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WO2025080631A1 - Procédé de fabrication d'un inhibiteur de kras g12c - Google Patents

Procédé de fabrication d'un inhibiteur de kras g12c Download PDF

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Publication number
WO2025080631A1
WO2025080631A1 PCT/US2024/050451 US2024050451W WO2025080631A1 WO 2025080631 A1 WO2025080631 A1 WO 2025080631A1 US 2024050451 W US2024050451 W US 2024050451W WO 2025080631 A1 WO2025080631 A1 WO 2025080631A1
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Prior art keywords
fluoro
pharmaceutically acceptable
cancer
compound
inhibitor
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English (en)
Inventor
Lee J. BURNS
Kevin P. Cole
Xueqian Gong
David Michael HYMAN
Douglas P. Kjell
Ryan J. LINDER
Sheng-Bin Peng
Chong Si
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Eli Lilly and Co
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Eli Lilly and Co
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Publication of WO2025080631A1 publication Critical patent/WO2025080631A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to processes that can be used to prepare the compound of Formula I, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compound of Formula I, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis.
  • the compound of Formula I and pharmaceutical compositions can be used to treat cancer.
  • WO 2021/118877 discloses certain KRas G12C inhibitors, or salts thereof, that can be used to treat cancer. Methods of preparing these compounds are also disclosed. The methods disclosed in the ‘877 reference use a phosphate buffer. These methods result in greater quantities of impurities than desired.
  • impurities include, in greater quantities than desired, a Michael adduct impurity, 4-[(13aS)- 2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-10-chloro-8-fluoro-6- oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-2-yl]-3-oxo-propyl]- 10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-9- yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M,M atropisomer, , which can be difficult to remove.
  • a Michael adduct impurity 4-[(13aS)- 2-[
  • a method of preparing a compound of the formula, , or a pharmaceutically acceptable salt thereof comprising: combining citrate buffer, an acryloyl group, and 4-[(13aS)-10-chloro-8-fluoro-6- oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, M atropisomer, .
  • a pharmaceutical composition comprising a compound of the formula, , or a a Michael adduct impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-10-chloro-8- fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-2-yl]-3-oxo- propyl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M,M atropisomer, , an as Analysis, and a pharmaceutically acceptable carrier, dilu
  • the cancer is advanced non-small cell lung cancer, pancreatic cancer, or colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the present disclosure comprises a method of treating cancer, comprising administering to a patient in need thereof, a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis.
  • the cancer is non-small cell lung carcinoma.
  • the cancer is colorectal carcinoma.
  • the cancer is mutant pancreatic cancer.
  • pembrolizumab is dosed (or administered) 200 mg once every three weeks. In an embodiment, pemetrexed is dosed (or administered) 500 mg/m2 once every three weeks. In an embodiment, cisplatin is dosed (or administered) 75 mg/m2 once every three weeks. In an embodiment, pemetrexed and cisplatin are administered on the same day. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, cisplatin is administered for up to four cycles. In an embodiment, the patient in need thereof is treatment na ⁇ ve to KRAS G12Ci, PD-1, or PD-L1 therapy.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and cisplatin in the treatment of KRAS G12C-mutant advanced NSCLC.
  • pembrolizumab is dosed (or administered) 200 mg once every three weeks.
  • pemetrexed is dosed (or administered) 500 mg/m2 once every three weeks.
  • cisplatin is dosed (or administered) 75 mg/m2 once every three weeks.
  • pemetrexed and cisplatin are administered on the same day.
  • pembrolizumab is administered for up to thirty-five cycles.
  • cisplatin is administered for up to four cycles.
  • the patient in need thereof is treatment na ⁇ ve to KRAS G12Ci, PD-1, or PD-L1 therapy.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 50 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and cisplatin in the treatment of KRAS G12C-mutant advanced NSCLC.
  • pembrolizumab is dosed (or administered) 200 mg once every three weeks.
  • pemetrexed is dosed (or administered) 500 mg/m2 once every three weeks.
  • cisplatin is dosed (or administered) 75 mg/m2 once every three weeks.
  • pemetrexed and cisplatin are administered on the same day.
  • pembrolizumab is administered for up to thirty-five cycles.
  • cisplatin is administered for up to four cycles.
  • the patient in need thereof is treatment na ⁇ ve to KRAS G12Ci, PD-1, or PD-L1 therapy.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 150 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and carboplatin in the treatment of KRAS G12C-mutant advanced NSCLC.
  • pembrolizumab is dosed (or administered) 200 mg once every three weeks.
  • pemetrexed is dosed (or administered) 500 mg/m2 once every three weeks.
  • carboplatin is dosed (or administered) area under the curve (AUC) 5 mg/ml/minute once every three weeks for a maximum dose of 750 mg.
  • pemetrexed and carboplatin are administered on the same day.
  • pembrolizumab is administered for up to thirty-five cycles.
  • carboplatin is administered for up to four cycles.
  • the patient in need thereof is treatment na ⁇ ve to KRAS G12Ci, PD-1, or PD-L1 therapy.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and carboplatin in the treatment of KRAS G12C-mutant advanced NSCLC.
  • pembrolizumab is dosed (or administered) 200 mg once every three weeks.
  • pemetrexed is dosed (or administered) 500 mg/m2 once every three weeks.
  • carboplatin is dosed (or administered) area under the curve (AUC) 5 mg/ml/minute once every three weeks for a maximum dose of 750 mg.
  • pemetrexed and carboplatin are administered on the same day.
  • pembrolizumab is administered for up to thirty-five cycles.
  • carboplatin is administered for up to four cycles.
  • the patient in need thereof is treatment na ⁇ ve to KRAS G12Ci, PD-1, or PD-L1 therapy.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 50 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and carboplatin in the treatment of KRAS G12C-mutant advanced NSCLC.
  • pembrolizumab is dosed (or administered) 200 mg once every three weeks.
  • pemetrexed is dosed (or administered) 500 mg/m2 once every three weeks.
  • carboplatin is dosed (or administered) area under the curve (AUC) 5 mg/ml/minute once every three weeks for a maximum dose of 750 mg.
  • pemetrexed and carboplatin are administered on the same day.
  • pembrolizumab is administered for up to thirty-five cycles.
  • carboplatin is administered for up to four cycles.
  • the patient in need thereof is treatment na ⁇ ve to KRAS G12Ci, PD-1, or PD-L1 therapy.
  • the starting materials and intermediates leading to the compounds of the present disclosure, or salts thereof, may be prepared by a variety of procedures, some of which are illustrated in the following Preparations and Examples and by Preparations and Examples in the ‘877 reference.
  • the starting materials and intermediates leading to the compounds of the present disclosure may be prepared by methods well known and appreciated in the art according to the following Preparations and Examples and by Preparations and Examples of the ‘877 reference. Suitable reaction conditions for the steps of these Preparations and Example are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art.
  • ACN refers to acetonitrile
  • APCI- MS atmospheric pressure chemical ionization mass spectrometry
  • Boc refers to tert-butoxycarbonyl
  • CDI refers 1,1’-carbonyldiimidazole
  • CDMT refers to 2- chloro-4,6-dimethoxy-1,3,5-triazine
  • DCC refers to 1,3-dicyclohexylcarbodiimide
  • DCM refers to dichloromethane
  • DIPEA or “DIEA” refers to N,N-diisopropylethylamine
  • DMAc or “DMA” refer to dimethylacetamide
  • DMAP refers to 4-dimethylaminopyridine
  • DMF 4-dimethylaminopyridine
  • DMF 4-dimethylaminopyridine
  • DMF 4-dimethylaminopyridine
  • DMF 4-dimethylaminopyridine
  • DMF 4-dimethylaminopyridine
  • CM continuous manufacturing
  • flow flow
  • flow chemistry involve the continuous feeding of input materials into, the transformation of in- process materials within, and the concomitant removal of output materials from a manufacturing process, such as a continuous stirred-tank reactor.
  • the terms are applicable to CM for new products (e.g., new drugs, generic drugs, biosimilars) and the conversion of batch manufacturing to CM for existing products.
  • FDA "Q13 Continuous Manufacturing of Drug Substances and Drug Products, Guidance for Industry" March 2023.
  • a continuous stirred-tank reactor is a vessel in which reactants are added and products are removed continuously and the reactor contents are stirred using internal agitation.
  • batch processes and processes so that it is expected to be homogeneous within specified limits.
  • the batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval. (See for example, FDA, “Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Guidance for Industry", September 2016).
  • a “catalyst” is a substance that increases the rate of a chemical reaction without itself undergoing any permanent chemical change.
  • R is a protecting group developed for the amino group, such as carbamates and amides.
  • Such protecting groups are well known and appreciated in the art, such as carbamate protecting groups including allyloxycarbonyl, fluorenylmethoxycarbonyl, or benzyloxycarbonyl.
  • a common and preferred protecting group can be Boc.
  • Step 2 the intramolecular cyclization of compound (3) is completed using an appropriate base such as potassium tert-butoxide, sodium tert-amylate, sodium tert- butoxide, sodium tert-pentoxide, DIPEA, TEA, DBU, sodium hydride in a solvent such as DMF to give compound 4.
  • an appropriate base such as potassium tert-butoxide, sodium tert-amylate, sodium tert- butoxide, sodium tert-pentoxide, DIPEA, TEA, DBU, sodium hydride in a solvent such as DMF to give compound 4.
  • Other possible solvents could be NMP, DMAc, DMSO, and THF.
  • This intramolecular cyclization of compound (3) to compound (4) may be conducted by slowly adding a solution of compound (3) to an excess of base so as to minimize intermolecular reaction derived impurities.
  • Step 3 compound (4) can be chlorinated with under acidic conditions using an acid such as TFA, H 3 PO 4 , with a chlorinating agent such as trichloroisocyanuric acid or NCS in a solvent such as acetonitrile or DMF to give compound (5).
  • Scheme 1a a can be prepared as described by Medicinal Chemistry route to 1, Development of an Alternative Route to the Bicyclic Piperazine, Retrosynthetic analysis of bicyclic piperazine core 2, and/or Coupling, cyclization, reduction, and Michael addition to afford Piperazine 24 in Org Proc Res Dev., 2011, 15(6). 1328-1335.
  • Compounds (3a), (4a), and (5a) can be prepared as described in Scheme 1.
  • Scheme 2 depicts the formation of products arising from reaction of amine (1) with acryloyl chloride (2). With a 1,2-addition, the compound of Formula I (3) is achieved. A 1,4-addition produces an amine impurity, acid chloride (4). Reaction of either acid chloride (4) or compound of Formula I (3) with an additional molecule of amine (1) results in Michael adduct impurity (6), while hydrolysis of acid chloride (4) with water results in acid impurity (5).
  • the compound of Formula I may be used, either as a monotherapy, in combination with one or more other therapeutic agents, or as part of neoadjuvant, adjuvant, advanced, or metastatic therapy, to treat cancer.
  • cancers include but are not limited to lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma or esophageal cancer.
  • Compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization.
  • the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical.
  • enantiomers can be separated using methods known in the art, such as chiral chromatography or by converting the enantiomers to diastereomeric salts, separating the diastereomeric salts, converting the diastereomeric salt into a non-salt form and isolating the enantiomer.
  • Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the disclosure, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L.
  • K2CO3 (842 g, 6.09 mol), water (5.0 L), and tert-butyl (3S)-3-(2-hydroxyethyl)piperazine-1- carboxylate:phosphoric acid (1:1) (1000 g, 3.05 mol) were combined.
  • the aqueous piperazine solution was added to the acetonitrile coupling solution over 5 min while maintaining an internal temperature of 0 oC.
  • the mixture was stirred for 2.5 h at 0 oC.
  • the bottom layer was drained from the reactor.
  • the reaction mixture was stirred for an additional 64 h at 0 oC, then concentrated to 2 L/kg.2-MeTHF (10.0 L) and n-heptane (3.0 L) were added.
  • the 1.30 kg of product solution was added to the water over 3 h at 25 oC.
  • the mixture was stirred for 64 h at 25 oC.
  • the resulting solids were isolated by filtration and washed with a mixture of DMF (0.3 L) and water (0.3 L).
  • the crude solids were added to a reactor along with EtOH (628 mL).
  • the mixture was heated to 55 oC and stirred for 30 min.
  • Water (314 mL) was added over 2 h and the mixture was held at 55 oC for an additional 30 min.
  • the slurry was cooled to 20 oC over 2 h, then held at 20 oC for 2 h.
  • reaction flask was sealed and heated at 105°C for 14 hours. Additional tert- butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2- yl]carbamate (3.54 g, 8.75 mmol) and dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'- binaphthyl]palladium(II) (0.97 g, 1.12 mmol) were added. The reaction flask was sealed and heated at 105°C for 14 hours.
  • Preparation 18 4-[(4aR)-7-Chloro-9-fluoro-11-oxo-1,2,3,4,4a,5-hexahydropyrazino[2,1- c][1,4]benzoxazepin-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, P atropisomer TFA (2 mL) of tert-butyl (4aR)-8-[2-(tert- butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-7-chloro-9-fluoro-11-oxo- 2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine-3-carboxylate, P atropisomer (0.018 g, 0.027 mmol) in DCM (2 mL).
  • Example 1 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer (Example 1) HCl gas was bubbled for five minutes into an ice-cooled solution of tert-butyl (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-10- chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2- carboxylate, M atropisomer (0.786 g, 1.17 mmol) in DCM (12 m
  • HPLC analysis comprise an Inertsil ODS-3V column (4.6 x 250 mm; 5 mm) eluted with 20% to 95% ACN in 0.1% aqueous H 3 PO 4 using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.14% MA impurity as shown in Table 2. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present.
  • HPLC analysis comprise an CSH Phenyl Hexyl column (3.0 x 100 mm, 2.5 mm) eluted with 20% to 95% ACN in 0.1% aqueous TFA using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.07% MA impurity as shown in Table 2. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present.
  • a surprising result is that the use of a higher rpm, such as the range of approximately 300 rpm to approximately 800 rpm, the range of approximately 400 rpm to approximately 500 rpm, and specific examples, such as approximately 300 rpm, approximately 450 rpm, or approximately 600 rpm, in the continuous stirred-tank reactor lowers the Michael adduct impurity amount.
  • HPLC analysis comprise an CSH Phenyl Hexyl column (3.0 x 100 mm, 2.5 mm) eluted with 20% to 95% ACN in 0.1% aqueous TFA using an Agilent 1260 chromatograph with UV detector.
  • This MA impurity is a Michael adduct wherein unreacted [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H- pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer reacts with the compound of Formula I and thereby forms a dimer. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present.
  • HPLC analysis conditions comprise an CSH Phenyl Hexyl column (3.0 x 100 mm, 2.5 mm) eluted with 20% to 95% ACN in 0.1% aqueous TFA using an Agilent 1260 chromatograph with UV detector.

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Abstract

La présente invention concerne des procédés qui peuvent être utilisés pour préparer le composé de formule I : ou des sels pharmaceutiquement acceptables de celui-ci, et des compositions pharmaceutiques comprenant le composé de formule I, une impureté d'adduit de Michael étant présente en une quantité inférieure à 0,3 % telle que mesurée par analyse HPLC, et des méthodes de traitement du cancer à l'aide du composé de formule I et des compositions pharmaceutiques.
PCT/US2024/050451 2023-10-11 2024-10-09 Procédé de fabrication d'un inhibiteur de kras g12c Pending WO2025080631A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021118877A1 (fr) 2019-12-11 2021-06-17 Eli Lilly And Company Inhibiteurs de kras g12c

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021118877A1 (fr) 2019-12-11 2021-06-17 Eli Lilly And Company Inhibiteurs de kras g12c

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Q13 Continuous Manufacturing of Drug Substances and Drug Products, Guidance for Industry", FDA, March 2023 (2023-03-01)
"Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Guidance for Industry", FDA, September 2016 (2016-09-01)
"Remington: The Science and Practice of Pharmacy", 2012, MACK PUBLISHING CO.
E.L. ELIELS.H. WILEN: "Stereochemistry of Organic Compounds", 1994, WILEY-INTERSCIENCE
J. JACQUES ET AL.: "Enantiomers, Racemates. and Resolutions", 1981, JOHN WILEY AND SONS, INC.
PETER G.M. WUTSTHEODORA W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2007, JOHN WILEY AND SONS, INC.

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