Patent Application
20220380382
wherein the groups R to R, A, B and L and p and q 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 (EGFR) 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 (del19) 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+. Del19 and L858R mutations in EGFR sensitize NSCLC tumors to the treatment with EGFR tyrosine kinase inhibitors (TKIs). Clinical experience shows an objective response rate of approximately 60-85% in EGFR M+ NSCLC patients treated in 1st line with the 1st, 2nd and 3rd generation EGFR TKIs erlotinib, gefitinib, afatinib and osimertinib (Mitsudomi, 2010; Park, 2016; Soria, 2017; Zhou, 2011). These responses demonstrate that EGFR M+ NSCLC cells and tumors depend on oncogenic EGFR activity for survival and proliferation, establishing del19 or L858R mutated EGFR as a validated drug target and predictive biomarker for the treatment of NSCLC. The 1st generation EGFR TKIs erlotinib and gefitinib as well as the 2nd generation TKI afatinib are FDA-approved for the 1st line treatment of EGFR M+ NSCLC patients.
While tumor responses are accompanied by marked tumor shrinkage in patients, the response is usually not durable and most patients relapse within 10 to 12 months of treatment with 1st and 2nd generation EGFR TKIs (Mitsudomi, 2010; Park, 2016; Soria, 2017; Zhou, 2011). 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 1st and 2nd generation EGFR inhibitors. This mutation attenuates the inhibitory activity of 1st and 2nd generation TKIs in cellular assays (see data in Table 16).
Mutant selective and covalent 3rd generation EGFR TKIs, such as osimertinib, have been developed that effectively inhibit the primary EGFR mutations del19 and L858R with and without the secondary T790M resistance mutation (Cross, 2014; Wang, 2016). The recently demonstrated efficacy of the 3rd generation EGFR TKI osimertinib in the 2nd line treatment of EGFR M+T790M-positive NSCLC demonstrates clinically that tumor cell survival and proliferation is dependent on the mutated EGFR allele (Janne, 2015; Mok, 2016). Approximately 70% of EGFR M+ T790M-positive patients that were previously treated with earlier generation EGFR TKI respond to osimertinib treatment in 2nd line. However, disease progression occurs after an average duration of 10 months (Mok, 2016). The mechanisms underlying acquired resistance to 3rd generation EGFR TKIs have been studied in small cohorts of patients and are beginning to emerge (Ou, 2017). Recent data suggest that one major resistance mechanism is the acquisition of the tertiary EGFR mutation C797S in about 20-40% of 2nd line patients relapsing on osimertinib TKI (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015). 3rd generation TKIs, such as osimertinib, covalently attach to EGFR via the residue C797 (Cross, 2014; Wang, 2016). In cellular models the C797S mutation abolishes the activity of 3rd generation TKIs tested (Thress, 2015) (see data in Table 16). In 2nd line patients, the mutation C797S is preferentially found in conjunction with the EGFR del19 genotype and on the same allele as the T790M mutation (cis configuration) (82% of C797S+ patients) (Piotrowska, 2017). Crucially, the EGFR del19/L858R T790M C797S cis mutant kinase variant that emerges in 2nd line patients progressing on osimertinib (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015) can no longer be inhibited by 1st, 2nd or 3rd generation EGFR TKIs (Thress, 2015) (see data in Table 16). Based on the fact that the C797S mutation is detected at progression on osimertinib (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015), it is likely that tumor cell survival and proliferation in EGFR del19/L858R T790M C797S patients is dependent on this mutant allele and can be inhibited by targeting this allele. Additional EGFR resistance mutations with a lower incidence than C797S were recently described in 2nd line EGFR M+ NSCLC patients progressing on osimertinib: L718Q, L792F/H/Y and C797G/N (Bersanelli, 2016; Chen, 2017; Ou, 2017).
The 3rd 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 1st 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).
The fact that no approved EGFR TKI can inhibit the EGFR del19/L858R T790M C797S variant, an allele occurring after progression of patients on 2nd line osimertinib treatment, highlights the medical need for a next generation EGFR TKI, a “4th generation EGFR TKI”. This 4th generation EGFR TKI should potently inhibit EGFR del19 or L858R irrespective of the presence of the two common resistance mutations T790M and C797S, especially EGFR del19 T790M C797S. The utility of such a 4th generation EGFR TKI would be enhanced by activity of the compound on additional resistance mutations, such as the potential osimertinib resistance mutations C797X (X=S, G, N) and L792F/H/Y. The broad activity of the molecule on the EGFR del19 or L858R variants also without T790M and/or C797S mutations would ensure that the new compound can effectively cope with the expected allelic complexity in patient tumors as a monotherapy agent. To facilitate efficacious dosing and reduce EGFR-mediated on-target toxicities, a 4th generation EGFR TKI should not inhibit wild-type EGFR. High selectivity across the human kinome would reduce off-target toxicity of the compound. Another desirable property of a 4th generation EGFR TKI is the ability to efficiently penetrate into the brain (blood-brain barrier penetration) in order to be able to treat brain metastasis and leptomeningeal disease. Lastly, a 4th generation EGFR TKI should display a reduced resistance liability compared to existing EGFR TKIs in order to increase the duration of response in patients.
The aforementioned properties of a 4th generation EGFR TKI would allow to treat patients progressing on 2nd line treatment with a 3rd 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 4th generation EGFR TKI to provide a longer duration of response in earlier treatment line patients, such as patients progressing on 1st line osimertinib treatment with EGFR C797S mutations as well as 1st line patients. The activity of a 4th generation EGFR TKI on resistance mutations such as T790M, C797X (X=S, G, N) and L792X (X=F, H, Y) has the potential to delay the development of resistance through EGFR intra target mutations in NSCLC tumors. The characteristics outlined above define a 4th generation EGFR TKI as the first EGFR TKI able to effectively target patients with NSCLC tumors carrying the EGFR del19/L858R T790M C797X/L792X variants. Furthermore, a 4th generation EGFR TKI will be the first C797X active compound that also inhibits T790M-positive alleles, possesses EGFR wild-type sparing activity and effectively penetrates into the brain.
The aforementioned characteristics have not been achieved in previously described EGFR inhibitor compounds. Over the past years, selective targeting of mutated EGFR has gained increasing attention. Until today several efforts to identify and optimize inhibitors, which target either the catalytic site of EGFR mutants or an allosteric site of the EGFR protein, have been made with limited success in respect of the above mentioned characteristics.
Recently, a number of 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 2nd generation EGFR inhibitors. (Patel, 2017; Park, 2017; Chen, 2017). However, these published molecules are either weak inhibitors with low selectivity over EGFR wt (Patel, 2017; Chen, 2017) or were designed to specifically bind only to the del19/T790M/C797S mutant without activity to other EGFR variant combinations and mutations (Park, 2017). Other published compound classes show activity only against the T790M and T790M/C797S resistance mutation in the L858R activation background (Bryan 2016; Juchum, 2017; Gunther, 2017). However, since these mutations and mutation combinations were only observed in a small fraction of the patient population and since allelic complexity in metastatic tumors is likely high, they are very unlikely to fulfill the necessary criteria in order to be developed towards effective EGFR inhibitors.
The following prior art documents disclose non-covalent compounds as mutant selective EGFR inhibitors with activity toward T790M bearing EGFR: WO 2014/210354; WO 2014/081718; Heald, 2015; Hanan, 2014; Lelais, 2016; Chan, 2016.
Although the compounds from the above mentioned documents are claimed to be active against the two most common EGFR activation/resistance mutation combinations del19/T790M and L858/T790M, most of them display only weak activity against the more prevalent del19/T790M mutation, they also display no affinity towards EGFR harboring the primary activation mutations del19 and L858R alone. Such a selective inhibition of the double mutated EGFR over the activity against the single activation mutations is highly unfavorable due to the heterogeneity of EGFR mutations in patients and would likely lead to a limited efficacy. Additionally, most of the compounds show only a small selectivity towards EGFR wt which is known to be the major factor for common side effects in EGFR targeted therapies (diarrhea, skin-rash) leading to a target specific toxicity. This specific cytotoxic component is undesirable, because it potentially leads to adverse events in treated patients.
The following prior art documents disclose aminobenzimidazole based compounds as EGFR selective inhibitors with activity toward both oncogenic driver mutations L858R and del19 as well as activity against the T790M resistance mutation and combination of them: WO 2013/184757; WO 2013/184766, WO 2015/143148, WO 2015/143161, WO 2016/185333; Lelais, 2016; Jia, 2016.
The following prior art documents disclose further aminobenzimidazole based compounds: WO 2003/030902, WO 2003/041708, WO 2004/014369, WO 2004/014905, WO 2005/079791, WO 2007/133983, WO 2012/018668, WO 2014/036016, WO 2014/121942, WO 2016/176473, WO 2017/049068, WO 2017/049069.
Some of the compounds (1) according to the invention have such aminobenzimidazole scaffold as a substructure, but these published prior art compounds do not comprise a macrocycle. Aminobenzimidazoles as part of macrocycles are disclosed in WO 2014/121942 as IRAK inhibitors, which, however, only display a weak inhibitory activity against EGFR mutants (see data in table 16). Furthermore, structurally related previously published aminobenzimidazoles are designed as covalent EGFR inhibitors bearing a reactive (warhead) group in the molecule. The activity of these inhibitors is mostly driven by a covalent binding to the C797 residue of the EGFR protein and is therefore dependent on the reactive group. This leads to a high susceptibility toward the C797S resistance mutation (Engel, 2016). Corresponding compounds without the reactive (warhead) group derived from these prior art aminobenzimidazoles, however, show only weak remaining activity against EGFR mutants (see data in Table 16). This renders them ineffective as non-covalent EGFR inhibitors and limits their use as broad EGFR mutant inhibitors. Thus, against this background, the skilled person would not have considered the previously known aminobenzimidazole scaffold to be a promising starting point to identify EGFR inhibitors with the profile of a 4th generation EGFR inhibitor as hereinbefore defined.
None of the aforementioned published compounds shows the desired characteristics for an effective and clinically relevant EGFR resistance mutation targeting inhibitor.
In summary, compounds (I) according to the invention show a broad activity on EGFR del19 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. To facilitate efficacious dosing and reduce EGFR-mediated on-target toxicities, the compounds according to the invention have a reduced inhibitory potential regarding wild-type EGFR. Compounds (1) show a high selectivity across the human kinome, which may reduce off-target toxicity of the compounds. Another property of the compounds (1) according to the invention is the ability to potentially penetrate into the brain (blood-brain barrier penetration) in order to be used to treat brain metastasis and leptomeningeal disease. In addition to the inhibitory effect and potency, the compounds disclosed herein show good solubility and fine-tuned DMPK properties.
Heald, R. et al. (2015). Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study. J. Med. Chem. 58, 8877-8895.
It has now been found that, surprisingly, compounds of formula (I) wherein the groups R1 to R3, A, B and L and p and q have the meanings given hereinafter act as inhibitors of mutant EGFR which is involved in controlling cell proliferation. Thus, the compounds according to the invention may be used for example for the treatment of diseases characterised by excessive or abnormal cell proliferation.
The present invention therefore relates to a compound of formula (I)
wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is selected from the group consisting of 0, 1, 2 and 3;
each R1 is independently selected from the group consisting of Ra1 and Rb1;
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
q is selected from the group consisting of 0, 1 and 2;
each R2 is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, —CN, C1-4alkoxy, C1-4haloalkoxy and halogen;
R3 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkinyl, halogen, —CN, —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2; and
L is selected from the group consisting of straight chain C3-7alkylene, straight chain C3-7alkenylene and straight chain C3-7alkynylene, wherein one or two methylene groups —CH2— in such straight chain C3-7alkylene, straight chain C3-7alkenylene and straight chain C3-7alkynylene are optionally and independently replaced by a group/atom selected from oxygen, —NH— and —N(C1-4alkyl)-;
In one aspect [A1] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is selected from the group consisting of 1, 2 and 3;
each R1 is independently selected from the group consisting of Ra1 and Rb1;
In another aspect [A2] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is selected from the group consisting of 1, 2 and 3;
each R1 is independently selected from the group consisting of Ra1 and Rb1;
In another aspect [A3] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is selected from the group consisting of 1, 2 and 3;
each R1 is independently selected from the group consisting of (a), (b), (c) and (d):
(a) —(O)n—(CH2)m-A, wherein
A is 3-11 membered heterocyclyl optionally substituted with one or more, identical or different substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkoxy-C1-4alkyl, —C(O)O—C1-4alkyl, —C(O)—C1-4alkyl, C3-6cycloalkyl, —NH(C1-4alkyl), —N(C1-4alkyl)2 and the bivalent substituent ═O;
n is 0 or 1;
m is selected from the group consisting of 0, 1 and 2;
(b) —NRARA, wherein
each RA is independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy-C1-4alkyl, C1-4alkyl substituted with 4-7 membered heterocyclyl, (C1-4alkyl)2amino-C1-4alkyl and (C1-4alkyl)2amino-C1-4alkoxy-C1-4alkyl;
(c) C1-6alkyl optionally substituted with a substituent selected from the group consisting of —N(C1-4alkyl)2, —NH(C1-4alkyl), —C(O)NH—C1-4alkyl, —C(O)-heterocyclyl with a 5-7 membered heterocyclyl, —OH, —CN and —C(O)O—C1-4alkyl;
(d) —O—C1-6alkyl, —C(O)NH—C1-4alkyl, —C(O)N(C1-4alkyl)2, —C(O)O—C1-6alkyl, —CN, halogen and —C(O)-heterocyclyl with a 5-7 membered heterocyclyl optionally substituted with C1-6alkyl.
In another aspect [A4] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is selected from the group consisting of 1, 2 and 3;
each R1 is selected from the group consisting of (a), (c) and (d):
(a) —(O)n—(CH2)m-A, wherein
A is 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C1-4alkyl,
n is 0 or 1;
m is selected from the group consisting of 0, 1 and 2;
(c) C1-6alkyl optionally substituted with a substituent selected from the group consisting of —N(C1-4alkyl)2 and —NH(C1-4alkyl);
(d) —O—C1-6-alkyl, —C(O)NH—C1-4alkyl, —C(O)N(C1-4alkyl)2, —C(O)O—C1-6-alkyl, halogen and —C(O)-heterocyclyl with a 5-7 membered heterocyclyl optionally substituted with C1-6alkyl.
In another aspect [A5] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is selected from the group consisting of 1, 2 and 3;
each R1 is —(O)n—(CH2)m-A, wherein
A is 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C1-4alkyl,
n is 0 or 1;
m is selected from the group consisting of 0, 1 and 2.
In another aspect [A6] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is selected from the group consisting of 1, 2 and 3;
each R1 is selected from the group consisting of halogen, C1-4alkyl, C1-4alkoxy, heterocyclyl-C1-4alkoxy with a 5-7 membered heterocyclyl which is optionally substituted with C1-4alkyl, heterocyclyl-C1-4alkyl with a 5-7 membered heterocyclyl which is optionally substituted with C1-4alkyl, 5-7 membered heterocyclyl optionally substituted with C1-4alkyl, (C1-4alkyl)2N—C1-4alkyl, —C(O)N(C1-4alkyl)2, —C(O)-heterocyclyl with a 5-7 membered heterocyclyl optionally substituted with C1-4alkyl and —C(O)O—C1-4alkyl.
In another aspect [A7] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
p is 0.
In further aspects [A8], [A9], [A10], [A11], [A12], [A13] and [A14], the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of
wherein R1 and p are defined as in any one of aspects [A0], [A1], [A2], [A3], [A4], [A5] or [A6].
In another aspect [A15] the invention relates to a compound of formula (I) or a salt thereof, wherein
In another aspect [A16] the invention relates to a compound of formula (I) or a salt thereof, wherein
In further aspects [A17], [A18], [A19], [A20], [A21], [A22] and [A23], the invention relates to a compound of formula (I) or a salt thereof, wherein
wherein
R1 is defined as in any one of aspects [A0], [A1], [A2], [A3], [A4], [A5] or [A6].
In further aspects [A24], [A25], [A26], [A27], [A28], [A29] and [A30], the invention relates to a compound of formula (I) or a salt thereof, wherein
wherein
R1 is defined as in any one of aspects [A0], [A1], [A2], [A3], [A4], [A5] or [A6].
In another aspect [A31] the invention relates to a compound of formula (I) or a salt thereof, wherein
In another aspect [A32] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of
In another aspect [B1] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
q is 0.
In another aspect [B2] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of phenylene and 5-6 membered heteroarylene;
q is 1;
R2 is selected from the group consisting of C1-4alkyl and halogen.
In further aspects [B3], [B4] and [B5] the invention relates to a compound of formula (I) or a salt thereof, wherein
is selected from the group consisting of
wherein
R2 and q are defined as in any one aspects [B0], [B1] or [B2].
In another aspect [B6] the invention relates to a compound of formula (I) or a salt thereof, wherein
In another aspect [B7] the invention relates to a compound of formula (I) or a salt thereof,
In another aspect [B8] the invention relates to a compound of formula (I) or a salt thereof,
In another aspect [C1] the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is selected from the group consisting of hydrogen, C1-4alkyl, halogen and —CN.
In another aspect [C2] the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is hydrogen.
In another aspect [C3] the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is —CN.
In another aspect [C4] the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is C1-4alkyl.
In another aspect [C5] the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is methyl.
In another aspect [C6] the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is halogen, preferably chlorine or fluorine.
In another aspect [D1] the invention relates to a compound of formula (I) or a salt thereof, wherein
L is straight chain C3-7alkylene, wherein one or two methylene groups —CH2— in such straight chain C3-7alkylene are optionally and independently replaced by a group/atom selected from oxygen, —NH— and —N(C1-4alkyl)-;
In another aspect [D2] the invention relates to a compound of formula (I) or a salt thereof, wherein
L is straight chain C3-7alkylene,
In another aspect [D3] the invention relates to a compound of formula (I) or a salt thereof, wherein
L is selected from the group consisting of straight chain C4alkylene, straight chain C5alkylene, straight chain C6alkylene and straight chain C7alkylene,
In another aspect [D4] the invention relates to a compound of formula (I) or a salt thereof, wherein
L is selected from the group consisting of
All the above-mentioned structural aspects [A1] to [A32], [B1] to [B8], [C1] to [C6] and [D1] to [D4] are preferred embodiments of the corresponding aspects [A0], [B0], [C0] and [D0], respectively. The structural aspects [A0] to [A32], [B0] to [B8], [C0] to [C6], [D0] to [D4] relating to different molecular parts of the compounds (I) according to the invention may be combined with one another as desired in combinations [A][B][C][D] to obtain preferred compounds (I). Each combination [A][B][C][D] represents and defines individual embodiments or generic subsets of compounds (I) according to the invention.
Preferred embodiments of the invention with structure (I) are example compounds I-1 to I-57 and any subset thereof.
All synthetic intermediates generically defined as well es specifically disclosed herein and their salts are also part of the invention.
All individual synthetic reaction steps as well as reaction sequences comprising these individual synthetic reaction steps, both generically defined or specifically disclosed herein, are also part of the invention.
The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein).
The present invention further relates to tautomers of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein).
Specifically, a compound of formula (I) may exist in any of the following tautomeric forms A, B and C, which shall all be part of the invention and shall all be covered by formula (I):
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).
Compounds of formula (I) (including all individual embodiments and generic subsets disclosed herein) which e.g. bear ester groups are potential prodrugs the ester being cleaved under physiological conditions and are also part of the invention.
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).
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.
The present invention is directed to compounds of formula (I) (including all individual embodiments and generic subsets disclosed herein), which are useful in the treatment and/or prevention of a disease and/or condition associated with or modulated 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.
In one aspect 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.
In another aspect 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.
In another aspect 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 wherein the inhibition of mutant EGFR is of therapeutic benefit, including but not limited to the treatment and/or prevention of cancer.
In another aspect 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.
In another aspect 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.
In another aspect 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.
In another aspect 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.
In another aspect 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 herein defined, wherein said compound is administered before, after or together with at least one other pharmacologically active substance.
In another aspect 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 herein defined, wherein said compound is administered in combination with at least one other pharmacologically active substance.
In another aspect 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 or in a method of treatment as herein defined.
In another aspect 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—for preparing a pharmaceutical composition for the treatment and/or prevention of cancer.
In another aspect 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—as herein defined wherein said compound is administered before, after or together with at least one other pharmacologically active substance.
In another aspect 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—as herein defined for the treatment.
In another aspect the invention relates to a method for the treatment and/or prevention of a disease and/or condition wherein the inhibition of mutant EGFR is of therapeutic benefit 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.
In another aspect the invention 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.
In another aspect the invention relates to a method as herein defined wherein the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein)—or a pharmaceutically acceptable salt thereof—is administered before, after or together with at least one other pharmacologically active substance.
In another aspect the invention relates to a method as herein defined wherein the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein)—or a pharmaceutically acceptable salt thereof—is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.
In another aspect the invention relates to a method for the treatment as herein defined.
In another aspect the invention relates to a kit comprising
In another aspect the invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I) (including all individual embodiments and generic subsets disclosed herein)—or a pharmaceutically acceptable salt thereof—and one or more pharmaceutically acceptable excipient(s).
In another aspect the invention relates to a pharmaceutical preparation comprising a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein)—or a pharmaceutically acceptable salt thereof—and at least one (preferably one) other pharmacologically active substance.
In one aspect the disease/condition/cancer to be treated/prevented with the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein), or in the medical uses, uses, methods of treatment and/or prevention as herein defined 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.
In another aspect the disease/condition/cancer to be treated/prevented with the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein), or in the medical uses, uses, methods of treatment and/or prevention as herein defined is lung cancer. Preferably, 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. Most preferably, the lung cancer to be treated is NSCLC adenocarcinoma.
In another aspect the disease/condition/cancer to be treated/prevented with the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein), or in the medical uses, uses, methods of treatment and/or prevention as herein defined is a disease/condition/cancer, preferably cancer (including all embodiments as disclosed herein), with an EGFR genotype selected from genotypes 1 to 16 according to table A (del19=Exon 19 deletion, specifically, e.g., delE746_A750 (most common), delE746_S752insV, delL747_A750insP, delL747_P753insS and delS752_1759):
Thus, in one aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del19 genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a first line treatment, i.e. the patients are treatment naïve in respect of EGFR TKIs.
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 T790M genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del19 T790M genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 C797S genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del19 C797S genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 C797X (preferably C797G or C797N) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del19 C797X (preferably C797G or C797N) genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 T790M C797S genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del19 T790M C797S genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment, i.e. the patients progressed on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on second line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010) upon C797S acquisition.
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 T790M C797X (preferably C797G or C797N) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del19 T790M C797X (preferably C797G or C797N) genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment, i.e. the patients progressed on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on second line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010) upon C797X (preferably C797G or C797N) acquisition.
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 L792X (preferably L792F, L792H or L792Y) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del 19 L792X (preferably L792F, L792H or L792Y) genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR del19 T790M L792X (preferably L792F, L792H or L792Y) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR del19 T790M L792X (preferably L792F, L792H or L792Y) genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment, i.e. the patients progressed on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on second line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010) upon L792X (preferably L792F, L792H or L792Y) acquisition.
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a first line treatment, i.e. the patients are treatment naïve in respect of EGFR TKIs.
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R T790M genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R T790M genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R C797S genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R C797S genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R C797X (preferably C797G or C797N) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R C797X (preferably C797G or C797N) genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R T790M C797S genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R T790M C797S genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment, i.e. the patients progressed on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on second line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010) upon C797S acquisition.
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R T790M C797X (preferably C797G or C797N) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R T790M C797X (preferably C797G or C797N) genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment, i.e. the patients progressed on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on second line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010) upon C797X (preferably C797G or C797N) acquisition.
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R L792X (preferably L792F, L792H or L792Y) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R L792X (preferably L792F, L792H or L792Y) genotype have the compound of formula (I) administered as a second line treatment, i.e. the patients are progressing on first line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010).
In another aspect the cancer (including all embodiments as disclosed herein) to be treated is a cancer with an EGFR L858R T790M L792X (preferably L792F, L792H or L792Y) genotype. Preferably, the cancer patients to be treated and suffering from a cancer with an EGFR L858R T790M L792X (preferably L792F, L792H or L792Y) genotype have the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) administered as a third line treatment, i.e. the patients progressed on first line therapy with a 1st or 2nd generation EGFR TKI (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib) upon T790M acquisition and are progressing on second line therapy with a 3rd generation EGFR TKI (i.e. treatment with osimertinib, olmutinib, nazartinib or AC0010) upon L792X (preferably L792F, L792H or L792Y) acquisition.
In another aspect the pharmacologically active substance to be used together/in combination with the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein), or in the medical uses, uses, methods of treatment and/or prevention as herein defined can be selected from any one or more of the following (preferably there is only one additional pharmacologically active substance used in all these embodiments):
Other pharmacologically active substances which may be used in combination with compounds (1) according to the invention (including all individual embodiments and generic subsets disclosed herein) are, e.g., state-of-the-art or standard-of-care compounds, such as e.g. cell proliferation inhibitors, anti-angiogenic substances, steroids or immune modulators/checkpoint inhibitors, and the like.
Further examples of pharmacologically active substances which may be administered in combination with the compounds (1) according to the invention (including all individual embodiments and generic subsets disclosed herein), 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. goserelin acetate, luprolide), inhibitors of growth factors and/or of their corresponding receptors (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. HER2, HER3, HER4) and hepatocyte growth factor (HGF) and/or their corresponding receptors), 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); antitumour 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. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g. tasquinimod), tubuline inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (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, PI3Kα 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 activator, Mcl-1, MDM2/MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2/Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g. everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1/2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents such as immune checkpont inhibitors (e.g. CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules/immunoglobulins, such as e.g. ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (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×BCMA, CD3×CD33, CD3×CD19), PSMA×CD3), tumor vaccines and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
Any disease/condition/cancer, medical use, use, method of treatment and/or prevention as disclosed or defined herein (including molecular/genetic features/genotype) may be treated/performed with any compound of formula (I) as disclosed or defined herein (including all individual embodiments and generic subsets disclosed herein).
Suitable preparations for administering the compounds (1) of 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 pharmaceutically active compound(s) 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.
Suitable tablets may be obtained, for example, by mixing the active substance(s) of the invention with known 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 substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly 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 the active substances or combinations thereof according to the invention may additionally contain 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 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. with the addition of 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 active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers 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. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may of course contain, apart from the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
For parenteral use, solutions of the active substances with suitable liquid carriers 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 1 to 1000 mg.
The dosage for intravenous use is from 1 mg to 1000 mg with different infusion rates, preferably between 5 mg and 500 mg with different infusion rates.
However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, age, the route of administration, severity of the disease, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered (continuous or intermittent treatment with one or multiple doses per day). Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.
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 directly final blend with the magnesium stearate and compressed to tablets of suitable shape and size. When wet-granulated, additional lactose or cellulose and magnesium stearate is added and the mixture is compressed to produce tablets of suitable shape and size.
The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
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. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to:
The use of the prefix Cx-y, wherein x and y each represent a positive integer (x<y), indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x carbon atoms.
The indication of the number of members in groups that contain one or more heteroatom(s) (e.g. 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) relates to the total number of carbon atoms of all the carbon ring and carbon chain members. Obviously, a ring structure has at least three members.
In general, for groups comprising two or more subgroups (e.g. heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the last named subgroup is the radical attachment point, for example, 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.
In groups like HO, H2N, (O)S, (O)2S, 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.
The term “C1-5alkyl” includes for example H3C—, H3C—CH2—, H3C—CH2—CH2—, H3C—CH(CH3)—, H3C—CH2—CH2—CH2—, H3C—CH2—CH(CH3)—, H3C—CH(CH3)—CH2—, H3C—C(CH3)2—, H3C—CH2—CH2—CH2—CH2—, H3C—CH2—CH2—CH(CH3)—, H3C—CH2—CH(CH3)—CH2—, H3C—CH(CH3)—CH2—CH2—, H3C—CH2—C(CH3)2—, H3C—C(CH3)2—CH2—, H3C—CH(CH3)—CH(CH3)— and H3C—CH2—CH(CH2CH3)—.
Further examples of alkyl are methyl (Me; —CH3), ethyl (Et; —CH2CH3), 1-propyl (n-propyl; n-Pr; —CH2CH2CH3), 2-propyl (i-Pr; iso-propyl; —CH(CH3)2), 1-butyl (n-butyl; n-Bu; —CH2CH2CH2CH3), 2-methyl-1-propyl (iso-butyl; i-Bu; —CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; —CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH3)3), 1-pentyl (n-pentyl; —CH2CH2CH2CH2CH3), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 3-methyl-1-butyl (iso-pentyl; —CH2CH2CH(CH3)2), 2-methyl-2-butyl (—C(CH3)2CH2CH3), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neo-pentyl; —CH2C(CH3)3), 2-methyl-1-butyl (—CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl; —CH2CH2CH2CH2CH2CH3), 2-hexyl (—CH(CH3)CH2CH2CH2CH3), 3-hexyl (—CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (—CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (—CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (—C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (—C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)3), 2,3-dimethyl-1-butyl (—CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (—CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (—CH2CH2C(CH3)3), 2-methyl-1-pentyl (—CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (—CH2CH2CH(CH3)CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.
By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.
The above definition for alkyl also applies if alkyl is a part of another (combined) group such as for example Cx-yalkylamino or Cx-yalkyloxy.
The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example —CH3 and —CH2—, —CH2CH3 and —CH2CH2— or >CHCH3 etc.
The term “C1-4alkylene” includes for example —(CH2)—, —(CH2—CH2)—, —(CH(CH3))—, —(CH2—CH2—CH2)—, —(C(CH3)2)—, —(CH(CH2CH3))—, —(CH(CH3)—CH2)—, —(CH2—CH(CH3))—, —(CH2—CH2—CH2—CH2)—, —(CH2—CH2—CH(CH3))—, —(CH(CH3)—CH2—CH2)—, —(CH2—CH(CH3)—CH2)—, —(CH2—C(CH3)2)—, —(C(CH3)2—CH2)—, —(CH(CH3)—CH(CH3))—, —(CH2—CH(CH2CH3))—, —(CH(CH2CH3)—CH2)—, —(CH(CH2CH2CH3))—, —(CH(CH(CH3))2)— and —C(CH3)(CH2CH3)—.
Other examples of alkylene are 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.
By the generic terms propylene, butylene, pentylene, hexylene etc. 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. The above definition for alkylene also applies if alkylene is part of another (combined) group such as for example in HO—Cx-yalkyleneamino or H2N—Cx-yalkyleneoxy.
Unlike alkyl, 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.
Examples of alkenyl are 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-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbuta-1,3-diene etc.
By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. 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 when alkenyl is part of another (combined) group such as for example in Cx-yalkenylamino or Cx-yalkenyloxy.
Unlike alkylene, 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. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed.
Examples of alkenylene are 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.
By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. 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).
The above definition for alkenylene also applies when alkenylene is a part of another (combined) group as for example in HO—Cx-yalkenyleneamino or H2N—Cx-yalkenyleneoxy.
Unlike alkyl, 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.
Examples of alkynyl are 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.
By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. 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.
If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup.
The above definition for alkynyl also applies if alkynyl is part of another (combined) group, as for example in Cx-yalkynylamino or Cx-yalkynyloxy.
Unlike alkylene, alkynylene 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 alkylene 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 alkynylene is formed.
Examples of alkynylene are 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.
By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.
The above definition for alkynylene also applies if alkynylene is part of another (combined) group, as for example in HO—Cx-yalkynyleneamino or H2N—Cx-yalkynyleneoxy.
By heteroatoms are meant oxygen, nitrogen and sulphur atoms.
Haloalkyl (haloalkenyl, haloalkynyl) 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. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further 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.
Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF3, —CHF2, —CH2F, —CF2CF3, —CHFCF3, —CH2CF3, —CF2CH3, —CHFCH3, —CF2CF2CF3, —CF2CH2CH3, —CF═CF2, —CCl═CH2, —CBr═CH2, —C≡C—CF3, —CHFCH2CH3, —CHFCH2CF3 etc.
From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkylene (haloalkenylene, haloalkynylene). Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl (haloalkenyl, haloalkynyl), is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl).
Corresponding groups are for example —CH2F and —CHF—, —CHFCH2F and —CHFCHF— or >CFCH2F etc.
The above definitions also apply if the corresponding halogen-containing groups are part of another (combined) group.
Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms in common. In spiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two rings together.
If a cycloalkyl 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. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.
Examples of cycloalkyl are 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.
The above definition for cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in Cx-ycycloalkylamino, Cx-ycycloalkyloxy or Cx-ycycloalkylalkyl.
If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained.
The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example:
(cyclohexylene).
The above definition for cycloalkylene also applies if cycloalkylene is part of another (combined) group as for example in HO—Cx-ycycloalkyleneamino or H2N—Cx-ycycloalkyleneoxy.
Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, 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.
If 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.
Examples of cycloalkenyl are 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-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl etc.
The above definition for cycloalkenyl also applies when cycloalkenyl is part of another (combined) group as for example in Cx-ycycloalkenylamino, Cx-ycycloalkenyloxy or Cx-ycycloalkenylalkyl.
If the free valency of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained.
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:
cyclopentenyl and
(cyclopentenylene) etc.
The above definition for cycloalkenylene also applies if cycloalkenylene is part of another (combined) group as for example in HO—Cx-ycycloalkenyleneamino or H2N—Cx-ycycloalkenyleneoxy.
Aryl denotes mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle. Preferably, it 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, however, may also be partially saturated.
If an aryl 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. Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system.
Examples of aryl are 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.
The above definition of aryl also applies if aryl is part of another (combined) group as for example in arylamino, aryloxy or arylalkyl.
If the free valency of an aryl is saturated, then an aromatic group is obtained.
The term 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:
(o, m, p-phenylene), naphthyl and
etc.
The above definition for arylene also applies if arylene is part of another (combined) group as for example in HO-aryleneamino or H2N-aryleneoxy.
Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups —CH2— independently of one another in the hydrocarbon rings by the groups —O—, —S— or —NH— or by replacing one or more of the groups ═CH— by the group ═N—, wherein a total of not more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between two sulphur atoms or between an oxygen and a sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be present in all the possible oxidation stages (sulphur→sulphoxide —SO—, sulphone —SO2—; nitrogen→N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is part of an aromatic system.
A direct result of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclic heterorings and spiro-heterorings, which may be present in saturated or unsaturated form.
By unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterorings two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterorings one carbon atom (spiroatom) 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.
Examples of heterocyclyl are 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, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4,5]decyl etc.
Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):
Preferably, 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, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl.
The above definition of heterocyclyl also applies if heterocyclyl is part of another (combined) group as for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl.
If the free valency of a heterocyclyl is saturated, then a heterocyclic group is obtained.
The term 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. Corresponding groups are for example:
2,3-dihydro-1H-pyrrolyl and
etc.
The above definition of heterocyclylene also applies if heterocyclylene is part of another (combined) group as for example in HO-heterocyclyleneamino or H2N-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. 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.
Examples of heteroaryl are 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, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.
Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):
Preferably, heteroaryls are 5-6 membered monocyclic or 9-10 membered bicyclic, each with 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.
The above definition of heteroaryl also applies if heteroaryl is part of another (combined) group as for example in heteroarylamino, heteroaryloxy or heteroarylalkyl.
If the free valency of a heteroaryl is saturated, a heteroaromatic group is obtained.
The term heteroarylene is also derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example:
etc.
The above definition of heteroarylene also applies if heteroarylene is part of another (combined) group as for example in HO-heteroaryleneamino or H2N-heteroaryleneoxy.
By 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 with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (i.e. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or elimination).
Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N2 or the like, may only be substituents on carbon atoms, whereas the bivalent substituents ═O and ═NR may also be a substituent on sulphur. Generally, 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. Substitution by a bivalent substituent is therefore only possible at the group —CH2— or sulphur atoms (═O group or ═NR group only, one or two ═O groups possible or, e.g., one ═O group and one ═NR group, each group replacing a free electron pair) of a ring system.
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.
In general, 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. by chromatographic separation or crystallization) and/or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.
Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases, or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt, or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group, or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.
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.
As used herein “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.
For example, 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.
Further pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2′-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.
The pharmaceutically acceptable salts 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 (e.g. trifluoro acetate salts), also comprise a part of the invention.
In a representation such as for example
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.
In a representation such as for example
the dashed lines indicate where ring A (with the respective definition of A) is condensed with an adjacent ring, i.e. two vicinal atoms of ring A are in common with such adjacent ring.
For bivalent groups in which it is crucial to determine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets where necessary for clarification purposes, as in the following representations:
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.
By 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.
Features and advantages of the present invention will become apparent from the following detailed examples which illustrate the principles of the invention by way of example without restricting its scope:
Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).
The compounds according to the invention are named in accordance with CAS rules using the software Autonom (Beilstein). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula prevails.
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 columns made by Waters (names: Sunfire C18 OBD, 10 μm, 30×100 mm Part. No. 186003971; X-Bridge C18 OBD, 10 μm, 30×100 mm Part. No. 186003930). The compounds are eluted using different gradients of H2O/AcCN wherein 0.2% HCOOH is added to the water (acid conditions). For chromatography under basic conditions the water is 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 carried out on a JASCO SFC-system with the following columns: Chiralcel OJ (250×20 mm, 5 μm), Chiralpak AD (250×20 mm, 5 μm), Chiralpak AS (250×20 mm, 5 μm), Chiralpak IC (250×20 mm, 5 μm), Chiralpak IA (250×20 mm, 5 μm), Chiralcel OJ (250×20 mm, 5 μm), Chiralcel OD (250×20 mm, 5 μm), Phenomenex Lux C2 (250×20 mm, 5 μm).
The analytical HPLC (reaction monitoring) of intermediate compounds is carried out with columns made by Waters and Phenomenex. The analytical equipment is also provided with a mass detector in each case.
The retention times/MS-ESI+ for characterizing the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent. Compounds that elute at the injection peak are given the retention time tRet.=0.00.
The compounds according to the invention and intermediates are prepared by the methods of synthesis described hereinafter in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis.
Compounds (I) according to the invention can be synthesized using an amide formation for the macrocyclization starting from open-chain aminobenzimidazoles C-1 (scheme 1, method A or A′). The macrocyclization can either be achieve directly using strong bases like, e.g., 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (scheme 1, method A) or the ester function of C-1 is cleaved first and then coupling reagents like TBTU or HATU are used to form the amide bond (scheme 1, method A′).
Alternatively, compounds (1) according to the invention can be synthesized applying an ether formation for the macrocyclization starting from open-chain aminobenzimidazoles C-2 (scheme 1, method B). Different methods can be used for the ether formation like, e.g. M
Key ether intermediates C-1 for macrocyclization can be synthesized applying three different strategies (scheme 2):
One possibility is an ether formation using intermediates A-2 and B-1 (scheme 2, method D). Second option is an alkylation reaction using aminobenzimidazole A-1 and ether intermediate B-2 obtained by reaction of intermediates E-1 and B-1 (→Scheme 2, method E). The key step of the third ring closure strategy is an aminobenzimdazole formation reaction applying reagents like cyanogen bromide (see e.g. WO 2005/079791; WO 2005/070420; WO 2004/014905). To do so the nitro group of ether intermediate C-3 needs to be reduced, which can, e.g., be achieved using hydrogen gas and a catalyst like Pd/C or Ra—Ni. Intermediate C-3 is synthesized by an ether formation reaction starting from A-3 and B-1 (→Scheme 2, method F).
Key amide intermediates C-2 can be synthesized (→scheme 3) by an amide formation using coupling reagents like HATU or TBTU and starting from intermediates A-4 or A-5 reacted with B-3 or B-4.
Aminobenzimidazole A-2 can be synthesized (→Scheme 4) applying an alkylation reaction starting from aminobenzimdazole A-1 and an alkylating agent E-1. Furthermore, aminobenzimdazole A-2 can be also obtained from A-4 via a deprotecting reaction followed by transforming the hydroxy group into a halogen or a sulfonester. Aminobenzimdazole A-4 can be synthesized applying a nucleophilic aromatic substitution reaction of A-6 and E-2 (see e.g. Helvetica Chimica Acta 2013, 96, 2160-2172; Organic Preparations and Procedures Int. 2004, 36, 76-81) followed by a reduction of the nitro group of A-7 and applying an aminobenzimdazole formation reaction by using reagents like cyanogen bromide (e.g. WO 2005/079791; WO 2005/070420; WO 2004/014905).
Intermediate A-3 can be synthesized from A-7 via a deprotecting reaction followed by transforming the free hydroxy group into a halogen or a sulfonester.
Intermediates A-5 can be synthesized from A-7 by reduction of the nitro group of A-7 followed by a reaction with 1-(1H-imidazole-1-carboximidoyl)-1H-imidazole.
Intermediate B-1 can be either synthesized (→Scheme 5) starting from 2-halogen-isonicotinic acid derivative F-1 and boronic acid derivative B-5 applying a SUZUKI reaction (see e.g. J. Org. Chem., 2007, 72, 4067-4072; Org. Lett., 2011, 13, 252-255; J. Org. Chem., 2004, 69, 7779-7782) followed by deprotection of the hydroxy group of B-6, or from boronic acid derivative F-2 and electrophile B-7 also applying a SUZUKI reaction followed by deprotection of the heteroaromatic ring system of B-8.
Intermediate B-4 and B-3 can be synthesized via ester cleavage of B-6 and B-8, respectively.
A stirred solution of starting material IM-1 (10.0 g, 42.87 mmol) in THF (40.0 mL) is cooled to −78° C. Sodium bis(trimethylsilyl)amide (47.2 mL, 47.16 mmol, 1.1 eq) is added and the reaction mixture is stirred at −78° C. for 1 h. Then allyl bromide (15.3 mL, 171.48 mmol, 4.0 eq) is added and the reaction mixture is stirred at −78° C. for 1 h. After that the reaction mixture is slowly warmed to rt. The reaction is quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (2×). The combined organic layers are dried over MgSO4, filtrated and the solvent is evaporated under reduced pressure to provide intermediate IM-2 (HPLC-MS: (M+H)+=274, tRet.=1.4 min, method LCMS3, basisch_1).
To a stirred solution of IM-2 (10.5 g, 38.42 mmol) in THF (40.0 mL) and water (10.0 mL) are added LiOH (2.8 g, 115.25 mmol, 3.0 eq) and H2O2 (11.9 mL, 115.25 mmol, 3.0 eq). The mixture is acidified to pH 1-2 using 1 N aqueous HCl solution and extracted with DCM (2×). After drying the combined organic layers over MgSO4 the solution is filtered and the solvent is evaporated under reduced pressure to afford product IM-3. The crude product is used for further synthesis without any additional purification.
To a stirred solution of IM-3 (4.3 g, 37.67 mmol) in dioxane (15.0 mL) are added DIPEA (19.3 mL, 113.02 mmol, 3.0 eq) and HATU (17.2 g, 45.21 mmol, 1.2 eq). The reaction mixture is stirred at rt for 5 min. Then dibenzylamine (7.4 g, 37.67 mmol, 1.0 eq) is added and stirring at rt is continued for 3 h. The crude product is purified by normal phase chromatography (DCM/MeOH 95:5) and reversed phase chromatography (method: prep. HPLC2) to afford the desired product IM-4 (HPLC-MS: (M+H)+=294, tRet.=1.5 min, method LCMS3, basisch_1).
IM-4 (4.3 g, 14.66 mmol) is dissolved in THF (5.0 mL), cooled to 0° C. and a solution of 9-borabicyclo[3.3.1]nonane (73.3 mL, 36.64 mmol, 2.5 eq) in THF is added. The reaction mixture is stirred at rt for 1 h. Then 1 M aqueous NaOH solution is added. The reaction mixture is cooled to 0° C. before H2O2 (15.0 mL, 146.56 mmol, 10.0 eq) is added. After addition the reaction mixture is stirred at rt for 16 h. The reaction mixture is diluted with water and extracted with EtOAc (2×). The combined organic layers are dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by reversed phase chromatography (method: prep. HPLC2) to obtain the desired product IM-5 (HPLC-MS: (M+H)+=312, tRet.=1.2 min, method LCMS3, basisch_1).
IM-5 (30.0 g, 96.33 mmol) is dissolved in THF (300.0 mL) and the solution is cooled to 0° C. 1 M LiAlH4 in THF (674.3 mL, 674.33 mmol, 7.0 eq) is added and the reaction mixture is stirred at rt for 2 h. Then the reaction is quenched with a saturated aqueous Na2SO4 solution (1 mL), filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (method: Combiflash) to afford product IM-6 (HPLC-MS: (M+H)+=298, tRet.=1.7 min, method LCMS3, basisch_1).
To a stirred solution of IM-6 (10.0 g, 33.62 mmol) in DCM (100.0 mL) are added TEA (23.3 mL, 168.10 mmol, 5.0 eq), DMAP (4.1 g, 33.62 mmol, 1.0 eq) and TBDMS-Cl (6.1 g, 40.35 mmol, 1.2 eq). The reaction mixture is stirred at rt for 3 h. Then the reaction mixture is diluted with water and extracted with DCM. After drying over MgSO4 and filtration the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (method: Combiflash) to obtain the desired product IM-7 (HPLC-MS: (M+H)+=412, tRet.=4.1 min, method LCMS_TCG).
To a stirred solution of IM-7 (75.0 g, 182.17 mmol) in MeOH (750.0 mL) is added Pd/C (3.9 g, 18.22 mmol, 10 mol %, 0.1 eq) and the reaction mixture is stirred at rt under a pressure of 3 bar hydrogen for 3 h. The reaction mixture is filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (method NP1) to obtain the pure product E-2a (HPLC-MS: (M+H)+=232).
Experimental procedure for the synthesis of IM-8 and IM-9 To a stirred solution of IM-4 (50.0 g, 0.170 mol) in water (750.0 mL) and THF (1.250 L) is added N-methyl-morpholineoxide (26.3 mL, 0.256 mol, 1.5 eq). After 10 min of stirring at rt OsO4 (5.4 g, 1.70 mmol, 0.01 eq) is added to the reaction mixture. Stirring at rt is continued for 16 h. Then brine is added to the reaction mixture and extraction is done using EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated to obtain the crude product. Purification by normal phase chromatography affords the pure product as a mixture of diastereomers IM-8 and IM-9 (HPLC-MS: (M+H)+=328).
To a stirred solution of the mixture of diastereomers IM-8 and IM-9 (40.0 g, 0.122 mol) in DMF (400.0 mL) is added 2,2-dimethoxy propane (17.8 g, 0.171 mol, 1.4 eq). After stirring at rt for 10 min CSA (3.3 g, 0.014 mol, 0.1 eq) is added and the reaction mixture is stirred at rt for 16 h. Then brine is added to the reaction mixture and extraction is performed using EtOAc. The combined organic layers are washed with a saturated aqueous Na2CO3 solution, dried over MgSO4, filtered and the filtrate is concentrated under reduced pressure to obtain the crude product. Purification and separation of the diastereomers by normal phase chromatography affords the pure products IM-10 and IM-11.
Diastereomer IM-10 (11.5 g, 0.031 mol) is dissolved in THF (150.0 mL) and cooled to 0° C. Then LAH (8.3 g, 0.219 mol, 7.0 eq) is added to the stirred solution and the reaction mixture is stirred at rt for 2 h. The reaction is quenched by the addition of a saturated aqueous Na2SO4 solution (1 mL), filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography to yield product IM-12.
Product IM-13 is available in an analogous manner starting from diastereomer IM-11.
To a stirred solution of IM-12 (5.7 g, 0.016 mol) in MeOH (60.0 mL) is added Pd/C (0.4 g, 2.0 mmol, 10 mol %, 0.1 eq) and the reaction mixture is stirred at rt under a pressure of 3 bar hydrogen for 3 h. Then the reaction mixture is filtered and concentrated under reduced pressure to afford the crude product, which is purified by normal phase chromatography to obtain product E-2b.
Product E-2c is available in an analogous manner starting from diastereomer IM-13.
A stirred solution of IM-1 (10.0 g, 42.87 mmol) in DCM (25.0 mL) is cooled to −78° C. and 1 M Bu2BOTf in DCM (72.9 mL, 72.88 mmol, 1.7 eq) and TEA (14.6 mL, 107.18 mmol, 2.5 eq) is added. Then the reaction mixture is stirred at −78° C. for 10 min. Stirring is continued at 0° C. for 1 h. The reaction mixture is again cooled to −78° C. followed by the slow addition of 3-(tert-butyl-dimethyl-silanyloxy)-propionaldehyde (8.1 g, 42.87 mmol, 1.0 eq) and stirring at −78° C. for 20 min. After stirring at 0° C. for another hour the reaction is quenched by the successive addition of phosphate buffer (pH=7; 40 mL), MeOH (112 mL) and 30% H2O2 in MeOH (120 mL). Stirring is continued at 0° C. for 1 h. Afterwards water is added to the reaction mixture and extraction is done using DCM. The organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (n-hexane/EtOAc) to afford the desired product IM-14.
A stirred solution of IM-14 (8.0 g, 18.98 mmol) in DCM (80.0 mL) is cooled to 0° C. and 2,6-lutidine (5.5 mL, 47.45 mmol, 2.5 eq) and TBDMSOTf (5.7 mL, 24.67 mmol, 1.3 eq) are added. The reaction mixture is stirred at rt for 3 h. Then the reaction mixture is diluted with water and extracted with DCM. The organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography to obtain the desired product IM-15.
A stirred solution of IM-15 (4.0 g, 7.47 mmol) in THF (15.0 mL) and H2O (2.0 mL) is cooled to 0° C. and NaBH4 (1.4 g, 37.32 mmol, 5.0 eq) is added. The reaction mixture is stirred at rt for 16 h. Then the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography to yield the desired product IM-16.
A stirred solution of IM-16 (2.8 g, 7.72 mmol) in THF (30.0 mL) is cooled to 0° C. and PPhs (5.1 g, 19.30 mmol, 2.5 eq) and DEAD (3.1 mL, 19.30 mmol, 2.5 eq) are added. The reaction mixture is stirred at 0° C. for 10 min. Then isoindole-1,3-dione (1.7 g, 11.58 mmol, 1.5 eq) is added and the reaction mixture is stirred at rt for 16 h. Afterwards the reaction is quenched by the addition of a saturated aqueous NaHCO3 solution and extraction is done using EtOAc. The organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography to afford the desired product IM-17.
To a stirred solution of IM-17 (4.0 g, 8.13 mmol) in EtOH (40.0 mL) is added hydrazine hydrate (4.0 mL, 81.33 mmol, 10.0 eq) and the reaction mixture is stirred under reflux for 2 h. A white precipitate forms. The reaction mixture is cooled to rt and filtered. The filtrate is concentrated to dryness under reduced pressure. The residue is suspended in a saturated aqueous NaHCO3 solution and extraction is done using MeOH/DCM (1:9). The organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography to get the desired product E-2d.
A stirred solution of IM-18 (10.0 g, 0.044 mol) and TEA (9.1 mL, 0.065 mol) in THF (20.0 mL) is cooled to −20° C. and ethyl chloroformate (5.7 g, 0.052 mol) is added. The reaction mixture is stirred at −20° C. for 1 h. Then a freshly prepared solution of diazomethane in diethyl ether (20.0 mL, 0.052 mol) is added to the reaction mixture and stirring is continued at rt for 2 h. Afterwards the reaction is quenched using a saturated aqueous citric acid solution. After that the mixture is extracted with EtOAc, the organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. Purification is done by normal phase chromatography (n-hexane/EtOAc 98:2) to yield the crude product IM-19. The crude product is used for further synthesis without additional purification.
The crude starting material IM-19 (4.0 g, 0.016 mol) is dissolved in MeOH (25.0 mL) and TEA (8.8 mL, 0.063 mol) and silver benzoate (720 mg, 0.003 mol) are added. Then the reaction mixture is stirred at rt for 1 h. The solvent is removed under reduced pressure followed by quenching with a saturated aqueous solution of NaHCO3. Extraction is performed using EtOAc. The organic layer is dried over Na2SO4 and the solvent is evaporated under reduced pressure. Purification by normal phase chromatography (n-hexane/EtOAc 7:3) affords the crude product IM-20, which is used for further synthesis without additional purification.
The crude starting material IM-20 (550 mg, 2.14 mmol) is dissolved in THF (25.0 mL) and 1 M LAH in THF (3.2 mL, 3.21 mmol) is added. The reaction mixture is stirred at rt for 2 h. After that the reaction is quenched by the addition of a saturated aqueous Na2SO4 solution and filtered. The filtrate is concentrated under reduced pressure and purified by normal phase chromatography (n-hexane/EtOAc 65:35) to obtain the crude product IM-21, which is used for further synthesis without additional purification.
To a solution of the crude starting material IM-21 (1.7 g, 7.41 mmol) in DMF (10.0 mL) is added NaH (534 mg, 11.12 mmol) and the reaction mixture is stirred at rt for 15 min. bromomethyl benzene (1.0 mL, 8.16 mmol, 1.1 eq) is added to the reaction mixture and stirring at rt is continued for 2 h. The reaction is quenched by the addition of a saturated aqueous solution of NH4Cl and extraction is done using EtOAc. The organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The crude product is sequentially purified by normal phase chromatography and reversed phase HPLC (alkaline water/AcCN) to afford the pure product IM-22.
To a stirred solution of IM-22 (3.8 g, 0.012 mol) in MeOH (100.0 mL) is added Pd/C (500 mg, 0.001 mol, 3 mol %) and the reaction mixture is stirred at rt under a pressure of 3 bar hydrogen for 6 h. The reaction mixture is filtered, concentrated under reduced pressure and purified by normal phase chromatography (n-hexane/EtOAc 65:35) to obtain the desired pure product IM-21.
Starting material IM-21 (5.0 g, 21.80 mmol) is dissolved in DCM (50.0 mL) and TFA (3.0 mL, 39.20 mmol) is added to the stirred solution. Stirring of the reaction mixture is continued at rt for 16 h. The solvents are removed under reduced pressure to obtain the product as TFA salt E-2e.
A stirred solution of TiCl4 (162.7 g, 0.857 mol) in DCM (600.0 mL) is cooled to 0° C. and titanium isopropylate (76.6 mL, 0.257 mol) is added. Stirring at 0° C. is continued for 10 min. Then DIPEA (166.7 mL, 0.943 mol) is added and after another 10 min of stirring at 0° C. IM-1 (100.0 g, 0.429 mol) is added to the reaction mixture. Afterwards the reaction mixture is stirred at 0° C. for 1 h. Finally, acrylic acid tert-butyl ester (186.7 mL, 1.286 mol) is added to the reaction mixture and stirring at 0° C. is continued for 6 h. The reaction is quenched by the addition of a saturated aqueous solution of NH4Cl and extraction is done using DCM. The organic layer is washed with a saturated aqueous Na2CO3 solution, dried over MgSO4 and filtered. After evaporation of the solvent the crude product is purified by normal phase chromatography to obtain product IM-23.
A stirred solution of IM-23 (120.0 g, 0.332 mol) in THF (600.0 mL) is cooled to 0° C. and LiBH4 (8.0 g, 0.365 mol) and MeOH (6.0 mL) are added. After the addition the reaction mixture is stirred at rt for 2 h. The reaction is quenched with a saturated aqueous NH4Cl solution and extraction is done using EtOAc. The organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography to yield product IM-24.
A stirred solution of IM-24 (30.0 g, 0.159 mol) in THF (500.0 mL) is cooled to 0° C. and a 1 M solution of LAH in THF (200.0 mL, 0.200 mol) is cautiously added. The reaction mixture is stirred at rt for 16 h. The reaction is quenched with a 1 N aqueous NaOH solution and water. After that extraction is done using EtOAc. The organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography to yield product IM-25.
To a stirred solution of IM-25 (8.0 g, 67.70 mmol) in DCM (100.0 mL) are added TEA (46.3 mL, 338.48 mmol), DMAP (10.0 mg, 0.08 mmol) and tosyl chloride (38.6 g, 203.09 mmol). The reaction mixture is stirred at rt for 4 h. Extraction is done using water/DCM. The organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (n-hexane/EtOAc 85:15) to obtain product E-1a.
Starting material A-6a (375 mg, 2.21 mmol) and Na2CO3 (563 mg, 5.31 mmol) are dissolved in THF (3.8 mL) and E-2a (525 mg, 2.27 mmol) is added to the reaction mixture. The reaction mixture is stirred under microwave irradiation at 125° C. for 4 h. Then the solvent is evaporated under reduced pressure. Water is added to the residue and extraction is performed using DCM. The combined organic layers are dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. Purification is done by reversed phase chromatography (method: prep. HPLC1) affording product A-7a.
A-6b (670 mg, 4.75 mmol) and K2CO3 (1.3 g, 9.47 mmol) are dissolved in AcCN (13.5 mL). E-2b (1.0 g, 4.73 mmol) is added and the reaction mixture is stirred at 80° C. for 16 h. After filtration of the reaction mixture the solvent is evaporated under reduced pressure and purification is performed by reversed phase chromatography (method: prep. HPLC1) to yield product A-7b.
The starting materials A-6c (45 mg, 0.20 mmol), E-2a (50 mg, 0.21 mmol) and K2CO3 (100 mg, 0.72 mmol) are suspended in THF (0.5 mL) and the reaction mixture is stirred at 80° C. for 1 h. Stirring is continued at rt for 16 h. Then the reaction mixture is filtered and the solvent is evaporated under reduced pressure. The residue is purified by reversed phase chromatography (method: prep. HPLC1) to obtain product A-7c.
The following intermediates A-7 (table 1) are available in an analogous manner starting from different building blocks A-6 and E-2. Intermediates A-7 can be deprotected to obtain the corresponding deprotected intermediates A-8.
Starting material A-7c (70 mg, 0.16 mmol) is dissolved in 1,4-dioxane (4.0 mL) and a 1 N aqueous solution of HCl (1.0 mL, 1.00 mmol) is added to the solution. The reaction mixture is stirred at rt for 19 h. Then the solvent is evaporated under reduced pressure. The residue is purified by reversed phase chromatography (method: prep. HPLC1) to afford deprotected A-8a (HPLC-MS: (M+H)+=317/319, tRet.=1.0 min, method VAB) as intermediate product.
A stirred solution of the deprotected intermediate A-8a (5.1 g, 15.44 mmol) and TEA (5.5 mL, 39.68 mmol) is cooled to 0° C. and a solution of methanesulfonyl chloride (1.8 mL, 22.16 mmol) in THF (20 mL) is cautiously added. The reaction mixture is stirred at 0° C. for 1 h. Then the reaction mixture is filtered. Purification is done by normal phase chromatography (cyclohexane/EtOAc) to yield product A-3a.
The following intermediates A-3 (table 2) are available in an analogous manner starting from different building blocks A-7.
Starting material A-7a (368 mg, 1.03 mmol) is dissolved in THF (25 mL) and RANEY-Nickel (200 mg, 2.25 mmol, 2.2 eq) is added. The reaction mixture is stirred at rt under a pressure of 6 bar hydrogen for 25 h. After filtration of the reaction mixture the solvent is evaporated under reduced pressure to yield the intermediate product A-9a (HPLC-MS: (M+H)+=327, tRet.=1.6 min, method LCMS3, basisch_1).
The crude intermediate product A-9a (336 mg, 1.03 mmol) is dissolved in THF (2 mL) and 1-(1H-imidazole-1-carboximidoyl)-1H-imidazole (250 mg, 1.55 mmol, 1.5 eq) is added. The reaction mixture is stirred at rt for 21 h. Then the solvent is evaporated under reduced pressure and purification is done by reversed phase chromatography (method: prep. HPLC1) to obtain product A-5a (HPLC-MS: (M+H)+=420, tRet.=1.4 min, method LCMS3, basisch_1).
The following intermediates A-5 (table 3) are available in an analogous manner starting from different building blocks A-7.
Starting material A-7b (990 mg, 3.36 mmol) is dissolved in MeOH (20.0 mL) and RANEY-Nickel (80 mg) is added. The reaction mixture is stirred at rt under a pressure of 5 bar hydrogen for 2 h. After filtration and evaporation of the solvent the crude intermediate product A-10a is used for further synthesis without any additional purification (HPLC-MS: (M+H)+=265, tRet.=1.0 min, method VAB).
The crude intermediate product A-10a (888 mg, 3.36 mmol) is dissolved in tert-BuOH (50.0 mL) and 5 M CNBr in AcCN (1.0 mL) is added. The reaction mixture is stirred at 50° C. for 3 h. Afterwards the reaction mixture is mixed with a saturated aqueous solution of NaHCO3, stirred for 15 min and extracted once with DCM. The organic phase is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. Purification is done by reversed phase chromatography (method: prep. HPLC1) to afford product A-4a.
The following intermediates A-4 (table 4) are available in an analogous manner starting from different building blocks A-7.
To a stirred solution of A-1a (209 mg, 0.94 mmol) and E-1a (400 mg, 0.94 mmol) in AcCN (3.0 mL) is added 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.2 mL, 1.59 mmol) and the reaction mixture is stirred at rt for 16 h. After filtration of the reaction mixture and washing with AcCN the solvent of the filtrate is evaporated under reduced pressure. The residue is purified by reversed phase chromatography (method: prep. HPLC1) to afford the regioisomers A-2a and A-2b in a 1:1 mixture.
The following intermediates A-2 (table 5) are available in an analogous manner starting from different building blocks A-1 and E-1.
Starting material IM-26 (25.0 g, 0.247 mol) and K2CO3 (75.0 g, 0.543 mol) are dissolved in AcCN (1.0 L) and the solution is cooled to 0° C. SEM-Cl (75.0 g, 0.432 mol) is added dropwise under stirring. The reaction mixture is stirred at rt for 1 h. After filtration and purification by normal phase chromatography (DCM/MeOH/NH3 94.5:5:0.5) the desired product IM-27 (HPLC-MS: (M+H)+=229, tRet.=1.0 min, method LCMS3, basisch_1) is obtained.
Starting material IM-27 (38.0 g, 0.133 mol) is dissolved in AcCN (570 mL) and the solution is cooled to 0° C. Then N-iodosuccinimide (32.2 g, 0.136 mol) is cautiously added under stirring. Stirring is continued at 0° C. for 2 h. After that another portion of N-iodosuccinimide (3.2 g, 0.014 mol) is added and stirring is continued at 0° C. for another 30 min. Afterwards the reaction mixture is slowly warmed to rt and water is added. Extraction is performed using DCM. The organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (cyclohexane/EtOAc) to afford the desired product B-7a (HPLC-MS: (M+H)+=355, tRet.=1.2 min, method LCMS3, basisch_1).
Bis(pinacolato)diboron (273.3 g, 1.076 mol) is suspended in MTBE (2.5 L) and the mixture is heated to 70° C. The volume of the reaction mixture is reduced by ⅓ by distillation and the mixture is cooled down to 20° C. Then (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (8.9 g, 0.013 mol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (7.2 g, 0.027 mol) are added and the reaction mixture is stirred at rt for 15 min. After that the reaction mixture is cannulated to a melt of IM-28 (157.0 g, 0.897 mol) and the reaction mixture is stirred at rt for 90 h. Then the solvent is removed under reduced pressure. The crude product oil is stirred in n-hexane (1.0 L) at rt for 16 h. The precipitated product is filtered and rinsed with n-hexane. Drying in at rt for 16 h affords F-2a.
The following intermediates F-2 (table 6) are available in an analogous manner starting from different precursors.
B-7a (4.0 g, 10.60 mmol), F-2a (4.2 g, 12.72 mmol), tris(dibenzylideneacetone)-dipalladium(0) (243 mg, 0.27 mmol), di(1-adamantyl)-n-butylphosphine (285 mg, 0.80 mmol) and Cs2CO3 (10.4 g, 31.81 mmol) are suspended in toluene (48 mL) and water (12 mL). The reaction mixture is stirred at 65° C. for 5 h. Then the reaction mixture is cooled to rt and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is dissolved in toluene (30 mL) and hexane (300 mL) are added slowly while stirring to cause precipitation of the product. After filtration and washing of the precipitate (1×5 mL toluene/hexane 1:10, 2×5 mL hexane) drying in vacuo yields product B-8a.
To a solution of B-8a (990 mg, 2.14 mmol) in dioxane (20 mL) are added trimethylboroxine (805 mg, 6.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (49 mg, 0.05 mmol), butyl-di-1-adamantylphosphine (61 mg, 0.16 mmol) and Cs2CO3 (2.1 g, 6.41 mmol). The reaction mixture is stirred at 65° C. for 16 h. After filtration and concentration of the reaction mixture under reduced pressure water is added to the residue. Extraction is performed using DCM. The combined organic layers are dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (DCM/MeOH 95:5) to yield B-8b.
The following intermediates B-8 (table 7) are available in an analogous manner starting from different building blocks F-2 and B-7.
B-8b (114.6 g, 0.256 mol) is dissolved in THF (360 mL). Then a solution of NaOH (11.3 g, 0.281 mol) in water (180 mL) is added and the reaction mixture is stirred at rt for 30 min. After that the reaction mixture is acidified to pH 5 using a 6 N aqueous solution of HCl. Filtration of the formed slurry and washing with water affords the crude product, which is dried under vacuum at 50° C. The crude product is redissolved in EtOAc (200 mL) and stirred at 60° C. for 1 h. After cooling down to room temperature n-heptane (150 mL) is added dropwise. Stirring at rt is continued for 3 h. Then filtration followed by washing of the solid with heptane and drying under vacuum at 50° C. affords product B-3a.
The following intermediates B-3 (table 8) are available in an analogous manner starting from different building blocks B-8.
To a stirred solution of B-8b (400 mg, 0.91 mmol) in 1,4-dioxane (2.4 mL) is added a 4 M solution of HCl in 1,4-dioxane (2.3 mL, 9.09 mmol). The reaction mixture is stirred at rt for 6 h. Then the precipitated product is filtered and washed with 1,4-dioxane (10 mL) and DCM (10 mL). After drying in vacuo the HCl salt form of the product is obtained. This intermediate is washed with a saturated aqueous solution of Na2CO3 and extraction is done using DCM to afford product B-1a.
To a stirred solution of B-6a (100 mg, 0.43 mmol) in dioxane (3 mL) are added 2 M aqueous solution of K2CO3 (0.3 mL, 0.65 mmol) and Pd dppf (18 mg, 0.02 mmol). The reaction mixture is stirred under microwave irradiation at 90° C. for 1 h. After filtration of the reaction mixture and washing with MeOH the solvent of the filtrate is evaporated under reduced pressure. The residue is resolved in water and extraction is done using DCM. The combined organic layers are dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. Purification is done by normal phase chromatography (DCM/MeOH 50:1) to afford product B-1b.
The following intermediates B-1 (table 9) are available in an analogous manner starting from different building blocks B-6 and B-8, respectively.
To a stirred solution of B-1b (89 mg, 0.366 mmol) in AcCN (5 mL) is added 1,5-dibromopentane (E-1b). The reaction mixture is stirred at 110° C. for 8 h and afterwards the solvent is evaporated under reduced pressure. The residue is resolved in water and extracted with DCM. The organic layer is dried over MgSO4, filtered and the solvent is removed under vacuum. The crude product is purified by normal phase chromatography (cyclohexane/EtOAc 7:3) to obtain product B-2a.
To a stirred solution of B-1h (1500 mg, 5.81 mmol) in AcCN (30 mL) and DMF (30 mL) is added K2CO3 (1.20 g, 8.71 mmol) and cooled down to 0° C. To this reaction mixture is added a solution of E-1a (5.0 g, 11.6 mmol) and the mixture is stirred at this temperature for 16 h. The solvents are evaporated under reduced pressure and water is added and the mixture is extracted with DCM. The collected organic phase is dried over Na2SO4 and the solvents are evaporated under reduced pressure. The crude product is purified by flash chromatography with DCM:MeOH (50:1) yielding B-2p.
The following intermediates B-2 (table 10) are available in an analogous manner starting from different building blocks B-1 and E-1.
The starting materials A-3a (3.1 g, 7.34 mmol), B-1a (2.3 g, 8.84 mmol) and K2CO3 (3.1 g, 22.01 mmol) are dissolved in AcCN (208 mL) and the reaction mixture is stirred under reflux for 12 h. Then the reaction mixture is filtered and washed with AcCN. The solvent is evaporated from the filtrate under reduced pressure. The residue is purified by normal phase chromatography (cyclohexane/EtOAc) to afford product C-3a.
The following intermediates C-3 (table 11) are available in an analogous manner starting from different building blocks A-3 and B-1.
To a stirred solution of the starting material B-2a (60 mg, 0.15 mmol) in AcCN (1 mL) is added a suspension of K2CO3 (40 mg, 0.30 mmol) and A-1b (30 mg, 0.22 mmol) in AcCN (1 mL). The reaction mixture is stirred at 90° C. for 16 h, afterwards filtered and concentrated under vacuum. The residue is redissolved in water and extracted with DCM. The organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (DCM/MeOH 50:1) to yield the desired product C-1a.
A 1:1 mixture of the regioisomers A-2a and A-2b (132 mg, 0.28 mmol), starting material B-1a (70 mg, 0.28 mmol) and K2CO3 (59 mg, 0.43 mmol) are dissolved in AcCN (1 mL). The reaction mixture is stirred at 80° C. for 48 h. Then the reaction mixture is filtered and the precipitate is washed with AcCN. The solvent is evaporated under reduced pressure. The crude product is purified by reversed phase chromatography (method: prep. HPLC1) to obtain the 1:1 mixture of the ester-regioisomeres C-1b and C-1c.
Intermediates C-1b and C-1c obtained are dissolved in THF (2 mL), aqueous LiOH solution (0.5 mL; 50 mg, 2.1 mmol) is added and the mixture is stirred for 4 h at 50° C. The organic solvents are evaporated and the aqueous phase adjusted to a pH value of 6-7. The precipitate is collected and dried yielding C-4a and C-4b.
The starting material C-3b (3.0 g, 5.36 mmol) is dissolved in a mixture of THF (1000 mL) and cyclohexane (1000 mL). Then aqueous slurry of a RANEY-Nickel sponge (50%) is added and the reaction mixture is stirred under a pressure of 5 bar hydrogen for 6 h. After that the reaction mixture is filtered and the solvent is evaporated under reduced pressure. The crude product C-5a is dissolved in toluene, again evaporated to dryness and used for the subsequent reaction without further purification.
The intermediate product C-5a (2.7 g, 5.23 mmol) is dissolved in tert-butanol (20 mL). Then 3 M cyanic bromide in DCM (2.6 mL, 7.84 mmol) is added and the reaction mixture is stirred at 50° C. for 3 h. After that the reaction mixture is diluted with DCM and the reaction is quenched with a aqueous solution of NaHCO3. After extraction with DCM, drying of the organic layer over MgSO4 and filtration the solvent is evaporated under reduced pressure. The crude product is purified by reversed phase chromatography (method: prep. HPLC1) yielding the ester C-1d, which is dissolved in THF and treated with an aqueous 1 M NaOH solution (400 μL). After 1 h the solvents are evaporated yielding product C-4c.
The following intermediates C-1 and C-4 (table 12) are available in an analogous manner starting from different building blocks A-1, A-2, B-1, B-2 and C-3.
Starting material B-3a (1.2 g, 3.42 mmol) is dissolved in 1,4-dioxane (33 mL). TEA (2.9 mL) and HATU (1.6 g, 4.12 mmol) are added to the solution, which is stirred at rt for 20 min. Then A-4j (1.1 g, 3.42 mmol) is added and the reaction mixture is stirred at rt for 48 h. After that extraction is done using DCM/water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure to obtain the crude intermediate product C-6a, which is used for further synthesis without any additional purification step.
The crude intermediate product C-6a (512 mg, 0.42 mmol) is dissolved in EtOH (10 mL) and a 4 M solution of HCl in 1,4-dioxane (5.0 mL, 20.00 mmol) is added to the solution. The reaction mixture is stirred at rt for 16 h. Then a saturated aqueous solution of NaHCO3 is added and the reaction mixture is extracted twice with DCM. The combined organic layers are dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by reversed phase chromatography (prep. HPLC1) to afford product C-2a.
Starting material B-3a (1.0 g, 2.75 mmol), HATU (1.1 g, 2.84 mmol) and DIPEA (2.0 mL, 11.76 mmol) are dissolved in 1,4-dioxane (20 mL) and the reaction mixture is stirred at 55° C. for 30 min. Then A-5a (1.0 g, 2.38 mmol) is added to the reaction mixture and stirring is continued at 55° C. for 1 h followed by stirring at rt for 48 h. After that the reaction mixture is concentrated under reduced pressure and the residue is purified by reversed phase chromatography (method: prep. HPLC1) to obtain the intermediate product C-6b.
The intermediate product C-6b (633 mg, 0.91 mmol) is dissolved in THF (20 mL) and a 1 M solution of TBAF in THF (3.5 mL, 3.50 mmol) is added to the solution. The reaction mixture is stirred at rt for 72 h. Stirring is continued at 50° C. for 72 h. After that acetone is added to the reaction mixture and the solvent is evaporated under reduced pressure. The solid is suspended in AcCN and the solid material is collected by filtration yielding the product C-2b.
The following intermediates C-2 (table 13) are available in an analogous manner starting from different building blocks A-4, A-5 and B-3.
Starting material C-1s (34 mg, 0.07 mmol) is dissolved in DMSO (0.8 mL), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.02 mL, 0.13 mmol) is added and the reaction mixture is stirred at 80° C. for 48 h. Then the reaction mixture is filtered and purification is done by reversed phase chromatography (method: prep. HPLC1) to afford product 1-003.
Experimental procedure for the synthesis of I-057 and I-020 (Method A′)
C-4c (227 mg, 0.421 mmol) and DIPEA (0.37 mL, 2.10 mmol) are dissolved in dioxane (5 mL) and the reaction mixture is stirred at 25° C. for 10 min. Then HATU (240 mg, 0.63 mmol) is added and stirring of the reaction mixture at 25° C. is continued for 2 h. The solvent is evaporated under reduced pressure and the crude product is purified by normal phase chromatography (EtOAc/MeOH 90:10) to afford I-057.
I-057 (50 mg; 0.096 mmol) is dissolved in dioxane (750 μL) and N-methylpiperazine (0.042 mL; 0.38 mmol) and methansulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)paladium(II) (8.6 mg; 0.01 mmol) is added. The reaction mixture is flushed with argon and LiHMDS (0.28 mL; 0.28 mmol) is slowly added at rt. Then the reaction mixture is stirred at 65° C. for 30 min. The solvents are evaporated under reduced pressure and the crude product is purified by reversed phase chromatography (method: prep. HPLC1) to yield product 1-020.
B-2b (1200 mg, 1.88 mmol) is dissolved in AcCN (10 mL) and K2CO3 (393 mg, 2.82 mmol) and A-1b (275 mg, 2.07 mol) are added. The reaction mixture is stirred at 100° C. for 4 d. The solvents are evaporated under reduced pressure and water is added and the mixture is extracted with DCM. The collected organic phase is dried over Na2SO4 and the solvents are evaporated under reduced pressure. The crude product is purified by column chromatography (40 g SiO2, cyclohexane/EtOAc 1:1) yielding D-1a (HPLC-MS: (M+H)+=567.0, tRet.=1.86 min, method LCMS3, basisch_1).
Intermediate D-1a is dissolved in THF (2 mL) and TBAF (1 M in THF; 0.200 mL; 0.200 mmol) is added. The reaction mixture is stirred at 25° C. for 18 h. The solvents are evaporated under reduced pressure and water is added and the mixture is extracted with DCM. The collected organic phase is dried over Na2SO4 and the solvents are evaporated under reduced pressure. The crude product is purified by reversed phase chromatography (method: prep. HPLC1) to yield product 1-012.
C-2a (50 mg, 0.12 mmol) is dissolved in THF (4.0 mL) and triphenylphosphine (130 mg, 0.47 mmol) is added to the solution. After the reaction mixture has been stirred at rt for 20 min diisopropyl azodicarboxylate (0.1 mL, 0.48 mmol) is added to the reaction mixture. Then the reaction is stirred at rt for 1 h. After that extraction is done using DCM/water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by reversed phase chromatography (method: prep. HPLC1) to yield product I-001.
C-2d (25 mg, 0.052 mmol) is dissolved in dry AcCN (3 mL) and K2CO3 (43 mg, 0.31 mmol) is added. The mixture is stirred at 90° C. for 16 h. The reaction mixture is filtered off and is purified by reverse phase chromatography (prep. HPLC1 method) yielding I-006.
I-013 (50 mg, 0.11 mmol), benzoic acid (30 mg, 0.24 mmol) and triphenylphosphine (100 mg, 0.36 mmol) are dissolved in THF (5 mL) and diisopropyl azodicarboxylate (0.09 mL, 0.43 mmol) is added. The reaction mixture is shaken at rt for 16 h. The solvents are evaporated under reduced pressure and the crude product is purified using prep. HPLC1 method yielding intermediate D-1b (HPLC-MS: (M+H)+=551, tRet.=0.83 min, method VAB).
Intermediate D-1b (43 mg, 0.074 mmol) is dissolved in 1,4-dioxan (0.5 mL) and LiOH (1 M solution, 0.5 mL) is added. The reaction is shaken at 25° C. for 3 h. The solvents are evaporated under reduced pressure and the crude product is purified using prep. HPLC1 method yielding I-014.
C-2k (160 mg, 0.35 mmol) is dissolved in dry AcCN, K2CO3 (97 mg, 0.70 mmol) is added. Then p-toluensulfonyl chloride (80 mg, 0.42 mmol) is added. The reaction mixture is stirred at rt for 18 h. The solvents are evaporated under reduced pressure and water is added and the mixture is extracted with DCM. The collected organic phase is dried over Na2SO4 and the solvents are evaporated under reduced pressure yielding intermediate C-2z (HPLC-MS: (M+H)+=611, tRet.=0.65 min, method 2_FEC_PN).
Intermediate C-2z (90 mg, 0.15 mmol) is dissolved in dry THF and K2CO3 (41 mg, 0.30 mmol) is added. The reaction mixture is stirred at 90° C. for 3 d. The solvents are evaporated under reduced pressure and water is added and the mixture is extracted with DCM. The collected organic phase is dried over Na2SO4 and the solvents are evaporated under reduced pressure. The crude product is purified by flash chromatography with DCM:MeOH (10:1) yielding I-023.
The following compounds (I) (table 14) are available in an analogous manner starting from different building blocks A-1, B-2, C-1 and C-2 or by derivatization of compounds (I) initially obtained.
The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples:
Initially, the inhibitory effect of compounds according to the invention is measured in biochemical assays which measure the phosphorylation activity of EGFR enzyme forms on poly-GT substrate in the presence of different concentrations of ATP (5 μM and 100 μM final assay concentration).
The following enzyme forms of EGFR are representative examples that can be used in these assays at the given concentrations:
EGFR wt (Life technologies; PV4190); final assay concentration 1.5 nM
EGFR (d746-750 T790M C797S) (SignalChem; E10-12UG); final assay concentration 15 nM
EGFR (mutated) 695-1022, T790M, C797S, L858R (in house prep); final assay concentration 3 nM
Test compounds dissolved in DMSO are dispensed onto assay plates (Proxiplate 384 PLUS, white, PerkinElmer; 6008289) using an Access Labcyte Workstation with the Labcyte Echo 55x. For the chosen highest assay concentration of 100 μM, 150 nL of compound solution is transferred from a 10 mM DMSO compound stock solution. A series of eleven fivefold dilutions per compound is transferred to the assay plate, compound dilutions are tested in duplicates. DMSO is added as backfill to a total volume of 150 nL. The assay runs on a fully automated robotic system.
5 μL of EGFR enzyme form in assay buffer (50 mM HEPES pH 7.3, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween 20, 2 mM DTT) are dispensed into columns 1-23, than 5 μL of ATP and ULight-poly-GT substrate (PerkinElmer; TRF0100-M) mix in assay buffer is added to all wells (final assay concentration of the ULight-poly-GT substrate 200 nM). Each of the different EGFR enzyme form assays is available at low ATP (final assay concentration 5 μM) and high ATP levels (final assay concentration 100 μM). After 90 minutes incubation at room temperature 5 μL EDTA (final assay concentration 50 mM) and LANCE Eu-anti-P-Tyr (PT66) antibody (PerkinElmer, AD0069) (final assay concentration 6 nM) mix are added to stop the reaction and start the binding of the antibody. After additional 60 minutes incubation at room temperature the signal is measured in a PerkinElmer Envision HTS Multilabel Reader using the TR-FRET LANCE Ultra specs of PerkinElmer (used wavelengths: excitation 320 nm, emission 1 665 nm, emission 2 615 nm). Each plate contains 16 wells of a negative control (diluted DMSO instead of test compound; w EGFR enzyme form; column 23) and 16 wells of a positive control (diluted DMSO instead of test compound; w/o EGFR enzyme form; column 24). Negative and positive control values are used for normalization and IC50 values are calculated and analysed using a 4 parametric logistic model.
These biochemical EGFR enzyme form compound dose-response assays quantify the kinase activity via phosphorylation of a tagged poly-GT substrate. The results of the assay are provided as IC50 values. The lower the reported IC50 values for a given compound, the more potent the compound inhibits the kinase activity of the EGFR enzyme on poly-GT substrate.
Table 15 contains IC50 data of compounds according to the invention generated in the corresponding biochemical assays as described above:
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% CO2 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. To ensure infection, 4 μg/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 μg/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. Approximately ten days before conducting the experiments, puromycin was left out. For proliferation assays (data in table 13), Ba/F3 cells were seeded into 96-well plates at 5×103 cells/100 μL in growth media. Compounds were added by using a HP D3000 Digital Dispenser. All treatments were performed in technical triplicates. Treated cells were incubated for 72 h at 37° C. with 5% CO2. CellTiter-Glo® Luminescent Cell Viability Assay (Promega) was performed and chemoluminescence was measured by using the multilabel Plate Reader VICTOR X4. The raw data were imported into and analyzed with the Boehringer Ingelheim proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).
pEGFR Assay
This assay quantifies the phosphorylation of EGFR at Tyr1068 and was used to measure the inhibitory effect of compounds on the transgenic EGFR del19 T790M C797S protein in Ba/F3 cells. 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). For the assay, 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 μL were added. Cells were incubated with compound for 4 h at 37° C. Following centrifugation and removal of the medium supernatant, 20 μL 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. After centrifugation, 4 μL of the lysate were transferred to Proxiplates. 5 μL of Acceptor Mix (Activation Buffer diluted 1:25 in combined Reaction Buffer 1 and Reaction Buffer 2 (TGRERS Assay Kit, PerkinElmer) plus 1:50 of Protein A Acceptor Beads 6760137) were added to each well. Plates were shaken for 1 min (1400 rpm) and incubated for 2 h at room temperature in the dark. 3 μL of donor mix (AlphaScreen Streptavidin-coated Donor Beads (6760002, PerkinElmer) 1:50 diluted in Dilution Buffer (TGRERS Assay Kit, PerkinElmer) were added to each well. Plates were shaken for 1 min (1400 rpm) and incubated for 2 h at room temperature in the dark. Plates were subsequently analyzed using an Envision reader platform. Results were computed in the following way: The ratio of the value of the test compound and the value of the negative control (DMSO) was calculated. IC50 values are computed from these values in the MEGASTAR IC50 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 IC50 values (see table 14). The lower the reported pEGFR IC50 values for a given compound, the more potent the compound inhibits the EGFR del19 T790M C797S target protein in Ba/F3 cells.
| Number | Date | Country | Kind |
|---|---|---|---|
| 19181952.3 | Jun 2019 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/067451 | 6/23/2020 | WO |
