Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • 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
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings

Definitions

• the present invention relates to new substituted 1/7-pyrazolo[4,3-c]pyridines and derivatives of formula (I) wherein the groups R 1 to R 4 and X 1 to X 5 have the meanings given in the claims and specification, their use as inhibitors of mutant EGFR, pharmaceutical compositions which contain compounds of this kind and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases.
• the epidermal growth factor receptor is a receptor tyrosine kinase that transduces mitogenic signals. Mutations in the EGFR gene are found in approximately 12 % to 47 % of non-small cell lung cancer (NSCLC) tumors with adenocarcinoma histology (Midha, 2015). The two most frequent EGFR alterations found in NSCLC tumors are short in-frame deletions in exon 19 (dell 9) of the EGFR gene and L858R, a single missense mutation in exon 21 (Konduri, 2016). These two mutations cause ligand-independent EGFR activation and are collectively referred to as EGFR M+.
• the most prominent molecular mechanism underlying progression is the acquisition of a secondary mutation in EGFR, namely T790M (Blakely, 2012; Kobayashi, 2005), in 50 % to 70 % of patients progressing on 1 st and 2 nd generation EGFR inhibitors. This mutation attenuates the inhibitory activity of 1 st and 2 nd generation TKIs in cellular assays (see e.g. data in Table A).
• 3 rd generation TKIs such as osimertinib, covalently attach to EGFR via the residue C797 (Cross, 2014; Wang, 2016).
• C797S mutation abolishes the activity of 3 rd generation TKIs tested (Thress, 2015) (see e.g. data in Table A).
• the mutation C797S is preferentially found in conjunction with the EGFR dell 9 genotype and on the same allele as the T790M mutation (cis configuration) (82 % of C797S+ patients) (Piotrowska, 2017).
• the EGFR del19/L858R T790M C797S cis mutant kinase variant that emerges in 2 nd line patients progressing on osimertinib can no longer be inhibited by 1 st , 2 nd or 3 rd generation EGFR TKIs (Thress, 2015) (see e.g. data in Table A).
• the 3 rd generation EGFR TKI osimertinib has recently also shown efficacy in previously untreated EGFR M+ NSCLC patients (Soria, 2017). Disease progression occurs after an average duration of 19 months. While the EGFR resistance mutation spectrum after 1 st line osimertinib treatment has not been extensively studied yet, first available data also suggest the emergence of the mutation C797S that abrogates osimertinib activity (Ramalingam, 2017). Based on the efficacy of osimertinib in untreated EGFR M+ NSCLC patients and T790M-positive 2 nd line patients, the drug has been approved in both settings.
• a 4 th generation EGFR TKI molecule that has activity on EGFR dell 9 and EGFR L858R primary activating mutations irrespective of the presence of the resistance mutations T790M and C797S would allow the treatment and prevention of resistance disease.
• a 4 th generation EGFR TKI should not inhibit wild-type EGFR.
• EGFR TKI Another desirable property of a 4 th generation EGFR TKI is the ability to efficiently penetrate into the brain (blood-brain barrier penetration) in order to be able to prevent ans/or treat brain metastasis and leptomeningeal disease.
• a 4 th generation EGFR TKI would allow to treat patients progressing on 2 nd line treatment with a 3 rd generation TKI, such as osimertinib, (e.g. with the genotype EGFR del19/L858R T790M C797S), who have currently no targeted therapy treatment option. Furthermore, these properties also have the potential to allow a 4 th generation EGFR TKI to provide a longer duration of response in earlier treatment line patients, such as patients progressing on 1 st line osimertinib treatment with EGFR C797S mutations as well as in 1 st line patients.
• the characteristics outlined above define a 4 th generation EGFR TKI as the first EGFR TKI able to effectively target patients with NSCLC tumors carrying the EGFR del 19 or L858R genotype as well as the EGFR del19/L858R T790M C797X/L792X variants.
• a 4 th generation EGFR TKI will be the first C797S active compound that also inhibits T790M-positive alleles, possesses EGFR wild-type sparing activity and effectively penetrates into the brain.
• EGFR inhibitors which can overcome EGFR resistance mutations including the mutation T790M, as well as the C797S mutation and combinations of both have been published (Zhang, 2017; Park, 2017; Chen, 2017; Bryan 2016; Juchum, 2017; Gunther, 2017; WO 2017/004383). Most of the published molecules are non-covalent variants of quinazoline based 2 nd generation EGFR inhibitors. (Patel, 2017; Park, 2017; Chen, 2017).
• compounds (I) according to the invention show a broad activity on EGFR dell 9 or EGFR L858R variants, with or without T790M and/or C797S mutations, which ensures that the compounds may effectively cope with the expected allelic complexity in patient tumors as a monotherapy agent.
• the compounds according to the invention have a reduced inhibitory potential regarding wild-type EGFR.
• Compounds (I) show a high selectivity across the human kinome, which may reduce off-target toxicity of the compounds.
• Another property of the compounds (I) according to the invention is the ability to potentially penetrate into the brain (blood-brain barrier penetration) in order to be used to prevent and/or treat brain metastasis and leptomeningeal disease.
• the compounds disclosed herein show good solubility and suitable DMPK properties for use in organismal settings.
• the present invention therefore relates to a compound of formula (I) , wherein [A0] R1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyloxy and 3-6 membered heterocyclyl;
• R2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, C 3-6 cycloalk
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyloxy and 3-6 membered heterocyclyl; R2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyloxy and 3-6 membered heterocyclyl; R 2 is hydrogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is selected from the group consisting of C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -OH, C 3-6 cycloalkyl and C 3-6 cycloalkoxy; R 2 is hydrogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is selected from the group consisting of methoxy, isopropyloxy, -OH, cyclopropyl and cyclopropyloxy; R 2 is hydrogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is selected from the group consisting of C 1-4 alkoxy and -OH; R 2 is hydrogen.
• R 1 is selected from the group consisting of C 1-4 alkoxy and -OH; R 2 is hydrogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is methoxy; R 2 is hydrogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 is -OH; R 2 is hydrogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 and R 2 together with the carbon atoms they are attached form a 5-6 membered heterocyle or a 5-6 membered heteroaromatic ring.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 1 and R 2 together with the carbon atoms they are attached form a ring selected from the group consisting of pyrrole, 2,3-dihydrofuran and furan.
• the invention in another aspect [B1] relates to a compound of formula (I) or a salt thereof, wherein R3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and halogen.
• R3 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl and halogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is C 1-4 alkyl.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is methyl.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R4 is selected from the group consisting of Ra1 and R b1 ; Ra1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting of R a1 and R b1 ; R a1 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R b1 and/or R c1 ; each R b1 is independently selected from the group consisting of -OR c1 , -N(R c1 )R c1 and halogen; each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalky
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is R a1 ; R a1 is 3-11 membered heterocyclyl optionally substituted with one or more, identical or different R b1 and/or R c1 ; each R b1 is independently selected from the group consisting of -OR c1 , -N(R c1 )R c1 and halogen; each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ; each R d1 is independently selected from the group consisting of -OR e1 ; R a1 is
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is R a1 ; R a1 is selected from the group consisting of wherein each R a1 is optionally substituted with one or more, identical or different R b1 and/or R c1 ; each R b1 is independently selected from the group consisting of -OR c1 , -N(R c1 )R c1 and halogen; each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ; each R d1 is independently selected from the group consisting of
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is R a1 ; R a1 is selected from the group consisting of wherein each R a1 is optionally substituted with one or more, identical or different R b1 and/or R c1 ; each R b1 is independently selected from the group consisting of -OR c1 and halogen; each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl and 5-6 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ; each R d1 is independently selected from the group consisting of -OR e1 and halogen; each R e1 is independently selected from the group consisting of hydrogen and C 1-6 alkyl.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting of
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting of -NH 2 , -NH(C 1-4 alkyl) and -N(C 1-4 alkyl) 2 .
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is -N(C 1-4 alkyl) 2 .
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is -OR c1 ;
• R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
• each R d1 is independently selected from the group consisting of -OR e1 , -N(R e1 )R e1 and halogen;
• each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cyclo
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is -OR c1 ;
• R c1 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ; each R d1 is halogen;
• each R e1 is independently selected from the group consisting of C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 3-10 cycloalkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different halogen.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting of
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R b1 and/or R c1 ; each R b1 is independently selected from the group consisting of -OR c1 , -N(R c1 )R c1 and halogen; each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl and 5-6 membered heteroaryl, wherein the C
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R b1 and/or R c1 ; each R b1 is independently selected from the group consisting of -OR c1 and halogen; each R c1 is independently selected from the group consisting of hydrogen and C 1-6 alkyl.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 4 is selected from the group consisting of
• the invention relates to a compound of formula (I) or a salt thereof, wherein
• R 7 is selected from the group consisting of R a2 and R b2 ;
• R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b2 and/or R c2 ; each R b2 is independently selected from the group consisting of -OR c2 , -N(
• the invention relates to a compound of formula (I) or a salt thereof, wherein s ; R 7 is selected from the group consisting of R a2 and R b2 R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b2 and/or R c2 ; each
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-4 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 7 is selected from the group consisting of R a2 and R b2 R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-4 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, halogen, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 7 is selected from the group consisting of R a2 and R b2 R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocycl
• the invention relates to a compound of formula (I) or a salt thereof, wherein R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 7 is selected from the group consisting of R a2 and R b2 R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alky
• R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
• R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.
• the invention relates to a compound of formula (I) or a salt thereof, wherein R5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-4 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.
• R5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C
• R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
• R 9 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, halogen, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl and 3-6 membered heterocyclyl.
• each R 5 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy.
• the invention in another sub-aspect [E2] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D4], [D5] and [D8], wherein each R 5 is C 1-4 alkyl.
• the invention in another sub-aspect [E3] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D4], [D5] and [D8], wherein each R 5 is methyl.
• aspects [F1] to [F3] are sub-aspects of aspects [D0], [D1], [D6], [D7] and [D9] in respect of residue R 6 :
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D6], [D7] and [D9], wherein each R 6 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl.
• the invention in another sub-aspect [F2] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D6], [D7] and [D9], wherein each R 6 is C 1-4 alkyl.
• the invention in another sub-aspect [F3] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D6], [D7] and [D9], wherein each R 6 is methyl.
• aspects [G1] and [G2] are sub-aspects of aspects [D0] and [D1] in respect of residue R 8 :
• the invention in one sub-aspect [G1] the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0] and [D1], wherein each R 8 is C 1-4 alkyl.
• the invention in another sub-aspect [G2] the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0] and [D1], wherein each R 8 is methyl.
• aspects [H1] to [H3] are sub-aspects of aspects [D0], [D1], [D4], [D6] and [D9] in respect of residueR 9 :
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D4], [D6] and [D9], wherein each R 9 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl.
• the invention in another sub-aspect [H2] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D4], [D6] and [D9], wherein each R 9 is C 1-4 alkyl.
• the invention in another sub-aspect [H3] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D4], [D6] and [D9], wherein each R 9 is methyl.
• aspects [I1] to [I3] are sub-aspects of aspects [D0], [D1], [D2], [D5], [D7] and [D8] in respect of residue R 10 :
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D5], [D7] and [D8], wherein each R 10 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.
• the invention in another sub-aspect [I2] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D5], [D7] and [D8], wherein each R 10 is C 1-4 alkyl.
• the invention in another sub-aspect [I3] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D5], [D7] and [D8], wherein each R 10 is independently selected from the group consisting of methyl, ethyl and isopropyl.
• each R 7 is independently selected from the group consisting of R a2 and R b2
• R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of R a2 and R b2
• R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are all optionally substituted with one or more, identical or different R b2 and/or R c2 ; each R b2 is independently selected from the group consisting of -OR c2 , -N(R
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of R a2 and R b2
• R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R b2 and/or R c2
• each R 7 is independently selected from the group consisting of R a2 and R b2
• R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R b2 and/or R c2
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of R a2 and R b2
• R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R b2 and/or R c2
• each R c2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl and 3-11 membered heterocyclyl, wherein the
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of R a2 and R b2
• R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R b2 and/or R c2
• each R c2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-11
• the invention in another sub-aspect [J6] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, ,
• the invention in another sub-aspect [J6a] the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl,
• the invention relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of
• the invention in another sub-aspect [J9] relates to a compound of formula (I) or a salt thereof according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], wherein each R 7 is independently selected from the group consisting of
• the invention in another aspect [L1] the invention relates to a compound of formula (I) or a salt thereof according to aspect [D2] in combination with aspects [A5] or [A6].
• the invention in another aspect [L2] the invention relates to a compound of formula (I) or a salt thereof according to aspect [D2] or to aspect [L1] each of which is taken in combination with aspects [B3] or [B4].
• the invention relates to a compound of formula (I) or a salt thereof according to aspect [D2] or to aspects [L1] or [L2] each of which is taken in combination with aspects [I2] or [I3].
• the invention relates to a compound of formula (I) or a salt thereof according to anyone of aspects [D2] or [L1]-[L3] each of which is taken in combination with anyone of aspects [C5]-[C8]
• the invention relates to a compound of formula (I) or a salt thereof, according to anyone of aspects [D2] or [L1]-[L4] each of which is taken in combination with anyone of aspects [J1]-[J7], [J3a], [J4a], [J6a] and [J6b].
• the invention relates to a compound of formula (I) or a salt thereof, according to anyone of aspects [D2] or [L1]-[L5], each of which is taken in combination with R 4 is a 3-11 membered heterocyclyl or R 4 is a 7 membered heterocyclyl.
• the present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein).
• the present invention further relates to a hydrate of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein).
• the present invention further relates to a solvate of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein).
• the present invention further relates to a pharmaceutically acceptable salt of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) with anorganic or organic acids or bases.
• compositions for administering the compounds of formula (I) according to the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions - particularly solutions for injection (s.c., i.v., i.m.) and infusion (injectables) - elixirs, syrups, sachets, emulsions, inhalatives or dispersible powders.
• the content of the compounds (I) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
• the doses specified may, if necessary, be given several times a day, e.g. twice daily.
• Suitable tablets may be obtained, for example, by mixing the compounds (I) with known pharmaceutically acceptable excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
• the tablets may also comprise several layers.
• Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with excipients normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• excipients normally used for tablet coatings for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core may also consist of a number of layers.
• the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
• Syrups or elixirs containing one or more compounds (I) or combinations with one or more other pharmaceutically active substance(s) may additionally contain excipients like a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain excipients like suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. Solutions for injection and infusion are prepared in the usual way, e.g.
• excipients like isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
• excipients like isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
• Capsules containing one or more compounds (I) or combinations with one or more other pharmaceutically active substance(s) may for example be prepared by mixing the compounds/active substance(s) with inert excipients such as lactose or sorbitol and packing them into gelatine capsules.
• Suitable suppositories may be made for example by mixing with excipients provided for this purpose such as neutral fats or polyethyleneglycol or the derivatives thereof.
• Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g.
• pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly disper
• lignin e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
• lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
• the pharmaceutical compositions are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route.
• the tablets may of course contain, apart from the above-mentioned excipients, additional excipients such as sodium citrate, calcium carbonate and dicalcium phosphate together with various excipients such as starch, preferably potato starch, gelatine and the like.
• additional excipients such as sodium citrate, calcium carbonate and dicalcium phosphate together with various excipients such as starch, preferably potato starch, gelatine and the like.
• lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
• the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
• solutions of the active substances with suitable liquid excipients may be used.
• the dosage range of the compounds of formula (I) applicable per day is usually from 1 mg to 2000 mg, preferably from 250 mg to 2000 mg.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one (preferably one) compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) and one or more pharmaceutically acceptable excipient(s).
• the compounds of formula (I) - or the pharmaceutically acceptable salts thereof - and the pharmaceutical compositions comprising such compound and salts may also be coadministered with other pharmacologically active substances, e.g. with other anti-neoplastic compounds (e.g. chemotherapy), i.e. used in combination (see combination treatment further below).
• other pharmacologically active substances e.g. with other anti-neoplastic compounds (e.g. chemotherapy), i.e. used in combination (see combination treatment further below).
• the elements of such combinations may be administered (whether dependently or independently) by methods customary to the skilled person and as they are used in monotherapy, e.g. by oral, enterical, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or implant), nasal, vaginal, rectal, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.
• oral, enterical, parenteral e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or implant
• nasal, vaginal, rectal, or topical routes of administration e.g., nasal, vaginal, rectal, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.
• the combinations may be administered at therapeutically effective single or divided daily doses.
• the active components of the combinations may be administered in such doses which are therapeutically effective in monotherapy, or in such doses which are lower than the doses used in monotherapy, but when combined result in a desired (joint) therapeutically effective amount.
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).
• the invention also relates to a pharmaceutical preparation
• a pharmaceutical preparation comprising a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).
• compositions to be co-administered or used in combination can also be provided in the form of a kit.
• the invention also relates to a kit comprising
• a first pharmaceutical composition or dosage form comprising a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) and, optionally, one or more pharmaceutically acceptable excipient(s), and
• a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipient(s).
• such kit comprises a third pharmaceutical composition or dosage form comprising still another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipient(s).
• the present invention is mainly directed to EGFR inhibitors, in particular compounds of formula (I) (including all individual embodiments and generic subsets disclosed herein), which are potetnially useful in the treatment and/or prevention of diseases and/or conditions associated with or modulated/mediated by mutant EGFR, especially wherein the inhibition of the mutant EGFR is of therapeutic benefit, including but not limited to the treatment and/or prevention of cancer.
• EGFR inhibitors in particular compounds of formula (I) (including all individual embodiments and generic subsets disclosed herein) (including all individual embodiments and generic subsets disclosed herein), which are potetnially useful in the treatment and/or prevention of diseases and/or conditions associated with or modulated/mediated by mutant EGFR, especially wherein the inhibition of the mutant EGFR is of therapeutic benefit, including but not limited to the treatment and/or prevention of cancer.
• the invention relates to a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - for use as a medicament.
• the invention relates to a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - for use in a method of treatment of the human or animal body.
• the invention relates to a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - for use in the treatment and/or prevention of a disease and/or condition mediated by mutant EGFR.
• the invention relates to the use of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - in the manufacture of a medicament for the treatment and/or prevention of a disease and/or condition mediated by mutant EGFR.
• the invention in another aspect relates to a method for the treatment and/or prevention of a disease and/or condition mediated by mutant EGFR comprising administering a therapeutically effective amount of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - to a human being.
• the invention relates to a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - for use in the treatment and/or prevention of cancer.
• the invention relates to a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - for use in a method of treatment and/or prevention of cancer in the human or animal body.
• the invention relates to the use of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - in the manufacture of a medicament for the treatment and/or prevention of cancer.
• the invention in another aspect relates to a method for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - to a human being.
• the invention relates to a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - for use in providing an inhibitory effect on mutant EGFR.
• the invention relates to the use of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - in the manufacture of a medicament for use in providing an inhibitory effect on mutant EGFR.
• the invention in another aspect relates to a method for providing an inhibitory effect on mutant EGFR comprising administering a therapeutically effective amount of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - to a human being.
• Another aspect is based on identifying a link between the EGFR mutation status of a patient and potential susceptibility to treatment with a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein).
• An EGFR inhibitor such as a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) may then advantageously be used to treat patients with EGFR mutations who may be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients for treatment with a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein), particularly cancer patients. The selection is based on whether the tumor cells to be treated possess wild-type or mutant EGFR gene.
• EGFR gene status could therefore be used as a biomarker to indicate that selecting treatment with a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) may be advantageous.
• a method for selecting a patient for treatment with a compound of formula (I) comprising
• a tumor cell-containing sample preferably a tumor DNA-containing sample
• the method may include or exclude the actual patient sample isolation step.
• Wild EGFR refers to both a mutant EGFR gene and/or the corresponding protein derived from such mutant EGFR gene, and includes, but is not limited to:
• the mutant EGFR comprises mutations del19 T790M.
• the mutant EGFR comprises mutations del19 C797mut.
• the mutant EGFR comprises mutations del19 C797S. In another aspect of the invention [K16] the mutant EGFR comprises mutations del19 C797G.
• the mutant EGFR comprises mutations del19 C797N.
• the mutant EGFR comprises mutations del19 T790M C797mut.
• the mutant EGFR comprises mutations del 19 T790M C797S.
• the mutant EGFR comprises mutations del19 T790M C797G.
• the mutant EGFR comprises mutations del 19
• the mutant EGFR comprises mutations del 19
• the mutant EGFR comprises mutations del 19
• the mutant EGFR comprises mutations del19 L792H.
• the mutant EGFR comprises mutations del19 L792Y.
• the mutant EGFR comprises mutations del19 T790M L792mut.
• the mutant EGFR comprises mutations del19 T790M L792F.
• the mutant EGFR comprises mutations del19 T790M L792H.
• the mutant EGFR comprises mutations del19
• the mutant EGFR comprises EGFR L858R T790M.
• the mutant EGFR comprises EGFR L858R C797mut.
• the mutant EGFR comprises mutations L858R C797S. In another aspect of the invention [K33] the mutant EGFR comprises mutations L858R C797G.
• the mutant EGFR comprises mutations L858R C797N.
• the mutant EGFR comprises mutations L858R T790M C797mut.
• the mutant EGFR comprises mutations L858R T790M C797S.
• the mutant EGFR comprises mutations L858R T790M C797G.
• the mutant EGFR comprises mutations L858R T790M C797N.
• the mutant EGFR comprises mutations L858R L792mut.
• the mutant EGFR comprises mutations L858R L792F.
• the mutant EGFR comprises mutations L858R L792H.
• the mutant EGFR comprises mutations L858R L792Y.
• the mutant EGFR comprises mutations L858R T790M L792mut.
• the mutant EGFR comprises mutations L858R T790M L792F.
• the mutant EGFR comprises mutations L858R T790M L792H.
• the mutant EGFR comprises mutations L858R T790M L792Y.
• the patient is selected for treatment with a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) if the tumor cell DNA harbours a mutant EGFR gene, wherein the mutant EGFR gene is preferably selected from any one of [K1] to [K46],
• a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene is preferably selected from any one of [K1] to [K46],
• a method of treating a cancer with tumor cells harbouring a mutant EGFR gene comprising administering a therapeutically effective amount of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - to a human being, wherein the mutant EGFR gene is preferably selected from any one of [K1] to [K46],
• the invention relates to the use of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) - or a pharmaceutically acceptable salt thereof - in the manufacture of a medicament for use in treating a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene is preferably selected from any one of [K1] to [K46],
• Determining whether a tumor or cancer comprises a mutant EGFR can be undertaken by assessing the nucleotide sequence encoding the EGFR protein at DNA or RNA level, by assessing the amino acid sequence of the EGFR protein, or by assessing the characteristics of a putative EGFR mutant protein.
• the sequence of wild-type human EGFR is known in the art. Methods for detecting a mutation in an EGFR nucleotide sequence are known by those of skill in the art.
• PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
• PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
• real-time PCR assays PCR sequencing
• mutant allele-specific PCR amplification (MASA) assays digital droplet PCR
• direct sequencing primer extension reactions
• electrophoresis oligonucleotide ligation assays
• hybridization assays TaqMan assays
• SNP genotyping assays high resolution melting assays
• microarray analyses and next generation sequencing.
• samples are evaluated for EGFR mutations by realtime PCR.
• fluorescent probes specific for the EGFR mutation are used. When a mutation is present, the probe binds and fluorescence is detected.
• the EGFR mutation is identified using a direct sequencing method of specific regions in the EGFR gene. This technique will identify all possible mutations in the region sequenced. Methods for detecting a mutation in an EGFR protein are known by those of skill in the art. These methods include, but are not limited to, detection of an EGFR mutant using a binding agent (e.g. an antibody) specific for the mutant protein, protein electrophoresis, Western blotting and direct peptide sequencing.
• a binding agent e.g. an antibody
• Methods for determining whether a tumor or cancer comprises an EGFR mutation can use a variety of samples.
• the sample is taken from a subject having a tumor or cancer.
• the sample is a fresh tumor/cancer sample.
• the sample is a frozen tumor/cancer sample.
• the sample is a formalin-fixed paraffin-embedded sample.
• the sample is processed to a cell lysate.
• the sample is processed to DNA or RNA.
• the sample is a liquid biopsy and the test is done on a sample of blood, urine, sputum or other body fluid to look for cancer cells from a tumor that are contained within these samples or for pieces of DNA from tumor cells that are contained within these samples.
• the disease/condition/cancer to be treated/prevented with the compound of formula (I) is selected from the group consisting of lung cancer, brain cancers, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastasis (in particular brain metastasis) of all cancers listed.
• the disease/condition/cancer to be treated/prevented with the compound of formula (I) is lung cancer.
• the lung cancer to be treated is non-small cell lung cancer (NSCLC) including, e.g., locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology and NSCLC with non-squamous histology.
• NSCLC non-small cell lung cancer
• the lung cancer to be treated is NSCLC adenocarcinoma.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a first line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are treatment naive in respect of EGFR TKIs.
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations del 19 T790M.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 1 st or 2 nd generation EGFR TKI ⁇ i.e. the patients are progressing after prior treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations del 19 C797S.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 3 rd generation EGFR TKI i.e. the patients are progressing after prior treatment with, e.g., osimertinib, olmutinib, toartinib, lazertinib, almonertinib or avitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations dell 9 C797mut (preferably C797G or C797N).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 3 rd generation EGFR TKI ⁇ i.e. the patients are progressing after prior treatment with, e.g., osimertinib, olmutinib, toartinib, lazertinib, almonertinib or avitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations del19 T790M C797S.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment (in respect of treatment with EGFR TKIs), i.e. the patients progressed on earlier therapy with a 1 st or 2 nd generation EGFR TKI ⁇ i.e.
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations del19 T790M C797mut (preferably C797G or C797N).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment (in respect of treatment with EGFR TKIs), i.e. the patients progressed on earlier therapy with a 1 st or 2 nd generation EGFR TKI (/.e.
• the patients progressed after earlier treatment with gefitinib, erlotinib, icotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on additional therapy with a 3 rd generation EGFR TKI ⁇ i.e. the patients are progressing after additional treatment with, e.g., osimertinib, olmutinib, soloartinib, lazertinib, almonertinib or avitinib) upon C797mut (preferably C797G or C797N) acquisition.
• C797mut preferably C797G or C797N
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations del 19 L792mut (preferably L792F, L792H or L792Y).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 3 rd generation EGFR TKI i.e. the patients are progressing after prior treatment with, e.g., osimertinib, olmutinib, toartinib, lazertinib, almonertinib or avitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations del 19 T790M L792mut (preferably L792F, L792H or L792Y).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment (in respect of treatment with EGFR TKIs), i.e. the patients progressed on earlier therapy with a 1 st or 2 nd generation EGFR TKI ⁇ i.e.
• the patients progressed after earlier treatment with gefitinib, erlotinib, icotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on additional therapy with a 3 rd generation EGFR TKI (/.e. the patients are progressing after additional treatment with, e.g., osimertinib, olmutinib, soloartinib, lazertinib, almonertinib or avitinib) upon L792mut (preferably L792F, L792H or L792Y) acquisition.
• L792mut preferably L792F, L792H or L792Y
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises L858R mutation.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a first line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are treatment naive in respect of EGFR TKIs.
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations L858R T790M.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 1 st or 2 nd generation EGFR TKI ⁇ i.e. the patients are progressing after prior treatment with gefitinib, erlotinib, icotinib, afatinib or dacomitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations L858R C797S.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 3 rd generation EGFR TKI i.e. the patients are progressing after treatment with, e.g., osimertinib, olmutinib, toartinib, lazertinib, almonertinib or avitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations L858R C797mut (preferably C797G or C797N).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 3 rd generation EGFR TKI ⁇ i.e. the patients are progressing after prior treatment with, e.g., osimertinib, olmutinib, toartinib, lazertinib, almonertinib or avitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations L858R T790M C797S.
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment (in respect of treatment with EGFR TKIs), i.e. the patients progressed on earlier therapy with a 1 st or 2 nd generation EGFR TKI ⁇ i.e.
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations L858R T790M C797mut (preferably C797G or C797N).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment (in respect of treatment with EGFR TKIs), i.e. the patients progressed on earlier therapy with a 1 st or 2 nd generation EGFR TKI ⁇ i.e.
• the patients progressed after earlier treatment with gefitinib, erlotinib, icotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on additional therapy with a 3 rd generation EGFR TKI ⁇ i.e. the patients are progressing after additional treatment with, e.g., osimertinib, olmutinib, soloartinib, lazertinib, almonertinib or avitinib) upon C797mut (preferably C797G or C797N) acquisition.
• C797mut preferably C797G or C797N
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations L858R L792mut (preferably L792F, L792H or L792Y).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs), i.e. the patients are progressing on earlier therapy with a 3 rd generation EGFR TKI ⁇ i.e. the patients are progressing after prior treatment with, e.g., osimertinib, olmutinib, toartinib, lazertinib, almonertinib or avitinib).
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer with tumor cells harbouring a mutant EGFR gene, wherein the mutant EGFR gene comprises mutations L858R T790M L792mut (preferably L792F, L792H or L792Y).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment (in respect of treatment with EGFR TKIs), i.e. the patients progressed on earlier therapy with a 1 st or 2 nd generation EGFR TKI (/.e.
• the patients progressed after earlier treatment with gefitinib, erlotinib, icotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on additional therapy with a 3 rd generation EGFR TKI ⁇ i.e. the patients are progressing after additional treatment with, e.g., osimertinib, olmutinib, soloartinib, lazertinib, almonertinib or avitinib) upon L792mut (preferably L792F, L792H or L792Y) acquisition.
• L792mut preferably L792F, L792H or L792Y
• the cancer (including all embodiments as disclosed herein) to be treated is a cancer which is progressing after earlier treatment with a 3 rd generation EGFR TKI i.e. the cancer is progressing after prior treatment with, e.g., osimertinib, olmutinib, tonicartinib, lazertinib, almonertinib or avitinib).
• the cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment (in respect of treatment with EGFR TKIs).
• cancer patients to be treated and suffering from such a cancer have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment (in respect of treatment with EGFR TKIs).
• Preferred treatment in these settings is treatment after prior treatment with osimertinib.
• the compounds of the invention may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases/conditions/cancers/tumors, optionally also in combination with radiotherapy and/or surgery.
• the methods of treatment, methods, uses and compounds for use as disclosed herein can be performed with any compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) and with any pharmaceutical composition or kit comprising a compound of formula (I) - or a pharmaceutically acceptable salt thereof (including all individual embodiments and generic subsets disclosed herein).
• the compounds of formula (I) - or the pharmaceutically acceptable salts thereof - (including all individual embodiments and generic subsets disclosed herein) and the pharmaceutical compositions comprising such compound and salts may also be co-administered with other pharmacologically active substances, e.g. with other anti-neoplastic compounds ⁇ e.g. chemotherapy), or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
• the pharmacologically acive substance(s) for co-administration is/are (an) anti-neoplastic compound(s).
• the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) for use as hereinbefore disclosed, wherein said compound is administered before, after or together with one or more other pharmacologically active substance(s).
• the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) for use as hereinbefore disclosed, wherein said compound is administered in combination with one or more other pharmacologically active substance(s).
• the invention relates to the use of a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) as hereinbefore disclosed wherein said compound is to be administered before, after or together with one or more other pharmacologically active substance(s).
• the invention relates to a method ⁇ e.g. a method for the treatment and/or prevention) as hereinbefore disclosed wherein the compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) is administered before, after or together with a therapeutically effective amount of one or more other pharmacologically active substance(s).
• the invention relates to a method e.g. a method for the treatment and/or prevention) as hereinbefore disclosed wherein the compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substance(s).
• the invention relates to a method for the treatment and/or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) and a therapeutically effective amount of one or more other pharmacologically active substance(s), wherein the compound of formula (I) - or the pharmaceutically acceptable salt thereof - is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the one or more other pharmacologically active substance(s).
• the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) for use in the treatment and/or prevention of cancer, wherein the compound of formula (I) - or the pharmaceutically acceptable salt thereof - is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the one or more other pharmacologically active substance(s).
• the invention relates to a kit comprising
• a first pharmaceutical composition or dosage form comprising a compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments and generic subsets disclosed herein) and, optionally, one or more pharmaceutically acceptable excipient(s), and
• a second pharmaceutical composition or dosage form comprising another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable excipient(s), for use in the treatment and/or prevention of cancer, wherein the first pharmaceutical composition is to be administered simultaneously, concurrently, sequentially, successively, alternately or separately with the second and/or additional pharmaceutical composition or dosage form.
• kit for said use comprises a third pharmaceutical composition or dosage form comprising a third pharmaceutical composition or dosage form comprising still another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable excipient(s).
• the components (/.e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention are administered simultaneously.
• the components (/.e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention are administered concurrently.
• the components (/.e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention are administered sequentially.
• the components (/.e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention are administered successively.
• the components (/.e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention are administered alternately.
• the components (/.e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention are administered separately.
• the pharmacologically active substance(s) to be used together/in combination with the compound of formula (I) - or a pharmaceutically acceptable salt thereof - (including all individual embodiments or generic subsets of compounds (I)) or in the medical uses, uses, methods of treatment and/or prevention as herein (above and below) disclosed can be selected from any one or more of the following (preferably there is one or two additional pharmacologically active substance used in all these embodiments):
• an inhibitor of EGFR and/or ErbB2 (HER2) and/or ErbB3 (HER3) and/or ErbB4 (HER4) or of any mutants thereof a. irreversible inhibitors: e.g. afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, olmutinib, osimertinib, almonertinib, Ricoartinib, lazertinib, pelitinib; b. reversible inhibitors: e.g.
• anti-EGFR antibodies e.g. necitumumab, panitumumab, cetuximab, amivantanab
• anti-HER2 antibodies e.g. pertuzumab, trastuzumab, trastuzumab emtansine; e. inhibitors of mutant EGFR; f. an inhibitor of HER2 with exon 20 mutations; g.
• preferred irreversible inhibitor is afatinib; h. preferred anti-EGFR antibody is cetuximab; 2. an inhibitor of MEK and/or of mutants thereof a. e.g. trametinib, cobimetinib, binimetinib, selumetinib, refametinib, BI 3011441; b. preferred are trametinib and BI 3011441; c. most preferred is BI 3011441; 3. an inhibitor of c-MET and/or of mutants thereof a. e.g. savolitinib, cabozantinib, foretinib; b. MET antibodies, e.g.
• emibetuzumab, amivantanab 4. an inhibitor of SOS1 and/or of any mutants thereof (i.e. a compound that modulates/inhibits the GEF functionality of SOS1, e.g. by binding to SOS1 and preventing protein-protein interaction between SOS1 and a (mutant) Ras protein, e.g. KRAS) a. e.g. BAY-293, BI-3406, BI 1701963; b. most preferred is BI 1701963; 5. an inhibitor of GDP-loaded or GTP-loaded RAS and/or of any mutants thereof (i.e.
• an immunotherapeutic agent a. e.g.
• b. e.g. an immuno modulator i. e.g. CD73 inhibitors or CD73 inhibitory antibodies 7.
• an inhibitor of ALK and/or of any mutants thereof a. e.g. crizotinib, alectinib, entrectinib, brigatinib, ceritinib; b. preferred are crizotinib and alectinib; c. most preferred is crizotinib; 8.
• inhibitors of CDK4/6 and/or of any mutants therof i. e.g. palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600; ii. preferred are palbociclib and abemaciclib; iii. most preferred is abemaciclib.
• an inhibitor of a Src family kinase and/or of any mutants thereof a. e.g. an inhibitor of a kinase of the SrcA subfamily and/or of any mutants thereof, i.e. an inhibitor of Src, Yes, Fyn, Fgr and/or of any mutants thereof; b. e.g.
• an inhibitor of a kinase of the SrcB subfamily and/or of any mutants thereof i.e. an inhibitor of Lck, Hck, Blk, Lyn and/or of any mutants thereof;
• an apoptosis inducing agent a. e.g.
• an MCL-1 inhibitor i. e.g. AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477; b. e.g. a Bcl-2 inhibitor; i. e.g. venetoclax, obatoclax, navitoclax, oblimersen; c. e.g. a Bcl-xL inhibitor 15.
• an anti-angiogenic agent a. e.g. bevacizumab, nintedanib; b. most preferred ist bevacizumab; c. e.g. an anti-VEGF/Ang2 bispecific antibody i. e.g.
• bispecific binding molecules as disclosed and described in WO 2012/131078 and WO 2018/220169; 16.
• an inhibitor of histone deacetylase 18.
• an inhibitor of IL6 19.
• an inhibitor of JAK and/or of any mutants thereof 20 a.
• encorafenib dabrafenib
• vemurafenib vemurafenib
• PLX-8394 RAF-709
• RAF-709 example 131 in WO 2014/151616
• an inhibitor of SHP2 and/or of any mutants thereof a. e.g. SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.
• one other pharmacologically active substance is to be administered before, after or together with the compound of formula (I) – or a pharmaceutically acceptable salt thereof – (including all individual embodiments and generic subsets disclosed herein) wherein said one other pharmacologically active substance is ⁇ a SOS1 inhibitor; or ⁇ BI 1701963; or ⁇ a MEK inhibitor; or ⁇ trametinib, or ⁇ BI 3011441, or ⁇ an anti-PD-1 antibody; or ⁇ ezabenlimab, or ⁇ cetuximab; or ⁇ afatinib; or ⁇ an inhibitor of GDP-loaded or GTP-loaded mutant KRAS; or ⁇ an MCL1 inhibitor; or ⁇ a PI3K inhibitor.
• one other pharmacologically active substance is to be administered in combination with the compound of formula (I) – or a pharmaceutically acceptable salt thereof – (including all individual embodiments and generic subsets disclosed herein) wherein said one other pharmacologically active substance is ⁇ a SOS1 inhibitor; or ⁇ BI 1701963 ⁇ a MEK inhibitor; or ⁇ trametinib, or ⁇ BI 3011441, or ⁇ an anti-PD-1 antibody; or ⁇ ezabenlimab, or ⁇ cetuximab; or ⁇ afatinib; or ⁇ an inhibitor of GDP-loaded or GTP-loaded mutant KRAS; or ⁇ an MCL1 inhibitor; or ⁇ a PI3K inhibitor.
• two other pharmacologically active substances are to be administered before, after or together with the compound of formula (I) – or a pharmaceutically acceptable salt thereof – (including all individual embodiments and generic subsets disclosed herein) wherein said two other pharmacologically active substances are ⁇ a MEK inhibitor and a SOS1 inhibitor; or ⁇ trametinib and a SOS1 inhibitor; or ⁇ trametinib and BI 1701963, or ⁇ BI 3011441 and BI 1701963, or ⁇ an anti-PD-1 antibody and an anti-LAG-3 antibody; or ⁇ an anti-PD-1 antibody and an anti-CTLA-4 antibody; or ⁇ an anti-PD-1 antibody and a SOS1 inhibitor; or ⁇ ezabenlimab and BI 1701963; or ⁇ a MEK inhibitor and an inhibitor selected from the group consisting of an
• two other pharmacologically active substances are to be administered in combination with the compound of formula (I) – or a pharmaceutically acceptable salt thereof – (including all individual embodiments and generic subsets disclosed herein) wherein said two other pharmacologically active substances are ⁇ a MEK inhibitor and a SOS1 inhibitor; or ⁇ trametinib and a SOS1 inhibitor; or ⁇ trametinib and BI 1701963, or ⁇ BI 3011441 and BI 1701963, or ⁇ an anti-PD-1 antibody and an anti-LAG-3 antibody; or ⁇ an anti-PD-1 antibody and an anti-CTLA-4 antibody; or ⁇ an anti-PD-1 antibody and a SOS1 inhibitor; or ⁇ ezabenlimab and BI 1701963; or ⁇ a MEK inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor
• Additional pharmacologically active substance(s) which can also be used together/in combination with the compound of formula (I) – or a pharmaceutically acceptable salt thereof – (including all individual embodiments or generic subsets of compounds (I)) or in the medical uses, uses, methods of treatment and/or prevention as herein (above and below) disclosed include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g.
• tamoxifen toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g.
• growth factors such as for example platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER, e.g.
• growth factors such as for example platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER, e.g.
• PDGF platelet derived growth factor
• FGF fibroblast growth factor
• VEGF vascular endothelial growth factor
• EGF epidermal growth factor
• IGF insuline-like growth factors
• HER human epidermal growth factor
• inhibitors are for example (anti-)growth factor antibodies, (anti-)growth factor receptor antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab); antimetabolites (e.g.
• antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (e.g.
• anthracyclins such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non- pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g.
• epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g.
• PDK 1 inhibitors Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1/2 inhibitors, PI3K inhibitors, PI3K ⁇ inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors), protein protein interaction inhibitors (e.g.
• IAP inhibitors/SMAC mimetics Mcl-1, MDM2/MDMX
• MEK inhibitors ERK inhibitors
• FLT3 inhibitors BRD4 inhibitors
• IGF-1R inhibitors TRAILR2 agonists
• Bcl-xL inhibitors Bcl-2 inhibitors (e.g. venetoclax)
• Bcl-2/Bcl-xL inhibitors ErbB receptor inhibitors
• BCR-ABL inhibitors e.g.
• anti-CD33 antibodies anti-CD37 antibodies, anti-CD20 antibodies
• t-cell engagers e.g. bi-specific T-cell engagers (BiTEs ® ) like e.g. CD3 x BCMA, CD3 x CD33, CD3 x CD19), PSMA x CD3
• tumor vaccines and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
• the combinations, compositions, kits, methods, uses or compounds for use according to this invention may envisage the simultaneous, concurrent, sequential, successive, alternate or separate administration of the active ingredients or components.
• the compound of formula (I) – or a pharmaceutically acceptable salt thereof – and the one or more other pharmacologically active substance(s) can be administered formulated either dependently or independently, such as e.g. the compound of formula (I) – or a pharmaceutically acceptable salt thereof – and the one or more other pharmacologically active substance(s) may be administered either as part of the same pharmaceutical composition/dosage form or, preferably, in separate pharmaceutical compositions/dosage forms.
• “combination” or “combined” within the meaning of this invention includes, without being limited, a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed (e.g. free) combinations (including kits) and uses, such as e.g. the simultaneous, concurrent, sequential, successive, alternate or separate use of the components or ingredients.
• the term “fixed combination” means that the active ingredients are administered to a patient simultaneously in the form of a single entity or dosage.
• non-fixed combination means that the active ingredients are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the compounds in the body of the patient.
• the administration of the compound of formula (I) – or a pharmaceutically acceptable salt thereof – and the one or more other pharmacologically active substance(s) may take place by co-administering the active components or ingredients, such as e.g. by administering them simultaneously or concurrently in one single or in two or more separate formulations or dosage forms.
• the administration of the compound of formula (I) – or a pharmaceutically acceptable salt thereof – and the one or more other pharmacologically active substance(s) may take place by administering the active components or ingredients sequentially or in alternation, such as e.g. in two or more separate formulations or dosage forms.
• simultaneous administration includes administration at substantially the same time.
• Concurrent administration includes administering the active agents within the same general time period, for example on the same day(s) but not necessarily at the same time.
• Alternate administration includes administration of one agent during a time period, for example over the course of a few days or a week, followed by administration of the other agent(s) during a subsequent period of time, for example over the course of a few days or a week, and then repeating the pattern for one or more cycles.
• Sequential or successive administration includes administration of one agent during a first time period (for example over the course of a few days or a week) using one or more doses, followed by administration of the other agent(s) during a second and/or additional time period (for example over the course of a few days or a week) using one or more doses.
• An overlapping schedule may also be employed, which includes administration of the active agents on different days over the treatment period, not necessarily according to a regular sequence. Variations on these general guidelines may also be employed, e.g. according to the agents used and the condition of the subject. Definitions Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context.
• heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl relates to the total number of atoms of all the ring members or the total of all the ring and carbon chain members.
• the indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure e.g. cycloalkylalkyl, arylalkyl
• a ring structure has at least three members.
• groups comprising two or more subgroups e.g.
• the last named subgroup is the radical attachment point
• the substituent aryl-C1-6alkyl means an aryl group which is bound to a C1-6alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.
• groups like HO, H 2 N, (O)S, (O) 2 S, NC (cyano), HOOC, F3C or the like the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself.
• Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.
• C1-5alkyl“ includes for example H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-C(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -CH 2 -, H 3 C-CH 2 -C(CH 3 ) 2 -, H 3 C-C(CH 3 ) 2
• alkyl examples include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-propyl, n-Pr, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, iso-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-butyl, n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (iso-butyl, i-Bu, -CH 2 CH(CH 3 ) 2 ), 2-butyl (sec-butyl, sec-Bu, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (tert-butyl, t-Bu, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH
• alkyl saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.
• alkyl also applies if alkyl is a part of another (combined) group like, e.g., Cx-yalkylamino or Cx-yalkyloxy.
• alkylene is derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is generated by removing a hydrogen atom from an alkyl.
• Corresponding groups are for example -CH 3 and -CH 2 -, -CH 2 CH 3 and -CH 2 CH 2 - or >CHCH 3 etc.
• C 1-4 alkylene includes for example -(CH 2 )-, -(CH 2 -CH 2 )-, -(CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 )-, -(C(CH 3 ) 2 )-, -(CH(CH 2 CH 3 ))-, -(CH(CH 3 )-CH 2 )-, -(CH 2 -CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 )-, -(CH 2 -CH 2 -CH(CH 3 ))-, -(CH 2 -CH 2 -CH(CH 3 ))-, -(CH(CH 3 )-CH 2 -CH 2 )-, -(CH 2 -CH(CH 3 )-
• alkylene examples include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene etc.
• propylene, butylene, pentylene, hexylene or the like without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.
• alkylene also applies if alkylene is part of another (combined) group like, e.g., in HO-Cx-yalkyleneamino or H 2 N-Cx-yalkyleneoxy.
• alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.
• alkenyl examples include vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbuty
• propenyl includes prop-1-enyl and prop-2-enyl
• butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.
• Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).
• the above definition for alkenyl also applies if alkenyl is part of another (combined) group like, e.g., in C x-y alkenylamino or C x-y alkenyloxy.
• alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond.
• alkenylene is formed.
• alkenylene examples include ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc.
• propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.
• Alkenylene may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).
• alkenylene also applies if alkenylene is a part of another (combined) group like for example in HO-Cx-yalkenyleneamino or H 2 N-Cx-yalkenyleneoxy.
• alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.
• alkynyl examples include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, etc.
• propynyl includes prop-1-ynyl and prop-2-ynyl
• butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.
• alkynyl belongs to the alkynyl subgroup.
• alkynyl is part of another (combined) group, like, e.g., in C x-y alkynylamino or C x-y alkynyloxy.
• alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond.
• alkynylene is formed.
• alkynylene examples include ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene etc.
• propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.
• alkynylene also applies if alkynylene is part of another (combined) group like, e.g., in HO-Cx-yalkynyleneamino or H 2 N-Cx-yalkynyleneoxy.
• heteroatoms are meant oxygen, nitrogen, phosphor and sulphur atoms.
• heteroatoms are selected from oxygen, nitrogen and sulphur.
• Haloalkyl haloalkenyl, haloalkynyl
• alkynyl is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different.
• haloalkyl haloalkenyl, haloalkynyl
• the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.
• haloalkyl haloalkenyl, haloalkynyl
• haloalkyl haloalkenyl, haloalkynyl
• -CCl CH 2
• -CBr CH 2 , -C ⁇ C-CF 3 , -CHFCH 2 CH 3 , -CHFCH 2 CF 3 etc.
• haloalkyl haloalkenyl, haloalkynyl
• haloalkynylene haloalkenylene, haloalkynylene
• Haloalkylene haloalkenylene, haloalkynylene
• haloalkenyl, haloalkynyl is bivalent and requires two binding partners.
• the second valency is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl).
• Corresponding groups are for example -CH 2 F and -CHF-, -CHFCH 2 F and -CHFCHF- or >CFCH 2 F etc.
• Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
• cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.
• cycloalkyl also applies if cycloalkyl is part of another (combined) group like, e.g., in Cx-ycycloalkylamino, Cx-ycycloalkyloxy or Cx-ycycloalkylalkyl. If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained (with all definitions for cycloalkyl applying accordingly to the alicyclic group).
• cycloalkylene is derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners.
• the second valency is obtained by removing a hydrogen atom from a cycloalkyl.
• Corresponding groups are for example: cyclohexyl and (cyclohexylene).
• the above definition for cycloalkylene also applies if cycloalkylene is part of another (combined) group like, e.g., in HO-C x-y cycloalkyleneamino or H 2 N-C x-y cycloalkyleneoxy.
• the systems are unsaturated, i.e. there is at least one C-C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained.
• a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.
• cycloalkenyl examples include cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dien
• cycloalkenyl also applies when cycloalkenyl is part of another (combined) group like, e.g., in C x-y cycloalkenylamino, C x-y cycloalkenyloxy or C x-y cycloalkenylalkyl. If the free valency of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained (with all definitions for cycloalkenyl applying accordingly to the unsaturated alicyclic group).
• the term cycloalkenylene can thus be derived from the previously defined cycloalkenyl.
• Cycloalkenylene unlike cycloalkenyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkenyl.
• Corresponding groups are for example: etc.
• the above definition for cycloalkenylene also applies if cycloalkenylene is part of another (combined) group like, e.g., in HO-Cx-ycycloalkenyleneamino or H 2 N-Cx-ycycloalkenyleneoxy.
• Aryl denotes mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle.
• aryl denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or may also be partially saturated.
• substitutions may take place independently of one another, in the form of mono or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.
• Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system.
• aryl examples include phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2- dihydronaphthyl), fluorenyl etc. Most preferred is phenyl.
• aryl also applies if aryl is part of another (combined) group like, e.g., in arylamino, aryloxy or arylalkyl.
• arylene can also be derived from the previously defined aryl.
• Arylene unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl.
• Corresponding groups are for example: phenyl (o, m, p-phenylene), naphthyl .
• arylene also applies if arylene is part of another (combined) group like, e.g., in HO-aryleneamino or H 2 N-aryleneoxy.
• Heteroatoms may optionally be present in all the possible oxidation stages (e.g., sulphur ⁇ sulphoxide -SO-, sulphone -SO2-; nitrogen ⁇ N- oxide).
• oxidation stages e.g., sulphur ⁇ sulphoxide -SO-, sulphone -SO2-; nitrogen ⁇ N- oxide.
• heterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is part of an aromatic system.
• unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed.
• bicyclic heterorings two rings are linked together so that they have at least two (hetero)atoms in common.
• one carbon atom belongs to two rings together. If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Substituents on heterocyclyl do not count for the number of members of a heterocyclyl, i.e. a given number of members of a heterocyclyl only refers to the number of atoms forming the ring/ring system of the heterocyclyl.
• heterocyclyl examples include tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothien
• heterocyclyls are 4 to 8 membered, monocyclic and have one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.
• Preferred heterocyclyls are: piperazinyl, piperidinyl, morpholinyl, homomorpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6- azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2-oxa-5- azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl.
• Preferred monocyclic heterocyclyl is 4 to 7 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.
• Preferred monocyclic heterocyclyls are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azetidinyl.
• Preferred bicyclic heterocyclyl is 6 to 10 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.
• Preferred tricyclic heterocyclyl is 9 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.
• Preferred spiro heterocyclyl is 7 to 11 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.
• heterocyclyl also applies if heterocyclyl is part of another (combined) group like, e.g., in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl. If the free valency of a heterocyclyl is saturated, then a heterocycle is obtained (with all definitions for heterocyclyl applying accordingly to the heterocycle).
• heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl.
• heterocyclylene is part of another (combined) group like, e.g., in HO-heterocyclyleneamino or H 2 N-heterocyclyleneoxy.
• Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable.
• heteroaryl The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system. If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molecule via every suitable position of the ring system, both carbon and nitrogen. Substituents on heteroaryl do not count for the number of members of a heteroaryl, i.e. a given number of members of a heteroaryl only refers to the number of atoms forming the ring/ring system of the heteroaryl.
• heteroaryl examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N- oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,
• heteroaryls are 5-6 membered monocyclic or 9-10 membered bicyclic, each with 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.
• heteroaryl also applies if heteroaryl is part of another (combined) group like, e.g., in heteroarylamino, heteroaryloxy or heteroarylalkyl. If the free valency of a heteroaryl is saturated, a heteroaromatic ring is obtained (with all definitions for heteroaryl applying accordingly to the heteroaromatic ring).
• the term heteroarylene is also derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners.
• the second valency is obtained by removing a hydrogen atom from a heteroaryl.
• Corresponding groups are for example: pyrrolyl etc.
• the above definition of heteroarylene also applies if heteroarylene is part of another (combined) group like, e.g., in HO-heteroaryleneamino or H 2 N-heteroaryleneoxy.
• substituted is meant that a hydrogen atom which is bound directly to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom.
• substitution may be carried out by a bivalent substituent only at ring systems and requires replacement of two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution.
• Stereochemistry/Solvates/Hydrates Unless specifically indicated, throughout the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates and hydrates of the free compound or solvates and hydrates of a salt of the compound.
• a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate
• substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents. Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g.
• salts The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl- benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.
• compositions of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
• Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention are also part of the invention.
• the letter A has the function of a ring designation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings.
• the dotted circle in ring A denotes that each bond between ring members in ring A can be independently selected from a single bond, a double bond or a (hetero)aromatic bond.
• a (hetero)aromatic bond is a bond comprising delocalized binding electrons with a bond order between a single and a double bond.
• ring A is a (hetero)aromatic ring.
• Groups or substituents are frequently selected from among a number of alternative groups/substituents with a corresponding group designation (e.g. Ra, Rb etc). If such a group is used repeatedly to define a compound according to the invention in different parts of the molecule, it is pointed out that the various uses are to be regarded as totally independent of one another.
• a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient. List of abbreviations
• Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM or in Synthos 3000 or Monowave 3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.
• Thin layer chromatography is carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescence indicator F-254) made by Merck.
• the preparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with, e.g., columns made by Waters (names: Sunfire C18 OBD, 10 pm, 30 x 100 mm Part. No. 186003971 ; X-Bridge C18 OBD, 10 pm, 30 x 100 mm Part. No. 186003930).
• the compounds are eluted using, e.g., different gradients of H2O/ACCN wherein 0.2 % HCOOH is added to the water (acidic conditions).
• the water is, e.g., made basic according to the following recipe: 5 mL of ammonium hydrogen carbonate solution (158 g to 1 L H2O) and 2 mL 32 % ammonia (aq ) are made up to 1 L with H2O.
• the supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is, e.g., carried out on a JASCO SFC-system with the following colums: Chiralcel OJ (250 x 20 mm, 5 pm), Chiralpak AD (250 x 20 mm, 5 pm), Chiralpak AS (250 x 20 mm, 5 pm), Chiralpak IC (250 x 20 mm, 5 pm), Chiralpak IA (250 x 20 mm, 5 pm), Chiralcel OJ (250 x 20 mm, 5 pm), Chiralcel OD (250 x 20 mm, 5 pm), Phenomenex Lux C2 (250 x 20 mm, 5 pm).
• SFC supercritical fluid chromatography
• the analytical HPLC (reaction monitoring) of intermediate compounds is carried out with, e.g., columns made by Waters and Phenomenex.
• the analytical equipment is also provided with a mass detector in each case.
• Solvent A: 10 mM NH4HCO3 in H 2 O; B: AcCN (HPLC grade)
• Solvent A: H 2 O + 0.2 % HCOOH; B: AcCN (HPLC grade) + 0.2 %
• Solvent A: 20 mM NH4HCO3/NH3 in H 2 O pH 9; B: AcCN (HPLC grade)
• VAB HPLC Agilent 1100/1200 Series MS: Agilent LC/MSD SL Column: Waters XBridge BEH C18, 2.5 ⁇ m, 2.1 x 30 mm XP Solvent: A: 5 mM NH 4 HCO 3 /19 mM NH 3 in H 2 O; B: AcCN (HPLC grade) Detection: MS: positive and negative mode Mass range: 100 – 1200 m/z Flow: 1.40 mL/min Column temperature: 45 °C Gradient: 0.00 – 1.00 min: 5 % B ⁇ 100 % B 1.00 – 1.37 min: 100 % B 1.37
• the A-1 building blocks needed can be synthesized ( ⁇ scheme 2) starting from pyridine derivatives A-7.
• a reduction of the ester group followed by an oxidation leads to the carbaldehydes A-5.
• the ring closure reaction with hydrazine monohydrate (see e.g. WO 2015/94929) followed by protection of the indazole nitrogen in A-4 (e.g. with a Boc or THP group) results in protected indazole A-3.
• a SUZUKI coupling with boronate esters C-1 see e.g. J. Org. Chem.2007, 72, 4067-4072; Org. Lett., 2011, 13, 252-255; J. Org. Chem.
• the key building blocks B-1 are, e.g., accessible via three different synthetic strategies starting from B-3 ( ⁇ scheme 3a): Building blocks B-1 with N-linked residues R4 are available through a nucleophilic aromatic substitution with an excess of the corresponding N-nucleophile/amine B-2 under neat conditions. Building blocks B-1 with O-linked residues R4 are available through a nucleophilic aromatic substitution carried out with an excess of the O-nucleophile/alcohol B-2 and a strong base, e.g. sodium hydride in a suitable solvent (see e.g. US 2016/207924).
• a strong base e.g. sodium hydride in a suitable solvent
• C-C-coupling of R4 can be achieved with a SUZUKI coupling of a boronic acid derivative B-2 of residue R4 using a palladium catalyst (e.g. [1,1'-bis (diphenylphosphino)ferrocene]di- chloropalladium(II)).
• a palladium catalyst e.g. [1,1'-bis (diphenylphosphino)ferrocene]di- chloropalladium(II)
• Building block B-3a can be obtained through the following sequence ( ⁇ scheme 4): Residue R10 is introduced in starting material B-9-a (e.g. via alkylation with the corresponding iodide and potassium carbonate in AcCN or a reductive amination, ⁇ B-8) followed by a reduction of the nitro group with iron to obtain intermediate B-7. B-6a is then available through a ring closure reaction with thiocarbonyldiimidazole (see e.g. WO 2016/196840).
• a chlorination with thionyl chloride leads to B-5a.
• Building block B-3a can then be finally obtained through a nucleophilic aromatic substitution with nucleophiles/amines B-4 (e.g. using potassium carbonate and AcCN as solvent - see e.g. J. Med. Chem. 2007, vol. 50, # 26, p.6450 – 6453).
• intermediate B-5a can be obtained beginning from 2,4,6-trichloropyridine via SNAr with an amine, providing aminopyridine E-4 (see e.g. WO 2006/53166, WO 2008/92942, New J. Chem. 2016, vol. 40, # 11, p.
• the ring closure on intermediate B-7 is performed via amidation with carboxylic acid B-11 to intermediate B-10 and ring condensation under acidic conditions (see e.g. Bioorg. Med. Chem. Lett., 2011, vol.21, # 14, p.4197 – 4202).
• carboxylic acid B-11 is activated, e.g. with polyphosphoric acid, and ring closure/condensation to B-3a can be achieved in a one-step/one-pot reaction.
• R7 H the ring closure can also be performed with trimethyl orthoformate (TMOF) as C1 acid equivalent.
• TMOF trimethyl orthoformate
• Building block B-3b can be obtained through the following sequence ( ⁇ scheme 6): One potential reaction sequence starts with a reduction of the nitro group of starting material B-13-a (e.g. with iron).
• the ring closure reaction on B-12 can be carried out with, e.g., potassium ethylxanthate ( ⁇ B-6b; see e.g. WO 2015/104688).
• a chlorination with sulfuryl chloride leads to B-5b.
• Building block B-3b can then be finally obtained through a nucleophilic aromatic substitution with nucleophiles/amines B-4 (e.g. using potassium carbonate and AcCN as solvent - see e.g. J. Med.
• Building block B-3c* can be obtained through the following sequence ( ⁇ scheme 7): Starting material B-18 is alkylated on the pyrrole ring to give B-17 which is then treated with hydrazine hydrate leading to B-16. A ring closure reaction under acetic conditions leads to B-15 which is then treated with sodium nitrite and hydrochloric acid resulting in B-14 (see e.g. Monatshefte für Chemie 2016, vol.147, # 4, p.783 – 789). In the final step B-3c* is available by a chlorination reaction with a mixture of phosphorus oxychloride and phosphorus pentachloride.
• Building block B-3d* can be obtained through the following sequence ( ⁇ scheme 8):
• the reaction sequence leading to building blocks B-3d* starts with the formylation of B-24 with, e.g., n-BuLi and ethylformate to optain the carbaldehyde B-23 (see e.g. WO 2015/25026).
• a GRIGNARD reaction followed by an oxidation leads to the intermediate B-21 (see e.g. WO 2017/42100).
• B-19 can be obtained through a nucleophilic aromatic substitution with the corresponding glycinate B-20 with, e.g., DIPEA in EtOH.
• the concluding ring closure reaction under basic conditions leads to B-3d*.
• Building block B-3e* can be obtained through the following sequence ( ⁇ scheme 9):
• the multi-step reaction sequence to building blocks B-3e* starts with a nitration of B-31 followed by the reaction of B-30 with oxalic acid diester B-29 to give B-28 (see e.g. WO 2004/104001).
• the reduction of the nitro group results in the ring closure to B-27 (see e.g. WO 2012/80450).
• An iodination with N-iodsuccinimide in DCM gives B-26 followed by an alkylation with the corresponding alkyl halide to obtain B-25.
• the sequence concludes with a SUZUKI coupling to introduce the R9 moieties resulting in B-3e* (see e.g. US 2013/210818).
• Compounds (I) according the invention thus obtained can then be further modified by saponification and derivatization/amidation of the free carboxyl group.
• Building block B-3f can be obtained through the following sequence ( ⁇ scheme 10): Starting again with dichloro pyridine B-7 (see scheme 4 and 5) intermediate B-32 is available through a ring closure. Introduction of residue R6, e.g.
• Building block B-3f can be obtained through the following sequence ( ⁇ scheme 11): Starting with trichloropyridin compounds B-34 the ring closure and introduction of residue R10 is achieved by using a corresponding hydrazine B-33, e.g. in a solvent like MeOH. Building block B-3h can be obtained through the following sequence ( ⁇ scheme 12): Starting with a diazotation of B-36 followed by a ring closure intermediates B-3h (see e.g. WO 2007/117778) can be obtained.
• ⁇ scheme 11 Starting with trichloropyridin compounds B-34 the ring closure and introduction of residue R10 is achieved by using a corresponding hydrazine B-33, e.g. in a solvent like MeOH.
• Building block B-3h can be obtained through the following sequence ( ⁇ scheme 12): Starting with a diazotation of B-36 followed by a ring closure intermediates B-3h (see e.g. WO 2007/117778) can be obtained.
• the mixture is stirred at 20 °C for 3 h, then heated to 78 °C for 8 h.
• the mixture is cooled to 22 °C, and toluene (46.3 mL) is added.
• the mixture is cooled to 15 °C, then water (15.8 mL) is added at a rate to control the internal temperature below 25 °C.
• a solution of sodium hydroxide (50 % in water, 12.64 g, 158.015 mmol, 8.0 eq.) in water (9.9 mL) is added at a rate to keep the temperature below 25 °C to reach pH 7.4.
• the mixture is filtered through Celite, rinsing with toluene (27.8 mL).
• the aqueous phase is removed, and the organic phase is washed with water (9.9 mL).
• the organic phase is circulated through a carbon filter, then the toluene is removed by vacuum distillation. Methylcyclohexane (66 mL) is added, and the vacuum distillation is continued.
• the mixture is heated to 70 °C until a clear solution is obtained, then the mixture is cooled to 20 °C.
• the mixture is filtered and the solid rinsed with heptane (13.2 mL) to give the desired product D-2-a ( 1 H-NMR (500 MHz, DMSO-d6) ⁇ 8.01 (1H, s), 2.70 (3H, s)).
• the mixture is warmed to - 10 °C and stirred for 15 min.
• a solution of tartaric acid (2.58 g, 17.184 mmol, 1.1 eq.) in water (11.4 mL) is added at a rate to control the internal temperature below 5 °C.
• the mixture is warmed to 5 °C and stirred for 15 min.
• a solution of potassium sodium tartrate tetrahydrate (4.41 g, 15.622 mmol, 1.0 eq.) in water (11.4 mL) is added to bring the pH to 6.5, allowing the mixture to warm to rt.
• Isopropyl acetate (18 mL) is added, and the mixture is stirred at rt for 1.5 h.
• B-1a and B-1b (table 3) are available in an analogous manner starting from different building blocks B-3a and B-3b.
• B-3a-a 250 mg, 0.73 mmol
• B-2-d 141 mg; 0.80 mmol
• Pd(II)dppf Cl2 * CH2Cl2 61 mg; 0.07 mmol
• sodium carbonate 196 mg; 1,82 mmol
• dioxane 2.0 mL
• water 1.0 mL
• the reaction mixture is stirred under microwave irradiation at 100 °C for 1 h. Purification via NP 1 yields the unsaturated intermediate which is directly used in the next step.
• a BUCHI lab autoclave is charged with the unsaturated intermediate (215 mg; 0.62 mmol), EtOH (5.0 mL) and tris(triphenylphosphine)rhodium(I)chloride (113 mg; 0.12 mmol). The mixture is stirred for 16 h under 5 bar H2 pressure. The reaction mixture is diluted with DCM and sat. aq. NaHCO3 solution and extracted. The organic phase is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure to give B-1a-z.
• a solution of B-3a-f (18.0 g, 77.56 mmol) in DCM (270.0 mL) is added DESS-MARTIN reagent (39.46 g, 93.08 mmol, 1.2 eq.) at 0 °C and stirred for 12 h at rt.
• the reaction mixture is diluted with sat. NaHCCh solution (500.0 mL) and extracted with DCM (2 x 500 mL). The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure.
• the mixture is cooled to 25 °C, then 30 wt % sodium hydroxide is added (22 eq.) to bring the pH to 7.4.
• the mixture is then filtered and rinsed with toluene (5 mL).
• the aqueous phase is removed, and the organic phase is washed with water (13 mL).
• the aqueous phase is removed, and toluene is removed by vacuum distillation until 7.5 mL remain.
• the mixture is cooled to rt, heptane (7.6 mL) is added, and the mixture is stirred at rt for 1 h before filtering.
• Step 1 B-1b-d (180 mg, 0.4 mmol), A-1-a (100 mg, 0.4 mmol, 1 eq.), tris-(dibenzylideneacetone)- dipalladium(0) (36 mg, 0.04 mmol, 0.1 eq.) and tert-butyl XPhos (36 mg, 0.04 mmol, 0.2 eq.) are charged to a pressure vessel. Toluene (1 mL) and 1,4-dioxane (1 mL) are added and the reaction mixture is purged with argon.
• Step 3 I-003 (40 mg, 0.07 mmol) is dissolved in a mixture of DCM (1 mL) and MeOH (1 mL). Glacial acetic acid (8.3 ⁇ L, 0.14 mmol, 2 eq.) and formaldehyde (37 % in water; 16 ⁇ L, 0.21 mmol, 3 eq.) are added and the reaction mixture is stirred at rt for 10 min. Sodium cyanoborohydride (23.8 mg, 0.36 mmol, 5 eq.) is added and the reaction mixture is stirred at rt for 1 h. The reaction mixture is diluted with water, the aqueous phase is extracted with DCM. The solvent is evaporated, the residue is purified (normal phase chromatography, mobile phase DCM/MeOH) to afford I-004.
• B-1c*-b (3.80 g; 12.63 mmol), A-1-1 (3.25 g; 12.85 mmol), tris-(dibenzylideneacetone)- dipalladium(0) (750 mg, 0.80 mmol) and tert-butyl XPhos (750 mg, 1.68 mmol) are charged to a flask.
• Toluene (100 mL) is added and the reaction mixture is purged with argon.
• Sodium tert-butoxide (2 M in THF; 12.5 mL, 25.0 mmol) is added and the reaction mixture is stirred at 80 °C for 6 h.
• Step 2 I-069 (1.56 g; 2.97 mmol) is dissolved in EtOH (15.0 mL) and water (5 mL) and LiOH (0.5 g; 20.5 mmol) is added and the reaction mixture is stirred for 6.5 h under reflux. The mixture is evaporated to dryness, slurried with water and acidified with aq. 1N HCl to pH 5. The resulting residue is filtered, washed with water and freeze-dried to afford I-070.
• Step 3 I-070 (1.10 g; 2.22 mmol) is dissolved in AcCN (15.0 mL) and DIPEA (1.00 mL; 5.70 mmol). To the solution HATU (1.50 g; 3.75 mmol) is added and the mixture is stirred for 30 min at rt. Morpholine (0.35 mL; 4.05 mmol) is added and stirring at rt is continued for 17 h. The reaction mixture is purified (normal phase chromatography, mobile phase DCM/MeOH/NH4OH) to afford I-071.
• Step 1 B-1d*-a (1.80 g, 4.67 mmol), A-1-a (1.40 g, 5.54 mmol), tris-(dibenzylideneacetone)- dipalladium(0) (350 mg, 0.38 mmol) and tert-butyl XPhos (330 mg, 0.74 mmol) are charged to a flask.
• Toluene (45 mL) is added and the reaction mixture is purged with argon.
• Sodium tert-butoxide (2 M in THF; 4.5 mL, 9.00 mmol) is added and the reaction mixture is stirred at 100 °C for 1 h.
• the reaction mixture is purified (prep HPLC 1) to afford I-082.
• Step 2 I-082 (1.18 g; 2.07 mmol) is dissolved in 1,4-dioxane (16.0 mL) and 4 N hydrogen chloride in 1,4-dioxane (4.0 mL; 46.67 mmol) is added. The reaction mixture is stirred for 3.5 h at 65 °C and afterwards cooled to rt. The resulting precipitate is filtered off, washed with 1,4- dioxane and dried in vacuum to afford I-083.
• Step 3 I-083 (1.10 g; 1.90 mmol) is dissolved in NMP (10.0 mL) and DIPEA (1.75 mL; 10.24 mmol).
• Ba/F3 cell model generation and proliferation assays Ba/F3 cells were ordered from DSMZ (ACC300, Lot17) and grown in RPMI-1640 (ATCC 30-2001) + 10 % FCS + 10 ng/ml IL-3 at 37 °C in 5 % CO 2 atmosphere. Plasmids containing EGFR mutants were obtained from GeneScript. To generate EGFR-dependent Ba/F3 models, Ba/F3 cells were transduced with retroviruses containing vectors that harbor EGFR isoforms. Platinum-E cells (Cell Biolabs) were used for retrovirus packaging. Retrovirus was added to Ba/F3 cells.
• polybrene 4 ⁇ g/mL polybrene was added and cells were spinfected. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10 % to 20 % were further cultivated and puromycin selection with 1 ⁇ g/mL was initiated. As a control, parental Ba/F3 cells were used to show selection status. Selection was considered successful when parental Ba/F3 cells cultures died. To evaluate the transforming potential of EGFR mutations, the growth medium was no longer supplemented with IL-3. Ba/F3 cells harboring the empty vector were used as a control. A switch from IL-3 to EGF was performed for Ba/F3 cells with the wildtype EGFR known for its dependency on EGF ligand.
• Murine Ba/F3 cells were grown in RPMI-1640 (ATCC 30-2001) + 10 % FCS + 10 ng/mL IL-3 at 37 °C in 5 % CO2 atmosphere and transduced with a retroviral vector encoding EGFR del19 T790M C797S. Transduced cells were selected using puromycin. Following selection, IL-3 was withdrawn and IL-3 independent cells cultured. p-EGFR Tyr1068 was determined using the AlphaScreen Surefire pEGF Receptor (Tyr1068) Assay (PerkinElmer, TGRERS).
• Ba/F3 EGFR del19 T790M C797S cells were seeded in DMEM medium with 10 % FCS.60 nL compound dilutions were added to each well of Greiner TC 384 plates using the Echo platform. Subsequently, 60.000 cells/well in 60 ⁇ L were added. Cells were incubated with compound for 4 h at 37 °C. Following centrifugation and removal of the medium supernatant, 20 ⁇ L of 1.6-fold lysis buffer from TGR/Perkin Elmer kit with protease inhibitors was added. The mixture was incubated at room temperature with shaking (700 rpm) for 20 min.
• IC 50 values are computed from these values in the MEGASTAR IC 50 application using a 4 parametric logistic model.
• This cellular phospho-EGFR (pEGFR) compound dose-response assay quantifies the phosphorylation of EGFR at Tyr1068 in Ba/F3 cells expressing the EGFR variant del19 T790M C797S. The results of the assay are provided as IC 50 values (see table 9).
• PC-9 EGFR del19 T790M C797S proliferation assay This assay quantifies the antiproliferative effect of compounds of Table 10 in PC-9 EGFR del19 T790M C797S cells.
• PC-9 is a non-small cell lung cancer cell line obtained from the European Collection of Authenticated Cell Cultures (ECACC #90071810; lot: 14A030) that expresses an oncogenic variant of EGFR called EGFR del19.
• the mutations T790M and C797S are introduced into exon 20 of the genomic EGFR locus in PC-9 parental cells using genome engineering. Successful introduction of the mutations is verified using sequencing.
• Cells are seeded into 96-well plates (150 ⁇ L) in growth medium (RPMI-1640 (Gibco #12633012) + 10% FCS (HyClone #SH30071)).
• Compounds are added by using a HP D3000 Digital Dispenser one day after plating the cells. All treatments are performed in technical triplicates. Treated cells are incubated for 96 h at 37 °C with 5 % CO2.
• Luminescent Cell Viability Assay Promega is performed and chemoluminescence is measured by using the multilabel Plate Reader VICTOR X4.
• the raw data are imported into and analysed with the Boehringer Ingelheim proprietary software MegaLab (curve fitting based on R (library DLC)).
• the quantifications of viable cells are calculated by normalization of compound treated cells to DMSO.
• the 4-Parameter logistic regression model was utilized to calculate dose-response curves.
• the relative IC50 value is defined as the drug concentration at the inflection point of the dose response curve.
• the results of the assay are provided as IC50 values (see table 10).
• the formulation examples which follow illustrate the present invention without restricting its scope:
• the finely ground active substance, lactose and some of the corn starch are mixed together.
• the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
• the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
• the mixture is compressed to produce tablets of suitable shape and size.
• the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
• the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
• the active substance, lactose and cellulose are mixed together.
• the mixture is screened, then either moistened with water, kneaded, wet-granulated and dried or dry-granulated or directely final blend with the magnesium stearate and compressed to tablets of suitable shape and size.

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