generation improvement over nirmatrelvir which has a similar chemical structure.^[2] One of the disadvantages of nirmatrelvir is that it has low metabolic stability and must be given in combination with ritonavir (as Paxlovid) to limit its metabolic degradation in the body.^[3] Ibuzatrelvir incorporates modifications to the chemical structure of nirmatrelvir that give it enhanced oral bioavailability, so it does not require coadministration with ritonavir.^[3]

Ibuzatrelvir (PF-07817883), a second-generation, orally bioavailable, is SARS-CoV-2 main protease (M^pro and 3CL^pro) inhibitor with improved metabolic stability. Ibuzatrelvir has demonstrated pan-human coronavirus antiviral activity and off-target selectivity profile in vitro and in preclinical animal studies. Ibuzatrelvir is well tolerated with a safety profile similar to placebo and prevents viral infection and transmission. Ibuzatrelvir can be used to inhibit COVID-19.

SCHEME

SIDECHAIN

MAIN

PATENT

WO2021250648 PFIZER

WO2023215910

PAPER

The Pfizer scientists described ibuzatrelvir’s medicinal chemistry campaign in a Journal of Medicinal Chemistry paper that was published in April 2024 (DOI: 10.1021/acs .jmedchem.3c02469).

https://pubs.acs.org/doi/10.1021/jacsau.4c00508

Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M^pro) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of M^pro hinders the processing of the proteins essential for viral replication in vivo. However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 M^pro at 2.0 Å resolution. In addition, we show that ibuzatrelvir also potently inhibits the M^pro of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV M^pro. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with M^pro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals.

General Boc-Deprotection and Coupling Procedure
This procedure was based on a literature procedure.1
The Boc-protected building block (1.0
equiv) was dissolved in 50/50 TFA/DCM and stirred for 1 h at room temperature. The reaction
mixture was then concentrated in vacuo and co-evaporated with DCM (5 × 5 mL). In a separate
RBF the carboxylic acid building block (1.0 equiv) and HATU (1.0 equiv) were dissolved in
DMF. HOAt (0.6 M in DMF) (0.1 equiv) and DIPEA (3.0 equiv) were added and the reaction
mixture was left to incubate at room temperature for 10 mins, as it turned yellow. The previously
concentrated Boc-deprotected building block was dissolved in DMF and added dropwise to the
incubating solution. The reaction mixture was capped under a blanket of argon and stirred at room
temperature for 2–3 h. The reaction mixture was diluted with 5 mL each of water and ethyl acetate
and the layers separated. The aqueous layer was extracted further with ethyl acetate (3 × 5 mL),
and all ethyl acetate layers combined and washed with sat. aq. NaHCO3 (10 mL), 1 M HCl (10
mL), water (2 × 10 mL) and brine (10 mL). It was then dried over Na2SO4, filtered, and
concentrated in vacuo to furnish the product.

Methyl ((S)-1-((2S,4R)-2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamoyl)-4-
(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1) Ibuzatrelvir
This known compound was synthesized according to the General Boc-Deprotection and
Coupling Procedure with building blocks 7 and 8. The characterization data matches the literature
report (IPN: WO2021250648A1). The crude material was obtained as a dark yellow sticky residue
that was then purified with flash column chromatography with an eluent of 92:8 EtOAc:MeOH.
The desired compound had an Rf
= 0.40 and was visible with KMnO4 stain. After concentration
of desired fractions, 1 was isolated as a clear, colorless oil that solidified to a white solid (0.051 g,
53%) This compound was isolated and used for all experiments as a mixture of diastereomers in a
ratio of about 2:1 and rotamers present, with only the major set of resonances reported, which are

for the desired isomer. It can be separated using high performance liquid chromatography (HPLC)
methods, as listed in the HPLC Separation of Ibuzatrelvir Diastereomers section.
IR (DCM cast film, vmax / cm–1) 3292, 3053, 2959, 2909, 2875, 1695, 1643, 1550, 1443, 1401,
1370, 1332, 1270, 1236, 1200, 1164, 1130
1H NMR (500 MHz, CDCl3) δH 8.32 (1H, d, J = 7.6 Hz), 6.22 (1H, br), 5.74 (1H, d, J = 9.3 Hz),
4.96 – 4.87 (1H, m), 4.54 (1H, dd, J = 8.6, 3.6 Hz), 4.30 (1H, d J = 9.9 Hz), 3.99 – 3.88 (2H, m),
3.65 (3H, s), 3.42 – 3.26 (2H, m), 2.66 – 2.57 (1H, m), 2.52 – 2.43 (1H, m), 2.40 – 2.28 (3H, m),
1.97 – 1.88 (1H, m), 1.84 – 1.75 (2H, m), 0.99 (9H, s)
13C {1H} NMR (125 MHz, CDCl3) δC 179.1, 171.4, 171.1, 156.9, 126.1 (q, J = 276.3 Hz), 118.3,
59.4, 58.9, 52.4, 47.3, 42.4 (q, J = 29.5 Hz), 40.4, 39.1 37.5, 35.6, 34.2, 28.2, 28.0, 26.3
SR: [α]D
26 = –35.71 (c = 0.21, DCM)
HRMS: (ESI) Calcd for C21H30F3N5NaO5 [M + Na]+
512.2091, found 512.2088

References

^ Allerton CM, Arcari JT, Aschenbrenner LM, Avery M, Bechle BM, Behzadi MA, et al. (August 2024). “A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19”. Journal of Medicinal Chemistry. 67 (16): 13550–13571. doi:10.1021/acs.jmedchem.3c02469. PMC 11345836. PMID 38687966.
^ Chen P, Van Oers TJ, Arutyunova E, Fischer C, Wang C, Lamer T, et al. (August 2024). “A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (M^pro) of SARS-CoV-2 and MERS-CoV”. JACS Au. 4 (8): 3217–3227. doi:10.1021/jacsau.4c00508. PMC 11350714. PMID 39211604.
^ Jump up to:^a ^b Brewitz L, Schofield CJ (July 2024). “Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment”. Journal of Medicinal Chemistry. 67 (14): 11656–11661. doi:10.1021/acs.jmedchem.4c01342. PMC 11284777. PMID 38967233.

Clinical data

Other names	PF-07817883
Routes of administration	Oral
Legal status
Legal status	Investigational
Identifiers
showIUPAC name
CAS Number	2755812-39-4
PubChem CID	163362000
DrugBank	111
ChemSpider	128942571
UNII	KZ2X7QH2VT
Chemical and physical data
Formula	C₂₁H₃₀F₃N₅O₅
Molar mass	489.496 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

[1]. Owen, et al. Preparation of peptidomimetic nitriles as SARS-CoV-2 3CL protease inhibitors and methods for the treatment of COVID-19. World Intellectual Property Organization, WO2021250648 A1. 2021-12-16.[2]. Mahta Mortezavi, et al. Virologic Response and Safety After Oral Administration of Ibuzatrelvir, a Novel SARS-CoV-2 Mpro Inhibitor, in Non-Hospitalized Adults With Symptomatic COVID-19. European Congress of Clinical Microbiology and Infectious Disease (ECCMID) 2024; 2024 April 27-30.[3]. Westberg M, et al. An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations[J]. Sci Transl Med. 2024 Mar 13;16(738):eadi0979.[4]. Allerton CMN, et al. A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19[J]. J Med Chem. 2024 Apr 30. [Content Brief]

////Ibuzatrelvir, PF 07817883, PF-07817883, PF07817883, KZ2X7QH2VT

Golcadomide (CC-99282)

June 7, 2025 9:00 am / Leave a comment

Golcadomide (CC-99282)

Gamcemetinib

June 6, 2025 3:04 am / Leave a comment

Gamcemetinib

CAS 1887069-10-4

CC-99677 , OS2IR8TV1O

Molecular Weight	469.94
Formula	C₂₂H₂₀ClN₅O₃S

(10R)-3-[[2-Chloro-5-(ethoxymethyl)-4-pyrimidinyl]oxy]-9,10,11,12-tetrahydro-10-methyl-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one (ACI)
(10R)-3-{[2-chloro-5-(ethoxymethyl)pyrimidin-4-yl]oxy}-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one
BMS 986371
BMS-986371
CC 99677
CC-99677

(R)-3-((2-Chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one

OriginatorCelgene Corporation
ClassAnti-inflammatories
Mechanism of ActionMAP-kinase-activated kinase 2 inhibitors
Orphan Drug StatusNo

14 Nov 2024Efficacy and adverse events data from a phase II trial in Ankylosing Spondylitis presented at the ACR Convergence 2024 (ACR-2024)
27 Mar 2024Pharmacokinetics and adverse events data from a phase I trial (In volunteers) presented at the 125^th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics 2024 (ASCPT-2024)
26 Oct 2023Discontinued – Phase-I for Inflammation (In volunteers) in USA, United Kingdom (PO) prior to October 2023 (Bristol-Myers Squibb pipeline, October 2023)

Gamcemetinib (CC-99677) is a potent, covalent, and irreversible inhibitor of the mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MK2) pathway in both biochemical (IC₅₀=156.3 nM) and cell based assays (EC₅₀=89 nM). Gamcemetinib is extracted from patent WO2020236636, compound 1.

SCHEME

SIDECHAIN

SIDECHAIN

MAIN

REF

WO2018170203

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018170203&_cid=P11-MBK7CL-38003-1

PATENT

WO2018170199 CELGENE

WO2018170203

US20160075720

WO2020236636, compound 1

US9790235, Number I-82

US9790235, Number I-135

////////////Gamcemetinib, BMS 986371, BMS-986371, CC 99677, CC-99677, OS2IR8TV1O

Alflutinib, Furmonertinib, Firmonertinib

June 3, 2025 3:09 am / Leave a comment

FIRMOMERTINIB, Furmonertinib, Alflutinib

CAS 1869057-83-9

, AST 2818, UNII-A49A7A5YN4

N-[2-[[2-(Dimethylamino)ethyl]methylamino]-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-2-propenamide

N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]prop-2-enamide

C₂₈H₃₁F₃N₈O₂ 568.6 g/mol

2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-

Alflutinib is under investigation in clinical trial NCT03452592 (Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients With T790M).

Firmonertinib is an orally available selective inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Upon administration, firmonertinib specifically binds to and inhibits the tyrosine kinase activity of EGFR T790M, a secondarily acquired resistance mutation. This prevents EGFR T790M-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. EGFR, a receptor tyrosine kinase that is mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. Compared to some other EGFR inhibitors, alflutinib may have therapeutic benefits in tumors with T790M-mediated drug resistance.

FIRMONERTINIB is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 4 investigational indications.

SCHEME

CONTD……..

REF

[US10072002B2]

https://patentscope.wipo.int/search/en/detail.jsf?docId=US201062358&_cid=P22-MBFXFH-62339-1

Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

Step 1: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine

The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 86%. MS m/z: 545 [M+1].

Step 2: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine

The compound was synthesized in the same manner as those in Step 2 of Example 2 with a yield of 56%. MS m/z: 515 [M+1].

Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 23%. MS m/z: 569 [M+1].

¹H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.27 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.28 (t, J=8.5 Hz, 2H), 8.18 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.29-7.14 (m, 3H), 6.98 (s, 1H), 6.28 (d, J=17.1 Hz, 1H), 5.76 (d, J=10.4 Hz, 1H), 5.00 (q, J=9.0 Hz, 2H), 3.89 (s, 3H), 3.61 (s, 2H), 3.28 (s, 2H), 2.80 (s, 3H), 2.73 (s, 6H).

PATENT

CN110606842

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN280196686&_cid=P22-MBFXJY-67679-1

Patent application CN105315259A protects the compound of formula I and discloses its preparation method as follows:

Example 1: Preparation of 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (XI-1)

Add toluene (24.0L) to the reactor, then add 2,6-dichloro-3-nitropyridine (3000g, 15.54mol), adjust the internal temperature between -20℃ and -10℃, and add sodium hydrogen (933g, 23.33mol) in batches. Add 2,2,2-trifluoroethanol (1586g, 16.00mol) toluene (6.0L) solution dropwise. React for 2h, and monitor the reaction end point by TLC and HPLC. After the reaction is completed, add 10% ammonium chloride solution (6.0L) dropwise. Let stand and separate. Wash the organic phase with water (6.0L) and concentrate under reduced pressure. Add ethyl acetate (0.3L), heat to 40-50℃, add n-heptane (2.7L) dropwise, cool to -15 to -5℃ after dripping, and continue crystallization for 3 hours, and filter with suction. Obtain 3017g of product solid, with a yield of 75.65%.

¹H NMR(500MHz，DMSO-d6)δ8.60(d，J＝8.0Hz，1H)，7.50(d，J＝8.5Hz，lH)，5.13(q，J＝9.0Hz，2H)；

¹³C NMR(126MHz，DMSO-d6)δ153.20，151.09，139.34，132.67，123.38(q，J＝277.2Hz)，119.14，63.34(q，J＝36Hz)；

MS m/z：256.99[M+1]。

Example 2: Preparation of 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (X-1)

At room temperature, add acetonitrile (21.0L) and water (21.0L) to the reactor, start stirring, add 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (3017.0g, 11.76mol) obtained in Example 1, and add hydrosulfite (15.1Kg, 70.54mol). Control the temperature at 27-33°C to react for 2 hours. Add 36% concentrated hydrochloric acid (11.9Kg, 117.60mol) dropwise, and continue to react for 1.5 hours. Add solid sodium bicarbonate (12.8Kg, 12.96mol). Filter, separate the mother liquor, wash the organic phase with saturated brine (21.0L), and concentrate under reduced pressure to obtain an oily substance. Theoretically calculated for the next step reaction.

¹H NMR(500MHz，DMSO-d6)δ7.03(d，J＝8.0Hz，1H)，6.90(d，J＝8.0Hz，1H)，5.21(s，2H)，4.93(q，J＝9.0Hz，2H)；

¹³C NMR(126MHz，DMSO-d6)δ148.16，131.72，130.55，123.93(q，J＝278.5Hz)，121.02，118.42，61.72(q，J＝34.0Hz)；

MS m/z：227.01[M+1]。

Example 3: Preparation of 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (IX-1)

At room temperature, dichloromethane (10.4 L) was added to the reaction kettle, stirring was started, 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (2664 g, 11.76 mol) obtained in Example 2 was added, diisopropylethylamine (2279 g, 17.64 mol) was added, the temperature was controlled at -15 to -10°C, a dichloromethane (5.2 L) solution of trifluoroacetic anhydride (2963 g, 14.11 mol) was added dropwise, and stirring was continued for 20 minutes after the addition was completed. Water (13.0 L) was added dropwise, the layers were separated, the organic phase was concentrated under reduced pressure, and the next step reaction was theoretically calculated.

¹ H NMR(400MHz,DMSO-d6)δ11.23(s,7H),7.95(d,J8.0Hz,1H),7.34(d,J8.0Hz,1H),5.03(q,J8.9Hz,2H)

¹³C NMR(101MHz，DMSO-d6)δ155.74(q，J＝46.6Hz)，155.60，145.37，140.24，124.01(q，J＝278.8Hz)，119.07，118.30，116.19(q，J＝289.9Hz)，62.99(q，J＝35.4Hz)；

MS m/z.322.99[M+1]。

Example 4: Preparation of 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (VIII-1)

At room temperature, concentrated sulfuric acid (11.7 L) was added to the reaction kettle, stirring was started, 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (3.9 Kg, 11.76 mol) obtained in Example 3 was added, and potassium nitrate solid (1783.4 g, 17.64 mol) was added in batches. After the addition, stirring was continued for about 40 minutes. After monitoring the reaction, the temperature was lowered to control the internal temperature at 10-25°C, and dichloromethane (27.3 L) was added dropwise. Stirring was continued, stirring was continued for 45 minutes, and the layers were separated. The organic phase was taken and washed once with water (11.7 L). The organic phase was concentrated under reduced pressure and theoretically calculated for the next step reaction.

¹H NMR(500MHz，DMSO-d6)δ11.58(s，1H)，8.78(s，1H)，5.17(q，J＝8.7Hz，2H)；

¹³C NMR(126MHz，DMSO-d6)δ155.89，155.43(q，J＝37.8Hz)，138.84，138.57，135.05，123.22(q，J＝273.4Hz)，118.47，115.51(q，J＝278.5Hz)，63.65(q，J＝35.3Hz)；

MS m/z：367.98[M+1]。

Example 5: Preparation of 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (VII-1)

At room temperature, methanol (13.0 L) was added to the reactor, 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (4322 g, 11.76 mol) obtained in Example 4 was added, p-toluenesulfonic acid monohydrate (3355 g, 17.64 mol) was added, the temperature was controlled at 60-65°C for 15 hours, and the methanol was removed under reduced pressure. Methyl tert-butyl ether (13.0 L) and water (6.5 L) were added, and the pH was adjusted to 7-8 with potassium carbonate. Layering was performed, the organic phase was washed once with water (8.6 L), separated, and concentrated under reduced pressure. n-heptane (21.5 L) was added, the temperature was controlled at 60-65°C and stirred for 1 hour, cooled to room temperature, filtered, and the filter cake was dried with air at 50°C for 18 hours to obtain 1475 g of the product.

The total yield of the five-step reaction from Example 1 to Example 5 is 34.9%.

¹H NMR(500 MHz，DMSO-d6)δ7.62(s，1H)，5.92(s，2H)，5.05(q，J＝8.9Hz，2H).

¹³C NMR(126MHz，DMSO-d6)δ149.30，139.53，132.84，123.46，123.44(q，J＝278.5Hz)，116.25，62.52(q，J＝35.3Hz)；

MS m/z：272.00[M+1]。

Example 6: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (V-1)

Toluene (50 mL) was added to a 100 mL reaction bottle, and the compound of formula VII-1, 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 18.4 mmol), the compound of formula VI, 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (5.8 g, 23.8 mmol), p-toluenesulfonic acid monohydrate (1.8 g, 9.2 mmol) were added in sequence, and the reaction mixture was heated to 110-115°C and reacted for 24 hours. The temperature was lowered to 22°C, filtered by suction, and the filter cake was dried at 50°C for 20 hours to obtain the compound of formula V-1, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 74.7 HPLC area% purity). According to the HPLC purity conversion, the next step reaction was carried out.

¹H NMR(400MHz，DMSO-d6)δ9.43(s，1H)，8.76(s，1H)，8.46-8.45(d，J＝5.4Hz，1H)，8.39(s，1H)，8.38-8.36(d，J＝7.8Hz，1H)，7.57-7.55(d，J＝8.2Hz，1H)，7.41-7.40(d，J＝5.4Hz，1H)，7.31-7.27(t，J＝7.5Hz，1H)，7.20-7.16(t，J＝7.5Hz，1H)，5.23-5.16(q，J＝8.8Hz，2H)，3.90(s，3H)；

MS m/z：479.08[M+1]。

Example 7: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)

Add N,N-dimethylformamide (30 mL) to a 250 mL reaction bottle, add the compound of formula V-1 obtained in Example 6, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 16.22 mmol), stir, add potassium carbonate (4.48 g, 32.44 mol), N,N,N’-trimethylethylenediamine (2.48 g, 24.33 mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (60 mL), and cool to room temperature after addition. Filter by suction, transfer the filter cake to a 50 L reactor, add acetonitrile (40 mL), and heat to reflux for 2 hours. The mixture was cooled to room temperature and filtered with suction. The filter cake was dried at 50°C for 18 hours to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (6.7 g). The total yield of the two-step reaction with Example 6 was 66.8%.

¹H NMR(500MHz，DMSO-d6)δ8.62(s，1H)，8.41(s，1H)，8.26(s，2H)，8.24(s，1H)，7.48(d，J＝8.2Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.16(d，J＝5.3Hz，1H)，7.05(t，J＝7.3Hz，1H)，5.04(q，J＝8.9Hz，2H)，3.84(s，3H)，3.69(t，J＝6.9Hz，2H)，2.89(s，3H)，2.55(t，J＝6.9Hz，2H)，2.17(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ162.15，160.55，156.99，154.98，148.42，137.53，132.83，132.68，125.50，123.58(q，J＝279.7Hz)，124.38，122.11，122.06，120.67，113.38，112.27，110.30，107.11，62.14(q，J＝35.3Hz)，56.10，49.51，45.34，45.33，39.35，32.98。

MS m/z.：545.22[M+1]。

Example 8: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (V-1′)

Toluene (7.43 L) was added to a 20 L reactor, and compound VII-1 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (743.0 g, 2.74 mol), compound VI 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (866.7 g, 3.56 mol), p-toluenesulfonic acid monohydrate (780.7 g, 4.10 mol) were added in sequence, stirred, and the reaction mixture was heated to 110-115°C and reacted for 36 hours. The temperature was controlled at 15-30°C, tetrahydrofuran (3.72 L) was added and stirred for 30 minutes. Filtered by suction, the filter cake was transferred to a 50 L reactor, tetrahydrofuran (4.46 L) was added, and heated to reflux for 3 hours. The temperature was lowered to 15-25°C, filtered, and the filter cake was dried at 50°C for 17 hours to obtain 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1719 g, 85.96 HPLC area% purity). The purity was calculated according to HPLC and used for the next step reaction.

Melting point: 216.0-218.3℃

¹H NMR(500MHz，DMSO-d6)δ9.70(s，1H)，9.21(s，1H)，8.62(s，1H)，8.40(d，J＝6.2Hz，1H)，8.24(d，J＝7.8Hz，1H)，7.59(d，J＝8.3Hz，1H)，7.50(d，J＝6.5Hz，1H)，7.49(d，J＝8.3Hz，2H)，7.32(t，J＝7.6Hz，1H)，7.18(t，J＝7.5Hz，1H)，7.12(d，J＝7.9Hz，2H)，5.17(q，J＝8.8Hz，2H)，3.91(s，3H)，2.29(d，J＝5.2Hz，3H)；

¹³C NMR(126MHz，DMSO-d6)δ166.66，157.35，155.72，147.40，140.87，139.90，139.72，138.59，135.83，130.09，129.99，129.98，129.97，127.39，127.38，127.37，127.15，125.22(q，J＝278.5Hz)，124.97，123.85，123.69，113.63，112.97，110.27，63.58(q，J＝35.3Hz)，35.57，22.81。

Example 9: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)

Add N,N-dimethylformamide (5.14L) to a 50L reactor, add 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1714.0g, 2.261mol) obtained in Example 8, stir, add potassium carbonate (624.7g, 4.52mol), N,N,N’-trimethylethylenediamine (346.2g, 3.39mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (10.28L), and cool to room temperature after adding. Filter by suction, transfer the filter cake to a 50L reactor, add acetonitrile (6.86L), and heat to reflux for 2 hours. The temperature was lowered to 15-25°C, filtered with suction, and the filter cake was dried at 50°C for 18 hours to obtain the compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1142 g). The total yield of the two-step reaction with Example 8 was 76.54%.

MS m/z：545.22[M+1]。

Example 10: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)

Acetonitrile (10 mL) was added to a 50 L reactor, and 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1.0 g, 1.5 mmol) obtained in Example 8 was added, and stirred. Potassium carbonate (577 mg, 3 mmol) and N,N,N’-trimethylethylenediamine (320 mg, 2.25 mmol) were added in sequence. The reaction mixture was heated to 77-82°C and kept for 1-2 hours. Water (10 mL) was added and the temperature was cooled to room temperature after the addition. The product was filtered to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (629 mg) with a purity of 95.94%. The total yield of the two-step reaction with Example 8 was 77%.

Example 11: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

Add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0 g, 7.34 mmol) to a 100 mL reaction bottle at room temperature, add tetrahydrofuran (27 mL) and water (13 mL), and stir for 10 to 20 minutes. Add hydrosulfite (9.6 g, 44.1 mmol) to the reactor in batches. After addition, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 30 to 35 ° C for reaction. The purity of the product compound of formula III’ was 64.68% after sampling the liquid phase after 2 hours of reaction. The reaction was continued until 17 hours after the reaction. 40 mL of water was added to the reaction solution, and the layers were separated by standing. The tetrahydrofuran phase was taken, and the aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed with saturated brine, separated by standing, and concentrated under reduced pressure to obtain 3.2 g of solid with a purity of 62.32%.

¹H NMR(500MHz，DMSO)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，2H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)；

MS m/z：515.24[M+1]。

Example 12: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

In a 100mL single-mouth bottle, there is 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (2.0g, 3.67mmol), palladium carbon (200mg), ethanol (20mL), hydrogen balloon replacement twice, hydrogen gas, magnetic stirring, room temperature overnight (17 hours). After the reaction is completed, suction filtration, the filtrate is taken, and it is concentrated to dryness under reduced pressure to obtain 2.1g of product with a purity of 56.93%.

Example 13: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1317.0 g, 2.42 mol) to a 50 L reactor, add tetrahydrofuran (8.8 L) and water (4.3 L), and stir for 10 to 20 minutes. Add hydrosulfite (2970.0 g, 14.52 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 40-45 ° C and react for 2 hours. Add concentrated hydrochloric acid (5882.2 g, 58.08 mol) to the reactor. After the addition is complete, heat to 42 to 47 ° C and react for 15 hours. Add 30% sodium hydroxide (2323.2g, 58.08mol) aqueous solution dropwise, and then add solid sodium bicarbonate (1219.7g, 14.52mol) in batches to adjust the pH value to 6-8. After stirring for 20 minutes, filter with suction, let the filtrate stand and separate. The organic phase is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine, with a purity of 97.1%. Calculated based on the theoretical yield of 100%, it is directly used in the next step reaction.

MS m/z：515.24[M+1]。

Example 14: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1)

To the 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine obtained in Example 13, THF (5.3 L) and ethanol (4.0 L) were added, the temperature was raised to 50-70°C, and concentrated hydrochloric acid (617.8 g, 6.1 mol) was added dropwise. After the addition was completed, the mixture was cooled to room temperature and stirred for 12 hours. Filtered by suction, the filter cake was dried by air at 50°C to obtain 1507.4 g of a crude product. Methanol (6.0 L) and ethanol (4.5 L) were added to a 20 L reaction bottle, and the above crude product was added, the temperature was raised to 55-60 ° C, hot slurry was added for 1-2 hours, the temperature was lowered to room temperature, and suction was filtered to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1335.6 g), the liquid phase purity was 99.80%, and the total yield of the two-step reaction with Example 13 was 94.0%. Melting point: 236.6-240.8 ° C.

¹H NMR(500MHz，DMSO-d6)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，1H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ166.81，153.27，152.17，150.76，138.61，138.16，138.15，125.46，124.94，123.83(q.J＝278.5Hz)，123.42，123.41，122.60，122.59，120.52，111.34，111.17，106.29，62.14(q，J＝35.3Hz)，53.53，46.28，42.27，42.26，40.92，33.67。

Example 15: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1)

At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1136.0 g, 2.09 mol) to a 50 L reactor, add acetonitrile (7.95 L) and water (7.95 L), and stir for 10 to 20 minutes. Add hydrosulfite (2563.9 g, 12.50 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 35 to 40 ° C and react for 3 hours. Add concentrated hydrochloric acid (2505.3 g, 25.08 mol) to the reactor. After the addition is complete, heat to 35 to 45 ° C and react for 18 hours. 30% sodium hydroxide (1003.2 g, 25.08 mol) aqueous solution was added dropwise to adjust the pH value to 6-8. Solid sodium bicarbonate (1053.5 g, 12.54 mol) was added to adjust the pH value to 7-8. After stirring for 40 minutes, the mixture was filtered, the filtrate was allowed to stand, the layers were separated, and the organic phase was concentrated under reduced pressure. The purity of the liquid phase was detected to be 97.60%.

Add ethanol (5.68 L) to the product of the previous step, raise the temperature to 50-70°C, and drop concentrated hydrochloric acid (522 g, 5.23 mol). After the dropwise addition is completed, cool to room temperature and stir for 15 hours. Filter by suction, and air dry the filter cake at 50°C to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (780 g), with a liquid phase purity of 98.74%.

Example 16: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1)

2-[2-(Dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1543.5 g, 2.63 mol) was added to a 50 L reactor, and dichloromethane (13.1 L) and triethylamine (532.2 g, 5.26 mol) were added. The mixture was stirred and cooled to -10 to -5 °C, and a solution of 3-chloropropionyl chloride (501.5 g, 3.95 mol) in dichloromethane (10.0 L) was added dropwise. After the addition is completed, keep warm and stir for 10 to 20 minutes, filter with suction, and the filter cake is formula II-12-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride wet product (2683.5g), which is calculated based on the theoretical yield of 100% and is directly used in the next reaction.

Melting point: 233.2-238.7℃

¹H NMR(500MHz，DMSO-d6)δ10.18(s，1H)，8.57(s，1H)，8.42(s，1H)，8.27(t，J＝6.6Hz，2H)，8.17(s，1H)，7.51(d，J＝8.1Hz，1H)，7.26-7.22(m，1H)，7.22-7.17(m，2H)，4.99(q，J＝9.1Hz，2H)，3.91(d，J＝6.3Hz，2H)，3.89(s，3H)，3.55(s，2H)，3.13(s，2H)，3.02(t，J＝6.1Hz，2H)，2.85(s，3H)，2.64(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ168.41，161.88，160.22，157.34，148.05，146.73，137.62，133.25，130.86，125.43，124.09(q，J＝279.2Hz)，122.04，121.74，120.88，118.51，116.60，112.33，110.40，107.09，61.65(q，J＝35.3Hz)，54.90，40.96，40.95，40.60，38.71，32.96，32.95，32.94。

Example 17: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

The wet product (2683.5 g) of Formula II 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 16 was added to a 20L reactor, and acetonitrile (16.8L) and triethylamine (1329.3g, 13.15mol) were added, stirred, and heated to reflux for 4 hours. Cooled to room temperature, purified water (4.20L) was added, stirred at room temperature for 3-4 hours, and filtered. The filter cake was transferred to a 50L reactor, dichloromethane (17L) was added, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution (17L). Liquid separation, the organic phase was transferred to a 20L reactor, activated carbon (84.3g) was added, refluxed for 1 hour, cooled to 20-30°C, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the compound of formula I 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1390g), with a total yield of 92.9% and a purity of 99.21% for the two-step reaction with Example 16.

¹H NMR(500MHz，DMSO-d6)δ9.96(s，1H)，8.71(s，1H)，8.44(s，1H)，8.29(d，J＝5.3Hz，1H)，8.26(d，J＝7.7Hz，1H)，8.13(s，1H)，7.51(d，J＝8.2Hz，1H)，7.24(t，J＝7.2Hz，1H)，7.20(d，J＝5.3Hz，1H)，7.15(t，J＝7.2Hz，1H)，6.51(dd，J＝17.0，10.2Hz，1H)，6.28(dd，J＝17.0，1.8Hz，1H)，5.78(dd，J＝10.2，1.8Hz，1H)，5.00(q，J＝9.1Hz，2H)，3.89(s，3H)，3.18(t，J＝6.5Hz，2H)，2.87(s，3H)，2.48(t，J＝6.5Hz，2H)，2.22(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ163.40，161.84，160.26，157.35，148.07，147.15，137.60，133.23，131.61，130.07，126.67，125.41，124.03(q，J＝278.5Hz)，122.00，121.68，120.80，118.39，116.13，112.36，110.37，107.02，61.29(q，J＝35.3Hz)，56.57，52.44，45.60，45.59，38.54，32.93；

MS m/z：569.25[M+1]。

Example 18: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (20.0 g, 36.73 mmol) to a 1L reaction bottle, add tetrahydrofuran (134 mL) and water (66 mL), and stir for 10 to 20 minutes. Add hydrosulfite (47.9 g, 220.38 mmol) to the reaction bottle in batches. After addition, continue stirring for 10 to 20 minutes. Control the internal temperature to 35-40°C and react for 3 hours. Add concentrated hydrochloric acid (89.3 g, 881.52 mmol) to the reaction bottle. After the addition is complete, heat to 42 to 47°C and react for 17 hours. 30% sodium hydroxide (35.26 g, 881.52 mmol) aqueous solution was added dropwise, and solid sodium bicarbonate (18.5 g, 220.38 mmol) was added in batches to adjust the pH value to 6-8. After stirring for 30 minutes, the mixture was filtered, and the filtrate was allowed to stand and separated. The organic phase was concentrated to dryness under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (19.2 g) with a purity of 95.8% and a yield of 97.12%.

Example 19: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1)

Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5 g, 9.72 mmol) to a 250 mL reaction bottle, add dichloromethane (42 mL), stir, protect with argon, cool to -5 to 0°C, and add 3-chloropropionyl chloride (1.851 g) and dichloromethane (33 mL) dropwise. After the addition is complete, the mixture is stirred for 10-20 minutes at a temperature maintained at room temperature. After the reaction is complete, the mixture is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (7.0 g) with a purity of 85.67%. Melting point: 233.5-238.9°C.

Example 20: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

The 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 19 was added to a 250 mL reaction bottle, and acetonitrile (45 mL) and triethylamine (4.9 g) were added. The mixture was stirred magnetically and protected by argon. The temperature was raised to reflux in an oil bath. The reaction was allowed to react for 6 h. Water (23 mL) was added dropwise, and the mixture was naturally cooled to room temperature in an oil bath. The mixture was filtered with suction, and the filter cake was transferred to a 500 mL reaction bottle. Dichloromethane (100 mL) was added, and the pH value was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution (100 mL). The liquids were separated and the organic phase was concentrated under reduced pressure. The solid was dried in an oven at 50°C to give 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.1 g) with a purity of 97.7%. The total yield of the two-step reaction with Example 19 was 74.17%.

Comparative Example 1: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1 g, 1.94 mmol) was added to a 50 mL multi-necked flask, tetrahydrofuran (10 mL) was used as the solvent, argon was replaced three times, and stirring was maintained at 0-5°C under argon protection, and 3-chloropropionyl chloride (0.37 g, 2.92 mmol), the addition was completed in 15 minutes, and the mixture was stirred at 0-5°C for 1 hour. Sodium hydroxide (0.31 g, 7.77 mmol) and water (1 mL) were added to the reaction solution, and the temperature was raised to 65°C and stirred for 15 hours. Saturated ammonium chloride solution (10 mL) was added, and the liquids were separated. The organic phase was washed with saturated sodium bicarbonate solution (10 mL). The liquids were separated and the organic phase was concentrated to dryness to obtain 1.04 g of a yellow solid with a yield of 94.9% and a purity of 87.35%.

Comparative Example 2: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g) to a 250 mL reaction bottle, add acetone (50 mL) and potassium carbonate (940 mg), stir, protect with argon, cool to -50°C, and add 3-chloropropionyl chloride (1.481 g) dropwise. After the addition is completed, the temperature is raised to -20°C and stirred for 30 minutes. A solution of sodium hydroxide (350 mg) and water (60 ml) is added dropwise over 10 minutes. The mixture is stirred at room temperature for 3 to 4 hours. The mixture is filtered and the filter cake is dried in an oven at 50°C to obtain a compound of formula II-1′, 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) with a purity of 64.18%.

¹H NMR(400MHz，DMSO-d₆)δ10.32(s，1H)，10.21(s，1H)，8.54(s，1H)，8.43(s，1H)8.29-8.28(d，J＝5.1Hz，1H)，8.28-8.26(d，J＝6.2Hz，1H)，8.19(s，1H)，7.54-7.52(d，J＝8.0Hz，1H)，7.27-7.18(m，3H)，5.77(s，2H)，5.00(q，J＝9.1Hz，1H)，3.92(t，J＝6.2Hz，1H)，3.63(t，J＝5.7Hz，2H)，3.28(t，J＝5.7Hz，2H)，3.06-3.03(t，J＝6.2Hz，2H)，2.85(s，3H)，2.74(s，6H).

MS m/z：605.23[M+1]。

Add 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) to a 250 mL reaction bottle, add acetonitrile (45 ml) and triethylamine (3.606 g), stir magnetically, protect with argon, heat in an oil bath to reflux, and react for 6 h. Water (23 ml) was added dropwise, the temperature was naturally lowered in an oil bath and stirring was continued overnight (16 h), filtered with suction, and the solid was dried to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.3 g) with a purity of 95.13% and a two-step yield of 59.42%.

Example 21: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

The crude product (1390 g) of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine was transferred to a 50L reactor, acetone (25.0L) was added, argon was replaced 3 times, the temperature was raised to 45-50°C, all the solids were dissolved, and purified water (6.95L) was added dropwise. After the addition was completed, the mixture was cooled to 20-25°C and stirred for 2 hours. The mixture was filtered and the filter cake was vacuum dried at 50°C for 24 hours to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (895g). The reaction yield is 66.7% and the purity is 99.89%.

Example 22: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath to dissolve all the solids, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.1g) with a purity of 99.73% and a yield of 62.0%.

Example 23: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 150mL of n-heptane. After the drop is complete, cool to 25°C in an oil bath, filter by suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.32% and a yield of 80%.

Example 24: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and drop 25mL of water. After dripping, naturally cool to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.3g), with a purity of 99.64% and a yield of 86%.

Example 25: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and continue to stir for 30min. Cool naturally to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.45% and a yield of 80%.

Example 26: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 20mL of tetrahydrofuran, heat in an oil bath to 45-50°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 40mL of n-heptane dropwise. After the addition was completed, the mixture was naturally cooled to 25°C in an oil bath, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.23 g) with a purity of 99.51% and a yield of 84.6%.

Example 27: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of isopropanol, heat to 50°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 22°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.25g), with a purity of 99.51% and a yield of 85%.

Example 28: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 75mL of methanol, and heat to 55-60°C in an oil bath to dissolve all the solids. Cool naturally to 17°C in the oil bath, stir overnight, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.55g), with a purity of 99.63% and a yield of 71%.

Example 29: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 50mL of dichloromethane, heat in an oil bath to 40°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 100mL of n-heptane dropwise. The mixture was naturally cooled to 15°C in an oil bath, stirred overnight, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.78 g) with a purity of 99.56% and a yield of 75.6%.

Example 30: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of toluene, heat to 65°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.27g), with a purity of 99.57% and a yield of 65.4%.

Example 31: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add DMF50mL, heat to 80°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 25mL of water. Naturally cool to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.84g), with a purity of 99.77% and a yield of 76.8%.

Example 32: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 25 mL single-necked bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (6 mL), protect with argon, heat in an oil bath to 40-45°C until all the solution is dissolved, continue to stir and keep warm for 30 min, cool naturally to 22°C in an oil bath, filter and obtain a solid. The solid was transferred to a crystallization dish and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (622 mg) with a purity of 99.83% and a yield of 62.2%.

Example 33: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add acetone (15 mL), protect with argon, heat in an oil bath to 45-50° C. until all the solution is dissolved, and then continue to stir and keep warm for 30 min, cool naturally to 22° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (537 mg) with a purity of 99.83% and a yield of 53.7%.

Example 34: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (8 mL), protect with argon, heat in an oil bath to 40-45° C. until all the solution is dissolved, and continue to stir and keep warm for 30 min. Add water (16 mL) dropwise, cool naturally to 21° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (880 mg) with a purity of 99.68% and a yield of 88.0%.

Example 35: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add ethanol (35 mL), protect with argon, heat in an oil bath to 75-80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (915 mg), with a yield of 91.5% and a purity of 99.49%.

Example 36: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add xylene (20 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (798 mg), with a yield of 79.8% and a purity of 99.48%.

Example 37: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethanol 125mL, heat in an oil bath to 75-80°C to dissolve all the solids, continue to stir and keep warm for 30min, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.7g) with a purity of 99.66% and a yield of 74%.

Example 38: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add methanol (35 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (912 mg), with a yield of 91.2% and a purity of 99.53%.

PATENT

CN110606842

WO2019238103

PAPER

https://www.nature.com/articles/s41401-020-0389-3

NCT Number	Sponsor	Condition	Start Date	Phase
NCT02973763	Allist Pharmaceuticals, Inc.	NSCLC	December 30, 2016	Phase 1
NCT03787992	Allist Pharmaceuticals, Inc.	Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non-small Cell Lung Cancer	May 30, 2019	Phase 3
NCT03452592	Allist Pharmaceuticals, Inc.	Advanced NSCLC Patients With T790M	April 30, 2018	Phase 2

[1]. Y. Shi, et al. P2.03-028 Third Generation EGFR Inhibitor AST2818 (Alflutinib) in NSCLC Patients with EGFR T790M Mutation: A phase1/2 Multi-Center Clinical Trial.[2]. Alexander I. Spira, et al. FURVENT: Phase 3 trial of furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations (FURMO-004). Journal of Clinical Oncology. Volume 42, Number 16_suppl.

/////////FIRMOMERTINIB, Furmonertinib, Alflutinib, AST 2818, UNII-A49A7A5YN4, PHASE 2, CANCER

Firibastat

June 2, 2025 10:07 am / Leave a comment

Firibastat

Lotilaner

May 31, 2025 2:58 am / Leave a comment

Lotilaner

CAS 1369852-71-0
Credelio
XDEMVY
lotilanerum
596.8 g/mol, C₂₀H₁₄Cl₃F₆N₃O₃S
TP 03
TP-03
TP03

3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]thiophene-2-carboxamide

FDA Xdemvy, 7/25/2023, To treat Demodex blepharitis
Drug Trials Snapshot

Lotilaner, sold under the brand name Xdemvy, is an ectoparasiticide (anti-parasitic) medication used for the treatment of blepharitis (inflammation of the eyelid) caused by infestation by Demodex (tiny mites).^[1]^[7] It is used as an eye drop.^[1]

It was approved for medical use in the United States in July 2023.^[1]^[7]^[8]^[9] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[10]

SYN

https://patents.google.com/patent/WO2022016490A1/en

Scheme 1

Scheme 1 depicts coupling the compound of formula (5) with an appropriate amine to give lotilaner. An appropriate amine refers to either 2-amino-2′, 2′, 2′-trifluoroethyl-acetamide or the sequential reaction of glycine optionally carboxyl protected, followed by coupling with 2, 2, 2-trifluorethylamine. Such coupling reactions of carboxylic acids or activated carboxylic acid derivatives such as acid halides with amines to form amides are well known in the art. The use of carboxyl protected glycine, deprotection, and an amide coupling with 2, 2, 2-trifluorethylamine is likewise readily accomplished. See WO 2010/070068 and WO 2014/090918.

Example 1

(5S) -3- (5-Bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H- isoxazole

Combined (Z/E) 1- (5-bromo-4-methyl-2-thienyl) -4, 4, 4-trifluoro-3- (3, 4, 5-trichlorophenyl) but-2-en-1-one (50.0 g, 104.5 mmol) and (R) – [ (2S) -1- [ [3, 5-bis (tert-butyl) phenyl] methyl] -5-vinyl-quinuclidin-1-ium-2-yl] – (6-methoxy-4-quinolyl) methanol bromide (0.11 eq. ) in dichloromethane (100 mL) and ethyl t-butyl ether (400 mL) . The reaction mixture was stirred at 30℃ for 30 minutes and then cooled to the range of-20℃ then slowly added a solution of hydroxylamine in water (50%, 40 mL, 313 mmol, 3.0 eq. ) and sodium hydroxide (34.5 mL, 345 mmol, 10 M, 3.3 eq. ) maintaining an internal temperature in the range of-15℃ to-20℃. After stirring 18 hours at-15℃ to-20℃ aqueous hydrochloric acid (1N, 500 mL) was added and the reaction mixture was stirred at 15℃ to 20℃ then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was extracted with aqueous hydrochloric acid (1N, 75 mL) , the layers separated and the organic layer again extracted with aqueous hydrochloric acid (1N, 100 mL) . The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (75 mL) and the layers were separated and again the organic layer was extracted with saturated aqueous sodium bicarbonate (100 mL) . The layers were separated and the organic layer was dried over sodium sulfate (10 g) . The organic layer was filtered, the cake washed with ethyl t-butyl ether (50 mL) and then montmorillonite clay (50 g) was added and the mixture was stirred at 10℃ to 20℃. After 2 hours the reaction mixture was filtered, the cake rinsed with ethyl t-butyl ether (50 mL) and the filtrate was concentrated to about 100 mL, twice added THF and concentrated again to about 100 mL, and then added THF (150 mL) to obtain the title compound as a solution in THF. The solution was evaluated by chiral HPLC which indicated 96.5%S-isomer and 3.5%R-isomer.

Example 2

3-Methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3- yl] thiophene-2-carboxylic acid

A 22%solution of (5S) -3- (5-bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazole (185.0 g, 374.8 mmol) in THF was cooled to 0℃ to 5℃. A solution of ethyl magnesium chloride in THF (2 M, 300 mL, 1.6 eq) was added dropwise maintaining an internal temperature below 10℃. The reaction mixture was stirred at 15℃ to 20℃ for 2 to 4 hours. Then carbon dioxide gas (58 g, 3.5 eq) was introduced subsurface at 0℃ to 5℃ after passing through concentrated sulfuric acid (50 mL) . The reaction mixture was stirred at 0℃ to 5℃ for 2 hours and an 8%aqueous sodium chloride solution (601 g) was added dropwise at below 10℃, followed by addition of 37%aqueous HCl solution (92.5 g) at below 0℃. The reaction mixture was stirred at 10℃ to 15℃ for 30 minutes then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was concentrated to about 370 mL under vacuum, followed by three iterations of THF (1850 mL) addition and concentration under vacuum to about 370 mL to 555 mL. After confirming the reaction mixture was dry, three cycles of acetonitrile (925 mL) addition followed by vacuum concentration to about 555 mL to 740 mL were performed. The reaction mixture was heated to 75℃ and gradually cooled to 50℃ over one hour. Product seeds (1.85 g) were added at 50℃ and the reaction mixture was stirred at 50℃ for 30 minutes. The batch was gradually cooled to-10℃ over three hours and kept at-10℃ for two hours. The batch was filtered and the cake was washed with cold acetonitrile (93 to 185 mL) . 110 g of the title compound was obtained after drying the wet cake at 50℃ under vacuum for 12 hours. The product was evaluated by chiral HPLC which indicated>99.9%S-isomer.

Above-referenced product seeds were prepared as follows. A solution of (5S) -3- (5-bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazole (48.93 g, 99.1 mmol) in 300mL of THF was cooled to 0℃ to 5℃. A solution of ethyl magnesium chloride in THF (2 M, 80 mL) was added dropwise maintaining an internal temperature below 10℃. The reaction mixture was stirred at 15℃ to 20℃ for 2 to 4 hours. Then carbon dioxide gas (25 g, 3.5 eq) was introduced subsurface at 0℃ to 5℃ after passing through concentrated sulfuric acid (50 mL) . The reaction mixture was stirred at 0℃ to 5℃ for 6 hours and an 5%aqueous sodium chloride solution (157 g) was added dropwise at below 10℃, followed by addition of 37%aqueous HCl solution (25 g) at below 0℃. The reaction mixture was stirred at 10℃ to 15℃ for 30 minutes then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was concentrated to remove the solvent. 50ml of heptane was added into the mixture then removed the solvent. The crude product was dissolved in 50mL of EA and 100mL of heptane at 40℃. Additional 1000mL of heptane was charged dropwise into the mixture slowly. Then the mixture was stirred at 40℃ for 15h. The mixture was filtered and the wet cake was obtained. The wet cake was slurried by acetone at 20℃. The mixture was filter and the wet cake was dried at 50℃ under vacuum for 3h to afford 9.7g of product. The product was evaluated by chiral HPLC which indicated>99.9%S-isomer.

Example 3

3-Methyl-N- [2-oxo-2- (2, 2, 2-trifluoroethylamino) ethyl] -5- [ (5S) -5- (3, 4, 5-trichlorophenyl) – 5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxamide

A solution of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid (101.5 g, 221.3 mmol) in DCM (1000 mL) was heated to 40℃. Thionyl chloride (50 g, 1.9 eq) was added dropwise and the reaction mixture was stirred at reflux for 2 to 4 hours. The reaction mixture was concentrated to 100 to 200 mL and DCM (500 mL) was added. Two more cycles of concentration followed by DCM addition were performed. In a separate vessel, a suspension of 2-amino-trifluoroethyl-acetamide HCl (50.26 g, 1.2 eq) in DCM (500 mL) was cooled to 0℃ to 5℃, triethylamine (70.15 g, 3.1 eq) was added, and the reaction mixture was stirred at 0℃ to 5℃ for 30 minutes. The acid chloride solution in DCM was then transferred to the reaction mixture containing 2-amino-trifluoroethyl-acetamide maintaining the internal temperature below 5℃. The reaction mixture was stirred at 0℃ to 5℃ for 2 to 4 hours. 1 N HCl (500 mL) was added dropwise and the reaction mixture was stirred at 15 to 25℃ for 30 minutes. The stirring was stopped and after 30 minutes the phases were separated. The organic layer was extracted with saturated sodium bicarbonate solution (1N, 1000 mL) , the layers separated and the organic layer extracted with water (1000 mL) . The layers were separated and the organic layer was concentrated under vacuum to 200 to 300 mL. Twice ethyl acetate (500 mL) was added and the batch was concentrated to 200 mL. The reaction mixture was heated to 55℃ and n-heptane (700 mL) was added dropwise at 55℃. Product seeds (1.0 g) was added and the reaction mixture was stirred at 55℃ for one hour. n-Heptane (1000 mL) was added dropwise and the mixture was stirred at 55℃ for three hours. The batch was gradually cooled to 35℃ over three hours, then to 20℃ over three hours. The batch was filtered and the cake was washed with n-heptane (200 mL) . 113 g of the title compound was obtained after drying at 50℃ under vacuum for 12 hours.

Above-referenced product seeds are prepared as follows. The crude product was dissolved in 7.9 wt-parts of cumene to obtain a solution at<150℃. Then 2.3 wt-parts of heptanes was added to the hot solution until slight haze was observed. The heating was turned off and the mixture was cooled to ambient temperature and stirred overnight. The desired polymorph G was obtained as powder after filtration and drying under vacuum, which was used as seeds to induce crystallization of polymorph G in future batches.

PATENT

https://patents.google.com/patent/WO2017176948A1/en

PATENT

CN112457267

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN320823634&_cid=P10-MBBMZO-15915-1

REFSatish Kumar RangarajuSatish Kumar Rangaraju •

The first FDA-approved treatment for Demodex Blepharitis, a common eyelid disease caused by microscopic mites living in the eyelashes’ hair follicles. hashtag#Lotilaner
For more information blog:
https://lnkd.in/gFTeKEtv

Research

Tarsus Pharmaceuticals has conducted phase II studies of lotilaner as a remedy to prevent tick bites in humans.^[16]^[11]

References

^ Jump up to:^a ^b ^c ^d ^e “Xdemvy- lotilaner ophthalmic solution solution/ drops”. DailyMed. 26 July 2023. Retrieved 23 August 2023.
^ Jump up to:^a ^b ^c “Credelio- lotilaner tablet, chewable”. DailyMed. Archived from the original on 5 August 2021. Retrieved 4 August 2021.
^ Jump up to:^a ^b ^c “Credelio- lotilaner tablet, chewable”. DailyMed. Archived from the original on 5 August 2021. Retrieved 4 August 2021.
^ Jump up to:^a ^b “Credelio EPAR”. European Medicines Agency (EMA). 17 September 2018. Archived from the original on 27 January 2022. Retrieved 4 August 2021.
^ Jump up to:^a ^b ^c “Lotimax EPAR”. European Medicines Agency. 13 March 2024. Retrieved 20 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Lotimax Product information”. Union Register of veterinary medicinal products. 29 April 2024. Retrieved 29 August 2024.
^ Jump up to:^a ^b “Novel Drug Approvals for 2023”. U.S. Food and Drug Administration (FDA). 25 July 2023. Archived from the original on 21 January 2023. Retrieved 5 August 2023.
^ “Xdemvy: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Archived from the original on 27 July 2023. Retrieved 5 August 2023.
^ “FDA Approves Xdemvy (lotilaner ophthalmic solution) 0.25% for the treatment of Demodex blepharitis” (Press release). Tarsus Pharmaceuticals. 25 July 2023. Retrieved 5 August 2023 – via GlobeNewswire.
^ New Drug Therapy Approvals 2023. U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original (PDF) on 10 January 2024. Retrieved 9 January 2024.
^ Jump up to:^a ^b ^c “A Pill That Kills Ticks Is a Promising New Weapon Against Lyme Disease”. Wired. 15 March 2024. Retrieved 17 March 2024.
^ Jump up to:^a ^b “Lotimax PI”. Union Register of medicinal products. 29 April 2024. Retrieved 17 June 2024.
^ Kuntz EA, Kammanadiminti S (November 2017). “Safety evaluation of lotilaner in dogs after oral administration as flavoured chewable tablets (Credelio)”. Parasites & Vectors. 10 (1): 538. doi:10.1186/s13071-017-2468-y. PMC 5664904. PMID 29089043.
^ “Freedom Of Information Summary, Supplemental New Animal Drug Application, NADA 141-494, Credelio, Lotilaner, Chewable Tablets, Dogs”. 3 September 2019. Archived from the original on 18 May 2022. Retrieved 1 December 2019.
^ Jump up to:^a ^b “Credelio Plus EPAR”. European Medicines Agency. 19 February 2021. Archived from the original on 7 December 2022. Retrieved 4 August 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Tarsus Announces Positive Topline Results from Carpo, a Phase 2a Proof-of-Concept “Tick-Kill” Trial Evaluating TP-05 (lotilaner) for the Prevention of Lyme Disease (press release)”. Tarsus Pharmaceuticals. 22 February 2024. Archived from the original on 17 March 2024. Retrieved 17 March 2024.

Clinical data

Trade names	Credelio, Xdemvy, others
Other names	TP-03
AHFS/Drugs.com	Monograph
License data	US DailyMed: Lotilaner
Routes of administration	By mouth, eye drops
Drug class	Antiparasitic
ATC code	S01AX25 (WHO) QP53BE04 (WHO)
Legal status
Legal status	US: ℞-only^[1]^[2]^[3]EU: Rx-only^[4]^[5]^[6]
Identifiers
showIUPAC name
CAS Number	1369852-71-0
PubChem CID	76959255
DrugBank	DB17992
ChemSpider	32699771
UNII	HEH4938D7K
KEGG	D11212
ChEBI	CHEBI:229657
ChEMBL	ChEMBL3707310
CompTox Dashboard (EPA)	DTXSID701027551
Chemical and physical data
Formula	C₂₀H₁₄Cl₃F₆N₃O₃S
Molar mass	596.75 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

Toutain CE, Seewald W, Jung M: Pharmacokinetics of lotilaner following a single oral or intravenous administration in cats. Parasit Vectors. 2018 Jul 13;11(1):412. doi: 10.1186/s13071-018-2966-6. [Article]
Rufener L, Danelli V, Bertrand D, Sager H: The novel isoxazoline ectoparasiticide lotilaner (Credelio): a non-competitive antagonist specific to invertebrates gamma-aminobutyric acid-gated chloride channels (GABACls). Parasit Vectors. 2017 Nov 1;10(1):530. doi: 10.1186/s13071-017-2470-4. [Article]
Lamassiaude N, Toubate B, Neveu C, Charnet P, Dupuy C, Debierre-Grockiego F, Dimier-Poisson I, Charvet CL: The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis. PLoS Pathog. 2021 Feb 18;17(2):e1008863. doi: 10.1371/journal.ppat.1008863. eCollection 2021 Feb. [Article]
FDA Approved Drug Products: XDEMVY (lotilaner) 0.25%, Ophthalmic Solution (July 2023) [Link]
Business Wire: FDA Approves XDEMVY™ (lotilaner ophthalmic solution) 0.25% for the treatment of Demodex blepharitis [Link]
EMA Medicines Overview: Credelio [Link]

///////////Lotilaner, Xdemvy, FDA 2023, APPROVALS 2023, Credelio, XDEMVY, lotilanerum

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Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine

Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine

Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

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Step 1: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine

Step 2: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine