EP4519265A1 - Irreversible stummschaltinhibitoren - Google Patents

Irreversible stummschaltinhibitoren

Info

Publication number: EP4519265A1
Authority: EP; European Patent Office
Prior art keywords: pyridin; pyrazin; dihydropyrazolo; methyl; alkyl
Prior art date: 2022-05-04
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

EP23725134.3A

Other languages

English (en)

French (fr)

Inventor

Stephan Siegel

Simon Anthony Herbert

Carsten Schmeck

Franziska SIEGEL

Jeremie Xavier G. MORTIER

Stefanie Zimmermann

Hans Briem

Benjamin Bader

Ulf Bömer

Jens SCHRÖDER

Douglas ORSI

Heidi GREULICH

Alexandra GOULD

Matthew Meyerson

Alexander Konstantin Christian ULRICH

Roman Hillig

Daniel Korr

Christian Lechner

Laura EVANS

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Bayer AG

Dana Farber Cancer Institute Inc

Broad Institute Inc

Original Assignee

Bayer AG

Dana Farber Cancer Institute Inc

Broad Institute Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2022-05-04

Filing date

2023-05-03

Publication date

2025-03-12

2023-05-03 Application filed by Bayer AG, Dana Farber Cancer Institute Inc, Broad Institute Inc filed Critical Bayer AG

2025-03-12 Publication of EP4519265A1 publication Critical patent/EP4519265A1/de

Status Pending legal-status Critical Current

Links

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

the present invention covers 6,7-dihydropyrazolo[1 ,5-a]pyrazin derivatives of formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular cancer, as a sole agent or in combination with other active ingredients.
the present invention covers 6,7-dihydropyrazolo[1 ,5-a]pyrazin derivatives of formula (I) which inhibit EGFR.
the Epidermal Growth Factor Receptor (EGFR or EGF-receptor) receptor tyrosine kinase family consists of 4 members: EGFR (Erbbl , Herl), ERBB2 (Her2), ERBB3 (Her3), and ERBB4 (Her4).
EGFR mediates activation of MAPK and PI3K signaling pathways and thereby regulates cell proliferation, differentiation, migration and survival (Pao et al., 2010).
EGFR gene amplification, overexpression, and mutations are frequently observed in various cancer indications and are associated with a poor prognosis (Gridelli et al., 2015).
EGFR In lung adenocarcinoma, mutations of EGFR are prevalent in approximately 15% of Western patients and up to 50% of East Asian patients (Paez et al., 2004). These mutations typically occur in one of four exons, exons 18-21 , in the kinase domain of EGFR (Paez et al., 2004).
the most common activating mutations in EGFR are a point mutation in exon 21 , substituting an arginine for a leucine (L858R), and a small in-frame deletion in exon 19 that removes four amino acids (del 19/del746-750) (Pao et al., 2010).
WO2019/081486 describes 4H-Pyrrolo[3,2- c]pyridine-4-one derivatives.
a third-generation irreversible inhibitor, osimertinib that maximizes activity towards T790M while minimizing activity towards wild-type EGFR, is effective in T790M mutant patients and is currently the standard treatment for T790M positive patients (Mok et al., 2017). Osimertinib is also approved as a front-line therapy for patients with mutations of EGFR exons 19 or 21 (Soria et al., 2018).
small in-frame insertions of EGFR exon20 are resistant to the classical EGFR inhibitors at doses achievable in lung cancer patients and comprise an unmet medical need (Yasuda et. al., 2013).
V774_C775insHV show particular low response rates to EGFR-targeted therapies, resulting in significantly reduced progression-free survival as well as overall survival (Chen et al., 2016). This has been shown for the first-generation inhibitors erlotinib and gefitinib as well as for the second-generation inhibitor afatinib (Chen et al., 2016; Yang et al., 2015).
EGFR exon20 insertion patients The standard of care for EGFR exon20 insertion patients is currently chemotherapy.
amivantamab and mobocertinib received accelerated approval for 2 nd line treatment post chemotherapy recently, and several other inhibitors are currently in clinical trials for the treatment of EGFR exon20 insertion mutation positive lung cancer patients (Friedlaender et al., 2022).
About 40% of patients with advanced EGFR mutant NSCLC develop brain metastases over the course of their disease (Rangachari et al., 2015).
the 1 st and 2 nd generation EGFR inhibitors show only limited brain permeability.
the 3 rd generation EGFR inhibitor Osimertinib shows clearly improved CNS activity and is currently the preferred treatment option for patients with classical activating EGFR mutations and brain metastasis (Reungwetwattana et al., 2018).
Osimertinib has only limited activity on EGFR exon20 insertion mutations.
the recently approved bispecific antibody amivantamab and also mobocertinib show only limited blood-brain-barrier permeability. So there still remains a high unmet medical need especially for lung cancer patients carrying EGFR exon20 insertion mutations and brain metastasis.
mutant EGFR is a promising drug target for cancer therapy.
patients with primary resistance to approved anti-EGFR therapies due to EGFR exon20 insertions and with brain metastases, have only few treatment options to date and there is a great need for novel alternative and/or improved therapeutics to provide these patients with an efficacious, well-tolerable therapy.
potent inhibitors of mutant EGFR particularly of mutant EGFR with exon20 insertion mutations that show improved permeability of the blood-brain-barrier and CNS activity, represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.
the invention provides compounds that inhibit a mutant EGFR; specifically, an EGFR comprising one or more exon 20 insertion mutations, an L858R mutation, or a small in- frame deletion of exon 19, in the presence or absence of a T790M mutation and show brain permeability.
said compounds of the present invention have surprisingly been found to effectively inhibit mutant EGFR with exon 20 insertion mutations, particularly those harboring a D770_N771ins SVD exon 20 insertion. Furthermore it has been found that these compounds additionally show high cellular potency in EGFR V769_D770insASV, D770__N771 insSVD, D770_N771insNPG, N771_P772insH, or H773_V774insNPH exon 20 insertion harboring BA/F3 cell lines.
the here described compounds retain high cellular activity in BA/F3 cell lines harboring D770_N771insSVD and the T790M mutation.
the here described compounds potently inhibit proliferation of BA/F3 cell lines carrying EGFR activating mutations with or without T790M acquired resistance mutations (EGFR E746_A750del, L858R, E746__A750del T790M, L858R T790M).
the here described compounds can therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses mediated by mutant EGFR with exon 20 insertion mutations, a L858R mutation, or a small in-frame deletion of exon 19 (e.g.
EGFR E746_A750dei in the presence or absence of a T790M mutation and/or reduce (or block) proliferation in cells harboring EGFR with exon 20 insertion mutations, a L858R mutation, or a small in-frame deletion of exon 19 (e.g.
EGFR E746__A750del in the presence or absence of a T790M mutation, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non- small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
haematological tumours, solid tumours, and/or metastases thereof e.g leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non- small cell and small cell lung tumours, gastrointestinal tumours,
the invention relates to compounds of formula (I), in which: represents a group selected from the group:
R 4a represents a hydrogen atom, fluoro, or methyl
R 4b represents a hydrogen atom, fluoro, or methyl
R 4c represents a hydrogen atom, fluoro, or methyl
R 4d represents a hydrogen atom, fluoro, or methyl
R 4e represents a hydrogen atom, fluoro, or methyl
R 4i represents a hydrogen atom, fluoro, methyl, C1-C 2 -hydroxyalkyl, -(CO)-NR 19 R 20 , or
R 53 represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C2-C3-alkinyl, C1-
C3-haloalkyl C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-
R 5b represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C2-C3-alkinyl, C1-
R 5c represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C 2 -C3-alkinyl, C1-
C3-haloalkyl C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-
C3-alkyl amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl) 2 amino-C1-
R 5d represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C 2 -C3-alkinyl, C1-
C3-haloalkyl C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-
C3-alkyl amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl) 2 amino-C1-
R 5e represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C2-C3-alkinyl, C1-
C3-haloalkyl O-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, CrCa-alkoxy-C1-
C3-alkyl amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyQzamino-C1-
R 6a represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C 2 -C3-alkinyl, C1-
C3-haloalkyl C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1-
C3-alkyl amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 6b represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C 2 -C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino- C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylJzamino-C1-
R 6c represents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl , cyano, fluoro, chloro, or bromo;
R 6ci represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- Ca-aikyi, or cyano;
R 73 represents a hydrogen atom, amino, C1-C3-alkyl, C3-C3-alkenyl, Cz-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
R 7b represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 7c represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
R 7d represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
R 83 represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 8b represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylJzamino-C1- C3-aikyi, cyano, fluoro, chloro, or bromo;
R 8c represents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, O-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 8ci represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 8e represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 9a represents a hydrogen atom, amino, Ci-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyQzamino-C1- C3-alkyl, C2-C2-cycloalkyl, cyano, fluoro, chloro, or bromo;
R 9b represents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
RSC re p resent8 a hydrOgen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, C1-C3-alkyl-amino, amino-C1-C3-aikyi, C1-C3-alkylamino-C1-C3-alkyl, (C1- C3-alkyl)2amino-C1-C3-alkyl, cyano, anilino, pyridin-2-yl-amino, or C2-Ce- cycloalkylformamido;
R 9d represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo; R ,Oa represents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, O-C3-hydroxyalkyl, C1-C3-al
Riot represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
RIOC represents a hyd rO g en atom or methyl
Riod represents a hydrogen atom, fluoro, or methyl
R" represents ⁇ -CH 2 -CsCH, -C(R 14 )-R 15 , or
R !2 represents a hydrogen atom, methyl, -CH2-NR !9 R 20 , or a group selected from the group:
R 15 represents a hydrogen atom, C1-C3-alkyl, fluoro, dimethylamino-methyl, or morpholino-methyl;
R 16 represents a hydrogen atom, methyl, chloro, C1-Cj-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy-C1-C3-alkyl, -CH2-NR 17a -CR 17b R 17G R 17d , or a group selected from the group: represents a hydrogen atom, methyl, or ethyl; R 17b represents a hydrogen atom or methyl;
R 17c represents a hydrogen atom or methyl
R !7d represents a hydrogen atom, methyl, hydroxymethyl, or methoxymethyl
R !8 represents a hydrogen atom or methyl
R 19 represents a hydrogen atom or methyl
R 20 represents a hydrogen atom, CrCU-alkyl, or tert-butoxycarbonyl
R 22 represents a hydrogen atom or fluoro
R 23 represents a hydrogen atom or fluoro
R 24 represents a hydrogen atom or fluoro
R 25 represents a hydrogen atom, fluoro, or chloro
R 26 represents a hydrogen atom or fluoro
R 27a represents a hydrogen atom or fluoro
R 27b represents a hydrogen atom or fluoro
R 28a represents a hydrogen atom or fluoro
R28O represents a hydrogen atom or fluoro
R 29 represents a hydrogen atom or methoxy
R3O represents a hyd rO g en atom or methoxy; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N ⁇ oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer.
the invention relates to compounds of formula (I) as described supra, wherein: represents a group selected from the group: R 2 represents a group selected from the group:
R 4a represents a hydrogen atom, or methyl
R 4b represents a hydrogen atom
R 4c represents a hydrogen atom, or methyl
R 4d represents a hydrogen atom
R 4e represents a hydrogen atom, or methyl
R 4i represents a hydrogen atom, methyl, C1-Cz-hydroxyalkyl, - ⁇ (CO)-NR 19 R 20 , or -CH 2 ⁇ (CO)-NR 19 R 20 ;
R 53 represents a hydrogen atom, methyl, hydroxymethyl, methoxy, hydroxy, fluoro, or chloro;
R 5b represents a hydrogen atom, C1-C2-alkyl, trifluoromethyl, hydroxymethyl, methoxy, cyano, fluoro, or chloro
R 5c represents a hydrogen atom, C1-C2-alkyl, ethinyl, C1-haloalkyl, C1-C2-alkoxy, C1- haloalkoxy, trifluoromethylsulfanyl, cyano, fluoro, or chloro;
R 5d represents a hydrogen atom, or chloro
R 5e represents a hydrogen atom
R 73 represents a hydrogen atom
R 7b represents a hydrogen atom
R 7c represents trifluoromethyl
R 7d represents a hydrogen atom
R 83 represents a hydrogen atom, or fluoro
R8b represents a hydrogen atom, or fluoro
R 8c represents a hydrogen atom, methoxy, trifluoromethyl, fluoro, or chloro
R 8d represents a hydrogen atom
R 8e represents a hydrogen atom
R 9a represents a hydrogen atom, , , ;
R 9b represents a hydrogen atom
R 9c represents a hydrogen atom, amino, methoxy, methyl-amino, anilino, or cyclopropylformamido
R 9d represents a hydrogen atom, methyl, methoxy, or cyclopropyl
R 10a represents a hydrogen atom, or fluoro
R 10b represents a hydrogen atom
R 10c represents a hydrogen atom or methyl
R 10d represents a hydrogen atom, fluoro, or methyl; represents ⁇ C(R 14 )-R 15 , or R 12 represents a hydrogen atom, methyl, -CH2-NR 19 R 20 , or a group selected from the group:
R !4 represents ⁇ CHR !6 ;
R 15 represents a hydrogen atom, methyl, fluoro, dimethylamino-methyl, or morpholino- methyl
R !6 represents a hydrogen atom, methyl, chloro, C1-haloalkyl, hydroxymethyl, methoxymethyl, -CH 2 -NR 17a -CR 17b R 17c R 17d , or a group selected from the group:
R 17a represents a hydrogen atom, methyl, or ethyl
R 17 represents a hydrogen atom or methyl
R 17c represents a hydrogen atom or methyl
R 17d represents a hydrogen atom, methyl, hydroxymethyl, or methoxymethyl
R 18 represents a hydrogen atom
R 19 represents a hydrogen atom or methyl
R 20 represents a hydrogen atom, methyl, or tert-butoxycarbonyl
R 2! represents a hydrogen atom or methyl
R 22 represents a hydrogen atom or fluoro
R 23 represents a hydrogen atom or fluoro
R 24 represents a hydrogen atom or fluoro
R 25 represents a hydrogen atom, fluoro, or chloro
R 26 represents a hydrogen atom or fluoro
R 27a represents a hydrogen atom or fluoro
R 27b represents a hydrogen atom or fluoro
p28a represents a hydrogen atom or fluoro
R 28b represents a hydrogen atom or fluoro
R 29 represents a hydrogen atom or methoxy
R 30 represents a hydrogen atom or methoxy; wherein * indicates the point of attachment of said group with the rest of the molecule; or an N ⁇ oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer.
the invention relates to compounds of formula (I) as described supra, wherein:
R 1 represents a group selected from the group: wherein 4 indicates the point of attachment of said group with the rest of the molecule
R 2 represents a group selected from the group: wherein 4 indicates the point of attachment of said group with the rest of the molecule;
R 3 represents -(CO)-R 11 , -(CO)-CsC-R 12 , -(SC ⁇ J-CH-CHs, or oxirane-2-carbonyl;
R 43 represents a hydrogen atom, fluoro, or methyl
R 4b represents a hydrogen atom, fluoro, or methyl
R 4c represents a hydrogen atom, fluoro, or methyl
R 4d represents a hydrogen atom, fluoro, or methyl
R 4e represents a hydrogen atom, fluoro, or methyl
R 4f represents a hydrogen atom, fluoro, methyl, C1-Ca-hydroxyalkyl, -(CO)-NR 19 R 20 , or -CH 2 -(CO)-NR 19 R 20 ;
R 5a represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C 2 -C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 5b represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C 2 -C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 5c represents a hydrogen atom, amino, C1-C3-alkyl, C 2 -C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-Cs-alkyl, (C1-C3-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 5ci represents a hydrogen atom, amino, C1-Cs-alkyl, C 2 -C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylJzamino-C1- C3-aikyi, cyano, fluoro, chloro, or bromo;
R 5e represents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chtoro, or bromo;
R 6a represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- Ca-aikyi, cyano, fluoro, chtoro, or bromo;
R 5b represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
R 6c represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 6d represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
R 7a represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
R 7b represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 7c represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylJzamino-C1- C3-aikyi, or cyano;
R 7d represents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, or cyano;
R 8a represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- Ca-aikyi, cyano, fluoro, chloro, or bromo;
R 8b represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 8c represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyQzamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 8d represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 8e represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 93 represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylamino-C1- C3-alkyl, cyano, fluoro, chloro, or bromo;
R 9b represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkylJzamino-C1- C3-aikyi, or cyano;
R 9c represents a hydrogen atom, amino, C1-C3-alkyl, Cz-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, O-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyl)2amino-C1- C3-alkyl, cyano, anilino, pyridin-2-ylamino, or C2-Ce-cycloalkylformamido;
R 9ci represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C 3 -alkyl)2amino-C1- Ca-aikyi, cyano, fluoro, chtoro, or bromo; pioa represents a hydrogen atom, amino, C1-C3-alkyl, C2-C3-alkenyl, Cz-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C
R 10b represents a hydrogen atom, amino, Ci-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl, C1- C3-haloalkyl, C1-C3-hydroxyalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C1-C3-alkoxy-C1- C3-alkyl, amino-C1-C3-alkyl, C1-C3-alkylamino-C1-C3-alkyl, (C1-C3-alkyQzamino-C1- C3-alkyl, or cyano;
R 11 represents -CHa-CsCH, or -C(R 14 )-R 15 ;
R 12 represents a hydrogen atom or methyl
R 15 represents a hydrogen atom, C1-C3-alkyl, or fluoro
R 15 represents a hydrogen atom or methyl
R 17 represents a hydrogen atom or methyl
R 18 represents a hydrogen atom or methyl
R 19 represents a hydrogen atom or methyl
R 20 represents a hydrogen atom or methyl
the invention relates to compounds of formula (I) as described supra, wherein:
R 1 represents a group selected from the group: wherein * indicates the point of attachment of said group with the rest of the molecule;
R 2 represents a group selected from the group: wherein * indicates the point of attachment of said group with the rest of the molecule;
R 5c re p resen f s a hydrogen atom, fluoro, or chloro
R5d represents a hydrogen atom, methyl, fluoro, or methoxy
R 9c represents a hydrogen atom, amino, methoxy, aniline, or cyclopropylformamido
R 9ci represents a hydrogen atom or methoxy
R 11 represents “C(R 14 )“R 15 ;
R 12 represents a hydrogen atom or methyl
R 15 represents a hydrogen atom, methyl, or fluoro
R !6 represents a hydrogen atom or methyl
R !7 represents a hydrogen atom or methyl; or an N-oxide, a salt, a tautomer, a rotamer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, rotamer, or stereoisomer.
the invention relates to compounds of formula (I) as described supra, which is selected from the group consisting of:
a further aspect of the invention relates to compounds of formula (I), which are present as their salts, such as pharmaceutically acceptable salts.
the present invention covers compounds of formula (I) which are disclosed in the Example section of this text, infra.
the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
Another embodiment of the invention are compounds according as disclosed in the Claims section or disclosed analogs of the exemplified compounds and subcombinations thereof.
subject is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline.
Suitable within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person.
C2-C2-cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms.
Said C2-Ce-cycloalkyl group is for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.
C2-Cs as used throughout this text, e.g. in the context of the definition of “C2-Ce-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “Ca-Ce” is to be interpreted as any sub-range comprised therein, e.g. C2-Ce , C4-C5 , C3-C5 , C3-C4 , C ⁇ Cs, C2-Cs; particularly C2-Cs.
substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
the term “one or more”, e.g. in the definition of the substituents of the compounds of the formulae of the present invention, is understood as meaning “one, two, three, four, five, etc. particularly one, two, three or four, more particularly one, two or three, even more particularly one or two”.
the compounds of formula (I) may exist as isotopic variants.
the invention therefore includes one or more isotopic variant(s) of the compounds of formula (I), particularly deuterium-containing compounds of formula (I).
isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
isotopic variant of the compound of formula (I) is defined as a compound of formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O, 18Q, 32p, 33p, 33g, 34g, 35g, 36g, 18p, 36Q
stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O, 18Q, 32p, 33p, 33g, 34g, 35g, 36g, 18p, 36Q
the isotopic variant(s) of the compounds of formula (I) in one embodiment contain deuterium (“deuterium-containing compounds of formula (I)”).
deuterium-containing compounds of formula (I) Isotopic variants of the compounds of formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
Positron emitting isotopes such as 18 F or "C may be incorporated into a compound of formula (I). These isotopic variants of the compounds of formula (I) are useful for in vivo imaging applications.
Deuterium-containing and 13 C-containing compounds of formula (I) can be used in mass spectrometry analyses (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131) in the context of preclinical or clinical studies.
Isotopic variants of the compounds of formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, in one embodiment for a deuterium-containing reagent.
a reagent for an isotopic variant of said reagent in one embodiment for a deuterium-containing reagent.
deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052).
Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information on the state of the art with respect to deuterium-hydrogen exchange is given for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; R. P.
deuterium-containing compound of formula (I) is defined as a compound of formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
the abundance of deuterium at each deuterated position of the compound of formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, in one embodiment higher than 90%, 95%, 96% or 97%, in other embodiments higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
the selective incorporation of one or more deuterium atom(s) into a compound of formula (I) may alter the physicochemical properties (such as for example acidity [A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759; C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144; C. L. Perrin et al., J. Am. Chem.
deuterium-containing compound of formula (I) can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of formula (I).
deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Uetrecht et al., Chemical Research in Toxicology, 2008, 21 , 9, 1862; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
Kassahun et al., WO2012/112363 are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
a compound of formula (I) may have multiple potential sites of attack for metabolism.
deuterium-containing compounds of formula (I) having a certain pattern of one or more deuterium-hydrogen exchangers) can be selected.
the deuterium atom(s) of deuterium- containing compound(s) of formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
the compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
Substituents on a ring may also be present in either cis or trans form, it is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
compounds of the present disclosure are those which produce the more desirable biological activity.
Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
the purification and the separation of such materials can be accomplished by standard techniques known in the art.
the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
the optically active bases or acids are then liberated from the separated diastereomeric salts.
a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
Enzymatic separations, with or without derivatisation are also useful.
the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
optionally asymmetry may be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
compounds of the present invention can exist as atropisomers, as shown in Figure 1.
Atropisomers represent a subclass of conformers which arise from restricted rotation around a single bond.
the conformers (called atropisomers) can be isolated as separated species (IUPAC Gold book, http://goldbook.iupac.org/A00511.html; Pure and Appt. Chem., 2009, 68, 2193- 2222).
This induced chirality belongs to the axial type of chirality.
compounds featuring said atropisomerism and an additional asymmetric centre can exist as diasteromeric mixtures as described supra.
the compounds of the present invention may optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple elements of asymmetry, such as axial chirality and asymmetric centres.
Preferred compounds are those which produce the more desirable biological activity.
Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
the purification and the separation of such materials can be accomplished by standard techniques known in the art, examples of which can be found in the experimental section. If the atropisomers were separated, said atropisomers are being referred to as “atrop 1” (for atropisomer 1) and “atrop 2” (for atropisomer 2), subsequent to the respective compound name. Names without any such indication but still naming a compound showing atropisomerism is to be understood to include both atropisomers which were not separated.
the compounds of the present invention may exist as tautomers.
any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, namely :
the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
the present invention includes all such possible N-oxides.
the present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
the amount of polar solvents, in particular water may exist in a stoichiometric or non- stoichiometric ratio.
stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
the present invention includes all such hydrates or solvates.
the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic,
an alkali metal salt for example a sodium or potassium salt
an alkaline earth metal salt for example a calcium or magnesium salt
an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4- butantriol.
basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
diamyl sulfates long chain halides such as decyl, lauryl
acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
the salts include water-insoluble and, particularly, water-soluble salts.
bioprecursors or pro-drugs are covered by the invention.
Said biological system is e g. a mammalian organism, particularly a human subject
the bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C3 alkoxymethyl esters, e.g. methoxy methyl, C1- Ce alkanoyloxymethyl esters, e.g.
pivaloyloxymethyl phthalidyl esters, C2-Cs cycloalkoxy- carbonyloxy-C1-C3 alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2- onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl, and C1-C3- alkoxycarbonyloxyethyl esters, e.g. 1 -methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alphaj-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
inorganic esters such as phosphate esters and [alphaj-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
[alphaj-acyloxyalkyl ethers include acetoxym ethoxy and 2,2-dimethylpropionyloxymethoxy.
a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
the present invention covers all such esters.
the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
pharmacokinetic profile means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment.
Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
the term “combination” in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts.
a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
Another example of a “fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
a non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. Any such combination of a compound of formula (I) of the present invention with an anti-cancer agent as defined below is an embodiment of the invention.
(chemotherapeutic) anti-cancer agents relates to any agent that reduces the survival or proliferation of a cancer cell, and includes but is not limited to
Epidermal Growth Factor Receptor (EGFR) Polypeptide is meant a polypeptide having at least about 95% amino acid sequence identity to the sequence provided at UniProt Accession No. P00533-1 or a fragment thereof.
the EGFR fragment binds an EFGR ligand and/or has kinase activity.
Mutant EGFR polypeptides include those having an insertion between, for example, amino acids V769 and D770 or between D770 and N771.
the amino acid sequence identity is 96, 97, 98, 99, or 100% to UniProt Accession No. P00533-1.
EGFR Epidermal Growth Factor Receptor
Polynucleotide a nucleic acid molecule encoding an EGFR polypeptide or fragment thereof.
An exemplary polynucleotide encoding EGFR is provided at NCBI Reference Sequence: NM__001346897.1 , which is reproduced below:
fragment is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide.
a fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids.
the compounds according to the invention can be prepared according to the following schemes 1 - 6.
R 4 e.g., R 4a , R 4b , R 4c , R 4d , R 4e , R 4f
R 5 e.g., R 5a , R 5b , R 5c , R 5d , R 5e
R 5 e.g., R 6a , R 6b , R 6c , R 6d
R 7 e.g., R 7a , R 7b , R 7c , R 7d
R 8 e.g., R 8a , R 8b , R 8c , R 8d , R 8e
R 9 e.g., R 9a , R 9b , R9C, p9d j an( j pg can ijg ac hieved before and/or after the exemplified transformations.
Scheme 1 Route for the preparation of compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 4G , R 4d , R 4e , and R 4f have the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boo), and LG, is a suitable leaving group such as a halide or sulfonate as known to one skilled in the art.
Compounds of the formula 1 can be converted to compounds of the formula 2 by reacting for example suitable boronic acids in a Suzuki-type reaction.
2 can be converted to compounds of the formula 3 by halogenation reactions e.g.
carboxylic acids are employed the corresponding reaction can be facilitated by the use coupling reagents such as HATU, EDC -HOBt or T3P or T4P.
coupling reagents such as HATU, EDC -HOBt or T3P or T4P.
further synthetic manipulations could be carried out at this position. For instance, elimination of hydrogen chloride, could be used to form an alkene, or transformations such as alkylation’s may be undertaken to introduce additional substituents such as alkylamines.
sequence shown here may be altered, for instance formula type 1 , could be halogenated, affording a halogenated intermediate, which through a sequence of selective cross coupling reactions could also be used to generate compounds of type 4, as obvious to one skilled in the art.
Scheme 2 Route for the preparation of compounds of formula (18), wherein R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 4e , R 4f R 8a , R 8b , R 8c , R 8d , R 8e , and R 18 have the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g tert- butoxycarbonyl (Boc).
X represents a halogen, preferably Cl, Br or I.
Compounds of the formula 13 can be converted to compounds of the formula 14 using various methods which are known to those skilled in the art. These transformations include Buchwald-Hartwig- or Ullmann- reactions with suitable anilins.
Compounds of the formula 14 can be converted to compounds of the formula 15 by reactions to introduce halogen known to a person skilled in the art. Introduction of Br is preferred by using N-Bromosuccinimide (NBS) in solvents such as DMF or acetonitrile in a temperature range from -30°C to the boiling point of the respective solvent.
N-Bromosuccinimide N-Bromosuccinimide
Compounds of the formular 15 can be converted to compounds of the formula 16 by reacting for example suitable boronic acids in a Suzuki-type reaction.
PG represents a protecting group such as tert-butoxycarbonyl compounds of the formula 17 can be prepared from compounds of the formula 16 by deprotection reactions known to those skilled in the art (or as generally described in the chemical literature such as in Greens Protecting Group in Organic Chemistry).
Compounds of the formula 17 can be converted to compounds of the formula 18 using various methods. Depending on the nature of R 3 corresponding acid chlorides, sulfonylchlorides or other electrophiles can be used under basic conditions in a suitable solvent. If carboxylic acids are employed the corresponding reaction can be facilitated by the use coupling reagents such as HATU, EDO -HOBt or T3P. Additionally, following the introduction of a substituent at position R 3 , further synthetic manipulations could be carried out at this position. For instance, elimination of hydrogen chloride, could be used to form an alkene, or transformations such as alkylation’s may be undertaken to introduce additional substituents such as alkylamines.
Scheme 3 Route for the preparation of compounds of formula 28, wherein R 4a and R 4b are defined as hydrogen atoms, and R 1 , R 2 , R 3 , R 4c , R 4d , R 4e , and R 4f have the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert- butoxycarbonyl (Boc), and LG, is a suitable leaving group such as a halide or sulfonate as known to one skilled in the art.
PG can be hydrogen or optionally a suitable protecting group, e.g. tert- butoxycarbonyl (Boc), and LG, is a suitable leaving group such as a halide or sulfonate as known to one skilled in the art.
Compounds of the formula 19 can be converted to compounds of the formula 20 using various methods include alkylation with various electrophiles such as halides, or with groups such as mesyl or tosyl, or by direct reaction of alcohols in the presence of triphenylphosphine with azo compounds (Mitsonubu type reactions).
20 can be converted to compounds of the formula 21 by reduction, with reagents such as sodium borohydride.
21 can be converted to compounds of the type 22 by reaction with for instance mesyl chloride, to convert the corresponding alcohol into a suitable leaving group (LG).
22 can be converted to compounds of the type 23 by treatment with a suitable base such as sodium hydride.
reagents such as N-iodosuccinimide in a suitable solvent such as DCE, DMF or MeCN in a temperature range from -30°C to the boiling point of the respective solvent.
Compounds of the formular 24 can be converted to compounds of the formula 25 by reacting for example suitable boronic acids in a Suzuki-type reaction.
25 can be converted to compounds like 26 by reacting for example suitable boronic acids in a Suzuki-type reaction.
compounds of the formula 27 can be prepared from compounds of the formula 26 by deprotection reactions known to those skilled in the art (or as generally described in the chemical literature such as in Greens Protecting Group in Organic Chemistry).
Compounds of the formula 27 can be converted to compounds of the formula 28 using various methods.
sulfonylchlorides or other electrophiles can be used under basic conditions in a suitable solvent. If carboxylic acids are employed the corresponding reaction can be facilitated by the use coupling reagents such as HATU, EDC -HOBt or T3P.
Scheme 4 Route for the preparation of compounds of formula (I), wherein atom and R 1 , R 2 , R 3 , R 4a , R 4!5 , R 4c , R 4d , R 4e , and R 4f have the meaning as given for formuia (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boc).
PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boc).
a compound of type 29 (here described as a ethyl ester, but not limited to specifically this ester), could be converted to formula 30 using various methods include alkylation with various electrophiles such as halides, or with groups such as mesyl or tosyl, or by direct reaction of alcohols in the presence of triphenylphosphine with azo compounds (Mitsonubu type reactions). Base or acid catalyzed hydrolysis of the ester produces compounds of formula type 31.
Scheme 5 Route for the preparation of compounds of formula (I), wherein R 43 , R 4b are hydrogen atoms, and R 1 , R 2 , R 3 , R 4c , R 4d , R 4e , and R 4f have the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert- butoxycarbonyl (Boc).
R 43 , R 4b are hydrogen atoms
R 1 , R 2 , R 3 , R 4c , R 4d , R 4e , and R 4f have the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert- butoxycarbonyl (Boc).
a compound of type 41 could be converted to formula 42 using various methods include alkylation with various electrophiles such as halides, or with groups such as mesyl or tosyl, or by direct reaction of alcohols in the presence of triphenylphosphine with azo compounds (Mitsonubu type reactions).
Removal of the protecting group (PG) by for instance treatment with hydrochloric acid (when the protecting group is BOC), yields a compound of formula 43, which can be cyclized to formula 44, by for instance treatment with a base such as triethyiamine.
Conversion of formula 44 to formula 45 can be accomplished by reaction with for instance a boronic acid in the presence of a suitable catalyst such as palladium ligated by a ligand such as DPPF.
a suitable catalyst such as palladium ligated by a ligand such as DPPF.
a suitable reagent such as but not limited to borane dimethyl sulfide
Scheme 6 Route for the preparation of compounds of formula (I), wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 4e , and R 4f have the meaning as given for formula (I) and PG can be hydrogen or optionally a suitable protecting group, e.g. tert-butoxycarbonyl (Boc) or benzyl, as preferable as known to one skilled in the art.
Compounds of formula type 52 may be prepared by the approaches described in Schemes 1-5, as obvious to one skilled in the art.
Deprotection of, for instance a benzyl protecting group, using for instance dihydrogen with a suitable catalyst such as palladium, in a suitable solvent can be performed, yielding compounds of type 53.
Oxidation of the corresponding alcohol, using for instance a suitable oxidant, such as for instance Dess-Martin periodane can be used to produce formula type 54, which can be further oxidized, with for instance sodium chlorite, to the corresponding acid of formula 55.
Amide coupling, using for instance HATU and a suitable amine can be used to produce formula type 56.
Deprotection, yielding formula 57, and further transformations, analogously to Schemes 1 - 5 can be used to produce compounds of formula type 58. Additionally, the order of the sequence could be altered, with for instance formula type 53, could be deprotected, and directly used to produce compounds of formula 58, as known to one skilled in the art.
the compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC may be applied.
the compounds of the present invention which possess a sufficiently basic or acidic functionality may result as a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of the compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, free acid, solvate, inclusion complex) of a compound of the present invention as isolated and described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
Salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
a suitable solvent for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol
the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar ratio or one differing therefrom.
the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts.
pharmaceutically unacceptable salts which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
hydrochlorides and the process used in the example section are especially preferred.
Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to the person skilled in the art.
diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography.
Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent.
chiral auxiliary agents for example, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids by formation of diastereomeric salts.
diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents.
diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures.
enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
One preferred aspect of the invention is the process for the preparation of the compounds of claims 1-4 according to the examples as well as the intermediates used for their preparation.
compounds of the formula (I) can be converted into their salts, or, optionally, salts of the compounds of the formula (I) can be converted into the free compounds.
Corresponding processes are customary for the skilled person.
the compounds of the present invention have surprisingly been found to effectively inhibit mutant EGFR in a cell (e.g., a cancer cell) contacted with the compound, thereby inducing cell death (e.g., apoptosis) and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by mutant EGFR, such as, for example, benign and malignant neoplasia, more specifically haematological tumours, solid tumours, and/or metastases thereof, e.g.
mutant EGFR such as, for example, benign and malignant neoplasia, more specifically haematological tumours, solid tumours, and/or
leukaemias and myelodysplastic syndrome malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof, especially haematological tumours, solid tumours, and/or metastases of breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (e.g., thyroid and adrenal cortex), endocrine tumours, endometrium, esophagus, gastrointestinal tumours, germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, stomach, skin
Haematological tumours can, e.g., be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site, as well as AIDS related malignancies.
a further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring mutant EGFR with exon 20 insertion mutations, more particularly lung cancer harboring V769_770ins ASV and/or D770__N771ins SVD exon 20 insertions, and/or metastases thereof, comprising administering an effective amount of a compound of formula (I).
a further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring a mutant EGFR with in- frame deletions in exon 19 (such as EGFR E746__A750del) or point mutations in exon 21 (e.g. L858R), and/or metastases thereof.
a further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring a mutant EGFR with a D770__N771 insSVD C797S, E746_A750del C797S, or L858R C797S acquired resistance mutation, and/or metastases thereof.
a further aspect of the invention is the use of the compounds according to formula (I) for the treatment of lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and/or metastases thereof.
lung cancer particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and/or metastases thereof.
the invention relates to a compound of formula I, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, especially for use in the treatment of a disease.
Another particular aspect of the present invention is therefore the use of a compound of formula I, described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of hyperproliferative disorders or disorders responsive to induction of cell death, i.e. , apoptosis.
hyperproliferative disease is meant a disease, such as cancer, associated with inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both.
inappropriate within the context of the present invention, in particular in the context of “inappropriate cellular immune responses, or inappropriate cellular inflammatory responses”, as used herein, is to be understood as generally meaning a response, which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
the use is in the treatment or prophylaxis of diseases, especially the treatment, wherein the diseases are haematological tumours, solid tumours and/or metastases thereof.
Another aspect is the use of a compound of formula (I) for the prophylaxis and/or treatment of lung cancer, particularly lung cancer harboring mutant EGFR with exon 20 insertion mutations, more particularly lung cancer harboring V769_770ins ASV and/or D770__N771 ins SVD exon 20 insertions, and/or metastases thereof, especially preferred for the treatment thereof.
Another aspect of the present invention is the use of a compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described herein, in the manufacture of a medicament for the treatment or prophylaxis of a disease, wherein such disease is a hyperproliferative disorder or a disorder responsive to induction of ceil death e.g., apoptosis.
the disease is a haematological tumour, a solid tumour and/or metastases thereof.
the disease is lung cancer, particularly lung cancer harboring mutant EGFR with exon 20 insertion mutations, more particularly lung cancer harboring V769_770ins ASV and/or D770_N771ins SVD exon 20 insertions, and/or metastases thereof.
the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders.
Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce cell death e.g. apoptosis.
This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective to treat the disorder.
Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
BPH benign prostate hyperplasia
solid tumours such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
Those disorders also include lymphomas, sarcomas, and leukaemias.
breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
brain cancers include, but are not limited to brain stem and hypothalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
Tumours of the male reproductive organs include, but are not limited to prostate and testicular cancer.
Tumours of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, inverted sinonasal papilloma, inverted sinonasal papilloma- associated sinonasal squamous cell carcinoma, Merkel cell skin cancer, and non- melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, inverted sinonasal papilloma, inverted sinonasal papilloma-associated sinonasal squamous cell carcinoma, lip and oral cavity cancer and squamous cell.
Lymphomas include, but are not limited to AIDS-related lymphoma, non- Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
the present invention relates to a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present invention relates to a method of treating cancer in a subject, wherein the cancer is or has acquired resistance to an anti-EGF receptor therapy, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present invention relates to a method of enhancing the efficacy of an anti-EGF-receptor therapy, the method comprising administering to the subject an anti-EGF receptor therapy in combination with a a compound of formula (I) as defined herein.
the present invention relates to a method of treating cancer in a subject, wherein the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, tumours of the thorax, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the cancer is selected from the group consisting of leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, tumours of the thorax, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, skin tumours, and sarcomas
the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present invention relates to a method of treating cancer in a subject, wherein the cancer is selected from the group consisting of inverted sinonasal papilloma or inverted sinonasal papilloma associated sinanonasal squamous cell carcinoma, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present invention relates to a method of treating cancer in a subject, wherein the tumour of the thorax is non-small cell lung cancer, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present invention relates to a method of treating cancer in a subject, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with in-frame deletions in exon 19 (such as EGFR E746__A750del) or point mutations in exon 21 (e.g. L858R), and/or metastases thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present invention relates to a a method of treating cancer in a subject, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant EGFR with a D770 Struktur.N771insSVD C797S, E746__A750del C797S, or L858R C797S acquired resistance mutation, and/or metastases thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present invention relates to a a method of treating cancer in a subject, wherein the cancer is lung cancer, particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and/or metastases thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
lung cancer particularly lung cancer harboring a mutant ERBB2 with exon 20 insertion mutations (such as ERBB2 A775_G776insYVMA), and/or metastases thereof
the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein.
the present disclosure is also related to method of selecting a patient for cancer treatment with a compound of formula (I) comprising detecting the presence of a mutation in exon 20 of the gene encoding the EGF-receptor in a biological sample of the subject, thereby determining that the patient should be treated with said compound.
the EGFR comprises aD770....N771insSVD C797S, E746. A750del C797S, or L858R C797S acquired resistance mutation, and/or metastases thereof.
the method of selecting a patient for cancer treatment with a compound of formula (I) may comprise detecting the presence of in-frame deletions in exon 19 or point mutations in exon 21 of the gene encoding EGF-receptor in a biological sample of the subject, thereby determining that the patient should be treated with said compound.
the in- frame deletion in exon 19 may be EGFR E746_A750del or the point mutation in exon 21 may be L858R.
the method of selecting a patient for cancer treatment with a compound of formula (I) may comprise detecting the presence of a mutation in exon 20 of the gene encoding ERBB2 in a biological sample of the subject, thereby determining that the patient should be treated with said compound.
the ERBB2 comprises an ERBB2 A775 or_G776insYVMA insertion mutation, and/or metastases thereof.
methods of treating a patient with cancer may comprise administering to the subject a compound of formula (I) (e.g., in combination with anti-EGF receptor therapy), wherein the subject is selected for therapy by detecting the presence of a mutation in EGFR in a biological sample of the subject.
the method may comprise obtaining a biological sample from a subject and detecting a mutation in exon 19, 20, or 21 of the gene encoding EGF-receptor in the biological sample obtained from the subject. Detection of the presence of a mutation in exon 20 is within the skill of one of the art.
the disclosure provides a method of treating a selected subject, the method comprising administering to the selected subject a compound described herein, wherein the subject is selected by detecting a mutant EGFR comprising an in-frame deletion in exon 19 (e.g., EGFR E746_A750del) or a point mutations in exon 21 (e.g. L858R).
a mutant EGFR comprising an in-frame deletion in exon 19 (e.g., EGFR E746_A750del) or a point mutations in exon 21 (e.g. L858R).
the detection of a mutation may be performed by sequencing (e.g., Sanger, Next Generation Sequencing) or a method selected from the group consisting of immunoblotting, mass spectrometry, immunoprecipitation quantitative PCR, Northern Blot, microarray, enzyme-linked immunosorbent assay (ELISA), in situ hybridization, and combinations thereof.
sequencing e.g., Sanger, Next Generation Sequencing
the present invention also provides methods for the treatment of disorders associated with aberrant mitogen extracellular kinase activity, including, but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Background section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention, regardless of the mechanism of action and/or the relationship between the kinase and the disorder.
aberrant kinase activity or “aberrant tyrosine kinase activity,” includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide; gene amplification; mutations which produce constitutively- active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc.
the present invention also provides for methods of inhibiting kinase activity, especially of mitogen extracellular kinase, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g'.: esters) thereof, and diastereoisomeric forms thereof.
Kinase activity can be inhibited in cells (e.g., in vitro), or in the cells of a mammalian subject, especially a human patient in need of treatment.
the present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
RA rheumatoid arthritis
restenosis in-stent restenosis
vascular graft restenosis etc.
the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumour enlargement and metastasis.
the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death e.g. apoptosis of such cell types.
the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.
the compounds of the present invention can be used in particular in therapy and prevention i.e. prophylaxis, especially in therapy of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
compositions of the compounds of the invention are provided.
This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition, disorder, or disease.
the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier or auxiliary and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
Another aspect of the invention is a pharmaceutical composition
a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable auxiliary for the treatment of a disease mentioned supra, especially for the treatment of haematological tumours, solid tumours and/or metastases thereof.
a pharmaceutically acceptable carrier or auxiliary may be a carrier that is non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
Carriers and auxiliaries are all kinds of additives assisting to the composition to be suitable for administration.
a pharmaceutically effective amount of compound may be that amount which produces a result or exerts the intended influence on the particular condition being treated.
the compounds of the present invention can be administered with pharmaceutically- acceptable carriers or auxiliaries well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing auxiliaries, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of Wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
binders such as acacia, corn starch or gelatine
disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, such as potato starch, algin
Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
the emulsions may also contain sweetening and flavouring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more colouring agents; one or more flavouring agents; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in, for example, a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2 !
a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or
2-dimethyl-1,1-dioxolane-4-methanol ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.
ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose,
Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene ⁇ oxypropylenejs or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
suitable detergents include cationic detergents, for example
compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) in one embodiment of from about 12 to about 17.
HLB hydrophile-lipophile balance
the quantity of surfactant in such formulation in one embodiment ranges from about 5% to about 15% by weight.
the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
compositions may be in the form of sterile injectable aqueous suspensions.
suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca- ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
Diluents and solvents that may be employed are, for example, water, Ringer’s solution, isotonic sodium chloride solutions and isotonic glucose solutions.
sterile fixed oils are conventionally employed as solvents or suspending media.
any bland, fixed oil may be employed including synthetic mono- or diglycerides.
fatty acids such as oleic acid can be used in the preparation of injectables.
composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
Such materials are, for example, cocoa butter and polyethylene glycol.
Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
a mechanical delivery device for the delivery of pharmaceutical agents is well known in the art.
Direct techniques for administration for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient’s ventricular system to bypass the blood-brain barrier.
One such implantable delivery system used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011 ,472, issued April 30, 1991.
compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
compositions for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-
CCIF2 and CCIF3 examples include but are not limited to nitrogen and argon;
examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic
FD&C Red No. 20 FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red
clarifying agents include but are not limited to bentonite
emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
encapsulating agents examples include but are not limited to gelatin and cellulose acetate phthalate
flavourants examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
humectants include but are not limited to glycerol, propylene glycol and sorbitol
levigating agents include but are not
compositions according to the present invention can be illustrated as follows:
Sterile i.v. solution A 5 mg/ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes.
Lyophilised powder for i.v. administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/ml, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
Hard Shell Capsules A large number of unit capsules are prepared by filling standard two- piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and in particular embodiments from about 0.01 mg/kg to about 20 mg/kg body weight per day.
Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
"drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
the average daily dosage for administration by injection will in other embodiments be from 0.01 to 200 mg/kg of total body weight.
the average daily rectal dosage regimen will in particular embodiments be from 0.01 to 200 mg/kg of total body weight.
the average daily vaginal dosage regimen will in other embodiments be from 0.01 to 200 mg/kg of total body weight.
the average daily topical dosage regimen will in still other embodiments be from 0.1 to 200 mg administered between one to four times daily.
the transdermal concentration will in other embodiments be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
the average daily inhalation dosage regimen will in other embodiments be from 0.01 to 100 mg/kg of total body weight.
the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
Those combined pharmaceutical agents can be other agents having antiproliferative effects such as for example for the treatment of haematological tumours, solid tumours and/or metastases thereof and/or agents for the treatment of undesired side effects.
the present invention relates also to such combinations.
anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et a/., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, especially (chemotherapeutic) anti- cancer agents as defined supra.
the combination can be a non-fixed combination or a fixed- dose combination as the case may be.
Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
SP4® or Isolera Four® Biotage autopurifier system
eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
SP4® or Isolera Four® Biotage autopurifier system
eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
regular silica gel was used in flash column chromatography.
the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
Instrument Knauer P2.1 L, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software.
Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm, 5 ⁇ m; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min, 0-60% B, 1.2-1.6 min, 60% B; flow 1.0 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
Instrument Agilent 1200 ⁇ G6110A SingleQuad; Column: XBridge C18 2.1*50 mm, 5 ⁇ m; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 10-80% B, 1.2-1.6 min 80% B; flow 1.2 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.
Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1*30 mm, 5um; eluent A: water + 0.025 vol% ammonium hydroxide, eluent B: acetonitrile; gradient: 0- 0.8 min, 5-95% B, 0.8-12 min, 95% B; flow 15 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
Instrument Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software.
multiplicities of proton signals in 1 H NMR spectra reflect the observed signal form and do not take into account any higher-order signal phenomena.
the chemical shift data refers to the center of the signal in question. In the case of wide multiplets, a range is specified. Signals hidden by solvent or water were either assigned tentatively or are not listed. Strongly broadened signals - e.g caused by rapid rotation of molecular moieties or by interchanging protons - have also been assigned tentatively (often referred to as a broad multiplet or broad singlet) or are not shown.
the 1 H-NMR data of selected compounds are listed in the form of 1 H-NMR peaklists. Therein, for each signal peak the 6 value in ppm is given, followed by the signal intensity, reported in round brackets. The 0 value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: 61 (intensityi), 82 (intensitya), ... , 0: (intensity,), ... , 0 R (intensity,,).
a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 'H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, 13 C satellite peaks, and/or spinning sidebands.
the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%).
Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints".
An expert who calculates the peaks of the target compound by known methods can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H-NMR interpretation.
the reaction vessel was flushed with nitrogen and tetrakis(triphenylphosphin)palladium(0) (612 mg, 52.9 ⁇ mol; CAS-RN:[14221-01-3]) was added.
the sealed vessel was heated at 110°C for 30 min in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure.
the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 0- 20%) yielding the title compound 126 mg (93 % purity, 64 % yield).
the reaction vessel flushed with nitrogen and 4-(4,4,5,5-tetramethyl-1,3 l 2-dioxaborolan-2-yl)pyridine (114 mg, 558 ⁇ mol), potassium carbonate (165 mg, 1.20 mmol; CAS-RN: [584-08-7]) and dichloro[1,1'- bis(dialkyl/diarylphosphino)ferrocene]palladium(ll) (9.76 mg, 12.0 ⁇ mol; CAS- RN: [95464- 05-4]) were added.
the sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added.
the reaction vessel was flushed with nitrogen and tetrakis(triphenylphosphin)palladium(0): (61.2 mg, 52.9 ⁇ mol; CAS-RN:[14221-01-3]) was added.
the sealed vessel was heated at 110°C for 30 min in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure.
the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 0- 20%) yielding the title compound 132 mg (90 % purity, 67 % yield).
the reaction vessel flushed with nitrogen and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (118 mg, 577 ⁇ mol), potassium carbonate (171 mg, 1.24 mmol; CAS-RN: [584-08-7]) and dichloro[1,T- bis(dialkyl/diarylphosphino)ferrocene]palladium(ll) (27.9 mg, 34.2 ⁇ mol; CAS-RN: [95464- 05-4]) were added.
the sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added.
the reaction vessel was flushed with nitrogen and tetrakis(triphenylphosphin)palladium(0) (76.5 mg, 66.2 ⁇ mol; CAS-RN:[14221-01-3]) was added.
the sealed vessel was heated at 110°C for 30 min in a microwave, ethyl acetate and water was added. After extraction 2x with ethyl acetate the combined organic phases were dried with an water-repellent filter and concentrated under reduced presssure.
the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 0- 16%) yielding the title compound 195 mg (95 % purity, 88 % yield).
the reaction vessel flushed with nitrogen and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (130 mg, 632 ⁇ mol), potassium carbonate (201 mg, 1.46 mmol; CAS-RN:[584-08-7]) and dichloro[1,1'- bis(dialkyl/diarylphosphino)ferrocene]palladium(ll) (32.9 mg, 40.3 ⁇ mol; CAS- RN: [95464- 05-4]) were added.
the sealed vessel was heated at 110°C for 1 hour in a microwave, ethyl acetate and water was added.

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