Substituted 1H-pyrazolo[4,3-c] and derivatives as EGFR inhibitors

Abstract

The present invention relates to a compound represented by the following formula (I): TIFF2023550591000176.tif47170 (in the formula, the group R 1 ~R 4 and X 1 ~X 5 have the meanings given in the claims and in the description), their use as inhibitors of mutant EGFR, pharmaceutical compositions containing compounds of this type and their use as pharmaceuticals / medical applications, in particular as agents for the treatment and / or prophylaxis of tumor diseases.

Description

[Technical Field]

[0001] The present invention relates to a compound represented by the following formula (I):

[0002] [ka]

[0003] (In the formula, the group R 1 ~R 4 and X 1 ~X 5 has the meaning given in the claims and in the description), their use as inhibitors of mutant EGFR, pharmaceutical compositions containing compounds of this type and their use as pharmaceuticals / medical applications, in particular as agents for the treatment and / or prophylaxis of tumor diseases. [Background technology]

[0004] Background of the Invention The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that transduces mitogenic signals. Approximately 12% to 47% of non-small cell lung cancer (NSCLC) tumors diagnosed as adenocarcinoma harbor mutations in the EGFR gene (Midha, 2015). The two most common EGFR alterations found in NSCLC tumors are a short in-frame deletion (del19) in exon 19 of the EGFR gene and L858R, a single missense mutation in exon 21 (Konduri, 2016). These two mutations cause ligand-dependent EGFR activation and are collectively referred to as EGFR M+. EGFR Del19 and L858R mutations sensitize NSCLC tumors to treatment with EGFR tyrosine kinase inhibitors (TKIs). Clinical experience has demonstrated response rates of approximately 60–85% in patients with EGFR M+ NSCLC treated with first-, second-, and third-generation EGFR TKIs (erlotinib, gefitinib, afatinib, and osimertinib) in the first-line setting (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 and establish del19 or L858R mutant EGFR as a validated drug target and predictive biomarker for NSCLC treatment. The first-generation EGFR TKIs (erlotinib and gefitinib) and the second-generation TKI (afatinib) are FDA-approved for the first-line treatment of patients with EGFR M+ NSCLC. Tumor responses are often accompanied by significant tumor shrinkage in patients, but these responses are generally not durable, and most patients relapse within 10–12 months of treatment with first- and second-generation EGFR TKIs (Mitsudomi, 2010; Park, 2016; Soria, 2017; Zhou, 2011). In 50%–70% of patients who progress on first- and second-generation EGFR inhibitors, the most prominent molecular mechanism underlying progression is the acquisition of a secondary EGFR mutation, namely, T790M (Blakely, 2012; Kobayashi, 2005). This mutation attenuates the inhibitory activity of first- and second-generation TKIs in cellular assays (see, for example, data in Table A).

[0005] Mutation-selective, covalent third-generation EGFR TKIs, such as osimertinib, have been developed, which effectively inhibit primary EGFR mutations del19 and L858R, regardless of the presence or absence of the secondary T790M resistance mutation (Cross, 2014; Wang, 2016). The efficacy observed with the third-generation EGFR TKI osimertinib in second-line treatment of EGFR M+ T790M-positive NSCLC clinically demonstrates that tumor cell survival and proliferation are dependent on the mutant EGFR allele (Janne, 2015; Mok, 2016). Approximately 70% of EGFR M+ T790M-positive patients previously treated with earlier-generation EGFR TKIs respond to second-line osimertinib treatment; however, disease progression occurs after a median duration of 10 months (Mok, 2016). The mechanisms underlying acquired resistance to third-generation EGFR TKIs are being investigated 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 approximately 20–40% of second-line patients relapsing on osimertinib TKI (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015). Third-generation TKIs, such as osimertinib, covalently bind to EGFR through residue C797 (Cross, 2014; Wang, 2016). In cell models, the C797S mutation abolishes the activity of tested third-generation TKIs (Thress, 2015) (see, for example, data in Table A). In second-line patients, the C797S mutation is preferentially found with the EGFR del19 genotype and on the same allele as the T790M mutation (cis configuration) (82% of C797S+ patients) (Piotrowska, 2017).Importantly, the EGFR del19 / L858R T790M C797S cis-mutated kinase variant that emerges in second-line patients progressing on osimertinib (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015) can no longer be inhibited by first-, second-, or third-generation EGFR TKIs (Thress, 2015) (see, e.g., data in Table A). Based on the fact that the C797S mutation is detected in patients with progression to osimertinib (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015), it is likely that tumor cell survival and proliferation in patients with EGFR del19 / L858R T790M C797S are dependent on this mutant allele and can be inhibited by targeting this allele. Recently, additional EGFR resistance mutations, namely L718Q, L792F / H / Y, and C797G / N, with a lower incidence than C797S, have been described in second-line EGFR M+ NSCLC patients progressing to osimertinib (Bersanelli, 2016; Chen, 2017; Ou, 2017).

[0006] The third-generation EGFR TKI osimertinib has also recently demonstrated efficacy in previously untreated patients with EGFR M+ NSCLC (Soria, 2017). Disease progression occurs after a median duration of 19 months. The spectrum of EGFR resistance mutations after first-line osimertinib treatment has not yet been extensively studied, and initial available data suggest the emergence of the C797S mutation, which abrogates osimertinib activity (Ramalingam, 2017). Based on the efficacy of osimertinib in previously untreated patients with EGFR M+ NSCLC and in second-line patients with T790M-positive disease, the drug has been approved in both settings. The inability of approved EGFR TKIs to inhibit the EGFR del19 / L858R T790M C797S variant, which arises after patients progress on first- or second-line osimertinib treatment, highlights the medical need for next-generation EGFR TKIs, or "fourth-generation EGFR TKIs." These fourth-generation EGFR TKIs should potently inhibit EGFR del19 or L858R, regardless of the presence of two common resistance mutations, T790M and C797S, particularly EGFR del19 T790M C797S. The utility of these fourth-generation EGFR TKIs would be enhanced by their activity against additional resistance mutations, such as the potential osimertinib resistance mutations C797X (X = S, G, N) and L792F / H / . The broad activity of this molecule against EGFR del19 or L858R variants will ensure that novel compounds can effectively address the expected allelic complexity in patient tumors as monotherapy, even in the absence of T790M and / or C797S mutations. A fourth-generation EGFR TKI molecule with activity against EGFR del19 and EGFR L858R, primarily activating mutations, regardless of the presence of resistance mutations T790M and C797S, would enable the treatment and prevention of resistant disease. It would be particularly useful to treat EGFR M+ NSCLC patients who have progressed on prior EGFR TKI therapy with first-, second-, or third-generation TKIs, as well as EGFR TKI-naive first-line patients. To facilitate effective dosing and reduce EGFR-mediated target toxicity, fourth-generation EGFR TKIs should not inhibit wild-type EGFR. High selectivity across the human kinome would reduce the compound's off-target toxicity. Another desirable property of fourth-generation EGFR TKIs is their ability to efficiently penetrate the brain (blood-brain barrier penetration) to enable the prevention and / or treatment of brain metastases and leptomeningeal disease.

[0007] The above-mentioned properties of fourth-generation EGFR TKIs will enable the treatment of patients who currently have no targeted therapy options (e.g., those with the EGFR del19 / L858R T790M C797S genotype) and are progressing on second-line treatment with third-generation TKIs, such as osimertinib. Furthermore, these properties may also enable fourth-generation EGFR TKIs to provide longer duration of response in first-line patients as well as earlier-line patients, such as those with the EGFR C797S mutation who are progressing on first-line osimertinib treatment. The activity of fourth-generation EGFR TKIs against resistance mutations, such as T790M, C797X (X = S, G, N), and L792X (X = F, H, Y), may delay the emergence of resistance due to EGFR internal target mutations in NSCLC tumors. The characteristics outlined above define the first EGFR TKI and fourth-generation EGFR TKI that can effectively target NSCLC tumor patients with not only the EGFR del19 or L858R genotype, but also the EGFR del19 / L858R T790M C797X / L792X variants. Furthermore, a fourth-generation EGFR TKI will be the first C797S-active compound that inhibits the T790M-positive allele, has EGFR wild-type sparing activity, and efficiently penetrates the brain.

[0008] Over the past few years, selective targeting of mutant EGFR has gained increasing attention. To date, various efforts have been made to identify and optimize inhibitors that target either the catalytic site of EGFR mutants or the allosteric site of the EGFR protein, but have only achieved limited success in terms of the above characteristics. Benzimidazole compounds that approach the desired properties are disclosed in WO2019 / 162323. Furthermore, several EGFR inhibitors have been published that can overcome EGFR resistance mutations, including the T790M mutation, the C797S mutation, and the combination of both mutations (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 quinalozines, which are second-generation EGFR inhibitors (Patel, 2017; Park, 2017; Chen, 2017). However, these published molecules are either weak inhibitors with low selectivity over wild-type EGFR (Patel, 2017; Chen, 2017) or designed to specifically bind only to the del19 / T790M / C797S mutant, lacking activity against other EGFR variant combinations and mutations (Park, 2017). Other published compound classes show activity only against T790M and T790M / C797S resistance mutations in the L858R activating background (Bryan 2016; Juchum, 2017; Gunther, 2017). However, because these mutations and mutation combinations were observed in only a small portion of the patient population, and because allelic complexity in metastatic tumors is likely high, it is highly unlikely that they will meet the criteria required to develop effective EGFR inhibitors.

[0009] The following prior art documents disclose non-covalently bonded compounds as mutation-selective EGFR inhibitors with activity against EGFR T790M-bearing EGFR: WO 2014 / 210354; WO 2014 / 081718; Heald, 2015; Hanan, 2014; Lelais, 2016; Chan, 2016. Although the compounds from the literature cited above are claimed to be active against the two most common EGFR activating / resistance mutation combinations, del19 / T790M and L858 / T790M, most of them exhibit only weak activity against the more dominant del19 / T790M mutation, and they lack affinity for EGFRs harboring only the primary activating mutations del19 and L858R. Selective inhibition of such double-mutated EGFRs over activity against single activating mutations is highly undesirable and likely results in limited efficacy due to the heterogeneity of EGFR mutations in patients. Furthermore, most of these compounds exhibit only limited selectivity for wild-type EGFR, which is known to be the main cause of common side effects leading to target-specific toxicity (diarrhea, skin rash) in EGFR-targeted therapy. This specific toxicity component is undesirable because it may lead to adverse events in treated patients. The following prior art documents disclose aminobenzimidazole compounds as selective EGFR inhibitors that have activity against both the oncogenic driver mutations L858R and del19, as well as against the T790M resistance mutation and their combination: WO2013 / 184757; WO2013 / 184766, WO2015 / 143148, WO2015 / 143161, WO2016 / 185333; Lelais, 2016; Jia, 2016. Summary of the Invention

[0010] In summary, Compound (I) of the present invention exhibits broad activity against EGFR del19 or EGFR L858R variants, regardless of the presence or absence of T790M and / or C797S mutations, ensuring that the compound can effectively address the expected allelic complexity in patient tumors as a monotherapy. To facilitate effective administration and reduce EGFR-mediated target toxicity, the compound of the present invention has reduced inhibitory potential with respect to wild-type EGFR. Compound (I) exhibits high selectivity across the human kinome, potentially reducing off-target toxicity of the compound. Another characteristic of Compound (I) of the present invention is its ability to penetrate the brain (blood-brain barrier penetration), potentially for preventing and / or treating brain metastases and leptomeningeal disease. In addition to inhibitory effect and efficacy, the compounds disclosed herein exhibit good solubility and suitable DMPK properties for use in living organisms.

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Chen, L. et al.; Novel 4-arylaminoquinazoline derivatives with (E)-propen-1-yl moiety as potent EGFR inhibitors with enhanced antiproliferative activities against tumor cells. Eu. J. Med. Chem. 2017, 138, 689-697. Cross, D.A.E. et al. (2014). AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discovery. 2014 Sep;4(9):1046-61. doi: 10.1158 / 2159-8290.CD-14-0337. Engel, J. et al.; Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR. Angew. Chem. Int. Ed. 2016, 55, 10909-10912. Gunther, M. et al.; Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R / T790M / C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site. J. Med. Chem. 2017, 60, 5613-5637. Hanan, E. J. et al.; Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation. 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EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discovery. 2016 Jun;6(6):601-11. doi: 10.1158 / 2159-8290.CD-16-0075. Le, N.; Methods for treating epidermal growth factor receptor (EGFR) mutant cancers. WO 2016 / 185333. Lelais, G. et al.; Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers. J. Med. Chem. 2016, 59, 6671-6689. Lelais, G. et al.; Preparation of fused imidazole compounds and compositions for modulating EGFR activity. WO 2013 / 184757. Midha, A. et al. (2015). EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015; 5(9): 2892-2911. Mitsudomi, T. et al. (2010). 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Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomized, phase 3 study. Lancet Oncol. 12, 735-742. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description of the Invention compound It has now been surprisingly discovered that compounds of formula (I) (wherein the group R 1 ~R 4 and X 1 ~X 5 has the meaning given below) have been found to act as inhibitors of mutant EGFR, which is involved in the control of cell proliferation. Thus, the compounds of the present invention can be used, for example, in the treatment of diseases characterized by excessive or abnormal cell proliferation. Therefore, the present invention provides a compound represented by the following formula (I):

[0013] [ka]

[0014] (In the formula, [A0] R 1 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 2 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; or R 1 and R 2 form a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring together with the carbon atoms to which they are attached; [B0] R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -CN, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; [C0] R 4 is R a1 and R b1 selected from the group consisting of: R a1 is hydrogen, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b1 and / or R c1 is replaced by; Each R b1 are independently -OR c1 , -N(R c1 )R c1 , halogen, -CN, -C(=O)R c1 , -C(=O)OR c1 , -C(=O)N(R c1 )R c1 , -C(=O)N(H)OR c1 , -C(=O)N(C 1-4 alkyl) OR c1 , -S(=O)2R c1 , -S(=O)2N(R c1 )R c1 , -N(H)C(=O)R c1 , -N(C 1-4 alkyl)C(=O)R c1 , -N(H)C(=O)OR c1 , -N(C 1-4 alkyl)C(=O)OR c1 , -N(H)S(=O)R c1 , -N(C 1-4 alkyl)S(=O)2R c1 and the divalent substituent ═O; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 are independently -OR e1 , -N(R e1 )R e1 , halogen, -CN, -C(=O)R e1 , -C(=O)OR e1 , -C(=O)N(R e1 )R e1 , -C(=O)N(H)OR e1 , -C(=O)N(C 1-4 alkyl) OR e1 , -S(=O)2R e1 , -S(=O)2N(R e1 )R e1 , -N(H)C(=O)R e1 , -N(C 1-4 alkyl)C(=O)R e1 , -N(H)C(=O)OR e1 , -N(C 1-4 alkyl)C(=O)OR e1 , -N(H)S(=O)R c1 , -N(C 1-4 alkyl)S(=O)2R c1 and the divalent substituent ═O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O;

[0015] [D0] X 1 is selected from the group consisting of carbon (C) and nitrogen (N); X 2 is selected from the group consisting of carbon (C) and nitrogen (N); X 1 and X 2 at least one of which is carbon (C); X 3 are nitrogen (N), C(R 5 ), N(R 6 ), C(R 5 )(R 5), oxygen (O), sulfur (S), S(=O), S(=O)2, and C(=O); X 4 are nitrogen (N), C(R 7 ), N(R 8 ), C(R 7 )(R 7 ), oxygen (O), sulfur (S), S(=O), S(=O)2, and C(=O); X 5 are nitrogen (N), C(R 9 ), N(R 10 ), C(R 9 )(R 9 ), oxygen (O), sulfur (S), S(=O), S(=O)2, and C(=O); each bond between ring members of ring A is independently selected from a single bond, a double bond, or a (hetero)aromatic bond; Each R 5 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-4 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 6 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 7 are independently, R a2 and R b2 selected from the group consisting of: Ra2 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 are independently -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2R c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 are independently -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2R e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R e2are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 9 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 10 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl or a salt thereof.

[0016] The following structural aspects represent preferred embodiments [A1] to [A9], [B1] to [B4], [C1] to [C16] and [D1] to [D9] of the corresponding structural aspects [A0], [B0], [C0] and [D0], respectively. In one aspect [A1], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH2, -NH(C1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof:

[0017] In another aspect [A2], the present invention provides a method for manufacturing a pharmaceutical composition comprising: R 1 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 2 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [A3], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 But C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, C 3-6 Cycloalkyl and C 3-6 selected from the group consisting of cycloalkoxy; R 2 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [A4], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 is selected from the group consisting of methoxy, isopropyloxy, —OH, cyclopropyl, and cyclopropyloxy; R 2 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [A5], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 But C 1-4 selected from the group consisting of alkoxy and -OH; R 2 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [A6], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 is methoxy; R 2 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [A7], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 is -OH; R 2 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [A8], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 and R 2 form a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring together with the carbon atom to which they are attached, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [A9], the present invention provides a method for manufacturing a semiconductor device comprising: R 1 and R 2 together with the carbon atoms to which they are attached form a ring selected from the group consisting of pyrrole, 2,3-dihydrofuran, and furan; The present invention relates to a compound of formula (I) or a salt thereof:

[0018] In another aspect [B1], the present invention provides a method for manufacturing a pharmaceutical composition comprising: R 3 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 selected from the group consisting of haloalkoxy and halogen; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [B2], the present invention provides a method for manufacturing a semiconductor device comprising: R 3 But hydrogen, C 1-4Alkyl, C 1-4 selected from the group consisting of haloalkyl and halogen; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [B3], the present invention provides a method for manufacturing a semiconductor device comprising: R 3 C 1-4 is alkyl, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [B4], the present invention provides a method for manufacturing a semiconductor device comprising: R 3 is methyl, The present invention relates to a compound of formula (I) or a salt thereof:

[0019] In another aspect [C1], the present invention provides a method for producing a composition comprising: R 4 But R a1 and R b1 selected from the group consisting of: R a1 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 , halogen, -CN, -C(=O)R c1 , -C(=O)OR c1 , -C(=O)N(Rc1 )R c1 , -C(=O)N(H)OR c1 , -C(=O)N(C 1-4 alkyl) OR c1 , -S(=O)2R c1 , -S(=O)2N(R c1 )R c1 , -N(H)C(=O)R c1 , -N(C 1-4 alkyl)C(=O)R c1 , -N(H)C(=O)OR c1 , -N(C 1-4 alkyl)C(=O)OR c1 , -N(H)S(=O)R c1 , -N(C 1-4 alkyl)S(=O)2R c1 and the divalent substituent ═O; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 , halogen, -CN, -C(=O)R e1 , -C(=O)OR e1 , -C(=O)N(R e1 )Re1 , -C(=O)N(H)OR e1 , -C(=O)N(C 1-4 alkyl) OR e1 , -S(=O)2R e1 , -S(=O)2N(R e1 )R e1 , -N(H)C(=O)R e1 , -N(C 1-4 alkyl)C(=O)R e1 , -N(H)C(=O)OR e1 , -N(C 1-4 alkyl)C(=O)OR e1 , -N(H)S(=O)R c1 , -N(C 1-4 alkyl)S(=O)2R c1 and the divalent substituent ═O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; The present invention relates to a compound of formula (I) or a salt thereof:

[0020] In another aspect [C2], the present invention provides a method for manufacturing a pharmaceutical composition comprising: R 4 But R a1 and R b1 selected from the group consisting of: R a1 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may optionally have one R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 , halogen, -CN, -C(=O)N(R c1 )R c1 , -S(=O)2N(R c1 )R c1 , -N(H)C(=O)R c1 , -N(C 1-4 alkyl)C(=O)R c1 , -N(H)C(=O)OR c1 , -N(C 1-4 alkyl)C(=O)OR c1 , -N(H)S(=O)R c1 , -N(C 1-4 alkyl)S(=O)2R c1 and the divalent substituent ═O; Each R c1 are independently hydrogen, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 , halogen, -CN, -C(=O)N(R e1 )R e1 , -S(=O)2N(R e1 )R e1 , -N(H)C(=O)R e1 , -N(C 1-4 alkyl)C(=O)R e1 , -N(H)C(=O)OR e1 , -N(C 1-4 alkyl)C(=O)OR e1 , -N(H)S(=O)R c1 , -N(C 1-4 alkyl)S(=O)2R c1 and the divalent substituent ═O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; The present invention relates to a compound of formula (I) or a salt thereof:

[0021] In another aspect [C3], the present invention provides a method for producing a composition comprising: R 4 But R a1 and R b1 selected from the group consisting of: R a1 But C 1-6 Alkyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 , halogen, and the divalent substituent =O; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 , halogen, and the divalent substituent =O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are all optionally substituted with one or more identical or different substituents selected from the group consisting of halogen and the divalent substituent =O; The present invention relates to a compound of formula (I) or a salt thereof:

[0022] In another aspect [C4], the present invention provides a method for producing a composition comprising: R 4 But R a1 and R b1 selected from the group consisting of: R a1 But C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl may each optionally have one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; The present invention relates to a compound of formula (I) or a salt thereof:

[0023] In another aspect [C5], the present invention provides a method for producing a composition comprising: R 4 R a1 and; R a1 However, optionally one or more identical or different R b1 and / or R c1 3- to 11-membered heterocyclyl substituted with; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6selected from the group consisting of haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl are all optionally each independently one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; The present invention relates to a compound of formula (I) or a salt thereof:

[0024] In another aspect [C6], the present invention provides a method for producing a composition comprising: R 4 R a1 and; R a1 However, the following base

[0025] [ka]

[0026] selected from the group consisting of Here, each R a1 may optionally be one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each Rc1 are independently hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl are all optionally each independently one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [C7], the present invention provides a method for producing a composition comprising: R 4 R a1 and; R a1 However, the following base

[0027] [ka]

[0028] selected from the group consisting of Here, each R a1 may optionally be one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 and halogen; Each R c1are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl and 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl and 5- to 6-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 and halogen; Each R e1 are independently hydrogen and C 1-6 selected from the group consisting of alkyl, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [C8], the present invention provides a method for producing a composition comprising: R 4 is selected from the group consisting of:

[0029] [ka]

[0030] In another aspect [C9], the present invention provides a method for producing a composition comprising: R 4 However, -NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [C10], the present invention provides a method for producing a composition comprising: R 4 -N(C 1-4 alkyl)2, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [C11], the present invention provides a method for producing a composition comprising: R 4 -OR c1 and; R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6selected from the group consisting of haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl are all optionally each independently one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; The present invention relates to a compound of formula (I) or a salt thereof:

[0031] In another aspect [C12], the present invention provides a method for producing a composition comprising: R 4 -OR c1 and; R c1 But independently, C 1-6 Alkyl, C 1-6 haloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 is a halogen; Each R e1 But independently, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 3-10cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [C13], the present invention provides a method for producing a composition comprising: R 4 is selected from the group consisting of:

[0032] [ka]

[0033] In another aspect [C14], the present invention provides a method for producing a composition comprising: R 4 But C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl may each optionally have one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl are all optionally each independently one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; The present invention relates to a compound of formula (I) or a salt thereof:

[0034] In another aspect [C15], the present invention provides a method for producing a composition comprising: R 4 But C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl may each optionally have one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 and halogen; Each R c1 are independently hydrogen and C 1-6 selected from the group consisting of alkyl, The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [C16], the present invention provides a method for producing a composition comprising: R 4 is selected from the group consisting of:

[0035] [ka]

[0036] In another aspect [D1], the present invention provides a method for manufacturing a semiconductor device comprising: The following group

[0037] [ka]

[0038] However, the following base

[0039] [ka] [ka]

[0040] Selected from the group consisting of: Each R 5 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-4 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 6 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: Each R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2R c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2R e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 9 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 10 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D2], the present invention provides a method for manufacturing a semiconductor device comprising: The following group

[0041] [ka]

[0042] is the following group:

[0043] [ka]

[0044] R 7 But R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2R c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2R e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; R 10 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D3], the present invention provides a method for producing a composition comprising: The following group

[0045] [ka]

[0046] is the following group:

[0047] [ka]

[0048] R 7 But R a2 and R b2selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2R c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2R e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each Re2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D4], the present invention provides a method for producing a composition comprising: The following group

[0049] [ka]

[0050] is the following group:

[0051] [ka]

[0052] R 5 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-4 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; R 7 But R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)ORc2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2R c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2, -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2R e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; R 9 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D5], the present invention provides a method for producing a composition comprising: The following group

[0053] [ka]

[0054] is the following group:

[0055] [ka]

[0056] R 5 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-4 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; R 7 But R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2R c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2R e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; R 10 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D6], the present invention provides a method for producing a composition comprising: The following group

[0057] [ka]

[0058] is the following group:

[0059] [ka]

[0060] R 6 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; R 7 But R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2R c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2R e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; R 9 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D7], the present invention provides a method for producing a composition comprising: The following group

[0061] [ka]

[0062] is the following group:

[0063] [ka]

[0064] R 6 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; R 10 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D8], the present invention provides a method for producing a composition comprising: The following group

[0065] [ka]

[0066] is the following group:

[0067] [ka]

[0068] R 5 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-4 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; R 10 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof: In another aspect [D9], the present invention provides a method for producing a composition comprising: The following group

[0069] [ka]

[0070] is the following group:

[0071] [ka]

[0072] R 6 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; R 9 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6Alkyl, halogen, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; The present invention relates to a compound of formula (I) or a salt thereof:

[0073] The following aspects [E1] to [E3] are residues R 5 It is a sub-aspect of [D0], [D1], [D4], [D5] and [D8]. In one sub-embodiment [E1], the present invention provides a method for producing a composition comprising: Each R 5 are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy, The embodiments [D0], [D1], [D4], [D5] and [D8] relate to a compound of formula (I) or a salt thereof. In another sub-embodiment [E2], the present invention provides a method for producing a composition comprising: Each R 5 C 1-4 is alkyl, The embodiments [D0], [D1], [D4], [D5] and [D8] relate to a compound of formula (I) or a salt thereof. In another sub-embodiment [E3], the present invention provides a method for producing a composition comprising: R 5 is methyl, The embodiments [D0], [D1], [D4], [D5] and [D8] relate to a compound of formula (I) or a salt thereof.

[0074] The following aspects [F1] to [F3] are residues R 6 It is a subembodiment of aspects [D0], [D1], [D6], [D7] and [D9]. In one sub-embodiment [F1], the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Each R 6 However, independently hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl, Aspects [D0], [D1], [D6], [D7] and [D9] relate to compounds of formula (I) or salts thereof. In another sub-embodiment [F2], the present invention provides a method for producing a composition comprising: Each R 6 C 1-4 is alkyl, Aspects [D0], [D1], [D6], [D7] and [D9] relate to compounds of formula (I) or salts thereof. In another sub-aspect [F3], the present invention provides a method for producing a method of manufacturing a semiconductor device comprising: Each R 6 is methyl, Aspects [D0], [D1], [D6], [D7] and [D9] relate to compounds of formula (I) or salts thereof.

[0075] The following embodiments [G1] and [G2] are the residues R 8 This is a sub-embodiment of embodiments [D0] and [D1]. In one sub-embodiment [G1], the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Each R 8 C 1-4 is alkyl, The embodiments [D0] and [D1] relate to a compound of formula (I) or a salt thereof. In another sub-embodiment [G2], the present invention provides a method for producing a composition comprising: Each R 8 is methyl, The embodiments [D0] and [D1] relate to a compound of formula (I) or a salt thereof.

[0076] The following aspects [H1] to [H3] are residues R 9 It is a subembodiment of aspects [D0], [D1], [D4], [D6] and [D9]. In one sub-aspect [H1], the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Each R 9 are independently hydrogen, C 1-4 Alkyl, C 1-4 haloalkyl, Aspects [D0], [D1], [D4], [D6] and [D9] relate to compounds of formula (I) or salts thereof. In another sub-aspect [H2], the present invention provides a method for producing a composition comprising: R 9 C1-4 is alkyl, Aspects [D0], [D1], [D4], [D6] and [D9] relate to compounds of formula (I) or salts thereof. In another sub-aspect [H3], the present invention provides a method for producing a composition comprising: R 9 is methyl, Aspects [D0], [D1], [D4], [D6] and [D9] relate to compounds of formula (I) or salts thereof.

[0077] The following aspects [I1] to [I3] are residues R 10 It is a subembodiment of aspects [D0], [D1], [D2], [D5], [D7] and [D8]. In one sub-embodiment [I1], the present invention provides a method for producing a composition comprising: Each R 10 are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Aspects [D0], [D1], [D2], [D5], [D7] and [D8] relate to a compound of formula (I) or a salt thereof. In another sub-embodiment [I2], the present invention provides a method for producing a composition comprising: R 10 C 1-4 is alkyl, Aspects [D0], [D1], [D2], [D5], [D7] and [D8] relate to a compound of formula (I) or a salt thereof. In another sub-embodiment [I3], the present invention provides a method for producing a composition comprising: R 10 are independently selected from the group consisting of methyl, ethyl, and isopropyl; Aspects [D0], [D1], [D2], [D5], [D7] and [D8] relate to a compound of formula (I) or a salt thereof.

[0078] The following aspects [J1] to [J9] are residues R 7 It is a subembodiment of aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6]. In one sub-aspect [J1], the present invention provides a method for manufacturing a semiconductor device comprising: Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O)2N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O)2N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O)R c2 , -N(C 1-4 alkyl)S(=O)2R c2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof.

[0079] In another sub-aspect [J2], the present invention provides a method for manufacturing a device comprising: Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(Rc2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are all optionally substituted with one or more identical or different substituents selected from the group consisting of halogen and the divalent substituent =O; Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof.

[0080] In another sub-aspect [J3], the present invention provides a method for manufacturing a device comprising: Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 and -C(=O)N(C 1-4 alkyl) OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof.

[0081] In another sub-aspect [J3a], the present invention provides a method for producing a composition comprising: Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 and -C(=O)N(C 1-4 alkyl) OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl and 3- to 11-membered heterocyclyl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -ORe2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof.

[0082] In another sub-aspect [J4], Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 However, independently, -N(R c2 )R c2 , halogen, -C(=O)R c2 and -C(=O)OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 and -C(=O)OR e2 selected from the group consisting of: Each R e2 are independently hydrogen and C 1-6 selected from the group consisting of alkyl, Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof.

[0083] In another sub-aspect [J4a], the present invention provides a method for producing a composition comprising: Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 However, independently, -N(R c2 )R c2 , halogen, -C(=O)R c2 and -C(=O)OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl and 3- to 11-membered heterocyclyl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 and -C(=O)OR e2 selected from the group consisting of: Each R e2are independently hydrogen, C 3-10 Cycloalkyl and C 1-6 selected from the group consisting of alkyl, Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof.

[0084] In another sub-aspect [J5], the present invention provides a method for manufacturing a device comprising: Each R 7 R a2 and; R a2 However, optionally one or more identical or different R b2 and / or R c2 3- to 11-membered heterocyclyl substituted with; Each R b2 are independently halogen, -C(=O)R c2 and -C(=O)OR c2 selected from the group consisting of: Each R c2 However, optionally one or more identical or different R d2 and / or R e2 C is replaced by 1-6 is alkyl; Each R d2 But independently, -OR e2 and -C(=O)OR e2 selected from the group consisting of: Each R e2 are independently hydrogen and C 1-6 selected from the group consisting of alkyl, Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof. In another sub-aspect [J6], the present invention provides a method for manufacturing a device comprising: Each R 7 are independently hydrogen, C 1-4 Alkyl,

[0085] [ka]

[0086] selected from the group consisting of Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof. In another sub-aspect [J6a]: Each R 7 are independently hydrogen, C 1-4 Alkyl,

[0087] [ka] [ka]

[0088] selected from the group consisting of Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof. In another sub-aspect [J6b], the present invention provides a method for producing a composition comprising: Each R 7 are independently selected from the group consisting of:

[0089] [ka] [ka]

[0090] In another sub-aspect [J7], the present invention provides a method for manufacturing a device comprising: Each R 7 R b2 and; Each R b2 But independently, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 and -C(=O)N(C 1-4 alkyl) ORc2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens; Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof.

[0091] In another sub-aspect [J8], the present invention provides a method for manufacturing a device comprising: Each R 7 R b2 and; Each R b2 But independently, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 and -C(=O)N(C 1-4 alkyl) OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different Rd2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , halogen, -C(=O)R e2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 selected from the group consisting of alkyl and 3- to 11-membered heterocyclyl; Aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6] relate to compounds of formula (I) or salts thereof. In another sub-aspect [J9], the present invention provides a method for manufacturing a device comprising: Each R 7 are independently selected from the group consisting of:

[0092] [ka]

[0093] In another embodiment [L1], the present invention relates to a compound of formula (I) or a salt thereof according to embodiment [D2] in combination with embodiment [A5] or [A6]. In another aspect [L2], the present invention relates to compounds of formula (I) or salts thereof according to aspect [D2] or aspect [L1] taken in combination with aspect [B3] or [B4] respectively. In another aspect [L3], the present invention relates to compounds of formula (I) or salts thereof according to aspect [D2] or aspect [L1] or [L2] taken in combination with aspect [I2] or [I3], respectively. In another embodiment [L4], the present invention relates to a compound of formula (I) or a salt thereof according to any one of embodiments [D2] or [L1] to [L3], each taken in combination with any one of embodiments [C5] to [C8]. In another aspect [L5], the present invention relates to a compound of formula (I) or a salt thereof according to any one of aspects [D2] or [L1] to [L4] taken in combination with any one of aspects [J1] to [J7], [J3a], [J4a], [J6a] and [J6b], respectively. In another aspect [L6], the present invention provides 4 is a 3- to 11-membered heterocyclyl or R 4

[0039] This relates to a compound of formula (I) or a salt thereof according to any one of embodiments [D2] or [L1] to [L5] taken in combination with the embodiment in which is 7-membered heterocyclyl.

[0094] All sub-modifications [E1] to [E3] (residues R 5 Regarding residues R 6 with respect to [G1] and [G2] (residue R 8 Regarding residues R 9 Regarding residues R 10 (for residues R 7 (Regarding the above) may be combined with each other based on the embodiments [D0] to [D9], if applicable, to form additional embodiment [D], and all of these should be understood to be included. All of the above structural aspects [A1] to [A9], [B1] to [B4], [C1] to [C16], and [D1] to [D9] (including, where applicable and as described above, the additional aspect [D] based on the combination of [D1] to [D9] with the sub-aspects [E1] to [E3], [F1] to [F3], [G1] and [G2], [H1] to [H3], [I1] to [I3], and [J1] to [J9]) are preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], and [D0], respectively. The structural aspects [A0] to [A9], [B0] to [B4], [C0] to [C16], and [D0] to [D9] (including the additional aspect [D] as described above) relating to different molecular portions of Compound (I) of the present invention can be combined with each other as desired in combinations [A][B][C][D] to obtain preferred Compound (I). Each such combination [A][B][C][D] represents and defines an individual embodiment or general subset of Compound (I) of the present invention.

[0095] Preferred embodiments of the present invention having structure (I) are compound examples I-1 to I-225 and any subset thereof. All synthetic intermediates specifically disclosed as well as generically defined herein and their salts are also part of the present invention. All individual synthetic reaction steps, both generally defined or specifically disclosed herein, as well as reaction sequences comprising these individual synthetic reaction steps, are part of the present invention.

[0096] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of compounds of formula (I) (including all individual embodiments and general subsets disclosed herein). The present invention further relates to hydrates of compounds of formula (I) (including all individual embodiments and general subsets disclosed herein). The present invention further relates to solvates of compounds of formula (I) (including all individual embodiments and general subsets disclosed herein). For example, compounds of formula (I) (including all individual embodiments and general subsets disclosed herein) having an ester group are prodrugs in which the ester may be cleaved under physiological conditions, and are also part of the present invention. The present invention further relates to pharmaceutically acceptable salts of the compounds of formula (I) (including all individual embodiments and general subsets disclosed herein). The present invention further relates to pharmaceutically acceptable salts of compounds of formula (I) (including all individual embodiments and general subsets disclosed herein) with inorganic or organic acids or bases.

[0097] Pharmaceutical Composition Pharmaceutical compositions suitable for administering the compounds of formula (I) of the present invention will be clear to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lotions, lozenges, liquids—particularly liquids for injection (sc, iv, im) and infusion (injectable)—elixirs, syrups, sachets, emulsions, inhalants, or dispersible powders. The content of compound (I) should be in the range of 0.1 to 90 wt.-% of the composition as a whole, preferably 0.5 to 50 wt.-%, i.e., an amount sufficient to achieve the dosage ranges specified below. If necessary, the specified doses may be given several times a day, for example twice a day. Suitable tablets can be obtained, for example, by mixing Compound (I) with known pharmaceutically acceptable excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. The tablets may comprise multiple layers. Thus, coated tablets can be prepared by coating a core made similarly to a tablet with an excipient commonly used in tablet coating, such as Kollidon or shellac, gum arabic, talc, titanium dioxide, or sugar. The core may consist of several layers to achieve delayed release or to prevent incompatibilities. Similarly, tablet coatings may consist of several layers, possibly using the excipients mentioned above for tablets.

[0098] Syrups or elixirs containing one or more compounds (I) or a combination thereof with one or more other pharmaceutically active substances may further contain excipients such as sweeteners, e.g., saccharin, cyclamate, glycerol, or sugar, and flavor enhancers, e.g., flavorings, e.g., vanillin or orange extract. They may also contain suspension adjuvants or thickeners, e.g., sodium carboxymethylcellulose, wetting agents, e.g., condensation products of fatty alcohols with ethylene oxide, or preservatives, e.g., p-hydroxybenzoates. Solutions for injection and infusion are prepared in the usual way, for example with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, and optionally with the use of emulsifiers and / or dispersants, but when water is used as the diluent, for example with the use of organic solvents as solvating or solubilizing agents, and may be transferred into injection vials or ampoules or infusion bottles.

[0099] Capsules containing one or more compounds (I) or combinations with one or more other pharmaceutically active substances can be prepared, for example, by mixing the compounds / active substances with an inert excipient such as lactose or sorbitol and filling them into gelatin capsules. Suitable suppositories can be prepared, for example, by mixing with excipients provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof. Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), mono- or polyalcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite liquor, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0100] The pharmaceutical composition is administered by a conventional method, preferably orally or transdermally, most preferably orally.For oral administration, tablets may naturally contain, apart from the above-mentioned excipients, additional excipients such as sodium citrate, calcium carbonate, and disodium phosphate, together with various excipients such as starch, preferably potato starch, gelatin, etc. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used simultaneously for the tableting process.In the case of aqueous suspensions, the active substance may be mixed with various flavor enhancers or colorants in addition to the above-mentioned excipients. For parenteral use, a solution of the active substance and a suitable liquid excipient may be used. The daily applicable dose range of the compound of formula (I) is usually 1 mg to 2000 mg, preferably 250 mg to 2000 mg. However, it may sometimes be necessary to deviate from the specified amount depending on the body weight, age, route of administration, severity of the disease, individual response to the drug, the nature of its formulation and the time or interval at which the drug is administered (continuous or intermittent treatment with one or more doses per day). Thus, in some cases it may be sufficient to use less than the minimum dose mentioned above, while in other cases the upper limit may have to be exceeded. When administering large amounts, it may be advisable to divide them into several small doses distributed over the day.

[0101] Accordingly, in a further aspect, the present invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) and one or more pharmaceutically acceptable excipients. The compounds of formula (I) or pharmaceutically acceptable salts thereof and pharmaceutical compositions containing said compounds and salts may be co-administered, i.e., used in combination with other pharmacologically active substances, for example other anti-neoplastic compounds (e.g., chemotherapy) (see further below on combination therapy). The elements of the combination can be administered by methods familiar to those skilled in the art and as they are used in monotherapy, for example, by oral, enteral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or implant), nasal, vaginal, rectal, or topical routes of administration (whether dependent or independent), and can be prepared, either alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration. These combinations may be administered in single or divided daily therapeutically effective doses. The active ingredients of the combination may be administered in doses that are therapeutically effective in monotherapy or in amounts that are lower than those used in monotherapy but that, when combined, result in the desired (joint) therapeutically effective amount. However, when the combination of two or more active substances or elements produces a synergistic effect, it may be possible to achieve the desired therapeutic effect by administering less of one, more or all of the substances or elements, which may be useful, for example, to avoid, limit or reduce any undesirable side effects associated with the use of one or more substances or elements when used in their normal amounts, while still obtaining the desired pharmacological or therapeutic effect.

[0102] Accordingly, in a further aspect, the present invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) and one or more (preferably one or two, most preferably one) other pharmacologically active substances. In a further aspect, the present invention also relates to pharmaceutical formulations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) and one or more (preferably one or two, most preferably one) other pharmacologically active substances. Pharmaceutical compositions to be administered simultaneously or in combination can also be provided in the form of a kit. Thus, in a further aspect, the present invention provides a method for producing a composition comprising: a first pharmaceutical composition or dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), and optionally one or more pharmaceutically acceptable excipients; and a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipients; The present invention also relates to a kit comprising: In one embodiment, the kit further comprises a third pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipients.

[0103] Medical uses - treatment methods Indications-Patient Population The present invention relates primarily to EGFR inhibitors, particularly compounds of formula (I) (including all individual embodiments and general subsets disclosed herein), which may be useful in the treatment and / or prevention of diseases and / or conditions associated with or modulated / mediated by mutant EGFR, and in particular where inhibition of mutant EGFR is of therapeutic benefit, including but not limited to the treatment and / or prevention of cancer. In one aspect, the present invention relates to a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof, for use as a medicament. In another aspect, the present invention relates to a compound of formula (I) (including all individual embodiments and general 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 present invention relates to compounds of formula (I) (including all individual embodiments and general subsets disclosed herein) or pharmaceutically acceptable salts thereof for use in the treatment and / or prevention of diseases and / or conditions mediated by mutant EGFR.

[0104] In another aspect, the present invention relates to the use of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of diseases and / or conditions mediated by mutant EGFR. In another aspect, the present invention relates to a method for treating and / or preventing diseases and / or conditions mediated by mutant EGFR, comprising administering to a human a therapeutically effective amount of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof. In another aspect, the present invention relates to a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof for use in a method for the treatment and / or prophylaxis of cancer. In another aspect, the present invention relates to a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof for use in a method for the treatment and / or prophylaxis of cancer in the human or animal body.

[0105] In another aspect, the present invention relates to the use of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of cancer. In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a human a therapeutically effective amount of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof. In another aspect, the present invention relates to a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof for use in providing an inhibitory effect on mutant EGFR. In another aspect, the invention relates to the use of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in providing an inhibitory effect on mutant EGFR. In another aspect, the present invention relates to a method for providing an inhibitory effect to mutant EGFR, comprising administering to a human a therapeutically effective amount of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof.

[0106] Another aspect is based on identifying a correlation between a patient's EGFR mutation status and their potential susceptibility to treatment with a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein). Therefore, EGFR inhibitors, such as the compounds of Formula (I) (including all individual embodiments and general subsets disclosed herein), may be advantageously used to treat patients with EGFR mutations who may be resistant to other therapies. This therefore provides patients, particularly cancer patients, with the opportunity, method, and means to select treatment with a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein). This selection is based on whether the tumor cells to be treated have a wild-type or mutated EGFR gene. Therefore, EGFR gene status could be used as a biomarker to indicate that treatment with a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) is advantageous.

[0107] According to one aspect, there is provided a method for selecting patients suitable for treatment with a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), comprising the steps of: - providing a tumor cell-containing sample, preferably a tumor DNA-containing sample, from a patient; determining whether the EGFR gene in the patient sample encodes a wild-type or mutant EGFR protein; and selecting patients suitable for treatment with a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) based thereon. A method is provided that includes:

[0108] This method may include or exclude the step of isolating the actual patient sample. As used herein in disclosing and defining aspects of the present invention, "mutated EGFR" refers to both a mutant EGFR gene and / or the corresponding protein derived from the mutant EGFR gene, including, but not limited to: [K1] EGFR with a deletion in exon 19 (=del19) for example -delE746_A750 (most common), -delE746_S752insV, -delL747_A750insP, -delL747_P753insS, -delS752_I759; · EGFR containing the mutation L858R in exon 21 (=L858R); EGFR containing the T790M mutation in exon 20 (=T790M) EGFR containing a mutation at residue C797 in exon 20 (=C797mut) for example -C797S, -C797G, -C797N, EGFR containing a mutation at residue L792 in exon 20 (=L792mut) for example -L792F, -L792H, -L792Y, or any mutant EGFR containing a combination of two or more mutations, e.g. del19 T790M del19 C797mut -del19 C797S -del19 C797G -del19 C797N del19 T790M C797mut -del19 T790M C797S -del19 T790M C797G -del19 T790M C797N del19 L792mut -del19 L792F -del19 L792H -del19 L792Y del19 T790M L792mut -del19 T790M L792F -del19 T790M L792H -del19 T790M L792Y L858R T790M L858R C797mut -L858R C797S -L858R C797G -L858R C797N L858R T790M C797mut -L858R T790M C797S -L858R T790M C797G -L858R T790M C797N L858R L792mut -L858R L792F -L858R L792H -L858R L792Y L858R T790M L792mut -L858R T790M L792F -L858R T790M L792H -L858R T790M L792Y

[0109] Thus, in one embodiment of the present invention [K2], the mutated EGFR contains a deletion in exon 19 (=del19). In another embodiment of the invention [K3], the mutated EGFR comprises the mutation L858R in exon 21 (=L858R). In another embodiment of the invention [K4], the mutated EGFR comprises the mutation T790M in exon 20 (=T790M). In another embodiment of the invention [K5], the mutated EGFR comprises a mutation at residue C797 in exon 20 (=C797mut). In another embodiment of the invention [K6], the mutated EGFR comprises a mutation C797S in exon 20 (=C797S). In another embodiment of the invention [K7] the mutant EGFR comprises the mutation C797G in exon 20 (=C797G). In another embodiment of the invention [K8], the mutant EGFR comprises the mutation C797N in exon 20 (=C797N). In another embodiment of the invention [K9], the mutant EGFR comprises a mutation at residue L792 in exon 20 (=L792mut). In another embodiment of the invention [K10], the mutant EGFR comprises the mutation L792F in exon 20 (=L792F). In another embodiment of the invention [K11], the mutant EGFR comprises the mutation L792H in exon 20 (=L792H). In another embodiment of the invention [K12], the mutant EGFR contains the mutation L792Y in exon 20 (=L792Y). In another embodiment of the invention [K13] the mutated EGFR comprises the mutation del19 T790M. In another embodiment of the invention [K14] the mutant EGFR comprises del19 C797mut. In another embodiment of the invention [K15] the mutated EGFR comprises the mutation del19 C797S. In another embodiment of the invention [K16] the mutated EGFR comprises the mutation del19 C797G. In another embodiment of the invention [K17] the mutated EGFR comprises the mutation del19 C797N. In another embodiment of the invention [K18] the mutated EGFR comprises the mutation del19 T790M C797mut. In another embodiment of the invention [K19] the mutated EGFR comprises the mutation del19 T790M C797S. In another embodiment of the invention [K20], the mutated EGFR comprises the mutation del19 T790M C797G. In another embodiment of the invention [K21] the mutated EGFR comprises the mutation del19 T790M C797N. In another embodiment of the invention [K22] the mutated EGFR comprises the mutation del19 L792mut. In another embodiment of the invention [K23] the mutated EGFR comprises the mutation del19 L792F. In another embodiment of the invention [K24] the mutant EGFR comprises the mutation del19 L792H. In another embodiment of the invention [K25] the mutant EGFR comprises the mutation del19 L792Y. In another embodiment of the invention [K26] the mutated EGFR comprises the mutation del19 T790M L792mut. In another embodiment of the invention [K27] the mutant EGFR comprises the mutation del19 T790M L792F. In another embodiment of the invention [K28] the mutant EGFR comprises the mutation del19 T790M L792H. In another embodiment of the invention [K29] the mutant EGFR comprises the mutation del19 T790M L792Y. In another embodiment of the invention [K30], the mutant EGFR comprises EGFR L858R T790M. In another embodiment of the invention [K31], the mutant EGFR comprises EGFR L858R C797mut. In another embodiment of the invention [K32] the mutated EGFR comprises the mutations L858R C797S. In another embodiment of the invention [K33] the mutated EGFR comprises the mutations L858R C797G. In another embodiment of the invention [K34] the mutated EGFR comprises the mutations L858R C797N. In another embodiment of the invention [K35] the mutated EGFR comprises the mutations L858R T790M C797mut. In another embodiment of the invention [K36] the mutated EGFR comprises the mutations L858R T790M C797S. In another embodiment of the invention [K37] the mutated EGFR comprises the mutations L858R T790M C797G. In another embodiment of the invention [K38] the mutated EGFR comprises the mutations L858R T790M C797N. In another embodiment of the invention [K39] the mutant EGFR comprises the mutation L858R L792mut. In another embodiment of the invention [K40] the mutated EGFR comprises the mutations L858R L792F. In another embodiment of the invention [K41] the mutated EGFR comprises the mutations L858R L792H. In another embodiment of the invention [K42] the mutated EGFR comprises the mutations L858R L792Y. In another embodiment of the invention [K43] the mutated EGFR comprises the mutations L858R T790M L792mut. In another embodiment of the invention [K44] the mutated EGFR comprises the mutations L858R T790M L792F. In another embodiment of the invention [K45] the mutated EGFR comprises the mutations L858R T790M L792H. In another embodiment of the invention [K46] the mutated EGFR comprises the mutations L858R T790M L792Y.

[0110] In one aspect, a patient is selected for treatment with a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) if the tumor cell DNA harbors a mutant EGFR gene, preferably selected from any one of [K1] to [K46]. In another aspect, there is provided a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof for use in treating a cancer having tumor cells harboring a mutated EGFR gene, preferably selected from any one of [K1] to [K46]. In another aspect, there is provided a method for treating cancer in which tumor cells harbor a mutated EGFR gene, the method comprising administering to a human a therapeutically effective amount of a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof, wherein the mutated EGFR gene is preferably selected from any one of [K1] to [K46]. In another aspect, the present invention relates to the use of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating a cancer having tumor cells harboring a mutated EGFR gene, wherein the mutated EGFR gene is preferably selected from any one of [K1] to [K46].

[0111] Determining whether a tumor or cancer contains a mutant EGFR can be performed by evaluating the nucleotide sequence encoding the EGFR protein at the DNA or RNA level, by evaluating the amino acid sequence of the EGFR protein, or by evaluating the characteristics of the putative mutant EGFR protein. The sequence of wild-type human EGFR is well known in the art. Methods for detecting mutations in EGFR nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, digital droplet PCR, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, microarray analysis, and next-generation sequencing. In some embodiments, samples are evaluated for EGFR mutations by real-time PCR. Real-time PCR uses fluorescent probes specific for EGFR mutations. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, EGFR mutations are identified using direct sequencing of a specific region of the EGFR gene. This technique will identify all possible mutations within the sequenced region. Methods for determining mutations in EGFR proteins are known to those skilled in the art. These methods include, but are not limited to, detection of EGFR mutants using binding agents (e.g., antibodies) specific to the mutant protein, protein electrophoresis, Western blotting, and direct peptide sequencing.

[0112] The method for determining whether a tumor or cancer contains an EGFR mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In some embodiments, the sample is a liquid biopsy, where blood, urine, sputum, or other bodily fluid is tested for tumor-derived cancer cells contained within the sample or fragments of DNA from tumor cells contained within the sample. In another aspect, the disease / condition / cancer to be treated / prevented with the compounds of formula (I) (including all individual embodiments and general subsets disclosed herein) or in the medical applications, uses, methods of treatment and / or prevention disclosed herein is selected from the group consisting of lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastases (especially brain metastases) of all of the listed cancers. In another aspect, the disease / condition / cancer to be treated / prevented with the compounds of formula (I) (including all individual embodiments and general subsets disclosed herein) or in the medical applications, uses, treatment and / or prevention methods disclosed herein is lung cancer. Preferably, the lung cancer to be treated is non-small cell lung cancer (NSCLC), including locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC without squamous histology. Most preferably, the lung cancer to be treated is NSCLC adenocarcinoma.

[0113] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer whose tumor cells harbor a mutated EGFR gene, where the mutated EGFR gene contains a deletion in exon 19 (=del19). Preferably, the cancer patient to be treated and afflicted with the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as a first-line treatment (with respect to treatment with an EGFR TKI). That is, the patient is naive to an EGFR TKI. In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer whose tumor cells harbor a mutated EGFR gene, where the mutated EGFR gene contains the mutation del19 T790M. Preferably, the cancer patient to be treated and afflicted with the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as a second-line treatment (with respect to treatment with an EGFR TKI). That is, patients have progressed during early treatment with first and second generation EGFR TKIs (ie, patients have progressed after prior treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, wherein the mutant EGFR gene comprises the mutation del19 C797S. Preferably, the cancer patient to be treated and afflicted with the cancer has been administered a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI), i.e., the patient has progressed during earlier treatment with a third-generation EGFR TKI (i.e., the patient has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib).

[0114] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, wherein the mutant EGFR gene comprises the mutation del19 C797mut (preferably C797G or C797N). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed during earlier treatment with a third-generation EGFR TKI (that is, the patient has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, the mutant EGFR gene including the mutation del19 T790M C797S. Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as third-line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed due to T790M acquisition during initial treatment with a first- or second-generation EGFR TKI (i.e., the patient has progressed after initial treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib), and has progressed due to C797S acquisition during additional treatment with a third-generation EGFR TKI (i.e., the patient has progressed after additional treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib).

[0115] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutated EGFR gene, wherein the mutated EGFR gene comprises the mutation del19 T790M C797mut (preferably C797G or C797N). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as third line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed due to T790M acquisition during early treatment with a first or second generation EGFR TKI (i.e., the patient has progressed after early treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib), and has progressed due to C797mut (preferably, C797G or C797N) acquisition during additional treatment with a third generation EGFR TKI (i.e., the patient has progressed after additional treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, where the mutant EGFR gene comprises the mutation del19 L792mut (preferably L792F, L792H, or L792Y). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed during earlier treatment with a third-generation EGFR TKI (that is, the patient has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib).

[0116] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, where the mutant EGFR gene comprises the mutation del19 T790M L792mut (preferably L792F, L792H, or L792Y). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as third line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed due to T790M acquisition during early treatment with a first or second generation EGFR TKI (i.e., the patient has progressed after early treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib), and has progressed due to L792mut (preferably, L792F, L792H, or L792Y) acquisition during additional treatment with a third generation EGFR TKI (i.e., the patient has progressed after additional treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, wherein the mutant EGFR gene comprises the L858R mutation. Preferably, the cancer patient to be treated and afflicted with the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as first-line therapy (with respect to treatment with an EGFR TKI). That is, the patient is naive to an EGFR TKI.

[0117] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, wherein the mutant EGFR gene includes the mutations L858R T790M. Preferably, the cancer patient to be treated and afflicted with the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI), i.e., the patient has progressed during earlier treatment with a first- or second-generation EGFR TKI (i.e., the patient has progressed after prior treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, wherein the mutant EGFR gene includes the mutation L858R C797S. Preferably, the cancer patient to be treated and afflicted with the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI), i.e., the patient has progressed during earlier treatment with a third-generation EGFR TKI (i.e., the patient has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib).

[0118] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, where the mutant EGFR gene comprises the mutation L858R C797mut (preferably C797G or C797N). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed during earlier treatment with a third-generation EGFR TKI (that is, the patient has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, the mutant EGFR gene including the mutations L858R T790M C797S. Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as third-line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed due to T790M acquisition during initial treatment with a first- or second-generation EGFR TKI (i.e., the patient has progressed after initial treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib), and has progressed due to C797S acquisition during additional treatment with a third-generation EGFR TKI (i.e., the patient has progressed after additional treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib).

[0119] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutated EGFR gene, wherein the mutated EGFR gene comprises the mutation L858R T790M C797mut (preferably C797G or C797N). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as third line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed due to T790M acquisition during early treatment with a first or second generation EGFR TKI (i.e., the patient has progressed after early treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib), and has progressed due to C797mut (preferably, C797G or C797N) acquisition during additional treatment with a third generation EGFR TKI (i.e., the patient has progressed after additional treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutant EGFR gene, where the mutant EGFR gene comprises the mutation L858R L792mut (preferably L792F, L792H, or L792Y). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed during earlier treatment with a third-generation EGFR TKI (that is, the patient has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib).

[0120] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer having tumor cells harboring a mutated EGFR gene, where the mutated EGFR gene comprises the mutation L858R T790M L792mut (preferably L792F, L792H, or L792Y). Preferably, the cancer patient to be treated and suffering from the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as third line therapy (with respect to treatment with an EGFR TKI). That is, the patient has progressed due to T790M acquisition during early treatment with a first or second generation EGFR TKI (i.e., the patient has progressed after early treatment with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib), and has progressed due to L792mut (preferably, L792F, L792H, or L792Y) acquisition during additional treatment with a third generation EGFR TKI (i.e., the patient has progressed after additional treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib). In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer that has progressed after earlier treatment with a third-generation EGFR TKI (i.e., the cancer has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almonertinib, or avitinib). In one aspect, the cancer patient to be treated and afflicted with the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as second-line therapy (with respect to treatment with an EGFR TKI). In another aspect, the cancer patient to be treated and afflicted with the cancer has been administered a compound of Formula (I) (including all individual embodiments and general subsets disclosed herein) as third-line therapy (with respect to treatment with an EGFR TKI). In these situations, the preferred treatment is treatment after prior treatment with osimertinib.

[0121] The compounds of the present invention may be used for the prophylaxis, short-term or long-term treatment of the above diseases / conditions / cancers / tumours, optionally in combination with radiation therapy and / or surgery. The methods of treatment, methods, uses and compounds for use as disclosed herein can be practiced with any compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), or with any pharmaceutical composition or kit comprising any compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein).

[0122] Combination treatment The compounds of formula (I) or pharmaceutically acceptable salts thereof (including all individual embodiments and general subsets disclosed herein) and pharmaceutical compositions comprising said compounds and salts may be co-administered with other pharmacologically active substances, such as other antineoplastic compounds (e.g., chemotherapy), or may be used in combination with other treatments, such as radiation or surgery, as a pre-surgical adjuvant or post-operatively. Preferably, the co-administered pharmacologically active substance is an antineoplastic compound. Thus, in a further aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) for use as described above, wherein said compound is administered before, after or together with one or more other pharmacologically active substances. In a further aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) for use as described above, wherein said compound is administered in combination with one or more other pharmacologically active substances.

[0123] In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore described (including all individual embodiments and general subsets disclosed herein), wherein said compound is to be administered before, after, or together with one or more other pharmacologically active substances. In a further aspect, the invention relates to a method (e.g., a method of treatment and / or prophylaxis) as described above, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) is administered before, after, or together with a therapeutically effective amount of one or more other pharmacologically active substances. In a further aspect, the invention relates to a method (e.g., a method of treatment and / or prophylaxis) as described above, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substances.

[0124] In a further aspect, the present invention relates to a method for the treatment and / or prevention of cancer, comprising the step of administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, concurrently, sequentially, sequentially, alternatingly or separately from the one or more other pharmacologically active substances. In a further aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein) for use in the treatment and / or prevention of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, concomitantly, sequentially, sequentially, staggered or separately from one or more other pharmacologically active substances.

[0125] In a further aspect, the present invention provides a method for the treatment and / or prevention of cancer. a first pharmaceutical composition or dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), and optionally one or more pharmaceutically acceptable excipients; and a first pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipients; wherein the second pharmaceutical composition is to be administered simultaneously, simultaneously, sequentially, sequentially, alternately or separately from the second and / or additional pharmaceutical compositions or dosage forms. In one embodiment, the kit for said use further comprises a third pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipients.

[0126] In a further embodiment of the invention, the components (ie combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered simultaneously. In a further embodiment of the invention, the components (ie combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered simultaneously. In a further embodiment of the present invention, the components (ie combination partners) of the combinations, kits, uses, methods and compounds for use according to the present invention (including all embodiments thereof) are administered sequentially. In a further embodiment of the invention, the components (ie combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments thereof) are administered sequentially. In a further embodiment of the invention, the components (ie combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered alternately. In a further embodiment of the invention, the components (ie combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered separately.

[0127] The pharmacologically active substance to be used together / in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets of compound (I)) or in the medical applications, uses, methods of treatment and / or prevention disclosed herein (above and below) can be selected from any one or more of the following (preferably, in all these embodiments, one or two additional pharmacologically active substances are used): 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutants thereof Irreversible inhibitors: e.g., afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib; b. Reversible inhibitors: e.g., erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340; c. Anti-EGFR antibodies: e.g., necitumumab, panitumumab, cetuximab, amivantanab; d. Anti-HER2 antibodies: e.g., pertuzumab, trastuzumab, trastuzumab emtansine; e. Mutant EGFR inhibitors; f. Inhibitors of HER2 with exon 20 mutations; g. The preferred irreversible inhibitor is afatinib; h. The preferred anti-EGFR antibody is cetuximab;

[0128] 2. MEK and / or its mutant inhibitors a. For example, trametinib, cobimetinib, binimetinib, selumetinib, refametinib, BI 3011441; b. Trametinib and BI 3011441 are preferred; c. BI 3011441 is most preferred; 3. c-MET and / or its mutant inhibitors a. For example, savolitinib, cabozantinib, foretinib; b. MET antibodies, e.g., emibetuzumab, amivantanab; 4. Inhibitors of SOS1 and / or any mutants thereof (i.e. compounds that modulate / inhibit the GEF functionality of SOS1, for example by binding to SOS1 and blocking the protein-protein interaction between SOS1 and (mutated) Ras proteins, such as KRAS) a. For example, BAY-293, BI-3406, BI 1701963; b. BI 1701963 is most preferred; 5. Inhibitors of GDP-loaded or GTP-loaded RAS and / or any mutants thereof (i.e., compounds that modulate / inhibit the functionality of (mutated) RAS proteins, e.g., by binding to GDP-loaded or GTP-loaded (mutated) RAS proteins, e.g., KRAS, NRAS and / or HRAS, preferably KRAS). a. Irreversible inhibitors of KRAS G12C; i For example, AMG-510, MRTX849, ARS-324, GDC-6036; b. Reversible or irreversible binders to GDP-loaded (mutated) KRAS; c. Reversible or irreversible binders to GTP-loaded (mutated) KRAS;

[0129] 6. Immunotherapy a. For example, immune checkpoint inhibitors i e.g. anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb; ii. Anti-PD1 mAb is preferred; iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, zurvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab; iv. Nivolumab, pembrolizumab, PDR-001 (= spartalizumab) and ezabenlimab are preferred; v. Pembrolizumab, nivolumab, and ezabenlimab are most preferred; b. For example, immunomodulatory drugs i. For example, a CD73 inhibitor or a CD73 inhibitor antibody 7. Inhibitors of ALK and / or any of its mutations a. For example, crizotinib, alectinib, entrectinib, brigatinib, ceritinib; b. Crizotinib and alectinib are preferred; b. Crizotinib is most preferred; 8. Taxanes a. For example, paclitaxel, nab-paclitaxel, docetaxel; b. Paclitaxel is preferred; 9. Platinum-containing compounds a. For example, cisplatin, carboplatin, oxaliplatin b. Carboplatin is preferred; 10. Antimetabolites a. For example, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, trifluridine and tipiracil (=TAS102); b. Pemetrexed is preferred;

[0130] 11. Cell cycle inhibitors a. Inhibitors of, for example, CDK4 / 6 and / or any mutants thereof i. For example, palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600; ii. Palbociclib and abemaciclib are preferred; iii. Abemaciclib is most preferred; b. For example, vinca alkaloids i. For example, vinorelbine c. Inhibitors of, for example, Aurora kinase and / or any mutant thereof i. For example, alisertib, barasertib; 12. mTOR inhibitors a. For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, torin 1, dactolisib, GDC-0349, VS-5584, vistusertib, AZD8055; 13. Inhibitors of Src family kinases and / or any mutants thereof a. inhibitors of kinases of the SrcA subfamily and / or any mutants thereof, i.e. inhibitors of Src, Yes, Fyn, Fgr and / or any mutants thereof; b. For example, inhibitors of kinases of the SrcB subfamily and / or any mutants thereof, i.e., inhibitors of Lck, Hck, Blk, Lyn and / or any mutants thereof; c. For example, inhibitors of kinases of the Frk subfamily and / or any mutants thereof, i.e., inhibitors of Frk and / or any mutants thereof; d. For example, dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU 6656, WH-4-023; 14. Apoptosis-inducing drugs a. For example, MCL-1 inhibitors; i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477; b. For example, Bcl-2 inhibitors; i. For example, venetoclax, obatoclax, navitoclax, oblimersen; c. For example, Bcl-xL inhibitors;

[0131] 15. Antiangiogenic drugs a. For example, bevacizumab, nintedanib; b. Bevacizumab is most preferred; c. e.g. anti-VEGF / Ang2 bispecific antibody i. bispecific binding molecules as disclosed and described, for example, in WO 2012 / 131078 and WO 2018 / 220169; 16. Inhibitors of PI3 kinase (=PI3K) and / or any mutant thereof a. Inhibitors of PI3Kα and / or any of its mutants i. For example, alpelisib, selavelisib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactolisib, pictilisib, taselisib; 17. Histone deacetylase inhibitors 18. IL6 inhibitors 19. Inhibitors of JAK and / or any of its mutants 20. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutants thereof a. For example, encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (= Example 131 of WO2014 / 151616), LXH254, sorafenib, LY-3009120 (= Example 1 of WO2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265; 21. Inhibitors of receptor tyrosine kinases (RTKs) and / or any mutants thereof 22. Inhibitors of SHP2 and / or any of its mutants a. For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0132] In further embodiments of the (combined) uses and methods (e.g., treatment and / or prophylaxis methods) as described above, one other pharmacologically active substance is administered before, after, or together with the compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), and said one other pharmacologically active substance is SOS1 inhibitors, or BI 1701963, or MEK inhibitors, or trametinib, or BI 3011441, or anti-PD-1 antibodies, or ezabenlimab, or cetuximab, or afatinib, or Inhibitors of GDP- or GTP-loaded mutant KRAS, or MCL1 inhibitors, or PI3K inhibitors is.

[0133] In further embodiments of the (combined) uses and methods (e.g., treatment and / or prophylaxis methods) as described above, one other pharmacologically active substance is administered before, after, or together with the compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), and said one other pharmacologically active substance is SOS1 inhibitors, or BI 1701963 MEK inhibitors, or trametinib, or BI 3011441, or anti-PD-1 antibodies, or ezabenlimab, or cetuximab, or afatinib, or Inhibitors of GDP- or GTP-loaded mutant KRAS, or MCL1 inhibitors, or PI3K inhibitors is.

[0134] In further embodiments of the (combined) uses and methods (e.g., treatment and / or prophylaxis methods) as described above, two other pharmacologically active substances are administered before, after or together with the compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), wherein said two other pharmacologically active substances are: MEK inhibitors and SOS1 inhibitors, or trametinib and an SOS1 inhibitor, or trametinib and BI 1701963, or BI 3011441 and BI 1701963, or anti-PD-1 antibody and anti-LAG-3 antibody, or anti-PD-1 and anti-CTLA-4 antibodies, or Anti-PD-1 antibodies and SOS1 inhibitors, or ezabenlimab and BI 1701963, or an inhibitor selected from the group consisting of MEK inhibitors and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants of EGFR and / or ErbB2 (HER2), or an inhibitor selected from the group consisting of BI 3011441 and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant of EGFR and / or ErbB2 (HER2), or an inhibitor selected from the group consisting of SOS1 inhibitors and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants of EGFR and / or ErbB2 (HER2), or an inhibitor selected from the group consisting of BI 1701963 and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant of EGFR and / or ErbB2 (HER2), or MEK inhibitors and afatinib, or BI 3011441 and afatinib, or MEK inhibitors and cetuximab, or BI 3011441 and cetuximab (cdetuximab), or trametinib and afatinib, or trametinib and cetuximab, or SOS1 inhibitors and afatinib, or BI 1701963 and afatinib, or SOS1 inhibitors and cetuximab, or BI 1701963 and cetuximab, or SOS1 inhibitors and inhibitors of GDP- or GTP-loaded mutant KRAS, or BI 1701963 and inhibitors of GDP- or GTP-loaded mutant KRAS, or Cisplatin and pemetrexed, or Carboplatin and pemetrexed is.

[0135] In further embodiments of the (combined) uses and methods (e.g., treatment and / or prophylaxis methods) as described above, two other pharmacologically active substances are to be co-administered with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), wherein said two other pharmacologically active substances are: MEK inhibitors and SOS1 inhibitors, or trametinib and an SOS1 inhibitor, or trametinib and BI 1701963, or BI 3011441 and BI 1701963, or anti-PD-1 antibody and anti-LAG-3 antibody, or anti-PD-1 and anti-CTLA-4 antibodies, or Anti-PD-1 antibodies and SOS1 inhibitors, or ezabenlimab and BI 1701963, or an inhibitor selected from the group consisting of MEK inhibitors and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants of EGFR and / or ErbB2 (HER2), or an inhibitor selected from the group consisting of BI 3011441 and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant of EGFR and / or ErbB2 (HER2), or an inhibitor selected from the group consisting of SOS1 inhibitors and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants of EGFR and / or ErbB2 (HER2), or an inhibitor selected from the group consisting of BI 1701963 and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant of EGFR and / or ErbB2 (HER2), or MEK inhibitors and afatinib, or BI 3011441 and afatinib, or MEK inhibitors and cetuximab, or BI 3011441 and cetuximab, or trametinib and afatinib, or trametinib and cetuximab, or SOS1 inhibitors and afatinib, or BI 1701963 and afatinib, or SOS1 inhibitors and cetuximab, or BI 1701963 and cetuximab, or SOS1 inhibitors and inhibitors of GDP- or GTP-loaded mutant KRAS, or BI 1701963 and inhibitors of GDP- or GTP-loaded mutant KRAS, or Cisplatin and pemetrexed, or Carboplatin and pemetrexed is.

[0136] Additional pharmacologically active substances that may also be used together / in combination with the compounds of formula (I) or pharmaceutically acceptable salts thereof (including all individual embodiments and general subsets of compound (I)) or in the medical applications, uses, methods of treatment and / or prevention disclosed herein (above and below) include, but are not limited to, hormones, hormone analogs and antihormonal drugs (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), growth factors and / or their corresponding receptors (e.g., platelet-derived growth factor ( and inhibitors of growth factors such as PDGF, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4), and hepatocyte growth factor (HGF) and / or their corresponding receptors, and examples of inhibitors include (anti-)growth factor antibodies, (anti-)growth factor receptor antibodies, and tyrosine kinase inhibitors, e.g., cetuximab, gefitinib, afatinib, nintedanib, imatinib, and the like. anti-metabolites (e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (cytosine arabinoside), fludarabine);Antitumor antibodies (e.g., anthracyclines such as doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride), Myoset (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, meclomustine, rituximab, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, such as carmustine and lomustine, thiotepa; mitotic inhibitors (e.g., vinca alkaloids, such as vinblastine, vindesine, vinorelbine, and vincristine; and taxanes, such as paclitaxel and docetaxel); angiogenesis inhibitors (e.g., tasquinimod), tubulin inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK1 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, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimetics, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g., venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogues (e.g., everolimus, temsirolimus, ridaforolimus, cilolimus) mus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g., carfilzomib), immunotherapeutics, such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, such as ipilimumab, nivolumab, pembrolizumab, etc.), ADCC (antibody-dependent cell-mediated cytotoxicity) activators (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers (BiTEs®) such as CD3 x BCMA, CD3 x CD33, CD3 x CD19), PSMA x CD3), tumor vaccines and various chemotherapeutic drugs such as amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer;

[0137] It should be understood that the combinations, compositions, kits, methods, uses or compounds employed in accordance with the present invention may envisage simultaneous, concurrent, sequential, sequential, alternating or separate administration of the active ingredients. It will be appreciated that the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances may be formulated so as to be administered dependently or independently, for example, the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances as part of the same pharmaceutical composition / dosage form or, preferably, in separate pharmaceutical compositions / dosage forms. In this context, "combination" or "combined" within the meaning of the present invention includes, but is not limited to, products resulting from the mixing or combining of multiple active ingredients, and includes both fixed and non-fixed (e.g., free) combinations (including kits) and uses, such as simultaneous, concurrent, sequential, sequential, alternating, or separate use of the ingredients. The term "fixed combination" means that the active ingredients are administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients are administered simultaneously, simultaneously, or sequentially without any specific time limit, which administration results in therapeutically effective levels of the compounds in the patient's body. The administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances may be carried out by simultaneous administration of the active ingredients, for example by administering the active ingredients simultaneously or contemporaneously in a single or two or more separate formulations or dosage forms. Alternatively, the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances may be carried out by administering the active ingredients sequentially or staggered, for example in two or more separate formulations or dosage forms.

[0138] For example, simultaneous administration includes administering at substantially the same time. This form of administration may also be referred to as "concomitant" administration. Concurrent administration includes administering the active ingredient within the same general time period, for example on the same day but not necessarily at the same time. Alternate administration includes administering one agent for a period of time, for example for several days or one week, and then administering another agent for a subsequent period of time, for example for several days or one week, and repeating this pattern over one or more cycles. Sequential or continuous administration includes administering one agent using one or more doses over a first period of time (e.g., over several days or one week) and then administering another agent using one or more doses over a second and / or additional period of time (e.g., over several days or one week). A repeated schedule may be utilized, which includes administering the active agent on different days over the course of the treatment period, not necessarily in a regular order. For example, depending on the agent used and the condition of the subject, variations of these general guidelines may be utilized.

[0139] Definitions Terms not specifically defined herein should be given the meaning that would be ascribed to them by one of ordinary skill in the art in view of the present disclosure and context. However, as used herein, unless otherwise specified, the following terms have the indicated meanings and follow the following conventions. Prefix C x-y (where x and y each represent positive integers (x < y)) is used to indicate that the directly related specified chain or ring structure or the combination of chain and ring structures as a whole can consist of a maximum of y and a minimum of x carbon atoms. The indication of the number of members in a group containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total number of all ring members or the total of all ring members and carbon chain members. The indication of the number of carbon atoms in a group consisting of a combination of a carbon chain and a carbon ring structure (e.g., cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all carbon ring members and carbon chain members. Clearly, the ring structure has at least three members. Generally, for groups containing two or more subgroups (e.g., heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, arylalkyl, etc.), the last named subgroup is the point of attachment for the group, e.g., the substituent aryl-C 1-6 Alkyl is C 1-6 It means an aryl bonded to an alkyl group, and its C 1-6 The alkyl group is attached to a core or group to which the substituents are attached. For groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., one skilled in the art will recognize the point of attachment of the group to the molecule from the free valence of the group itself.

[0140] "Alkyl" means a monovalent saturated hydrocarbon chain which may exist in both straight (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, on all hydrogen-carrying carbon atoms, by mono- or polysubstitution in each case. The term “C 1-5 "Alkyl" includes, for example, HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH(CH)-, HC-CH-CH(CH)-, HC-CH-CH(CH)-CH-, HC-CH(CH)-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH(CH)- and HC-CH-CH(CHCH)-. Further examples of alkyl are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-propyl, n-Pr, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-butyl, n-Bu, -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl, 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 (isopentyl, -CH2CH2CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neopentyl, - CH2C(CH3)3), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl, -CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 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. The general terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc., without any further definition, mean saturated hydrocarbon radicals with the corresponding number of carbon atoms, including all isomeric forms. The above definition of alkyl means that alkyl is, for example, C x-y Alkylamino or C x-y This also applies when it is part of another (combining) group such as alkyloxy.

[0141] The term "alkylene" is derived from alkyl. Unlike alkyl, alkylene is divalent and requires two binding partners. Formally, the second valency is created by removing a hydrogen atom from alkyl. Corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2-, or >CHCH3, etc. The term “C 1-4Examples of "alkylene" include -(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- These include -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, and the like. The general terms propylene, butylene, pentylene, hexylene, etc., without any further definition, mean all possible isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene, butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene. The above definition of alkylene means that alkylene is, for example, HO-C x-y Alkyleneamino or H2N-C x-y This also applies when it is part of another (combining) group, such as in alkyleneoxy.

[0142] Unlike alkyl, an "alkenyl" consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined by a C-C double bond, and a carbon atom can be only part of one C-C double bond. In an alkyl as defined above having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, forming the corresponding alkenyl. 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-dienyl, and the like. The general terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc., without any further definition, mean all the possible 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. The alkenyl may optionally be in the cis or trans or E or Z orientation about the double bond(s). The above definition of alkenyl means that alkenyl is, for example, Cx-y Alkenylamino or C x-y This also applies when it is part of another (combining) group, such as in alkenyloxy.

[0143] Unlike alkylene, an "alkenylene" consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined by a C-C double bond, and a carbon atom can be part of only one C-C double bond. In an alkylene as defined above having at least two carbon atoms, two hydrogen atoms from adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, forming the corresponding alkenylene. Examples of alkenylene include ethenylene, propenylene, 1-methylethenylene, butenylene, Examples include 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, and hexenylene. The general terms propenylene, butenylene, pentenylene, hexenylene etc., without any further definition, mean all the possible isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene, butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene. The alkenylene may optionally be in the cis or trans or E or Z orientation about the double bond(s). The above definition of alkenylene means that alkenylene is, for example, HO-C x-y Alkenyleneamino or H2N-C x-y This also applies when it is part of another (combining) group, such as in alkenyleneoxy.

[0144] Unlike alkyl, "alkynyl" consists of at least two carbon atoms, with at least two adjacent carbon atoms joined by a C—C triple bond. In an alkyl as defined above having at least two carbon atoms, formally, two hydrogen atoms are removed from each of the adjacent carbon atoms, saturating the free valences to form two additional bonds, forming the corresponding alkynyl. Examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, and the like. The general terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc., without any further definition, mean all possible 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 the hydrocarbon chain also contains at least one double bond and at least one triple bond, it by definition belongs to the subgroup of alkynyl. The above definition of alkynyl means that alkynyl is, for example, C x-y Alkynylamino or C x-y This also applies when it is part of another (combining) group, such as in alkynyloxy.

[0145] Unlike alkylene, "alkynylene" consists of at least two carbon atoms, with at least two adjacent carbon atoms joined by a C—C triple bond. In an alkylene as defined above having at least two carbon atoms, formally, two hydrogen atoms are removed from each of the adjacent carbon atoms, and the free valences are saturated to form two additional bonds, forming the corresponding alkynylene. 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, and the like. The general terms propynylene, butynylene, pentynylene, hexynylene, etc., without any further definition, mean all the possible isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene, butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene. The above definition of alkynylene means that alkynylene is, for example, HO-C x-y Alkynyleneamino or H2N-C x-y This also applies when it is part of another (combining) group, such as in alkynyleneoxy.

[0146] "Heteroatoms" means oxygen, nitrogen, phosphorus and sulfur atoms. Preferably, heteroatoms are selected from oxygen, nitrogen and sulfur. A "haloalkyl(alkenyl, haloalkynyl)" is derived from an alkyl(alkenyl, alkynyl) as previously defined by replacing one or more hydrogen atoms of the hydrocarbon chain, independently of one another, with halogen atoms, which may be the same or different. If a haloalkyl(alkenyl, haloalkynyl) is further substituted, the substitutions may occur independently of one another on all hydrogen-bearing carbon atoms, in the form of mono- or polysubstitutions in each case. 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, and the like. The term "haloalkylene (haloalkenylene, haloalkynylene)" is also derived from the previously defined haloalkyl (haloalkenyl, haloalkynyl). Haloalkylene (haloalkenylene, haloalkynylene) differs from haloalkyl (haloalkenyl, haloalkynyl) in that it is divalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from the haloalkyl (haloalkenyl, haloalkynyl). Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F, etc. The above definitions also apply when the corresponding halogen-containing group is part of another (combining) group. "Halogen" refers to fluorine, chlorine, bromine and / or iodine atoms.

[0147] "Cycloalkyl" consists of the subgroups monocyclic cycloalkyl (= monocyclic hydrocarbon ring), bicyclic cycloalkyl (= bicyclic hydrocarbon ring) and spirocycloalkyl (= spiro hydrocarbon ring). These ring systems are saturated. In bicyclic hydrocarbon rings, the two rings are connected in such a way that they share at least two carbon atoms. In spiro hydrocarbon rings, one carbon atom (spiro atom) belongs to both rings at the same time. 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 hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked to the molecule as a substituent at any 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, and the like. The above definition of cycloalkyl means that cycloalkyl is, for example, C x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y This also applies when it is part of another (combining) group, such as in cycloalkylalkyl. If the free valence of a cycloalkyl is saturated, then an "alicyclic radical" is obtained (and therefore all definitions of cycloalkyl apply to an alicyclic radical). The term "cycloalkylene" is derived from cycloalkyl, as previously defined. Cycloalkylene, unlike cycloalkyl, is divalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups include, for example, cyclohexyl and

[0148] [ka]

[0149] is. The above definition of cycloalkylene means that cycloalkylene is, for example, HO-C x-y Cycloalkyleneamino or H2N-C x-y This also applies when it is part of another (combining) group, such as in cycloalkyleneoxy. "Cycloalkenyl" also comprises the subgroups monocyclic cycloalkenyl (= monocyclic hydrocarbon ring), bicyclic cycloalkenyl (= bicyclic hydrocarbon ring) and spirocycloalkenyl (= spiro hydrocarbon ring). However, these systems are unsaturated, i.e., they have at least one C-C double bond, but are not aromatic. In cycloalkyl as defined above, formally, two hydrogen atoms from adjacent ring carbon atoms are removed and the free valences are saturated to form a second bond, resulting in the corresponding cycloalkenyl. 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 hydrogen-carrying carbon atoms. The cycloalkenyl itself may be linked to the molecule as a substituent at any suitable position of the ring system. Examples of cycloalkenyl include cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobut-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, and the like. The above definition of cycloalkenyl means that cycloalkenyl is, for example, C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C x-y This is also true when it is part of another (combining) group, such as in cycloalkenylalkyl. If the free valence of a cycloalkenyl is saturated, then an "unsaturated alicyclic radical" is obtained (and therefore all definitions of cycloalkenyl apply to unsaturated alicyclic radicals). Thus, the term "cycloalkenylene" can 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 cycloalkenyl. Corresponding groups include, for example, cyclopentenyl and

[0150] [ka]

[0151] etc. The above definition of cycloalkenylene means that cycloalkenylene is, for example, HO-C x-y Cycloalkenyleneamino or H2N-C x-y This is also true when it is part of another (combining) group, such as in cycloalkenyleneoxy.

[0152] "Aryl" refers to a mono-, bi-, or tri-carbocycle having at least one aromatic carbocycle. Preferably, aryl refers to a monocyclic group having 6 carbon atoms (phenyl) or a bicyclic group having 9 or 10 carbon atoms (two 6-membered rings or one 6-membered and one 5-membered ring), where the second ring may be aromatic or partially saturated. If an aryl is substituted, the substitutions may occur independently of one another, in the form of mono- or polysubstitutions in each case, on all hydrogen-carrying carbon atoms. The aryl itself may be linked to the molecule as a substituent at any 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. Phenyl is most preferred. The above definition of aryl also applies if aryl is part of another (combining) group, such as in, for example, arylamino, aryloxy or arylalkyl. When the free valence of an aryl is saturated, an "aromatic group" is obtained (and therefore all definitions of aryl apply to an aromatic group). The term "arylene" can also be derived from the previously defined aryl. Unlike aryl, arylene is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups include, for example, phenyl and

[0153] [ka]

[0154] Naphthyl and

[0155] [ka]

[0156] etc. The above definition for arylene also applies if arylene is part of another (combining) group, as in, for example, HO-aryleneamino or H2N-aryleneoxy.

[0157] "Heterocyclyl" is derived from the previously defined cycloalkyl, cycloalkenyl, and aryl by replacing one or more carbon atoms with heteroatoms, for example, by replacing the -CH2- groups of the hydrocarbon ring independently with, for example, -O-, -S-, -NH-, or -PH- groups, or by replacing one or more =CH- groups with =N- groups, where a total of up to five heteroatoms may be present, there must be at least one carbon atom between two oxygen atoms and two sulfur atoms or between an oxygen atom and a sulfur atom, and the ring as a whole must be chemically stable. Heteroatoms may optionally exist in all possible oxidation states (e.g., sulfur → sulfoxide -SO2-, sulfone -SO2-; nitrogen → N-oxide). In a heterocyclyl, there are no heteroaromatic rings, i.e., the heteroatoms are not part of an aromatic system. A direct consequence of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl consists of the subgroups monocyclic heterocyclyl (= monocyclic heterocycle), bicyclic heterocyclyl (= bicyclic heterocycle), tricyclic heterocyclyl (= tricyclic heterocycle) and spiroheterocyclyl (= spiroheterocycle), which can exist in saturated or unsaturated form. Unsaturated means that the ring system in question has at least one double bond, but does not form a heteroaromatic system. In bicyclic heterocycles, two rings are joined so that they share at least two (hetero)atoms. In spiroheterocycles, one carbon atom (spiroatom) belongs to both rings simultaneously. If a heterocyclyl is substituted, the substitutions may occur independently of one another on all hydrogen-bearing carbon and / or nitrogen atoms, in each case in the form of mono- or polysubstitutions. The heterocyclyl itself may be linked to the molecule as a substituent at any suitable position of the ring system. Substituents on a heterocyclyl do not count as members of the heterocyclyl; that is, the given member number of a heterocyclyl refers only to the number of atoms that form the ring / ring system of the heterocyclyl.

[0158] 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, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazeto, 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, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, and the like. Further examples are the following structures, each of which may be attached via (exchanged with) a hydrogen-bearing atom:

[0159] [ka] [ka] [ka]

[0160] Preferably, the heterocyclyl is a 4- to 8-membered monocyclic ring having 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur. Preferred heterocyclyls are piperazinyl, piperidinyl, morpholinyl, homomorpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl. Preferred monocyclic heterocyclyls are 4 to 7 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur. Preferred monocyclic heterocyclyls are piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azetidinyl. Preferred bicyclic heterocyclyls are 6-10 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Preferred tricyclic heterocyclyls are nine-membered and have one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. Preferred spiroheterocyclyls are 7-11 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. The above definition of heterocyclyl also applies if heterocyclyl is part of another (combining) group, as for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl. If the free valence of a heterocyclyl is saturated, a "heterocycle" is obtained (and therefore all definitions for heterocyclyl apply to heterocycles). 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 include, for example, piperidinyl and

[0161] [ka]

[0162] 2,3-dihydro-1H-pyrrolyl,

[0163] [ka]

[0164] etc. The above definition of heterocyclylene also applies if heterocyclylene is part of another (combining) group, as for example in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy. "Heteroaryl" means a monocyclic heteroaromatic ring or a polycyclic ring having at least one heteroaromatic ring, which, compared to the corresponding aryl or cycloalkyl(alkenyl), contains, in place of one or more carbon atoms, one or more identical or different heteroatoms selected independently from nitrogen, sulfur, and oxygen, and the resulting group must be chemically stable. The presence of a heteroaryl is prerequisite for the heteroatom and the heteroaromatic system. When a heteroaryl is substituted, the substitutions can occur independently on all hydrogen-bearing carbon and / or nitrogen atoms, in the form of mono- or polysubstitutions in each case. The heteroaryl itself can be attached to the molecule as a substituent at any suitable position, either carbon or nitrogen, in the ring system. Substituents on a heteroaryl are not included in the number of members of the heteroaryl. That is, the given number of members of a heteroaryl refers only to the number of atoms that form the ring / ring system of the 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, benzophenone ... Examples of the benzothiazolyl include 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, and benzimidazolyl-N-oxide. Further examples are the following structures, each of which may be attached via (exchanged with) a hydrogen-bearing atom:

[0165] [ka]

[0166] Preferably, heteroaryl is a 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring having 1 to 4 heteroatoms each independently selected from oxygen, nitrogen, and sulfur. The above definition of heteroaryl also applies if heteroaryl is part of another (combining) group, such as in, for example, heteroarylamino, heteroaryloxy or heteroarylalkyl. When the free valence of a heteroaryl is saturated, a "heteroaromatic ring" is obtained (and therefore all definitions for heteroaryl apply to heteroaromatic rings). 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 include, for example, pyrrolyl and

[0167] [ka]

[0168] etc. The above definition of heteroarylene also applies if heteroarylene is part of another (combining) group, as for example in HO-heteroaryleneamino or H2N-heteroaryleneoxy. "Substituted" means that a hydrogen atom directly attached to the atom under consideration is replaced by another atom or another group of atoms (substituents). Depending on the starting conditions (number of hydrogen atoms), mono- or polysubstitutions can occur on an atom. Substitution with a specific substituent is only possible if the allowed valencies of the substituent and the atom to be substituted correspond to each other and if the substitution results in a stable compound (i.e., a compound that does not spontaneously transform, for example, by rearrangement, cyclization, or elimination). For example, divalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, etc., can only be substituents on carbon atoms, while the divalent substituents =O and =NR can also be substituents on sulfur and phosphorus. Generally, substitution in ring systems is only by divalent substituents and requires two geminal hydrogen atoms, i.e., hydrogen atoms attached to the same carbon atom that is saturated before substitution. Thus, substitution by divalent substituents is only possible on the -CH2-, sulfur, and phosphorus atoms of the ring system (either only =O or =NR groups, one or two =O groups are possible, or, for example, one =O and one =NR group, each group replacing an unshared electron pair).

[0169] Stereochemistry / Solvates / Hydrates: Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) as well as racemates thereof, mixtures of individual enantiomers in different ratios, mixtures of diastereomers, or mixtures of any of the aforementioned forms in which said isomers and enantiomers exist, as well as pharmaceutically acceptable salts and solvates thereof, such as 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 those skilled in the art, for example, by separation of corresponding mixtures, by use of stereochemically pure starting materials and / or by stereoselective synthesis. It is well known in the art how to prepare optically active forms, for example, by resolution of racemic forms or by synthesis, for example, by starting from optically active starting materials and / or using chiral reagents.

[0170] Enantiomerically pure compounds or intermediates of the present invention can be prepared, for example, by the 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 via asymmetric synthesis by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries. Furthermore, those skilled in the art know how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, for example by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases, or by resolution of the racemic mixtures using suitable resolving agents, for example by formation of diastereomeric salts of the racemate with an optically active acid or base followed by separation of the salts and liberation of the desired compound from the salt, or by derivatization of the corresponding racemate with an optically active chiral auxiliary reagent followed by diastereomeric separation and removal of the chiral auxiliary, or by kinetic resolution of the racemates (for example 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.

[0171] Salts: The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds where 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, the 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.

[0172] Additional 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 a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, the salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Other acid salts than those mentioned above, which are useful, for example, in the purification or isolation of the compounds of the invention (eg, trifluoroacetates), also form part of the invention. For example:

[0173] [ka]

[0174] In expressions such as: the letter A has the function of ring designation, for example, to make it easy to indicate the attachment of the ring in question to other rings. For example,

[0175] [ka]

[0176] In such an expression, the dotted circle in ring A means that each bond between ring members of ring A can be independently selected from a single bond, a double bond, or a (hetero)aromatic bond. A (hetero)aromatic bond is a bond containing delocalized bonding electrons with a bond order between that of a single bond and a double bond. Preferably, ring A is a (hetero)aromatic ring. A group or substituent is a group with the corresponding group name (e.g., R a , R bIt is noted that when such groups are used repeatedly in different parts of the molecule to define the compounds of the invention, these individual uses should be considered totally independent of each other. For purposes of the present invention, the term "therapeutically effective amount" means an amount of a substance capable of eliminating symptoms of disease or preventing or alleviating these symptoms or prolonging the survival of the treated patient.

[0177] List of abbreviations [Table 1-1] [Table 1-2] [Table 1-3]

[0178] The features and advantages of the present invention will become apparent from the following detailed examples which illustrate, by way of example, the principles of the invention without limiting its scope. Preparation of Compounds of the Invention General rules Unless otherwise stated, all reactions are carried out with commercially available equipment using methods commonly used in chemical laboratories. Air- and / or moisture-sensitive starting materials are stored under protective gas, and the corresponding reactions and procedures with them are carried out under protective gas (nitrogen or argon). The compounds of the present invention are named according to IUPAC rules using the software ChemDraw. If a compound is represented by both a structural formula and its nomenclature, the structural formula takes precedence in the case of a conflict. Microwave reactions are carried out in an initiator / reactor from Biotage or an Explorer from CEM or a Synthos 3000 or Monowave 3000 from Anton Paar in sealed vessels (preferably 2, 5 or 20 mL), preferably with stirring.

[0179] Chromatography Thin layer chromatography is performed on silica gel 60 pre-made TLC plates from Merck glass (with fluorescent indicator F-254). Preparative high performance chromatography (HPLC) of exemplary compounds of the present invention is carried out, for example, using a Waters column (designation: Sunfire C18 OBD, 10 μm, 30 × 100 mm, part number 186003971; X-Bridge C18 OBD, 10 μm, 30 × 100 mm, part number 186003930). Compounds are eluted, for example, with various gradients of HO / AcCN, with 0.2% HCOOH added to water (acidic conditions). For chromatography under basic conditions, water is made basic, for example, according to the following recipe: 5 mL of ammonium bicarbonate solution (158 g in 1 L of HO) and 2 mL of 32% ammonia. (aq) The water is replenished with H2O up to 1L. Supercritical fluid chromatography (SFC) of exemplary intermediates and compounds of the present invention is carried out, for example, on a JASCO SFC system using 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). Analytical HPLC (reaction monitoring) of intermediate compounds is carried out using, for example, columns from Waters and Phenomenex. The analytical equipment is in each case also equipped with a mass detector. HPLC mass spectrometry / UV spectroscopy Retention Time / MS-ESI for Characterizing Exemplary Compounds of the Invention + The peaks were generated using an Agilent HPLC-MS system (high performance liquid chromatography with a mass detector). The compounds eluting at the injection peaks were assigned retention times t Ret. =0.00 is given.

[0180] HPLC method (preparative) NP1 NP purification: GLASS COLUMN Column: 100-200 mesh silica gel Solvent: A: DCM; B: MeOH Detection: KMnO4 Flow rate: 100mL / min Gradient: 0-60 min: 1% B 60-100 minutes: Varies 100~200 minutes: 10%B Preparative HPLC1 HPLC: 333 and 334 pumps Column: Waters XBridge C18 OBD, 10 μm, 30 x 100 mm, part number 186003930 Solvents: A: 10 mM NH4HCO3 in H2O; B: AcCN (HPLC grade) Detection: UV / Vis-155 Flow rate: 50mL / min Gradient: 0.00-1.50 min: 1.5% B 1.50~7.50 min: Varies 7.50~9.00 minutes: 100%B Preparative HPLC3 HPLC / MS: Semi-preparative HPLC Agilent Column: Triart Prep C18, 10 μm, 30 x 100 mm, part number 3010000120 Solvents: A: HO + 0.2% HCOOH; B: AcCN (HPLC grade) + 0.2% HCOOH Detection: UV / Vis-155 Mass: Agilent G6120B MSD-API-ES, positive mode range 120-820 Flow rate: 50mL / min Gradient: 0.00-0.80 min: 28% B 0.80 to 6.80 minutes: variable 6.80~9.00 minutes: 98%B

[0181] HPLC method (analysis) LCMS3, basisch_1 HPLC: Agilent 1100 series MS: Agilent LC / MSD (API-ES+ / -3000V, quadrupole, G6140) Column: Waters, XBridge C18, 2.5 μm, 2.1 × 20 mm Solvents: A: 20 mM NH4HCO3 / NH3 in H2O, pH 9; B: AcCN (HPLC grade) Detection: MS: positive and negative mode Mass range: 120-900 m / z Flow rate: 1.00mL / min Column temperature: 60℃ Gradient: 0.00-1.50 min: 10% → 95% B 1.50~2.00 minutes: 95%B 2.00~2.10 minutes: 95%→10%B VAB HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD SL Column: Waters XBridge BEH C18, 2.5 μm, 2.1 × 30 mm XP Solvents: A: 5mM NH4HCO3 / 19mM NH3 in H2O; B: AcCN (HPLC grade) Detection: MS: positive and negative mode Mass range: 100-1200 m / z Flow rate: 1.40mL / min Column temperature: 45℃ Gradient: 0.00-1.00 min: 5% B → 100% B 1.00~1.37 minutes: 100%B 1.37~1.40 minutes: 100%→5%B VAS HPLC: Agilent 1100 / 1200 series MS: Agilent LC / MSD SL Column: YMC TriART C18 2.0 x 30 mm, 3 μm Solvent: A: HO + 0.2% formic acid; B: AcCN (HPLC grade) Detection: MS: positive and negative mode Mass range: 105-1200 m / z Flow rate: 1.40mL / min Column temperature: 35℃ Gradient: 0.0 min: 5% B 0.0~1.00 minutes: 5%B→100%B 1.00~1.37 minutes: 100%B 1.37~1.40 minutes: 100%B→5%B

[0182] TCG_LCMS, basisch_1 HPLC: Waters ACQUITY UPLC MS: ACQUITY SQD mass spectrometer (from Waters) Column: YMC triart Waters, 1.8 μm, 2.1 × 33 mm Solvent: A: 10 mM NH4OAc, pH 6.5; B: AcCN (HPLC grade) Detection: MS: positive and negative mode Mass range: 100-1000 m / z Flow rate: 1.00mL / min Column temperature: 50℃ Gradient: 0.00-0.75 min: 2% B 0.75~1.00 minutes: 2%→10%B 1.00~2.00 minutes: 10%→98%B 2.00~2.50 minutes: 98%B 2.50~2.90 minutes: 98%B 2.90~3.00 minutes: 98%→2%B TCG_LCMS, basisch_2 HPLC: Shimadzu Prominance MS: LCMS / MS-API Q trap Column: Waters XBridge C18; 4.6 x 50 mm, 5 μm Solvent: A: 10 mM NH4OAc pH 6.5; B: AcCN (HPLC grade) Detection: MS: positive and negative mode Mass range: 100-800 m / z Flow rate: 1.20mL / min Column temperature: 25℃ Gradient: 0.00-0.01 min: 0% → 10% B 0.01~1.50 minutes: 10%→30%B 1.50~3.00 minutes: 30%→90%B 3.00~4.00 minutes: 90%B 4.00~5.00 minutes: 90%→10%B GVK_LCMS_19 HPLC: Agilent RRLC MS: Agilent Technologies-6130 Quadrupole LC / MS Column: Waters XBridge C18, 4.6 x 75 mm, 3.5 μm Solvent: A: 10 mM NH4OAc; B: AcCN (HPLC grade) Detection: MS: positive and negative mode Mass range: 70-1200 m / z Flow rate: 2.0mL / min Column temperature: 35℃ Gradient: 0.00-0.20 min: 10% B 0.20~2.50 minutes: 10%→75%B 2.50~3.00 minutes: 75%→100%B 3.00~4.80 minutes: 100%B 4.80~5.00 minutes: 100%→5%B

[0183] GVK_LCMS_41 UPLC / MS: Waters Acquity-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm Solvents: A: 0.07% formic acid in AcCN; B: 0.07% formic acid in water Detection: MS: positive and negative mode Mass range: 100-1500 m / z Flow rate: 0.6mL / min Column temperature: 35℃ Gradient: 0.00-0.30 min: 97% B 0.30~2.20 minutes: 97%→2%B 2.20~3.30 minutes: 2%B 3.30~4.50 minutes: 2%→97%B 4.50~4.51 minutes: 97%B GVK_LCMS_61 UPLC / MS: Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2 Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm Solvents: A: 0.07% formic acid in AcCN; B: 0.07% formic acid in water Detection: MS: positive and negative mode Mass range: 100-1500 m / z Flow rate: 0.6mL / min Column temperature: 35℃ Gradient: 0.00-0.40 min: 97% B 0.40~2.50 minutes: 97%→2%B 2.50~3.40 minutes: 2%B 3.40~3.50 minutes: 2%→97%B 3.50~4.00 minutes: 97%B XB5A HPLC: Agilent HPLC 1100 / 1200 Column: Waters XBridge BEH C18, 4.6 x 50 mm, p / n 186006037 Solvent: A: H2O + 0.01% HClO4; B: 100% AcCN (HPLC grade) Flow rate: 1.50mL / min Column temperature: 30℃ Gradient: 0.00-3.50: 10% B 3.50~4.50 minutes: 10%→95%B 4.50~5.00 minutes: 10%B

[0184] The compounds and intermediates of the present invention are prepared by the synthetic methods described below, and the substituents of the general formulae have the meanings given above. These methods are intended to be illustrative of the present invention, without limiting the scope of the subject matter and claimed compounds to these examples. If the preparation of starting compounds is not described, they can be obtained commercially, or their synthesis is described in the prior art, or they can be prepared analogously to known prior art compounds or the methods described herein. That is, it is within the skill of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to published synthetic methods. General reaction scheme and synthetic route overview Compounds (I) of the present invention can be synthesized using a Buchwald-Hartwig cross-coupling reaction (→ Scheme 1) starting from 1H-pyrazolo[4,3-c]pyridine A-1 and various halogenated building blocks B-1 using a palladium source (e.g., tris(dibenzylideneacetone)dipalladium(0)) and a phosphine ligand (e.g., tert-butylXPhos) (see, for example, WO2019 / 105886).

[0185] Scheme 1 [ka]

[0186] The required A-1 building blocks can be synthesized starting from the pyridine derivative A-7 (→ Scheme 2). Reduction of the ester group followed by oxidation leads to the carbaldehyde A-5. Protection of the indazole nitrogen of A-4 (e.g., with a Boc or THP critical group) followed by ring closure with hydrazine monohydrate (see, e.g., WO 2015 / 94929) affords the protected indazole A-3. Suzuki coupling with boronic ester C-1 (see, e.g., J. Org. Chem. 2007, 72, 4067-4072; Org. Lett. 2011, 13, 252-255; J. Org. Chem. 2004, 69, 7779-7782) or Stille coupling with the corresponding stannane C-2 (see, e.g., WO 2003 / 87037) followed by deprotection leads to 1H-pyrazolo[4,3-c]pyridine A-1. Alternatively, carbaldehyde A-5 can be obtained starting from malonyl chloride and nitrile (D-4). The resulting dihydroxypyridine D-3 is then subjected to chlorination conditions to give the dichloride D-2 (see, e.g., WO2018 / 93569, WO2014 / 52563, J. Med. Chem. 2009, 52, 7473-7487). Reduction of the nitrile group followed by hydrolysis affords the aldehyde A-5.

[0187] Scheme 2 [ka]

[0188] The key building block B-1 is accessible by three different synthetic strategies starting from B-3 (→ Scheme 3a): N-linked residue R 4 Building blocks B-1 with the formula: are accessible through nucleophilic aromatic substitution with an excess of the corresponding N-nucleophile / amine B-2 under neat conditions. O-linked residue R 4 Building blocks B-1 having the formula: are accessible through nucleophilic aromatic substitution carried out with an excess of O nucleophile / alcohol B-2 and a strong base such as sodium hydride in a suitable solvent (see, for example, US 2016 / 207924). R 4 The CC coupling of residue R can be carried out using a palladium catalyst (e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). 4 This can be achieved by Suzuki coupling of the boronic acid derivative B-2.

[0189] Scheme 3a [ka]

[0190] A more specific exemplary embodiment of building block B-1 is as follows (→Scheme 3b):

[0191] Scheme 3b [ka]

[0192] There are various approaches to the synthesis of the key building block B-3 depending on the exact nature of the bicyclic ring system. The building block B-3a can be obtained via the following sequence (→ Scheme 4). Starting material B-9-a is added with residue R 10 (e.g., via alkylation or reductive amination with the corresponding iodide and potassium carbonate in AcCN, →B-8) followed by reduction of the nitro group with iron gives intermediate B-7. B-6a is then accessible through a ring closure reaction with thiocarbonyldiimidazole (see, e.g., WO 2016 / 196840). Chlorination with thionyl chloride (see, e.g., WO 2003 / 74515) leads to B-5a. Building block B-3a can then be obtained through nucleophilic aromatic substitution with nucleophiles / amines B-4 (e.g., using potassium carbonate and AcCN as solvent—see, e.g., J. Med. Chem. 2007, vol. 50, # 26, pp. 6450-6453). Alternatively, intermediate B-5a can be obtained by S-reaction with amines starting from 2,4,6-trichloropyridine to give aminopyridine E-4. NThe oxoazabenzimidazole B-3f can be obtained via HCl (see, for example, WO2006 / 53166, WO2008 / 92942, New J. Chem. 2016, vol. 40, #11, pp. 9194-9204, and WO2006 / 122137). Subsequent iodination of E-4 leads to E-3, which can then be reacted with chlorosulfonyl isocyanate to give urea E-2 (see, for example, Org. Lett., 2006, vol. 8, #15, pp. 3311-3314). Ullmann-Goldberg amination affords oxoazabenzimidazole B-3f, which can finally be chlorinated to give trichloride B-5a.

[0193] Scheme 4 [ka]

[0194] In an alternative approach (→ Scheme 5), ring closure to intermediate B-7 is achieved via amidation of intermediate B-10 with carboxylic acid B-11 and ring condensation under acidic conditions (see, for example, Bioorg. Med. Chem. Lett., 2011, vol. 21, # 14, pp. 4197-4202). In yet another variation, carboxylic acid B-11 is activated, for example with polyphosphoric acid, and ring closure / ring condensation to B-3a can be achieved in a one-step / one-pot reaction. 7 In the case of =H, ring closure can also be achieved using trimethyl orthoformate (TMOF) as the C1 acid equivalent.

[0195] Scheme 5 [ka]

[0196] Building block B-3b can be obtained via the following sequence (→ Scheme 6). One possible reaction sequence begins with reduction of the nitro group of starting material B-13-a (e.g., with iron). Ring closure of B-12 can be carried out, for example, with potassium ethylxanthate (→ B-6b; see, for example, WO 2015 / 104688). Chlorination with sulfuryl chloride (see, for example, WO 2013 / 56679) leads to B-5b. Building block B-3b can then be finally obtained via nucleophilic aromatic substitution with nucleophile / amine B-4 (e.g., with potassium carbonate and AcCN as solvent—see, for example, J. Med. Chem. 2007, vol. 50, # 26, pp. 6450-6453).

[0197] Scheme 6 [ka]

[0198] Component B-3c * can be obtained through the following sequence (→ Scheme 7). Starting material B-18 is alkylated on the pyrrole ring to give B-17, which is then treated with hydrazine hydrate to give B-16. Ring closure under acetic acid conditions leads to B-15, which then reacts with sodium nitrite and hydrochloric acid to give B-14 (see, for example, Monatshefte fur Chemie 2016, vol. 147, # 4, pp. 783-789). In the final step, chlorination using a mixture of phosphorus oxychloride and phosphorus pentachloride gives B-3c. * can be obtained.

[0199] Scheme 7 [ka]

[0200] Component B-3d * can be obtained through the following sequence (→ Scheme 8). Component B-3d *The reaction sequence leading to B-19 begins with the formylation of B-24 using, for example, n-BuLi and ethyl formate to give the carbaldehyde B-23 (see, for example, WO 2015 / 25026). Grignard reaction followed by oxidation leads to intermediate B-21 (see, for example, WO 2017 / 42100). B-19 can be obtained through nucleophilic aromatic substitution with the corresponding glycinate B-20 using, for example, DIPEA in EtOH. Ring closure under basic conditions completes B-3d. * results.

[0201] Scheme 8 [ka]

[0202] Component B-3e * can be obtained through the following sequence (→ Scheme 9). Component B-3e * The multi-step reaction sequence to B-27 begins with the nitration of B-31, followed by the reaction of B-30 with the oxalic acid diester B-29 to give B-28 (see, e.g., WO 2004 / 104001). Reduction of the nitro group results in ring closure to B-27 (see, e.g., WO 2012 / 80450). Iodination with N-iodosuccinimide in DCM gives B-26, which is then alkylated with the corresponding alkyl halide to give B-25. This sequence can be used to prepare B-27 with R 9 Concluding with Suzuki coupling to introduce the B-3e * (See, for example, US2013 / 210818).

[0203] Scheme 9 [ka]

[0204] Component B-3c * , B-3d * and B-3e * are the R of the more general components B-3c, B-3d and B-3e, respectively. 7=-C(=O)OR * which can be converted to intermediate B-1 and then coupled with intermediate A-1. Compound (I) of the invention thus obtained can then be further modified by saponification and derivatization / amidation of the free carboxyl group. Building block B-3f can be obtained via the following sequence (→ Scheme 10). Again, starting with dichloropyridine B-7 (see Schemes 4 and 5), intermediate B-32 can be obtained via ring closure. For example, alkylation with the corresponding alkylating agent, such as an alkyl iodide, and a base (e.g., sodium hydride) in a solvent such as DMF affords the residue R 6 The introduction of B-3f results in B-3f.

[0205] Scheme 10 [ka]

[0206] Building block B-3g can be obtained via the following sequence (→ Scheme 11). Starting with the trichloropyridine compound B-34, the corresponding hydrazine B-33 is used in a solvent such as MeOH to effect ring closure and the formation of the residue R 10 The introduction of

[0207] Scheme 11 [ka]

[0208] Building block B-3h can be obtained via the following sequence (→ Scheme 12). Starting with diazotization of B-36, intermediate B-3h can then be obtained by ring closure (see, for example, WO 2007 / 117778). For example, other residues R can be obtained by alkylation using the corresponding alkylating agent B-35, such as dimethyl sulfate, and a base (e.g., potassium carbonate) in a solvent such as AcCN. 6 Introduction of leads to further intermediate B-3h.

[0209] Scheme 12 [ka]

[0210] Synthesis of intermediate A-1 Synthesis of A-1-a [ka]

[0211] Experimental procedure for the synthesis of A-6-a To a stirred solution of A-7-a (100.0 g; 42.70 mmol) in THF (100.0 mL) is added DIBAL-H (854.0 mL; 85.40 mmol) at 0 °C. The reaction mixture is stirred at rt for 4 h. The reaction is quenched with Rochelle's salt (1000 mL) and then EtOAc (1000 mL) is added. The reaction mixture is filtered through a pad of Celite and washed with EtOAc (1000 mL). 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 (EtOAc / petroleum ether 20:80) to give the desired product A-6-a (HPLC-MS: (M+H) + =192.1, t Ret. =1.60 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of A-5-a To a stirred solution of A-6-a (70.0 g; 36.50 mmol) in DCM (100.0 mL) is added Dess-Martin periodinane (170.0 g; 40.1 mmol) at rt. The reaction mixture is stirred at rt for 3 h. The reaction mixture is quenched with saturated NaHCO3 solution (2000 mL) and stirred for 15 min. The reaction mixture is filtered through a Celite pad and washed with DCM (1000 mL). 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 (EtOAc / petroleum ether 10:80) to give the desired product A-5-a (HPLC-MS: (M+H) + =190.0, t Ret.=2.00 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of A-4-a To a stirred solution of A-5-a (46.0 g, 24.2 mmol) in DMA (460.0 mL) is added hydrazine monohydrate (63.7 mL; 121.0 mmol) at 0 °C. The reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is poured into ice water (800 mL) and extracted with EtOAc (3x). 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 (EtOAc / petroleum ether 85:15) to give the desired product A-4-a (HPLC-MS: (M+H) + =168.1, t Ret. =1.54 minutes, method GVK_LCMS_19).

[0212] Experimental procedure for the synthesis of A-3-a To a stirred solution of A-4-a (25.0 g; 14.9 mmol) in THF (250.0 mL) is added TEA (24.5 mL, 17.9 mmol) and Boc anhydride (41.11 mL; 17.9 mmol) at rt. The reaction mixture is stirred at rt for 16 h. The reaction mixture is poured into ice-water (500 mL) and extracted with EtOAc (3×). The combined organic layers are dried over Na2SO4, filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (EtOAc / petroleum ether 20:80) to give the desired product A-3-a (HPLC-MS: (M+H) + =268, t Ret. = 1.31 min, method LCMS3, basisch_1). Experimental procedure for the synthesis of A-2-a To a stirred solution of A-3-a (34.0 g; 12.7 mmol) in 1,4-dioxane (340.0 mL) is added C-1-a (35.83 g; 15.2 mmol), cesium carbonate (2.0 M in water; 124.14 g; 38.1 mmol), and PdCl(dppf) (10.37 g; 1.13 mmol, 0.1 equiv.). The reaction mixture is stirred at 100 °C for 1 h. The reaction mixture is filtered through a pad of Celite and washed with EtOAc (2 × 250 mL). The combined organic layers are dried over NaSO, filtered, and the solvent is evaporated under reduced pressure to give the desired product A-2-a (HPLC-MS: (M+H) + =341, t Ret .=1.14 min, method LCMS3, basisch_1). Experimental procedure for the synthesis of A-1-a To a stirred solution of A-2-a (50.0 g; 14.7 mmol) in 1,4-dioxane (500.0 mL) at 0 °C is added 4.0 M HCl in dioxane (250.0 mL). The reaction mixture is stirred at rt for 6 h. The reaction mixture is filtered off and washed with EtOAc (2 × 200 mL). The resulting solid is dissolved in water (400 mL), cooled to 0 °C, and the pH is adjusted to 9 using 1 N aqueous NaOH. The precipitate is filtered off and washed with diethyl ether (2 × 250 mL) to give A-1-a (HPLC-MS: (M+H) + =241, t Ret. = 0.59 min, method LCMS3, basisch_1).

[0213] Alternative synthesis of building block A-4-a [ka]

[0214] Experimental procedure for the synthesis of D-3-a To a solution of malonyl chloride (5.00 g, 34.409 mmol, 1.0 equiv.) in acetonitrile (37.5 mL) is added a solution of D-4-a (2.825 g, 34.409 mmol, 1.0 equiv.) in acetonitrile (21.0 mL) at a rate that controls the internal temperature below 15 °C. The reaction mixture is stirred under nitrogen for 15 minutes at 20 °C, then filtered and rinsed with acetonitrile (19.5 mL). The resulting solid is dried under vacuum with a nitrogen bleed at 50 °C to give the desired product D-3-a ( 1 H-NMR (500MHz, DMSO-d6) δ 5.77 (1H, s), 2.37 (3H, s)). Experimental procedure for the synthesis of D-2-a To a suspension of D-3-a (6.61 g, 19.752 mmol, 1.0 equiv.) and benzyltriethylammonium chloride (4.50 g, 19.752 mmol, 1.0 equiv.) in acetonitrile (13.2 mL) is added phosphorus oxychloride (10.0 g, 65.181 mmol, 3.3 equiv.) at 20 °C. The mixture is stirred at 20 °C for 3 h and then heated to 78 °C for 8 h. The mixture is cooled to 22 °C and toluene (46.3 mL) is added. The mixture is cooled to 15 °C and water (15.8 mL) is added at a rate to control the internal temperature below 25 °C. A solution of sodium hydroxide (50% in water, 12.64 g, 158.015 mmol, 8.0 equiv.) in water (9.9 mL) is added at a rate to maintain the temperature below 25 °C to pH 7.4. The mixture is filtered through Celite and rinsed with toluene (27.8 mL). The aqueous phase is removed and the organic phase is washed with water (9.9 mL). The organic phase is circulated through a carbon filter and then the toluene is removed by vacuum distillation. Methylcyclohexane (66 mL) is added and vacuum distillation is continued. The mixture is heated to 70°C until a clear solution is obtained, then the mixture is cooled to 20°C. The mixture is filtered and the solid is rinsed with heptane (13.2 mL) to give the desired product D-2-a. 1 H-NMR (500MHz, DMSO-d6) δ 8.01 (1H, s), 2.70 (3H, s)).

[0215] Experimental procedure for the synthesis of A-3-a (via A-4-a and A-5-a) To a solution of D-2-a (3.04 g, 15.622 mmol, 1.0 equiv) in heptane (30.4 mL) at −30° C., 1 M diisobutylaluminum hydride in heptane (12.1 g, 17.184 mmol, 1.1 equiv) is added at a rate that controls the internal temperature below −20° C. The mixture is stirred at −25° C. for 50 minutes, and then EtOAc (1.1 g, 12.497 mmol, 0.8 equiv) is added at a rate that controls the internal temperature below −20° C. The mixture is warmed to −10° C. and stirred for 15 minutes. A solution of tartaric acid (2.58 g, 17.184 mmol, 1.1 equiv) in water (11.4 mL) is added at a rate that controls the internal temperature below 5° C. The mixture is warmed to 5° C. and stirred for 15 minutes. A solution of potassium sodium tartrate tetrahydrate (4.41 g, 15.622 mmol, 1.0 equiv.) in water (11.4 mL) is added to bring the pH to 6.5, and the mixture is warmed to rt. Isopropyl acetate (18 mL) is added, and the mixture is stirred at rt for 1.5 h. The aqueous phase is removed, and the heptane / isopropyl acetate is removed by vacuum distillation until approximately 9 mL remains, followed by the addition of EtOH (30 mL). Distillation is continued until approximately 12 mL remains (→ A-5-a). To this solution of A-5-a in EtOH, hydrazine hydrate (55% in water, 4.24 g, 46.865 mmol, 3.0 equiv.) is added, and the mixture is heated at 78 °C for 12 h. The mixture is cooled to rt, and then 2-methyltetrahydrofuran (30 mL) and water (15 mL) are added. Stirring is continued for 15 min, followed by the removal of the aqueous phase. Remove 2-methyltetrahydrofuran by vacuum distillation until approximately 6 mL remains, then add acetonitrile (30 mL) and continue distillation until approximately 6 mL remains (→ A-4-a). Cool the mixture to rt and add TEA (4.74 g, 46.865 mmol, 3.0 equiv.), followed by DMAP (0.191 g, 1.562 mmol, 0.1 equiv.) in acetonitrile (1.5 mL) and di-tert-butyl dicarbonate (4.43 g, 20.308 mmol, 1.3 equiv.) in acetonitrile (6.0 mL). Age the mixture at rt for 40 min, then add water (24 mL) over 1 h. Stir the mixture at rt for 1 h and then filter to collect A-3-a. Rinse the solid with water (6 mL) and dry under vacuum at 40 °C ( 1H-NMR (500MHz, CDCl3) δ 8.22 (s, 1H), 7.93 (s, 1H), 2.83 (s, 3H), 1.73 (s, 9H)).

[0216] Synthesis of A-1-b [ka]

[0217] Experimental procedure for the synthesis of A-3-b To a suspension of A-4-a (3.0 g; 167.6 mmol) in EtOAc (70.0 mL), p-TsOH (0.3 g; 172.1 mmol) and 2,3-dihydro-4H-pyran (4.5 g; 84 mmol) are added and stirred for 3 h at 60 °C. The reaction mixture is diluted with water and extracted with EtOAc. 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 10:50) to give the desired product A-3-b (HPLC-MS: (M+H) + =252.0, t Ret. =0.850 min, method VAB). Experimental procedure for the synthesis of A-2-b To a stirred solution of A-3-b (179.3 mg; 0.44 mmol) in DMF (4.0 mL) is added C-2-a (100.0 mg; 0.39 mmol), copper(I) iodide (3.0 mg; 0.02 mmol), cesium fluoride (120.7 mg; 0.80 mmol), and PdCl(dppf) (30.6 mg; 0.04 mmol). The reaction mixture is stirred under argon at 100 °C for 3 h. The reaction mixture is poured into water and extracted with DCM. The organic layer is dried over MgSO, filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by reverse phase chromatography HPLC1 to give the desired product A-2-b (HPLC-MS: (M+H) + =337, t Ret .=0.852 minutes, method VAB). Experimental procedure for the synthesis of A-1-b To a stirred solution of A-2-b (54.0 mg; 0.16 mmol) in DCM (1.5 mL) is added 4.0 M HCl in dioxane (0.8 mL) at rt. The reaction mixture is stirred at rt for 3 h. The reaction mixture is concentrated under reduced pressure to give A-1-b (HPLC-MS: (M+H) + =253.3, t Ret. =0.623 min, method VAB).

[0218] Synthesis of C-2-a [ka]

[0219] To a stirred solution of C-3-a (400.0 mg; 1.62 mmol) in degassed toluene, hexabutylditin (4.7 g; 8.1 mmol), DIPEA (1.49 mL, 8.1 mmol), and Pd(PPh3)4 are added at rt and stirred in a microwave reactor at 130 °C for 2 h. The reaction mixture is concentrated under reduced pressure, and the crude material is dissolved in EtOAc and washed with water (2 × 10 mL). 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 (hexane / EtOAc) to give the desired product C-2-a (HPLC-MS: (M+H) + =412.2, t Ret. =2.33 minutes, method GVK_LCMS_41). The following intermediate A-1 (Table 1) can be obtained in an analogous manner starting from different building blocks A-7, A-3, C-1 and C-2.

[0220] Table 1: [Table 2]

[0221] Synthesis of intermediate B-1 Synthesis of B-1a-a [ka]

[0222] To the starting material B-3a-a (1.5 g, 4.36 mmol) is added B-2-a (3.84 mL, 43.6 mmol). The reaction mixture is stirred at 140° C. under microwave irradiation for 1 h. Purification by normal phase chromatography using DCM / MeOH gives the pure product B-1a-a. The following intermediates B-1a, B-1b, and B-1c * , B-1d * and B-1e * (Table 2) shows the different components B-3a, B-3b, and B-3c * , B-3d * and B-3e * It can be obtained in a similar way starting from.

[0223] Table 2: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

[0224] Synthesis of B-1a-s [ka]

[0225] To a stirred solution of B-3a-d (100 mg; 0.44 mmol) in AcCN (0.50 mL) was added B-2-b (75.0 mg; 0.78 mmol) and CsCO (500 mg; 1.54 mmol). The mixture was stirred at 75 °C for 48 h. Purification by preparative HPLC yielded B-1a-s.

[0226] Synthesis of B-1b-g [ka]

[0227] To a solution of B-2-c (75 mg; 0.20 mmol) in DMSO is added NaH (32 mg; 0.80 mmol). After 5 minutes at ambient temperature, B-3b-a is added to the reaction mixture and stirring is continued for 3 days. Purification by preparative HPLC1 gives the pure product B-1b-g. The following intermediates B-1a and B-1b (Table 3) are available in an analogous manner starting from different building blocks B-3a and B-3b.

[0228] Table 3: [Table 4-1] [Table 4-2]

[0229] Synthesis of B-1a-z [ka]

[0230] B-3a-a (250mg, 0.73mmol), B-2-d (141mg; 0.80mmol), Pd(II)dppfCl2 *CHCl (61 mg; 0.07 mmol) and sodium carbonate (196 mg; 1.82 mmol) are suspended in dioxane (2.0 mL) and water (1.0 mL). The reaction mixture is stirred under microwave irradiation at 100° C. for 1 h. Purification with NP1 gives the unsaturated intermediate, which is used directly in the next step. A Buchi lab autoclave is charged with the unsaturated intermediate (215 mg; 0.62 mmol), EtOH (5.0 mL), and tris(triphenylphosphine)rhodium(I) chloride (113 mg; 0.12 mmol). The mixture is stirred under 5 bar H pressure for 16 h. The reaction mixture is diluted with DCM and saturated aqueous NaHCO and extracted. The organic phase is dried over MgSO, filtered, and the solvent is evaporated under reduced pressure to give B-1a-z.

[0231] Synthesis of B-1b-i [ka]

[0232] A stirred solution of B-3b-a (130 mg; 0.37 mmol) was added to Pd(II) dppfCl2 * CHCl (61 mg; 0.07 mmol), sodium carbonate (196 mg; 1.82 mmol), and B-2-e (77 mg; 0.90 mmol) are added and the mixture is stirred for 16 h. The reaction mixture is poured into saturated aqueous NaHCO and extracted with DCM. The organic phase is dried over MgSO, filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by preparative HPLC to give B-1b-1. The following intermediates B-1a, B-1b, and B-1c * , B-1d * and B-1e * (Table 4) shows the different components B-3a, B-3b, and B-3c * , B-3d * and B-3e * It can be obtained in a similar way starting from

[0233] Table 4: [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0234] Synthesis of intermediate B-3 Synthesis of B-3a-a [ka]

[0235] The starting materials B-5a-a (30.0 g, 126.9 mmol) and B-4-a (18.3 g, 126.9 mmol) are suspended in AcCN. The reaction mixture is stirred at 60 °C for 3 h under microwave irradiation. The reaction mixture is diluted with DCM, mixed with semi-saturated aqueous NH4Cl and extracted once. The organic phase is dried over MgSO4, filtered, and the solvent is evaporated under reduced pressure to give B-3a-a. The following intermediates B-3a and B-3b (Table 5) are available in an analogous manner starting from different building blocks B-5a and B-5b.

[0236] Table 5: [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7]

[0237] B-3c * Synthesis of -a [ka]

[0238] Experimental procedure for the synthesis of B-17-a To a stirred solution of B-18-a (65.0 g; 271.6 mmol) in DMF (650.0 mL) is added dropwise NaH (32.46 mL; 814.98 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 10 min, then chloroethyl acetate is added at 0° C. The reaction mixture is stirred at rt for 16 h. The reaction mixture is poured into ice water (2000 mL) and the precipitate is filtered and dried under vacuum to give B-17-a (HPLC-MS: (M+H) + =326, t Ret. = 1.41 min, method LCMS3, basisch_1). Experimental procedure for the synthesis of B-16-a To a stirred solution of B-17-a (75.0 g; 230.52 mmol) in EtOH (1000 mL) is added hydrazine hydrate (500 mL) at rt. The reaction mixture is stirred at 80 °C for 6 h. The reaction mixture is cooled to rt, and the precipitate is filtered, washed with EtOAc, and dried under vacuum to give B-16-a. Experimental procedure for the synthesis of B-15-a Dissolve B-16-a (160 g; 538.15 mmol) in acetic acid (1500 mL) and stir the reaction mixture at rt for 16 h. Then, add diethyl ether (2500 mL) to the reaction mixture and filter the precipitate, which is then dried under vacuum to give B-15-a (HPLC-MS: (M+H) + =266.1, t Ret. =0.775 minutes, method VAB). Experimental procedure for the synthesis of B-14-a To a stirred solution of B-15-a (35.0 g; 131.65 mmol) in 4 N aqueous HCl (1500 mL) is added a solution of sodium nitrite (45.52 g, 659.72 mmol) in water at 0 °C. The reaction mixture is allowed to warm to room temperature over 16 h. The precipitate is filtered, washed with water (500 mL), and dried under vacuum to give B-14-a (HPLC-MS: (M+H) + =251.0, t Ret. = 0.92 min, method LCMS3, basisch_1). B-3c * Experimental procedure for the synthesis of -a To a stirred solution of B-14-a (23.0 g; 91.91 mmol) in toluene (100.0 mL) is added POCl3 (400.0 mL), DIPEA (76.0 mL; 459.54 mmol), and PCl5 (19.1 g; 91.91 mmol) at 0 °C. The reaction mixture is then stirred at reflux for 48 h. POCl3 and toluene are removed under reduced pressure, and the resulting residue is dissolved in EtOAc (1000 mL), extracted with saturated aqueous NaHCO3 (2 × 1000 mL), and then washed with brine (500 mL). 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 (EtOAc / hexane 0:10) to give the desired product B-3c. * -a (HPLC-MS: (M+H) + =287.1, t Ret. =2.40 minutes, method GVK_LCMS_61).

[0239] B-3d * Synthesis of -a [ka]

[0240] Experimental procedure for the synthesis of B-23-a A stirred solution of B-24-a (500.0 g; 2.74 mol) in THF (5.0 L) is cooled to −78 °C. 1.6 M n-butyllithium in hexane (1.7 L; 2.74 mol) is added under nitrogen. The reaction mixture is stirred at −78 °C for 60 min, then ethyl formate (220.45 mL; 2.74 mol) is added dropwise at −78 °C, and the reaction mixture is stirred at −78 °C for 4 h. The reaction is quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (2 × 2.0 L). 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 (EtOAc / hexane 0:10) to give the desired product B-23-a (HPLC-MS: t Ret. =2.11 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of B-22-a A stirred solution of B-23-a (170 g; 807.8 mmol) in THF (1.7 L) is cooled to −78° C. Then, 2 M methylmagnesium in THF (807.8 mL, 1.62 mol) is added under nitrogen. The reaction mixture is stirred for 4 h at −78° C. The reaction is quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (1×2.0 L). 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 (EtOAc / hexane 5:20) to give the desired product B-22-a (HPLC-MS: t Ret. =1.75 minutes, method GVK_LCMS_61).

[0241] Experimental procedure for the synthesis of B-21-a To a stirred solution of B-22-a (170 g, 0.76 mol) in DCM (1.7 L) is added n-methylmorpholine (131.7 g, 1.13 mol, 1.5 equiv.) at rt. The reaction mixture is stirred at rt for 30 min. Tetrapropylammonium perruthenate (8.7 g, 24.7 mmol) is then added and the reaction mixture is stirred at rt for 4 h. The reaction mixture is filtered through a pad of Celite and washed with DCM (3000 mL). The solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (EtOAc / hexane 10:50) to give the desired product B-21-a (HPLC-MS: t Ret. =2.02 minutes, method GVK_LCMS_61). Experimental procedure for the synthesis of B-19-a To a stirred solution of B-21-a (268 g; 1.19 mol) and tert-butylmethylglycinate B-20-a (259.0 g; 1.43 mol) in EtOH (2.6 L) is added DIPEA (256.7 mL, 1.43 mol) at rt. The reaction mixture is stirred at 80 °C for 12 h. The reaction mixture is quenched with water (200 mL), the solvent is removed under reduced pressure, and then extracted with EtOAc (2 × 200 mL). 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 (EtOAc / hexane 2:5) to give the desired product B-19-a (HPLC-MS: (M+H) + =333.0, t Ret. = 1.39 min, method LCMS3, basisch_1). B-3d * Experimental procedure for the synthesis of -a To a stirred solution of B-19-a (100 g, 0.30 mol) in DME (800 mL) at −15 °C, potassium tert-butoxide (16.84 g; 0.15 mol) is added. The reaction mixture is stirred at −15 °C for 6 h. The reaction mixture is quenched with ice water (2 L), and the precipitate is filtered, washed with n-pentane, and dried under vacuum to give B-3d. * -a (HPLC-MS: (M+H) + =315.0, t Ret. = 1.67 min, method LCMS3, basisch_1).

[0242] B-3e * Synthesis of -a [ka]

[0243] Experimental procedure for the synthesis of B-30-a B-31-a (350.0 g; 2.2 mol) in trifluoroacetic anhydride (1.7 L) is cooled to 0 °C. Nitric acid (285.8 g; 4.5 mol) is then added dropwise at 0 °C and the reaction mixture is allowed to warm to rt over 18 h. The reaction mixture is quenched with sodium disulfite and stirred at rt for 2 h. The reaction mixture is neutralized to pH = 7 with 8 N aqueous NaOH, extracted with DCM (2 × 600 mL) and washed with brine. The combined organic layers are dried over NaSO, filtered and the solvent is evaporated under reduced pressure to give B-30-a (HPLC-MS: (M+H) + =207.0, t Ret. =2.62 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of B-28-a To a stirred solution of potassium ethoxide (40.56 g; 0.48 mol) in diethyl ether (2.5 L) and EtOH (0.3 L) under an argon atmosphere, B-30-a (70.5 g; 0.48 mol) is added and the reaction mixture is stirred at rt for 30 min. A solution of B-29-a (100.0 g; 0.48 mol) in diethyl ether (150 mL) is added to the reaction. The reaction mixture is stirred at rt for 16 h. The solvent is removed under reduced pressure, acidified to pH = 4 with acetic acid and extracted with EtOAc (2 x 600 mL). The combined organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure to give B-28-a (HPLC-MS: (M+H) + =307.0, t Ret. =2.37 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of B-27-a To a stirred solution of B-28-a (50.0 g; 0.16 mol) in EtOH (1.75 L) and EtOH (0.75 L) is added iron (54.7 g; 0.98 mol) and aqueous ammonium chloride (750.0 mL) at rt. The reaction mixture is stirred at 90 °C for 5 h. The reaction mixture is filtered through a pad of Celite and washed with hot EtOH and THF. The solvent is diluted with water and extracted with EtOAc (2 × 1 L). The combined organic layers are dried over NaSO, filtered, and the solvent is evaporated under reduced pressure to give the desired product B-27-a (HPLC-MS: (M+H) + =269, t Ret. =2.25 minutes, method GVK_LCMS_41).

[0244] Experimental procedure for the synthesis of B-26-a To a stirred solution of B-27-a (40.0 g; 0.15 mol) in DCM (400 mL) and DMF (200 mL) is added NIS (69.5 g; 0.31 mol) at rt and the reaction mixture is stirred at rt for 24 h. The reaction mixture is quenched with ice water and extracted with DCM (2 × 2 L). The combined organic layers are dried over NaSO, filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (EtOAc / petroleum ether 50:70) to give the desired product B-26-a (HPLC-MS: (M+H) + =273.38, t Ret. =3.12 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of B-25-a A stirred solution of B-26-a (50.5 g; 0.13 mol) in DMF (500 mL) is cooled to 0 °C, then NaH (6.3 g; 0.26 mol) is added and the reaction mixture is stirred at rt for 30 min. After the reaction mixture is cooled to 0 °C, methyl iodide (37.25 g; 0.26 mol) is added. The reaction mixture is stirred at rt for 3 h and then quenched with water. The precipitate is filtered, washed with diethyl ether and dried under vacuum to give B-25-a (HPLC-MS: (M+H) + =398.90, t Ret. =2.73 minutes, method GVK_LCMS_41). B-3e *Experimental procedure for the synthesis of -a To a stirred solution of B-25-a (20.0 g; 0.05 mol) in THF (400 mL) at rt, Fe(acac) (1.77 g; 0.005 mol) is added and the reaction mixture is cooled to 0 °C. 1N MeMgBr solution (100 mL) is then added at 0 °C and the reaction mixture is allowed to warm to rt over 8 h. The reaction is quenched with saturated ammonium chloride solution and extracted with EtOAc (2 × 200 mL). The combined organic layers are dried over NaSO, filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by normal phase chromatography (EtOAc / petroleum ether 1:10) to give the desired product B-3e. * -a (HPLC-MS: (M+H) + =287.19, t Ret. =2.46 minutes, method GVK_LCMS_61).

[0245] Synthesis of B-3f-a and B-3f-b [ka]

[0246] Experimental procedure for the synthesis of B-3f-a To a stirred solution of B-7-a (336 mg, 1.66 mmol) in DCE (6 mL) is added CDI (350 mg, 2.16 mmol) and the reaction mixture is stirred overnight at 50 °C. The residue is treated with AcCN (4 mL) and the precipitate is filtered, washed with AcCN, and dried overnight in a vacuum drying oven at 45 °C to give B-3f-a (HPLC-MS: (M+H) + =218, t Ret. =0.50 min, method VAB). Experimental procedure for the synthesis of B-3f-b To a stirred solution of B-3f-a (29.38 g, 134.75 mmol) in DMF (293.4 mL) at −5° C., sodium hydride (6.47 g, 161.69 mmol) is added and stirred for 10 min. Iodomethane (10.07 mL, 161.69 mmol) is added and stirred for 45 min at −5° C. The reaction mixture is quenched with saturated NH4Cl (300 mL) and diluted with saturated brine (200 mL). The precipitate is filtered, washed with water, and dried in a vacuum oven at 50° C. to give B-3f-b (30.06 g; 129.53 mmol) (HPLC: t Ret. =2.42 minutes, method XB5A).

[0247] Synthesis of B-3g-a [ka]

[0248] Experimental procedure for the synthesis of B-3g-a To a stirred solution of B-34-a (50.00 mg; 0.223 mmol) in MeOH (1 mL) is added methylhydrazine (0.023 mL; 0.445 mmol) and stirred overnight at 60 °C. The reaction mixture is filtered and purified by preparative HPLC to give the desired product B-3g-a (20 mg, 0.093 mmol). HPLC-MS: (M+H) + =216, t Ret. = 1.24 min, method LCMS3, basis ch_1). The following intermediate B-3g (Table 6) can be obtained in an analogous manner starting from different building blocks B-34 and the corresponding hydrazine derivatives.

[0249] Table 6: [Table 7]

[0250] Synthesis of B-3h-a [ka]

[0251] Experimental procedure for the synthesis of B-3h-a A solution of B-36-a (200.0 mg; 0.975 mmol) in concentrated HCl (2.0 mL) was stirred for 10 min at rt, cooled to 0 °C, and then NaNO2 (79.594 mg; 1.170 mmol) in water was added dropwise at -5 °C and stirred for 15 min at 0 to -5 °C. * 2H2O (511.507 mg; 2.243 mmol) is added dropwise and the resulting reaction mixture is stirred for 30 min. The reaction mixture is then filtered, washed with water, aqueous NaHCO3, and air-dried. The resulting crude material is purified by flash column chromatography using 0-30% EtOAc / PE as the eluent to give the desired product B-3h-a (50.0 mg, 0.247 mmol). HPLC-MS: (M+H) + =202, t Ret. =1.93 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of B-3h-b To a stirred solution of B-3h-a (50.00 mg, 0.247 mmol) and potassium carbonate (100.00 mg, 0.716 mmol) in AcCN (2 mL), add sulfuric acid dimethyl ester (25.0 μL, 0.258 mmol) dropwise and stir at rt for 30 min. Filter the reaction mixture and remove the solvent under reduced pressure. Purify the residue by preparative HPLC to give B-3h-b (22.00 mg, 0.102 mmol). HPLC-MS: (M+H) + =216, t Ret. = 1.23 min, method LCMS3, basis ch_1).

[0252] Synthesis of B-3a-c [ka]

[0253] Experimental procedure for the synthesis of B-10-a A stirred solution of B-7-a (200 mg, 1.04 mmol) in DCM (10 mL) is cooled to -20 °C. B-11-a (120 mg, 1.25 mmol, 1.2 equiv) is added and the reaction mixture is stirred at -20 °C for 2 h. The reaction mixture is made basic with sodium carbonate (saturated aqueous solution). The aqueous phase is extracted with DCM. The organic layer is concentrated to dryness. The crude compound is purified (normal phase chromatography) to give the desired product B-10-a (HPLC-MS: (M+H) + =248.0, t Ret. =1.46 min, method TCG_LCMS, basisch_1). Experimental procedure for the synthesis of B-3a-c To B-10-a (500 mg, 2.0 mmol) is added 1,4-dioxane (10 mL) and acetic acid (1.0 mL, 15.5 mmol, 8.7 equiv). The reaction mixture is heated to 110 °C. After complete conversion, the solvent is evaporated. The residue is made basic with sodium bicarbonate (saturated aqueous solution). The aqueous layer is extracted with EtOAc. The solvent is evaporated and the residue is purified (normal phase chromatography, mobile phase cyclohexane / EtOAc) to give B-3a-c. The following intermediate B-10 (Table 7) is also available similarly to the synthesis of B-10-a starting from different building blocks B-7 and B-11.

[0254] Table 7: [Table 8]

[0255] Synthesis of B-3a-d [ka]

[0256] To B-7-a (34.7 g, 174.8 mmol, 1 equiv.) is added acetic acid (100 mL, 1740 mmol, 10 equiv.) and polyphosphoric acid (135 mL, 2320 mmol, 13.3 equiv.). The reaction mixture is stirred at 100 °C for 3 h. The reaction mixture is cooled to rt, diluted with water, and basified with 6 N aqueous sodium hydroxide to pH 8. The aqueous phase is extracted with DCM. The organic layer is concentrated to dryness, and the residue is purified (normal phase chromatography, mobile phase cyclohexane / EtOAc 35% to 95%) to give B-3a-d.

[0257] Synthesis of B-3a-e [ka]

[0258] B-7-a (2.8 g, 14.58 mmol, 1 equiv.), trimethyl orthoformate (30 mL, 274 mmol, 18.8 equiv.), and acetic acid (3 mL, 52 mmol, 3.6 equiv.) are placed in a pressure reactor. The reaction mixture is stirred at 100 °C for 16 h. After cooling, the reaction mixture is made basic with aqueous sodium bicarbonate. The aqueous phase is extracted with EtOAc. The organic phase is washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue is purified by normal phase chromatography (mobile phase cyclohexene / EtOAc) to give B-3a-e.

[0259] Synthesis of B-3a-g [ka]

[0260] To a solution of B-3a-f (18.0 g, 77.56 mmol) in DCM (270.0 mL) is added Dess-Martin reagent (39.46 g, 93.08 mmol, 1.2 equiv.) at 0 °C and stirred at rt for 12 h. The reaction mixture is diluted with saturated NaHCO3 solution (500.0 mL) and extracted with DCM (2 × 500 mL). The combined organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude material is purified by normal phase chromatography (mobile phase cyclohexene / EtOAc 30–80%) to give B-3a-g (HPLC-MS: (M+H) + =248.0, t Ret. = 0.64 min, Method VAB). Starting materials B-3a-f can be obtained using hydroxyacetic acid as the carboxylic acid in analogy to the synthesis described for B-3a-d.

[0261] Synthesis of B-3a-h [ka]

[0262] A solution of B-3a-g (75.00 mg, 0.267 mmol) and 1-methylpiperazine (53.52 mg, 0.534 mmol) in DCM (1 mL) was shaken at rt for 10 min. Acetic acid (7.640 μL; 0.134 mmol) and sodium triacetoxyborohydride (141.565 mg; 0.668 mmol) were added, and the reaction mixture was shaken at rt for 2 h. The mixture was concentrated under reduced pressure, dissolved in DMF and water, filtered, and purified by preparative HPLC to give B-3a-h (41.00 mg, 0.112 mmol). The following intermediate B-3a (Table 8) can be obtained by methods similar to those described for intermediates B-3a-c to B-3a-e, B-3a-g and B-3a-h. The following intermediate B-3a (Table 8) is available in a similar manner starting from different building blocks B-7 and B-14.

[0263] Table 8: [Table 9-1] [Table 9-2]

[0264] Synthesis of intermediate B-5 Synthesis of B-5a-a [ka]

[0265] Experimental procedure for the synthesis of B-8-a To a stirred solution of B-9-a (100.0 g; 0.480 mol) in AcCN (1500 mL) is added K2CO3 (165.9 g; 1.20 mol) at 0 °C and stirred for 15 min. Then MeI (186.2 mL; 2.90 mol) is added at the same temperature and the reaction is heated to 80 °C for 16 h. The solvent is removed under reduced pressure and the resulting crude material is partitioned between ice-cold water and EtOAc. The separated organic layer is dried over Na2SO4 and concentrated under reduced pressure. The resulting crude material is purified by flash column chromatography using EtOAc / petroleum ether as eluent to give the desired product B-8-a (HPLC-MS: (M+H) + =222.0;t Ret .=1.11 min, method LCMS3, basisch_1). Experimental procedure for the synthesis of B-7-a To a stirred solution of B-8-a (85.0 g; 0.383 mol) in EtOH (750 mL), NH4Cl (101.5 g; 1.91 mol) and water (100.0 mL) are added and stirred for 10 min, followed by the addition of iron (105.3 g; 1.91 mol). The reaction mixture is stirred at 90 °C for 16 h. After complete conversion, the reaction mixture is evaporated under vacuum, taken up in EtOAc and water, and filtered through a pad of Celite. The organic layer is dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product. This crude product is triturated with 5% EtOAc / petroleum ether, stirred for 30 min, filtered, and dried under vacuum to give B-7-a (HPLC-MS: (M+H) + =192.0;t Ret .=0.81 min, method LCMS3, basisch_1). Experimental procedure for the synthesis of B-6a-a To a stirred solution of B-7-a (75.0 g; 0.391 mol) in THF (600 mL) is added 1,1'-thiocarbonyldiimidazole (139.0 g; 0.781 mol). The reaction mixture is stirred at 80 °C for 24 h, then cooled to rt and evaporated to dryness. EtOAc is added to the residue and the mixture is extracted with water. The organic layer is washed with water, dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product, which is triturated with diethyl ether, stirred for 30 min, filtered and dried under vacuum to give B-6a-a (HPLC-MS: (M+H) + =234.3, t Ret .=1.93 minutes, method GVK_LCMS_41). Experimental procedure for the synthesis of B-5a-a A solution of B-6a-a (60.0 g; 0.256 mol) in thionyl chloride (600 mL) and DMF (120 mL) is stirred at 80 °C for 30 min. The reaction mixture is evaporated in vacuo, diluted with EtOAc, and extracted with saturated NaHCO solution. The organic layer is dried over anhydrous NaSO and concentrated in vacuo to give the crude product. The crude product is purified by normal phase chromatography using DCM / petroleum ether to give B-5a-a (HPLC-MS: (M+H) + =236.0, t Ret .=2.03 minutes, method GVK_LCMS_41).

[0266] Alternative synthesis of B-5a-a [ka]

[0267] Experimental procedure for the synthesis of E-4-a To a suspension of 2,4,6-trichloropyridine (2.5 g, 13.7 mmol, 1.0 equiv) in EtOH (2.5 mL) at 80°C is added methylamine (33 wt%, 10.0 mL, 73.04 mmol, 5.33 equiv) in EtOH over 4 h. The mixture is stirred at 80°C for 4 h and then cooled to rt over 2 h. The mixture is stirred at rt for 1 h and then filtered. The solid is rinsed sequentially with water (5.0 mL), heptane (2.5 mL), and MTBE (2.5 mL). The solid is dried under vacuum at 50°C and then slurried in MTBE (10.0 mL) at rt for 1 h. The mixture is filtered and rinsed with MTBE (2.5 mL). The solid is dried under vacuum at 55°C to give E-4-a ( 1 H-NMR (500MHz, DMSO-d6) δ 7.35 (d, J = 5Hz, 1H), 6.51 (s, 2H), 2.72 (d, J = 5 Hz, 3H)). Experimental procedure for the synthesis of E-3-a A suspension of E-4-a (5.0 g, 27.715 mmol, 1.0 equiv) and N-iodosuccinimide (6.55 g, 29.101 mmol, 1.05 equiv) in acetonitrile (30 mL) is heated to 80 °C for 8 h. The mixture is cooled to rt over 1 h, and water (20 mL) is added over 1 h. The mixture is cooled to rt and stirred at rt for 1 h. The mixture is filtered and the solid is rinsed with water (13 mL). The solid is dried under vacuum at 55 °C to give E-3-a ( 1 H-NMR (500MHz, DMSO-d6) δ 6.58 (d, J = 4 Hz, 1H), 6.45 (s, 1H), 2.82 (d, J = 4 Hz, 3H)). Experimental procedure for the synthesis of E-2-a To a solution of chlorosulfonyl isocyanate (2.32 g, 25.107 mmol, 1.3 equiv.) in 2-methyltetrahydrofuran (6 mL) at −15° C. is added E-3-a (5.97 g, 19.313 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (30 mL) to maintain the temperature below −5° C. The mixture is stirred at −10° C. for 1 hour, and then 2.0 M sodium hydroxide solution (3.92 equiv.) is added at a rate that maintains the temperature below 18° C. The mixture is cooled to 0° C. and stirred at this temperature for 1 hour before filtering. The solid is rinsed with water (12 mL) and isopropyl acetate (12 mL). The solid is then dried under vacuum at 55° C. to give E-2-a ( 1 H-NMR (400MHz, DMSO-d6) δ 7.58 (s, 1H), 6.25 (s, 2H), 3.05 (s, 3H)).

[0268] Experimental procedure for the synthesis of B-3f-a To a suspension of E-2-a (10.0 g, 26.883 mmol, 1.0 equiv.), copper(I) iodide (57.5 mg, 0.5 mmol, 0.02 equiv.), and 1,10-phenanthroline (48.5 mg, 0.269 mmol, 0.01 equiv.) in acetonitrile (100 mL) is added N,N-diisopropylethylamine (9.37 mL, 53.765 mmol, 2.0 equiv.). The mixture is heated at 80 °C for 18 h and then cooled to rt. The mixture is filtered and rinsed with acetonitrile (10 mL). The filtrate is then vacuum distilled until 50 mL of solution remains. The mixture is then filtered to collect a second crop of solid. The combined crop of solid is treated with acetonitrile (5 mL) and 10 wt % ammonium chloride (aqueous, 10 mL) at 40 °C. The mixture is stirred at 40° C. for 2 h, then cooled to rt and filtered. The solid is dried under vacuum at 55° C. to give B-3f-a ( 1 H-NMR (400MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.40 (s, 1H), 3.30 (s, 3H)). Experimental procedure for the synthesis of B-5a-a A suspension of B-3f-a (2.54 g, 11.16 mmol, 1.0 equiv.) and benzyltriethylammonium chloride (5.08 g, 22.32 mmol, 2.0 equiv.) in phosphorus oxychloride (9.41 g, 61.386 mmol, 5.5 equiv.) was heated at 105 °C for 24 h. Toluene (25.4 mL) was added, and the mixture was cooled to rt. Water (12.7 mL) was added at a rate that maintained the temperature below 50 °C. The mixture was allowed to cool to 25 °C, and then 30 wt % sodium hydroxide (22 equiv.) was added to adjust the pH to 7.4. The mixture was then filtered and rinsed with toluene (5 mL). The aqueous phase was removed, and the organic phase was washed with water (13 mL). The aqueous phase was removed, and the toluene was removed by vacuum distillation until 7.5 mL remained. The mixture was allowed to cool to rt, heptane (7.6 mL) was added, and the mixture was stirred at rt for 1 h before being filtered. The solid is rinsed with water (5 mL) and then dried at 50 °C to give B-5a-a. 1 H-NMR (500MHz, DMSO-d6) δ 7.99 (s, 1H), 3.82 (s, 3H)).

[0269] Synthesis of B-5b-a [ka]

[0270] Experimental procedure for the synthesis of B-12-a To a stirred solution of B-13-a (150.0 g; 0.66 mol) in EtOH (1200 mL) is added water (300 mL) and NH4Cl (178.1 g; 3.30 mol). Iron powder (181.4 g; 3.30 mol) is then slowly added and the reaction mixture is stirred at 80 °C for 6 h. The reaction mixture is filtered through a pad of Celite and the solvent is evaporated under vacuum. The remaining residue is dissolved in EtOAc and extracted with water. The organic layer is dried over anhydrous Na2SO4 and concentrated under vacuum to give crude material. This crude material is stirred with petroleum ether for 1 h, filtered, and washed with petroleum ether to give B-12-a (HPLC-MS: (M+H) + =197.0, t Ret .=0.817 min, method VAB). Experimental procedure for the synthesis of B-6b-a To a stirred solution of B-12-a (2.46 g; 12.5 mmol) in AcCN (50 mL) is added potassium O-ethylcarbonodithioate (3.00 g; 18.7 mmol). The reaction mixture is stirred at 80 °C for 3 days. The mixture is diluted with water and extracted with DCM. The product-containing aqueous phase is acidified with 1 N aqueous HCl and extracted with DCM. The organic layer is dried over anhydrous MgSO4 and concentrated under vacuum to give B-6b-a (HPLC-MS: (M+H) + =237.1, t Ret .=0.562 minutes, method VAB). Experimental procedure for the synthesis of B-5b-a To a stirred solution of B-6b-a (1.10 g; 4.64 mmol) in 1,2-dichloroethane is added oxalyl chloride (0.5 mL; 5.80 mmol). DMF (0.36 mL; 4.64 mmol) is then added dropwise and the mixture is stirred at 80 °C for 16 h. The reaction mixture is cooled to rt, diluted with DCM and water, and extracted. The organic layer is dried over anhydrous MgSO and concentrated under vacuum to give B-5b-a (HPLC-MS: (M+H) + = 252.1., t Ret .=0.909 minutes, method VAB).

[0271] Synthesis of Compound (I) of the Present Invention Synthesis of I-001 [ka]

[0272] B-1b-b (80 mg, 0.2 mmol, 1 equiv.), A-1-a (50 mg, 0.2 mmol, 1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol, 0.1 equiv.), and tert-butyl XPhos (18 mg, 0.04 mmol, 0.2 equiv.) are placed in a pressure vessel. Toluene (1 mL) and 1,4-dioxane (1 mL) are added, and the reaction mixture is purged with argon. Sodium tert-butoxide (2 M in THF; 155 μL, 0.34 mmol, 1.75 equiv.) is added, and the reaction mixture is heated to 125 °C (microwave irradiation) for 20 min. The reaction mixture is purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-001.

[0273] Synthesis of I-002, I-003 and I-004 [ka]

[0274] Step 1 B-1b-d (180 mg, 0.4 mmol), A-1-a (100 mg, 0.4 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.04 mmol, 0.1 equiv), and tert-butyl XPhos (36 mg, 0.04 mmol, 0.2 equiv) are placed in a pressure vessel. Toluene (1 mL) and 1,4-dioxane (1 mL) are added, and the reaction mixture is purged with argon. Sodium tert-butoxide (2 M in THF; 320 μL, 0.7 mmol, 1.75 equiv) is added, and the reaction mixture is heated to 125 °C (microwave irradiation) for 20 min. The reaction mixture is purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-002. Step 2 I-002 (140 mg, 0.21 mmol) is dissolved in DCM (2.5 mL). Trifluoroacetic acid (0.5 mL, 6.5 mmol, 30 equiv) is added and the reaction mixture is stirred at rt for 4 h. Aqueous potassium bicarbonate is added and the basic aqueous layer is extracted with DCM. The organic phase is dried over sodium sulfate and filtered. The filtrate is reduced to dryness to give I-003. Step 3 I-003 (40 mg, 0.07 mmol) is dissolved in a mixture of DCM (1 mL) and MeOH (1 mL). Glacial acetic acid (8.3 μL, 0.14 mmol, 2 equiv.) and formaldehyde (37% in water; 16 μL, 0.21 mmol, 3 equiv.) are added and the reaction mixture is stirred at rt for 10 min. Sodium cyanoborohydride (23.8 mg, 0.36 mmol, 5 equiv.) is added and the reaction mixture is stirred at rt for 1 h. The reaction mixture is diluted with water and the aqueous phase is extracted with DCM. The solvent is evaporated and the residue is purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-004.

[0275] Synthesis of I-069, I-070 and I-071 [ka]

[0276] Step 1 B-1c * A flask is charged with I-b (3.80 g; 12.63 mmol), A-1-1 (3.25 g; 12.85 mmol), tris(dibenzylideneacetone)dipalladium(0) (750 mg, 0.80 mmol), and tert-butyl XPhos (750 mg, 1.68 mmol). Toluene (100 mL) is added and the reaction mixture is purged with argon. Sodium tert-butoxide (2 M in THF; 12.5 mL, 25.0 mmol) is added and the reaction mixture is stirred for 6 h at 80 °C. The reaction mixture is purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-069. Step 2 I-069 (1.56 g; 2.97 mmol) is dissolved in EtOH (15.0 mL) and water (5 mL), LiOH (0.5 g; 20.5 mmol) is added, and the reaction mixture is stirred at reflux for 6.5 h. The mixture is evaporated to dryness, slurried with water, and acidified to pH 5 with 1 N aqueous HCl. The resulting residue is filtered, washed with water, and lyophilized to give I-070. Step 3 I-070 (1.10 g; 2.22 mmol) is dissolved in AcCN (15.0 mL) and DIPEA (1.00 mL; 5.70 mmol). HATU (1.50 g; 3.75 mmol) is added to this solution and the mixture is stirred at rt for 30 min. Morpholine (0.35 mL; 4.05 mmol) is added and stirring at rt is continued for 17 h. The reaction mixture is purified (normal phase chromatography, mobile phase DCM / MeOH / NH4OH) to give I-071.

[0277] Synthesis of I-082, I-083, and I-084 [ka]

[0278] Step 1 B-1d * A-1-a (1.80 g, 4.67 mmol), A-1-a (1.40 g, 5.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (350 mg, 0.38 mmol), and tert-butyl XPhos (330 mg, 0.74 mmol) are placed in a flask. Toluene (45 mL) is added and the reaction mixture is purged with argon. Sodium tert-butoxide (2 M in THF; 4.5 mL, 9.00 mmol) is added and the reaction mixture is stirred at 100 °C for 1 h. The reaction mixture is purified (preparative HPLC 1) to give I-082. Step 2 I-082 (1.18 g; 2.07 mmol) is dissolved in 1,4-dioxane (16.0 mL) and 4 N hydrogen chloride in 1,4-dioxane (4.0 mL; 46.67 mmol) is added. The reaction mixture is stirred at 65 °C for 3.5 h and then cooled to rt. The resulting precipitate is filtered off, washed with 1,4-dioxane, and dried in vacuo to give I-083. Step 3 I-083 (1.10 g; 1.90 mmol) is dissolved in NMP (10.0 mL) and DIPEA (1.75 mL; 10.24 mmol). HATU (1.00 g; 2.50 mmol) is added to this solution and the mixture is stirred at 30 °C for 30 min. Pyrrolidine (0.20 mL; 2.32 mmol) is added and stirring is continued at 30 °C for 1 h. The mixture is diluted with water and extracted with DCM. The solvent is evaporated and the residue is purified (normal phase chromatography, mobile phase DCM / MeOH / NH4OH) to give I-084.

[0279] Synthesis of I-126 [ka]

[0280] I-107 (150 mg; 0.27 mmol), p-toluenesulfonic acid (467 mg; 2.71 mmol), and lithium chloride (115 mg; 2.71 mmol) are suspended in NMP in a pressure vessel and stirred for 25 min at 180 °C under microwave irradiation. The reaction mixture is purified by preparative HPLC1 to give I-126. The following compounds (I) (Tables 9 and 10) can be obtained by analogous methods described for compounds I-001 to I-004, I-069 to I-071, I-082 to I-084 and I-126 or by further derivatization of compounds (I) initially obtained by said methods.

[0281] Table 9: [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] Table 10-6 Table 10-7 Table 10-8 Table 10-9 Table 10-10 Table 10-11 Table 10-12 Table 10-13 Table 10-14 Table 10-15 Table 10-16 Table 10-17 Table 10-18 Table 10-19 Table 10-20 Table 10-21 Table 10-22 Table 10-23 Table 10-24 Table 10-25 Table 10-26 Table 10-27 Table 10-28 Table 10-29 Table 10-30

[0282] Table 10 Table 11-1 Table 11-2 Table 11-3 Table 11-4 Table 11-5 Table 11-6 Table 11-7 Table 11-8 [Table 11-9] [Table 11-10] [Table 11-11] [Table 11-12] [Table 11-13] [Table 11-14] [Example]

[0283] The following examples describe the biological activity of the compounds of the invention without limiting the invention to these examples. Ba / F3 cell model generation and proliferation assay Ba / F3 cells were ordered from DSMZ (ACC300, Lot 17) and grown in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10 ng / ml IL-3 at 37°C in a 5% CO2 atmosphere. EGFR mutant-containing plasmids were obtained from GeneScript. To generate an EGFR-dependent Ba / F3 model, Ba / F3 cells were transduced with a retrovirus-containing vector harboring an EGFR isoform. Platinum-E cells (Cell Biolabs) were used for retroviral packaging. Retrovirus was added to Ba / F3 cells. To ensure infection, cells were spinfected with 4 μg / mL polybrene. Infection efficiency was confirmed by counting GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10%–20% were further cultured and puromycin selection was initiated at 1 μg / mL. As a control, parental Ba / F3 cells were used to demonstrate the selection condition. Selection was considered successful when the parental Ba / F3 cell culture died. To assess the transforming potential of the EGFR mutations, the growth medium was no longer supplemented with IL-3. Ba / F3 cells harboring an empty vector served as a control. The switch from IL-3 to EGF was performed on Ba / F3 cells using wild-type EGFR, known for its dependence on the EGF ligand. Puromycin was removed approximately 10 days before the experiment. For proliferation assays (data in Table 13), Ba / F3 cells were cultured at 5 x 10 in growth medium. 3 Cells were seeded at 100 μL per well in a 96-well plate. Compounds were added using an HP D3000 digital dispenser. All treatments were performed in triplicate. Treated cells were incubated for 72 hours at 37°C with 5% CO2. Chemiluminescence was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) using a VICTOR X4 multilabel plate reader. Raw data were imported and analyzed using Boehringer Ingelheim's proprietary software, MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0284] Table A: Viability IC in nM of Ba / F3 cell lines induced by the indicated EGFR alleles and treated with the indicated compounds 50 Values ​​(representing the mean data of two independent biological experiments with technical triplicates). [Table 12]

[0285] [Table 13]

[0286] [Table 14]

[0287] [Table 15]

[0288] Ba / F3 EGFR del19 T790M C797S proliferation assay ( * Further compounds measured in the above assays indicated [Table 16]

[0289] pEGFR assay This assay quantifies EGFR phosphorylation at Tyr1068 and was used to measure the inhibitory effects 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 a 5% CO2 atmosphere and transduced with a retroviral vector encoding EGFR del19 T790M C797S. Transduced cells were selected using puromycin. After selection, IL-3 was withdrawn and IL-3-dependent cells were cultured. p-EGFR Tyr1068 was quantified using the AlphaScreen Surefire pEGF Receptor (Tyr1068) Assay (PerkinElmer, TGRERS). For this assay, Ba / F3 EGFR del19 T790M C797S cells were seeded in DMEM medium containing 10% FCS. 60 nL of compound dilutions were added to each well of a Greiner TC 384 plate using the Echo platform. Subsequently, 60,000 cells / well in 60 μL were added. Cells were incubated with compound for 4 hours at 37°C. After centrifugation and removal of the medium supernatant, 20 μL of 1.6x lysis buffer from the TGR / PerkinElmer kit with protease inhibitors was added. The mixture was incubated for 20 minutes at room temperature with shaking (700 rpm). After centrifugation, 4 μL of lysate was 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) + Protein A acceptor beads 6760137 at 1:50) was added to each well. The plate was shaken (1400 rpm) for 1 minute and incubated in the dark at room temperature for 2 hours. 3 μL of donor mix (AlphaScreen streptavidin-coated donor beads (6760002, PerkinElmer)) diluted 1:50 with dilution buffer (TGRERS Assay Kit, PerkinElmer) was added to each well.The plate was shaken (1400 rpm) for 1 minute and incubated in the dark at room temperature for 2 hours. The plate was then analyzed using the Envision reader platform. The results were computed as follows: the ratio of the test compound value to the negative control (DMSO) value was calculated. From these values, the MEGASTAR IC was calculated. 50 IC using a four-parametric logistic model in applications 50 Calculate the value. This cellular phospho-EGFR (pEGFR) compound dose-response assay quantifies phosphorylation of EGFR at Tyr1068 in Ba / F3 cells expressing the EGFR variant del19 T790M C797S. Assay results are expressed as IC 50 The reported pEGFR IC for a given compound is given as a value (see Table 9). 50 The lower the value, the more potently the compound inhibits the EGFR del19 T790M C797S target protein in Ba / F3 cells.

[0290] PC-9 EGFR del19 T790M C797S proliferation assay This assay quantifies the antiproliferative efficacy of compounds listed in Table 10 in PC-9 EGFR del19 T790M C797S cells. PC-9 is a small cell lung cancer cell line (ECACC #90071810; lot: 14A030) obtained from the European Collection of Authenticated Cell Cultures (ECACC) and expresses an oncogenic variant of EGFR called EGFR del19. To generate the PC-9_TMCS_10 clone expressing EGFR del19 T790M C797S, the mutations T790M and C797S were introduced into exon 20 of the genomic EGFR locus in PC-9 parental cells using genome engineering. Successful introduction of the mutations was verified using sequencing. Cells are seeded in 96-well plates (150 μL) in growth medium (RPMI-1640 (Gibco #12633012) + 10% FCS (HyClone #SH30071)). Compounds are added the day after cell plating using an HP D3000 digital dispenser. All treatments are performed in technical triplicate. Treated cells are incubated for 96 hours at 37°C with 5% CO2. The CellTiter-Glo® Luminescent Cell Viability Assay (Promega) is performed and chemiluminescence is measured using a VICTOR X4 multilabel plate reader. Raw data are imported and analyzed with Boehringer Ingelheim proprietary software MegaLab (curve fitting based on R (library DLC)). Quantification of viable cells is calculated by normalization of compound-treated cells to DMSO. Dose-response curves were calculated using a four-parameter logistic regression model. Relative IC 50 The value is defined as the drug concentration at the inflection point of the dose-response curve. IC assay results 50 The IC values ​​reported for the given compounds on the above cells are provided (see Table 10). 50 The lower the value, the stronger the antiproliferative effect of the compound.

[0291] The following formulation examples illustrate the invention without limiting its scope. Examples of pharmaceutical preparations A) Per tablet 100 mg of the active substance of formula (I) Lactose 140mg Corn starch 240mg Polyvinylpyrrolidone 15mg Magnesium stearate 5mg 500mg The finely ground active substance, lactose, and a portion of the corn starch are mixed together. The mixture is sieved, then moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated, and dried. The granules, the remaining corn starch, and magnesium stearate are sieved and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

[0292] B) Per tablet 80 mg of the active substance of formula (I) Lactose 55mg Corn starch 190mg Microcrystalline cellulose 35mg Polyvinylpyrrolidone 15mg Sodium carboxymethyl starch 23mg Magnesium stearate 2mg 400mg The finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together, the mixture is sieved, and the remaining corn starch and water are mixed to form granules, which are dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of suitable size.

[0293] C) Per tablet 25 mg of the active substance of formula (I) Lactose 50mg Microcrystalline cellulose 24mg Magnesium stearate 1mg 100mg The active substance, lactose and cellulose are mixed together. The mixture is screened, then moistened with water, kneaded, wet-granulated, dried, dry-granulated or directly final blended with magnesium stearate and compressed into tablets of appropriate shape and size. When wet-granulated, additional lactose or cellulose and magnesium stearate are added, and the mixture is compressed to produce tablets of appropriate shape and size.

[0294] D) Ampoule solution 50 mg of the active substance of formula (I) Sodium chloride 50mg Water for injection 5mL The active substance is dissolved in water at its own pH or, optionally, at pH 5.5-6.5, and sodium chloride is added to make it isotonic. The resulting solution is filtered without heating, and the filtrate is transferred under aseptic conditions into ampoules, which are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg, and 50 mg of the active substance. Another aspect of the present invention may be as follows. [1] The following formula (I) [ka] (In the formula, R 1 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 、C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 2 is hydrogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 、C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; or R 1 and R 2 form a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring together with the carbon atoms to which they are attached; R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -CN, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 、C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 4 is R a1 and R b1 selected from the group consisting of: R a1 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b1 and / or R c1 is replaced by; Each R b1 are independently -OR c1 , -N(R c1 )R c1 , halogen, -CN, -C(=O)R c1 , -C(=O)OR c1 , -C(=O)N(R c1 )R c1 , -C(=O)N(H)OR c1 , -C(=O)N(C 1-4 alkyl) OR c1 , -S(=O) 2 R c1 , -S(=O) 2 N(R c1 )R c1 , -N(H)C(=O)R c1 , -N(C 1-4 alkyl)C(=O)R c1 , -N(H)C(=O)OR c1 , -N(C 1-4 alkyl)C(=O)OR c1 , -N(H)S(=O) 2 R c1 , -N(C 1-4 Alkyl)S(=O) 2 R c1 and the divalent substituent ═O; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 are independently -OR e1 , -N(R e1 )R e1 , halogen, -CN, -C(=O)R e1 , -C(=O)OR e1 , -C(=O)N(R e1 )R e1 , -C(=O)N(H)OR e1 , -C(=O)N(C 1-4 alkyl) OR e1 , -S(=O) 2 R e1 , -S(=O) 2 N(R e1 )R e1 , -N(H)C(=O)R e1 , -N(C 1-4 alkyl)C(=O)R e1 , -N(H)C(=O)OR e1 , -N(C 1-4 alkyl)C(=O)OR e1 , -N(H)S(=O) 2 R c1 , -N(C 1-4 Alkyl)S(=O) 2 Rc1 and the divalent substituent ═O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH 2 , -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 and the divalent substituent ═O; X 1 is selected from the group consisting of carbon (C) and nitrogen (N); X 2 is selected from the group consisting of carbon (C) and nitrogen (N); X 1 and X 2 at least one of which is carbon (C); X 3 are nitrogen (N), C(R 5 ), N(R 6 ), C(R 5 )(R 5 ), oxygen (O), sulfur (S), S(=O), S(=O) 2 and C(=O); X 4 are nitrogen (N), C(R 7 ), N(R 8 ), C(R 7 )(R 7 ), oxygen (O), sulfur (S), S(=O), S(=O) 2 and C(=O); X 5 are nitrogen (N), C(R 9 ), N(R 10 ), C(R 9 )(R 9 ), oxygen (O), sulfur (S), S(=O), S(=O) 2 and C(=O); each bond between ring members of ring A is independently selected from a single bond, a double bond, or a (hetero)aromatic bond; Each R 5 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-4 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 、C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 6 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 7 are independently, R a2 and R b2 selected from the group consisting of: R a2 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 are independently -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O) 2 R c2 , -S(=O) 2 N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O) 2 R c2 , -N(C 1-4 Alkyl)S(=O) 2 R c2 and the divalent substituent ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 are independently -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )Re2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O) 2 R e2 , -S(=O) 2 N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O) 2 R c2 , -N(C 1-4 Alkyl)S(=O) 2 R c2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH 2 , -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 and the divalent substituent ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 9 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 、C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 10 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl or a salt thereof. 〔2〕R 1 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 、C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 、C 3-6 Cycloalkyl, C 3-6 The compound or salt according to [1] above, wherein the aryl group is selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl. 〔3〕R 1 and R 2 and (iii) form a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring together with the carbon atom to which they are bonded. 〔4〕R 3 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The compound or salt according to any one of [1] to [3] above, wherein the compound or salt is selected from the group consisting of haloalkoxy and halogen. 〔5〕R 4 But R a1 and R b1 selected from the group consisting of: Ra1 But C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 , halogen, and the divalent substituent =O; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 , halogen, and the divalent substituent =O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 The compound or salt according to any one of [1] to [4] above, wherein cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are all optionally substituted with one or more identical or different substituents selected from the group consisting of halogen and the divalent substituent =O. 〔6〕R 4 But R a1 and R b1selected from the group consisting of: R a1 But C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl may each optionally have one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 The compound or salt according to [5] above, wherein the cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens. 〔7〕R 4 R a1 and; R a1 However, optionally one or more identical or different R b1 and / or Rc1 3- to 11-membered heterocyclyl substituted with; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 The compound or salt according to [6] above, wherein the cycloalkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens. 〔8〕R 4 But -NH 2 , -NH(C 1-4 alkyl) and -N(C 1-4 alkyl) 2 selected from the group consisting of The compound or salt according to any one of the above [1] to [4]. 〔9〕R 4 -OR c1 and; R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 The compound or salt according to any one of the above [1] to [4], wherein the cycloalkyl and the 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens. 〔10〕R 4 But C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl may each optionally have one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(Re1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 The compound or salt according to any one of the above [1] to [4], wherein the cycloalkyl and the 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

[11] The following group

change

change

change

[10] , wherein the aryl group is selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl.

[12] Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 and -C(=O)N(C 1-4 alkyl) OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C1-6 Alkyl, C 3-6 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The compound or salt according to any one of the above [1] to

[11] , wherein the alkyl and the 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

[13] Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 However, independently, -N(R c2 )R c2 , halogen, -C(=O)R c2 and -C(=O)OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 and -C(=O)OR e2 selected from the group consisting of: Each R e2 are independently hydrogen, C 3-6 Cycloalkyl and C 1-6 The compound or salt according to

[12] above, wherein the compound or salt is selected from the group consisting of alkyl.

[14] Each R 7 R a2 and; R a2 However, optionally one or more identical or different R b2 and / or R c2 3- to 11-membered heterocyclyl substituted with; Each R b2 are independently halogen, -C(=O)R c2 and -C(=O)OR c2 selected from the group consisting of Each R c2 However, optionally one or more identical or different R d2 and / or R e2 C is replaced by 1-6 is alkyl; Each R d2 But independently, -OR e2 and -C(=O)OR e2 selected from the group consisting of: Each R e2 are independently hydrogen and C 1-6 The compound or salt according to

[13] above, wherein the alkyl is selected from the group consisting of alkyl.

[15] Each R 7 R b2 and; Each R b2 But independently, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 and -C(=O)N(C 1-4 alkyl) OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The alkyl and 3- to 11-membered heterocyclyl may each optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each Rd2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 and the divalent substituent ═O; Each R e2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The compound or salt according to

[12] above, wherein the alkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

[16] The compound according to any one of the above [1] to

[15] or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[17] The compound according to any one of [1] to

[15] above or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease and / or condition mediated by a mutant EGFR.

[18] The compound according to any one of the above [1] to

[15] or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of cancer.

[19] The compound according to any one of [1] to

[15] above, or a pharmaceutically acceptable salt thereof, for use in treating cancer having tumor cells harboring a mutated EGFR gene.

[20] The compound or pharmaceutically acceptable salt thereof for use according to any one of

[16] to

[19] above, wherein the compound or salt is administered before, after, or together with one or more other pharmacologically active substances.

[21] The compound or pharmaceutically acceptable salt thereof for use according to any one of

[15] to

[19] above, wherein the compound or salt is administered in combination with one or more other pharmacologically active substances.

[22] A method for treating and / or preventing a disease and / or condition mediated by a mutant EGFR, the method comprising administering to a human a therapeutically effective amount of the compound according to any one of [1] to

[15] above or a pharmaceutically acceptable salt thereof.

[23] A method for treating and / or preventing cancer, comprising administering to a human a therapeutically effective amount of the compound according to any one of [1] to

[15] above or a pharmaceutically acceptable salt thereof.

[24] A method for treating cancer having tumor cells harboring a mutant EGFR gene, the method comprising administering to a human a therapeutically effective amount of the compound according to any one of [1] to

[15] above or a pharmaceutically acceptable salt thereof.

[25] The method according to any one of

[22] to

[24] above, wherein the compound or a pharmaceutically acceptable salt thereof is administered before, after, or together with one or more othe...

Claims

1. The following formula (I) 【Chemistry 1】 (In the formula, R 1 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 2 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; or R 1 and R 2 form, together with the carbon atoms to which they are attached, a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring; R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -CN, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 4 is R a1 and R b1 selected from the group consisting of: R a1 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b1 and / or R c1 is replaced by; Each R b1 are independently -OR c1 , -N(R c1 )R c1 , halogen, -CN, -C(=O)R c1 , -C(=O)OR c1 , -C(=O)N(R c1 )R c1 , -C(=O)N(H)OR c1 , -C(=O)N(C 1-4 alkyl) OR c1 , -S(=O) 2 R c1 , -S(=O) 2 N(R c1 )R c1 , -N(H)C(=O)R c1 , -N(C 1-4 alkyl)C(=O)R c1 , -N(H)C(=O)OR c1 , -N(C 1-4 alkyl)C(=O)OR c1 , -N(H)S(=O) 2 R c1 and -N(C 1-4 Alkyl)S(=O) 2 R c1 selected from the group consisting of: Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 are independently -OR e1 , -N(R e1 )R e1 , halogen, -CN, -C(=O)R e1 , -C(=O)OR e1 , -C(=O)N(R e1 )R e1 , -C(=O)N(H)OR e1 , -C(=O)N(C 1-4 alkyl) OR e1 , -S(=O) 2 R e1 , -S(=O) 2 N(R e1 )R e1 , -N(H)C(=O)R e1 , -N(C 1-4 alkyl)C(=O)R e1 , -N(H)C(=O)OR e1 , -N(C 1-4 alkyl)C(=O)OR e1 , -N(H)S(=O) 2 R c1 , -N(C 1-4 Alkyl)S(=O) 2 R c1 and the divalent substituent =O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH 2 , -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 and the divalent substituent ═O; X 1 is selected from the group consisting of carbon (C) and nitrogen (N); X 2 is selected from the group consisting of carbon (C) and nitrogen (N); X 1 and X 2 at least one of is carbon (C); X 3 are nitrogen (N), C(R 5 ), N(R 6 ), C(R 5 )(R 5 ), oxygen (O), sulfur (S), S(=O), S(=O) 2 and C(=O); X 4 are nitrogen (N), C(R 7 ), N(R 8 ), C(R 7 )(R 7 ), oxygen (O), sulfur (S), S(=O), S(=O) 2 and C(=O); X 5 are nitrogen (N), C(R 9 ), N(R 10 ), C(R 9 )(R 9 ), oxygen (O), sulfur (S), S(=O), S(=O) 2 and C(=O); each bond between ring members of ring A is independently selected from a single bond, a double bond, or a (hetero)aromatic bond; Each R 5 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-4 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 6 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 7 are independently, R a2 and R b2 selected from the group consisting of: R a2 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 are independently -OR c2 , -N(R c2 )R c2 , halogen, -CN, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 , -C(=O)N(C 1-4 alkyl) OR c2 , -S(=O) 2 R c2 , -S(=O) 2 N(R c2 )R c2 , -N(H)C(=O)R c2 , -N(C 1-4 alkyl)C(=O)R c2 , -N(H)C(=O)OR c2 , -N(C 1-4 alkyl)C(=O)OR c2 , -N(H)S(=O) 2 R c2 and -N(C 1-4 Alkyl)S(=O) 2 R c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 are independently -OR e2 , -N(R e2 )R e2 , halogen, -CN, -C(=O)R e2 , -C(=O)OR e2 , -C(=O)N(R e2 )R e2 , -C(=O)N(H)OR e2 , -C(=O)N(C 1-4 alkyl) OR e2 , -S(=O) 2 R e2 , -S(=O) 2 N(R e2 )R e2 , -N(H)C(=O)R e2 , -N(C 1-4 alkyl)C(=O)R e2 , -N(H)C(=O)OR e2 , -N(C 1-4 alkyl)C(=O)OR e2 , -N(H)S(=O) 2 R c2 , -N(C 1-4 Alkyl)S(=O) 2 R c2 and the divalent substituent =O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 All aryl and 5- to 10-membered heteroaryl are optionally C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, halogen, -CN, -NH 2 , -C(=O)C 1-4 Alkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 and the divalent substituent ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 9 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, halogen, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Each R 10 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Haloalkoxy-C 1-6 Alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl or a salt thereof.

2. R 1 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl, C 3-6 selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl; R 2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 Cycloalkyl, C 3-6 2. The compound or salt of claim 1, wherein the cycloalkoxy is selected from the group consisting of cycloalkoxy, 3- to 6-membered heterocyclyloxy, and 3- to 6-membered heterocyclyl.

3. R 3 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The compound or salt of any one of claims 1 to 2, selected from the group consisting of haloalkoxy and halogen.

4. R 4 But R a1 and R b1 selected from the group consisting of: R a1 But C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl may all optionally be substituted with one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 , halogen, and the divalent substituent =O; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 4. The compound or salt of any one of claims 1 to 3, wherein cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are all optionally substituted with one or more identical or different substituents selected from the group consisting of halogen and the divalent substituent =O.

5. R 4 But R a1 and R b1 selected from the group consisting of: R a1 But C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl may each optionally have one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl are all optionally each independently one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 5. The compound or salt of claim 4, wherein the cycloalkyl and the 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

6. R 4 R a1 and R a1 However, optionally one or more identical or different R b1 and / or R c1 3- to 11-membered heterocyclyl substituted with Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl are all optionally each independently one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 6. The compound or salt of claim 5, wherein the cycloalkyl and the 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

7. R 4 But C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl may each optionally have one or more identical or different R b1 and / or R c1 is replaced by; Each R b1 But independently, -OR c1 , -N(R c1 )R c1 and halogen; Each R c1 are independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclyl, and 5- to 6-membered heteroaryl are all optionally each independently one or more of the same or different R d1 and / or R e1 is replaced by; Each R d1 But independently, -OR e1 , -N(R e1 )R e1 and halogen; Each R e1 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 Alkyl, C 3-10 The compound or salt of any one of claims 1 to 3, wherein the cycloalkyl and the 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

8. Each R 7 However, independently, R a2 and R b2 selected from the group consisting of: R a2 But hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The alkyl and 3- to 11-membered heterocyclyl may all optionally be one or more of the same or different R b2 and / or R c2 is replaced by; Each R b2 But independently, -OR c2 , -N(R c2 )R c2 , halogen, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 and -C(=O)N(C 1-4 alkyl) OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The alkyl and 3- to 11-membered heterocyclyl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 and the divalent substituent =O; Each R e2 are independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The compound or salt of any one of claims 1 to 7, wherein the alkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

9. Each R 7 R a2 and R a2 However, optionally one or more identical or different R b2 and / or R c2 3- to 11-membered heterocyclyl substituted with Each R b2 are independently halogen, -C(=O)R c2 and -C(=O)OR c2 selected from the group consisting of Each R c2 However, optionally one or more identical or different R d2 and / or R e2 C is replaced by 1-6 is alkyl; Each R d2 But independently, -OR e2 and -C(=O)OR e2 selected from the group consisting of: Each R e2 are independently hydrogen and C 1-6 9. The compound or salt of claim 8, wherein the alkyl is selected from the group consisting of alkyl.

10. Each R 7 R b2 and Each R b2 But independently, -C(=O)R c2 , -C(=O)OR c2 , -C(=O)N(R c2 )R c2 , -C(=O)N(H)OR c2 and -C(=O)N(C 1-4 alkyl) OR c2 selected from the group consisting of: Each R c2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 The alkyl and 3- to 11-membered heterocyclyl may all optionally be one or more of the same or different R d2 and / or R e2 is replaced by; Each R d2 But independently, -OR e2 , -N(R e2 )R e2 , halogen, -C(=O)R e2 , -C(=O)OR e2 and the divalent substituent =O; Each R e2 are independently hydrogen, C 1-6 alkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 9. The compound or salt of claim 8, wherein the alkyl and 3- to 11-membered heterocyclyl are all optionally substituted with one or more of the same or different halogens.

11. 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of the following compounds: 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3] 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 【Chemistry 2-10】 【Chemistry 2-11】 【Chemistry 2-12】 【Chemistry 2-13】 【Chemistry 2-14】 【Chemistry 2-15】 【Chemistry 2-16】 【Chemistry 2-17】 【Chemistry 2-18】 【Chemistry 2-19】 【Chemistry 2-20】 【Chemistry 2-21】 【Chemistry 2-22】 【Chemistry 2-23】 【Chemistry 2-24】

12. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and / or preventing cancer.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances.

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