Substituted 1h-pyrazolo[4,3-c]pyridines and derivatives as egfr inhibitors

Abstract

The present invention encompasses: compounds of formula (I), wherein the groups R 1 to R 4 and X 1 to X 5 have the meanings given in the claims and description; their use as inhibitors of mutant EGFR; pharmaceutical compositions containing such compounds; and their use as medicaments / medical uses, especially as agents for the treatment and / or prevention of carcinogenic diseases.

Description

TECHNICAL FIELD

[0001] The present invention relates to novel substituted 1 H-pyrazolo[4,3-c]pyridines and derivatives of formula (I)

[0002]

[0003] wherein the radicals R 1 to R 4 and X 1 to X 5 have the meanings given in the claims and the description; to the use thereof as inhibitors of mutant EGFR; to pharmaceutical compositions containing such compounds; and to the use thereof as medicaments / medical uses, especially as agents for the treatment and / or prevention of oncogenic diseases. BACKGROUND

[0004] The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that transduces cell division signals. Mutations in the EGFR gene are found in about 12% to 47% of non-small cell lung cancer (NSCLC) tumors by adenocarcinoma histology (Midha, 2015). The two most frequent EGFR variations found in NSCLC tumors are a short in-frame deletion in exon 19 (del19) and a single missense mutation L858R in exon 21 of the EGFR gene (Konduri, 2016). These two mutations cause ligand-independent activation of EGFR and are collectively referred to as EGFR M+. Del19 and L858R mutations in EGFR sensitize NSCLC tumors to EGFR tyrosine kinase inhibitor (TKI) therapy. Clinical experience shows that EGFR M+ NSCLC patients treated with 1st, 2nd, and 3rdgeneration EGFR TKIs erlotinib, gefitinib, afatinib, and osimertinib in 1stline therapy have an objective response rate of about 60-85% (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, making del19 or L858R mutant EGFR a validated drug target and a predictive biomarker for the treatment of NSCLC. The 1stgeneration EGFR TKIs erlotinib and gefitinib and the 2ndgeneration TKI afatinib have been approved by the FDA for 1stline therapy of EGFR M+ NSCLC patients.

[0005] Although the tumor response is characterized by significant tumor shrinkage, this response is usually short-lived, and most patients relapse within 10 to 12 months of treatment with first- and second-generation EGFR TKIs (Mitsudomi, 2010; Park, 2016; Soria, 2017; Zhou, 2011). The most significant molecular mechanism underlying progression is the acquisition of a secondary EGFR mutation, T790M, in 50% to 70% of patients who progress despite treatment with first- and second-generation EGFR inhibitors (Blakely, 2012; Kobayashi, 2005). This mutation attenuates the inhibitory activity of first- and second-generation TKIs in cellular analyses (see, for example, data in Table A).

[0006] Third-generation EGFR TKIs, such as osimertinib, have been developed that exhibit mutation selectivity and covalentity in effectively inhibiting primary EGFR mutations del19 and L858R, both in the presence and absence of secondary T790M resistance mutations (Cross, 2014; Wang, 2016). The efficacy of osimertinib, a third-generation EGFR TKI, observed in second-line treatment of EGFR M+T790M-positive NSCLC has been clinically demonstrated, indicating that tumor cell survival and proliferation depend on the mutation of the EGFR pair gene (…). 2015; Mok, 2016). Approximately 70% of EGFR M+T790M-positive patients previously treated with first-generation EGFR TKIs respond to second-line osimertinib therapy. However, disease progression occurs after a mean duration of 10 months (Mok, 2016). The potential mechanisms of acquired resistance to third-generation EGFR TKIs have been investigated, and these mechanisms are beginning to emerge (Ou, 2017). Recent data suggest that a major resistance mechanism is the acquisition of the grade 3 EGFR mutation C797S in approximately 20–40% of second-line patients who relapsed after treatment with osimertinib TKIs (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015). Third-generation TKIs such as osimertinib are covalently linked to EGFR via residue C797 (Cross, 2014; Wang, 2016). In cell models, the C797S mutation eliminates the activity of the tested third-generation TKIs (Thress, 2015) (see data in Table A, for example). In second-line patients, the EGFR del19 genotype-binding C797S (cis conformation) mutation is preferentially found on the same pair gene as the T790M mutation (82% of C797S+ patients) (Piotrowska, 2017). Crucially, the EGFR del19 / L858R T790M C797S cis mutant kinase variant present in second-line patients who have progressed despite osimertinib treatment (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thrress, 2015; Yu, 2015) may no longer be inhibited by first-, second-, or third-generation EGFR TKIs (Thress, 2015) (see data in Table A, for example). Based on the detection of the C797S mutation in patients with progression despite osimertinib treatment (Ortiz-Cuaran, 2016; Ou, 2017; Song, 2016; Thress, 2015; Yu, 2015), tumor cell survival and proliferation in EGFR del19 / L858R T790M C797S patients likely depend on this mutated pair gene and can be suppressed by targeting this pair gene. Recently, additional EGFR resistance mutations with a lower incidence than C797S have been described in second-line EGFR M+ NSCLC patients who have progressed despite osimertinib treatment: L718Q, L792F / H / Y, and C797G / N (Bersanelli, 2016; Chen, 2017; Ou, 2017).

[0007] The third-generation EGFR TKI osimertinib has recently shown efficacy in previously untreated EGFR M+ NSCLC patients (Soria, 2017). Disease progression occurred after a mean duration of 19 months. Although the range of EGFR resistance mutations following first-line osimertinib treatment has not been extensively studied, the first available data indicates the presence of the C797S mutation, which eliminates osimertinib activity (Ramalingam, 2017). Based on its efficacy in treatment-naïve EGFR M+ NSCLC patients and T790M-positive second-line patients, osimertinib has been approved in both cases.

[0008] The fact that unapproved EGFR TKIs inhibit the EGFR del19 / L858R T790M C797S variants—the paired gene that appears 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 will potently inhibit EGFR del19 or L858R, regardless of the presence of the two common resistance mutations T790M and C797S, especially EGFR del19 T790M C797S. The efficacy of these fourth-generation EGFR TKIs will be enhanced by the compound’s activity against additional resistance mutations, such as the potential osimertinib resistance mutations C797X (X = S, G, N) and L792F / H / Y. The broad activity of the molecule against EGFR del19 or L858R variants without T790M and / or C797S mutations will ensure that the new compound can effectively address the anticipated dual gene complexity of patients' tumors as a single therapeutic agent. A fourth-generation EGFR TKI molecule active against both EGFR del19 and EGFR L858R primary activating mutations, regardless of the presence of resistance mutations T790M and C797S, will allow for the treatment and prevention of resistant disease. Specifically, it will be suitable for treating EGFR M+ NSCLC patients who have progressed after prior EGFR TKI therapy with first-, second-, or third-generation TKIs, as well as first-line patients who have not received EGFR TKI therapy. To facilitate effective dosing and reduce EGFR-mediated on-target toxicity, the fourth-generation EGFR TKI should not inhibit wild-type EGFR. High selectivity to the human kinase community will reduce off-target toxicity of the compound. Another desirable property of the fourth-generation EGFR TKI is its ability to effectively penetrate the brain (blood-brain barrier penetration) to prevent and / or treat brain metastases and meningeal diseases.

[0009] The aforementioned characteristics of fourth-generation EGFR TKIs will allow for the treatment of patients who have progressed after second-line therapy with third-generation TKIs such as osimertinib (e.g., those with genotypes EGFR del19 / L858R T790M C797S) and who currently have no targeted therapy options. Furthermore, these characteristics may also allow fourth-generation EGFR TKIs to provide longer durations of response for both first-line and first-line patients (e.g., those who have progressed after first-line osimertinib treatment with EGFR C797S mutations). The activity of fourth-generation EGFR TKIs against resistance mutations such as T790M, C797X (X = S, G, N), and L792X (X = F, H, Y) can delay the development of resistance in NSCLC tumors via in-frame EGFR mutations. The characteristics outlined above define the fourth-generation EGFR TKI as the first EGFR TKI capable of effectively targeting NSCLC tumors carrying the EGFR del19 or L858R genotype and the EGFR del19 / L858RT790M C797X / L792X variant. Furthermore, the fourth-generation EGFR TKI will be the first C797S active compound that also inhibits the T790M positive pair gene, retains EGFR wild-type activity, and effectively penetrates the brain.

[0010] In recent years, selective targeting of mutant EGFR has gradually attracted attention. To date, several efforts have been made to identify and optimize inhibitors targeting the catalytic sites of EGFR mutants or ectopic sites of the EGFR protein, with regard to the properties mentioned above, but most have only yielded limited results. A benzimidazole compound with properties close to the desired characteristics is disclosed in WO2019 / 162323.

[0011] In addition, several EGFR inhibitors capable of overcoming EGFR resistance mutations have been disclosed, including the T790M and C797S mutations and combinations thereof (Zhang, 2017; Park, 2017; Chen, 2017; Bryan 2016; Juchum, 2017; Günther, 2017; WO 2017 / 004383). Most of the disclosed molecules are non-covalent variants of second-generation quinazoline-based EGFR inhibitors (Patel, 2017; Park, 2017; Chen, 2017). However, these disclosed molecules are weaker inhibitors with low selectivity for EGFR wt (Patel, 2017; Chen, 2017) or are designed to specifically bind only to the del19 / T790M / C797S mutant while being inactive against other EGFR variant combinations and mutations (Park, 2017). Other publicly disclosed compound classes have shown activity only against T790M and T790M / C797S resistance mutations in an L858R activation background (Bryan 2016; Juchum, 2017; Günther, 2017). However, these mutations and mutation combinations are unlikely to meet the criteria for developing effective EGFR inhibitors, given that they are observed only in small patient populations and the potentially high complexity of the paired genes in metastatic tumors.

[0012] The following background literature discloses non-covalent compounds that are active against EGFR carrying T790M as mutant selective EGFR inhibitors: WO 2014 / 210354; WO 2014 / 081718; Heald, 2015; Hanan, 2014; Lelais, 2016; Chan, 2016.

[0013] While the compounds mentioned in the literature claim activity against the two most common EGFR activating / resistance mutation combinations, del19 / T790M and L858 / T790M, most show only weak activity against the more prevalent del19 / T790M mutation and no affinity for EGFR carrying only the primary activating mutations del19 and L858R. This selective inhibition of activity against single activating mutations in dual-mutant EGFR is highly unfavorable due to the heterogeneity of EGFR mutations in patients and may lead to limited efficacy. Furthermore, most compounds show only low selectivity for EGFR wt, a known major contributor to common side effects (diarrhea, rash) of EGFR-targeted therapy, leading to target-specific toxicity. This specific cytotoxic component is undesirable as it may cause adverse events in treated patients.

[0014] The following background literature discloses aminobenzimidazole-based compounds as selective EGFR inhibitors, exhibiting activity against two oncogenic driver mutations, L858R and del19, and activity against the T790M resistance mutation, as well as combinations thereof: WO 2013 / 184757; WO 2013 / 184766, WO 2015 / 143148, WO 2015 / 143161, WO 2016 / 185333; Lelais, 2016; Jia, 2016.

[0015] In summary, the compound (I) according to the invention exhibits broad activity against EGFR del19 or EGFR L858R variants with or without T790M and / or C797S mutations, ensuring that the compound can effectively address the anticipated dual gene complexity of patient tumors as a single therapeutic agent. To facilitate effective administration and reduce EGFR-mediated on-target toxicity, the compound of the invention has reduced inhibitory potential against wild-type EGFR. Compound (I) exhibits high selectivity for the human kinase community, reducing off-target toxicity. Another characteristic of the compound (I) according to the invention is its potential to penetrate the brain (blood-brain barrier penetration) for the prevention and / or treatment of brain metastases and meningeal diseases. In addition to its inhibitory effects and potency, the compounds disclosed herein exhibit good solubility and DMPK properties suitable for use in the biological environment.

[0016] References

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[0049] Thress, KS et al. (2015). Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFRT790M. Nat. Med. 21, 560-562.

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[0051] Yu, HA et al. (2015). Acquired Resistance of EGFR-Mutant Lung Cancer toaT790M-Specific EGFR Inhibitor: Emergence of a Third Mutation(C797S) in theEGFRTyrosine Kinase Domain. JAMA Oncol. 1, 982-984.

[0052] Zhang, Y. et al.; Quinazoline-1-deoxynojirimycin hybrids as high activedual inhibitors of EGFR and α-glucosidase. Bioorg. Med. Chem. Lett. 2017, 27, 4309-4313.

[0053] Zhou, C. et al. (2011). 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, randomised, phase3 study. Lancet Oncol. 12, 735-742. Summary of the Invention

[0054] compound

[0055] It has now been unexpectedly discovered that the group R... 1 To R 4 and X 1 To X 5 Compounds of formula (I), having the meaning given below, are used as inhibitors of mutant EGFR involved in controlling cell proliferation. Therefore, the compounds of the present invention can be used, for example, to treat diseases characterized by excessive or abnormal cell proliferation.

[0056] Therefore, the present invention relates to a compound of formula (I).

[0057]

[0058] in

[0059] [A0]

[0060] R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic oxy and 3- to 6-membered heterocyclic groups;

[0061] R 2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic oxygen and 3- to 6-membered heterocyclic groups; or

[0062] R 1 and R 2 Together with the carbon atoms they are attached to, they form 5- to 6-membered heterocycles or 5- to 6-membered heteroaromatic rings;

[0063] [B0]

[0064] R 3 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic oxy and 3- to 6-membered heterocyclic groups;

[0065] [C0]

[0066] R 4 Selected from R a1 and R b1 ;

[0067] R a1 Selected from hydrogen, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b1 and / or R c1 replace;

[0068] Each R b1 Independently selected from -OR c1 -N(R) c1 )R c1 Halogens, -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)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 and divalent substituent = O;

[0069] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d1 and / or R e1 replace;

[0070] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 Halogens, -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)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 and divalent substituent = O;

[0071] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0072] [D0]

[0073] X 1 Selected from carbon (C) and nitrogen (N);

[0074] X 2 Selected from carbon (C) and nitrogen (N);

[0075] X 1 and X 2 At least one of them is carbon (C);

[0076] X 3 Selected from 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);

[0077] X 4 Selected from 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);

[0078] X 5 Selected from 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);

[0079] Each bond between members of ring A is independently selected from single bonds, double bonds, or (mixed) aromatic bonds;

[0080] Each R 5 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-4 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0081] Each R 6 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0082] Each R 7 Independently selected from R a2 and R b2 ;

[0083] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0084] Each R b2 Independently selected from -ORc2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0085] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d2 and / or R e2 replace;

[0086] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0087] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0088] Each R 8 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0089] Each R 9 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0090] Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0091] Or its salt.

[0092] The following structural aspects represent preferred embodiments [A1] to [A9], [B1] to [B4], [C1] to [C16], and [D1] to [D9] for the corresponding structural aspects [A0], [B0], [C0], and [D0], respectively:

[0093] In one aspect [A1], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0094] R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic oxy and 3- to 6-membered heterocyclic groups;

[0095] R 2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic oxy and 3- to 6-membered heterocyclic groups.

[0096] In another aspect [A2], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0097] R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic oxy and 3- to 6-membered heterocyclic groups;

[0098] R 2 It is hydrogen.

[0099] In another aspect [A3], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0100] R 1 Selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0101] R 2 It is hydrogen.

[0102] In another aspect [A4], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0103] R 1 Selected from methoxy, isopropoxy, -OH, cyclopropyl, and cyclopropoxy;

[0104] R 2It is hydrogen.

[0105] In another aspect [A5], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0106] R 1 Selected from C 1-4 Alkyl groups and -OH groups;

[0107] R 2 It is hydrogen.

[0108] In another aspect [A6], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0109] R 1 It is a methoxy group;

[0110] R 2 It is hydrogen.

[0111] In another aspect [A7], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0112] R 1 It is -OH;

[0113] R 2 It is hydrogen.

[0114] In another aspect [A8], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0115] R 1 and R 2 Together with the carbon atoms they are attached to, they form 5- to 6-membered heterocycles or 5- to 6-membered heteroaromatic rings.

[0116] In another aspect [A9], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0117] R 1 and R 2 Together with the carbon atom it is attached to, it forms a ring selected from pyrrole, 2,3-dihydrofuran, and furan.

[0118] In another aspect [B1], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0119] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and halogens.

[0120] In another aspect [B2], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0121] R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and halogens.

[0122] In another aspect [B3], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0123] R 3 C 1-4 alkyl.

[0124] In another aspect [B4], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0125] R 3 It is a methyl group.

[0126] In another aspect [C1], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0127] R 4 Selected from R a1 and R b1 ;

[0128] R a1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b1 and / or R c1 replace;

[0129] Each R b1 Independently selected from -OR c1 -N(R) c1 )R c1 Halogens, -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)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 and divalent substituent = O;

[0130] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d1 and / or R e1 replace;

[0131] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 Halogens, -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 )Re1 -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)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 and divalent substituent = O;

[0132] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O.

[0133] In another aspect [C2], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0134] R 4 Selected from R a1 and R b1 ;

[0135] R a1Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b1 and / or R c1 replace;

[0136] Each R b1 Independently selected from -OR c1 -N(R) c1 )R c1 Halogens, -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)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 and divalent substituent = O;

[0137] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl 5- to 10-membered heteroaryl groups, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl groups ranging from 5 to 10 ppm and heteroaryl groups are selected from one or more identical or different R groups. d1 and / or R e1 replace;

[0138] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1Halogens, -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)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 and divalent substituent = O;

[0139] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O.

[0140] In another aspect [C3], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0141] R 4 Selected from R a1 and R b1 ;

[0142] R a1 Selected from C 1-6 Alkyl, C3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. b1 and / or R c1 replace;

[0143] Each R b1 Independently selected from -OR c1 -N(R) c1 )R c1 Halogen and the divalent substituent = O;

[0144] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0145] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 Halogen and the divalent substituent = O;

[0146] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups are all optionally substituted by one or more substituents selected from halogens and divalent substituents = O.

[0147] In another aspect [C4], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0148] R 4 Selected from R a1 and R b1 ;

[0149] R a1 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. b1 and / or R c1 replace;

[0150] Each R b1 Independently selected from -OR c1 -N(R) c1 )R c1 and halogens;

[0151] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclic and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 11-membered heterocyclic groups, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0152] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 and halogens;

[0153] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups may be optionally substituted with one or more of the same or different halogens.

[0154] In another aspect [C5], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0155] R 4 For R a1 ;

[0156] R a1 For optional one or more identical or different R b1 and / or R c1 Substituted 3- to 11-membered heterocyclic groups;

[0157] Each R b1 Independently selected from -OR c1-N(R) c1 )R c1 and halogens;

[0158] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclic and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 11-membered heterocyclic groups, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0159] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 and halogens;

[0160] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups may be optionally substituted with one or more of the same or different halogens.

[0161] In another aspect [C6], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0162] R 4 For R a1 ;

[0163] R a1 Selected from

[0164] and

[0165] Among them, each R a1 Optional via one or more identical or different R b1 and / or Rc 1 replace;

[0166] Each R b1 Independently selected from -OR c1 -N(R) c1 )R c1 and halogens;

[0167] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6Haloalkyl, 3- to 11-membered heterocyclic and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 11-membered heterocyclic groups, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0168] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 and halogens;

[0169] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups may be optionally substituted with one or more of the same or different halogens.

[0170] In another aspect [C7], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0171] R 4 For R a1 ;

[0172] R a1 Selected from

[0173] and

[0174] Among them, each R a1 Optional via one or more identical or different R b1 and / or R c1 replace;

[0175] Each R b1 Independently selected from -OR c1 and halogens;

[0176] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 All haloalkyl groups and 5- to 6-membered heteroaryl groups are optionally annealed via one or more identical or different R groups. d1 and / or R e1 replace;

[0177] Each R d1 Independently selected from -ORe1 and halogens;

[0178] Each R e1 Independently selected from hydrogen and C 1-6 alkyl.

[0179] In another aspect [C8], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0180] R 4 Selected from

[0181] and

[0182] In another aspect [C9], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0183] R 4 Selected from -NH2, -NH(C 1-4 alkyl) and -N(C) 1-4 Alkyl)2.

[0184] In another aspect [C10], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0185] R 4 -N(C) 1-4 Alkyl)2.

[0186] In another aspect [C11], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0187] R 4 For -OR c1 ;

[0188] R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclic and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 11-membered heterocyclic groups, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0189] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 and halogens;

[0190] Each R e1 Independently selected from hydrogen and C 1-6Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups may be optionally substituted with one or more of the same or different halogens.

[0191] In another aspect [C12], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0192] R 4 For -OR c1 ;

[0193] R c1 Selected independently from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 All haloalkyl groups and 3- to 11-membered heterocyclic groups are optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0194] Each R d1 It is a halogen;

[0195] Each R e1 Selected independently from C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups may be optionally substituted with one or more of the same or different halogens.

[0196] In another aspect [C13], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0197] R 4 Selected from

[0198] and

[0199] In another aspect [C14], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0200] R 4 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. b1 and / or R c1 replace;

[0201] Each R b1 Independently selected from -OR c1 -N(R) c1 )R c1 and halogens;

[0202] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 11-membered heterocyclic and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 11-membered heterocyclic groups, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0203] Each R d1 Independently selected from -OR e1 -N(R) e1 )R e1 and halogens;

[0204] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups may be optionally substituted with one or more of the same or different halogens.

[0205] In another aspect [C15], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0206] R 4 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. b1 and / or R c1 replace;

[0207] Each R b1 Independently selected from -OR c1 and halogens;

[0208] Each R c1 Independently selected from hydrogen and C 1-6 alkyl.

[0209] In another aspect [C16], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0210] R 4 Selected from

[0211] and

[0212] In another aspect [D1], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0213]

[0214] Selected from

[0215]

[0216]

[0217] Each R 5 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-4 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0218] Each R 6 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0219] Each R 7 Independently selected from R a2 and R b2 ;

[0220] Each R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0221] Each R b2 Independently selected from -OR c2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0222] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d2 and / or R e2 replace;

[0223] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0224] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0225] Each R 8 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0226] Each R 9 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0227] Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0228] In another aspect [D2], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0229] for

[0230] R 7 Selected from R a2 and R b2 ;

[0231] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0232] Each R b2 Independently selected from -OR c2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0233] Each Rc2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d2 and / or R e2 replace;

[0234] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0235] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0236] R 10 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0237] In another aspect [D3], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0238] for

[0239] R 7 Selected from R a2 and R b2 ;

[0240] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0241] Each R b2 Independently selected from -OR c2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0242] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d2 and / or R e2 replace;

[0243] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0244] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O.

[0245] In another aspect [D4], the present invention relates to a compound of formula (I) or a salt thereof, wherein

[0246] for

[0247] R 5 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-4 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0248] R 7 Selected from R a2 and R b2 ;

[0249] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0250] Each R b2 Independently selected from -OR c2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0251] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups.d2 and / or R e2 replace;

[0252] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0253] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0254] R 9 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0255] In another aspect [D5], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0256] for

[0257] R 5 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-4 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0258] R 7 Selected from R a2 and R b2 ;

[0259] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0260] Each R b2 Independently selected from -OR c2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0261] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d2 and / or R e2 replace;

[0262] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0263] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0264] R 10 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0265] In another aspect [D6], the present invention relates to a compound of formula (I) or a salt thereof, wherein

[0266] for

[0267] R 6 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0268] R 7 Selected from R a2 and R b2 ;

[0269] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0270] Each R b2 Independently selected from -OR c2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0271] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d2 and / or R e2 replace;

[0272] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0273] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 11-membered heterocyclic groups, C 6-10All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0274] R 9 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0275] In another aspect [D7], the present invention relates to a compound of formula (I) or a salt thereof, wherein

[0276] for

[0277] R 6 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0278] R 10 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0279] In another aspect [D8], the present invention relates to a compound of formula (I) or a salt thereof, wherein

[0280] for

[0281] R 5 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-4 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0282] R 10 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0283] In another aspect [D9], the present invention relates to a compound of formula (I) or a salt thereof, wherein...

[0284] for

[0285] R 6 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0286] R 9 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, halogen, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0287] The following aspects [E1] to [E3] are aspects [D0], [D1], [D4], [D5] and [D8] concerning residue R. 5 Sub-aspects:

[0288] In one sub-aspect [E1], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D4], [D5] and [D8], or a salt thereof, wherein

[0289] Each R 5 Independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups.

[0290] In another sub-aspect [E2], the invention relates to a compound of formula (I) according to aspects [D0], [D1], [D4], [D5] and [D8], or a salt thereof, wherein

[0291] Each R 5 C 1-4 alkyl.

[0292] In another sub-aspect [E3], the invention relates to a compound of formula (I) according to aspects [D0], [D1], [D4], [D5] and [D8], or a salt thereof, wherein

[0293] Each R 5 It is a methyl group.

[0294] The following aspects [F1] to [F3] are about residues R in aspects [D0], [D1], [D6], [D7] and [D9]. 6 Sub-aspects:

[0295] In one sub-aspect [F1], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D6], [D7] and [D9], or a salt thereof, wherein

[0296] Each R 6 Independently selected from hydrogen and C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0297] In another sub-aspect [F2], the invention relates to a compound of formula (I) according to aspects [D0], [D1], [D6], [D7] and [D9], or a salt thereof, wherein

[0298] Each R 6 C 1-4 alkyl.

[0299] In another sub-aspect [F3], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D6], [D7] and [D9], or a salt thereof, wherein

[0300] Each R 6 It is a methyl group.

[0301] The following aspects [G1] to [G2] are aspects [D0] and [D1] concerning residue R. 8 Sub-aspects:

[0302] In one sub-aspect [G1], the present invention relates to a compound of formula (I) according to aspects [D0] and [D1], or a salt thereof, wherein...

[0303] Each R 8 C 1-4 alkyl.

[0304] In another sub-aspect [G2], the present invention relates to a compound of formula (I) according to aspects [D0] and [D1], or a salt thereof, wherein...

[0305] Each R 8 It is a methyl group.

[0306] The following aspects [H1] to [H3] are about residues R in aspects [D0], [D1], [D4], [D6] and [D9]. 9 Sub-aspects:

[0307] In one sub-aspect [H1], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D4], [D6] and [D9], or a salt thereof, wherein

[0308] Each R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl groups.

[0309] In another sub-aspect [H2], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D4], [D6] and [D9], or a salt thereof, wherein

[0310] Each R 9 C 1-4 alkyl.

[0311] In another sub-aspect [H3], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D4], [D6] and [D9], or a salt thereof, wherein

[0312] Each R 9 It is a methyl group.

[0313] The following aspects [I1] to [I3] are aspects [D0], [D1], [D2], [D5], [D7] and [D8] concerning residue R. 10 Sub-aspects:

[0314] In one sub-aspect [I1], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D5], [D7] and [D8], or a salt thereof, wherein

[0315] Each R 10 Independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclic groups.

[0316] In another sub-aspect [I2], the invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D5], [D7] and [D8], or a salt thereof, wherein

[0317] Each R 10 C 1-4 alkyl.

[0318] In another sub-aspect [I3], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D5], [D7] and [D8], or a salt thereof, wherein

[0319] Each R 10 It is independently selected from methyl, ethyl and isopropyl.

[0320] The following aspects [J1] to [J9] are about residues R in aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6]. 7 Sub-aspects:

[0321] In one sub-aspect [J1], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0322] Each R 7 Independently selected from R a2 and R b2 ;

[0323] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0324] Each R b2 Independently selected from -OR c2 -N(R) c2 )R c2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0325] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10Allyl groups and 5- to 10-membered heteroaryl groups are selected from one or more identical or different R groups. d2 and / or R e2 replace;

[0326] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogens, -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)2R c2 -N(C 1-4 Alkyl)S(=O)2R c2 and divalent substituent = O;

[0327] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 All aryl and 5- to 10-membered heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O.

[0328] In another sub-aspect [J2], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0329] Each R 7 Independently selected from R a2 and R b2 ;

[0330] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. b2 and / or R c2 replace;

[0331] Each R b2 Independently selected from -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 -C(=O)N(C 1-4 Alkyl)OR c2 and divalent substituent = O;

[0332] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups are all optionally derived from one or more identical or different R groups. d2 and / or R e2 replace;

[0333] Each R d2 Independently selected from -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 divalent substituent = O;

[0334] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, 3- to 11-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl groups are all optionally substituted by one or more substituents selected from halogens and divalent substituents = O.

[0335] In another sub-aspect [J3], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0336] Each R 7 Independently selected from R a2 and R b2 ;

[0337] R a2 Selected from hydrogen, C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. b2 and / or R c2 replace;

[0338] Each R b2 Independently selected from -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 ;

[0339] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. d2 and / or R e2 replace;

[0340] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogen, -C(=O)R e2 -C(=O)OR e2 and divalent substituent = O;

[0341] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 The alkyl group and the 3- to 11-membered heterocyclic group are all optionally substituted with one or more of the same or different halogens.

[0342] In another sub-aspect [J3a], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0343] Each R 7 Independently selected from R a2 and R b2 ;

[0344] R a2 Selected from hydrogen, C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. b2 and / or R c2 replace;

[0345] Each R b2 Independently selected from -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 ;

[0346] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups are optionally derived from one or more identical or different R groups. d2 and / or R e2 replace;

[0347] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogen, -C(=O)R e2 -C(=O)OR e2 and divalent substituent = O;

[0348] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups may be optionally substituted with one or more of the same or different halogens.

[0349] In another sub-aspect [J4], the invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0350] Each R 7 Independently selected from R a2 and R b2 ;

[0351] R a2 Selected from hydrogen, C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. b2 and / or R c2 replace;

[0352] Each R b2 Independently selected from -N(R) c2 )R c2 Halogen, -C(=O)R c2 and -C(=O)ORc2 ;

[0353] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. d2 and / or R e2 replace;

[0354] Each R d2 Independently selected from -OR e2 and -C(=O)OR e2 ;

[0355] Each R e2 Independently selected from hydrogen and C 1-6 alkyl.

[0356] In another sub-aspect [J4a], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0357] Each R 7 Independently selected from R a2 and R b2 ;

[0358] R a2 Selected from hydrogen, C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. b2 and / or R c2 replace;

[0359] Each R b2 Independently selected from -N(R) c2 )R c2 Halogen, -C(=O)R c2 and -C(=O)OR c2 ;

[0360] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3- to 11-membered heterocyclic groups are optionally derived from one or more identical or different R groups. d2 and / or R e2 replace;

[0361] Each R d2 Independently selected from -ORe2 and -C(=O)OR e2 ;

[0362] Each R e2 Independently selected from hydrogen and C 3-10 cycloalkyl and C 1-6 alkyl.

[0363] In another sub-aspect [J5], the invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0364] Each R 7 For R a2 ;

[0365] R a2 For optional one or more identical or different R b2 and / or R c2 Substituted 3- to 11-membered heterocyclic groups;

[0366] Each R b2 Independently selected from halogens, -C(=O)R c2 and -C(=O)OR c2 ;

[0367] Each R c2 For optional one or more identical or different R d2 and / or R e2 Replacement C 1-6 alkyl;

[0368] Each R d2 Independently selected from -OR e2 and -C(=O)OR e2 ;

[0369] Each R e2 Independently selected from hydrogen and C 1-6 alkyl.

[0370] In another sub-aspect [J6], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0371] Each R 7 Independently selected from hydrogen and C 1-4 alkyl,

[0372]

[0373] and

[0374] In another sub-aspect [J6a], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0375] Each R 7 Independently selected from hydrogen and C 1-4 alkyl,

[0376]

[0377]

[0378] and

[0379] In another sub-aspect [J6b], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0380] Each R 7 Selected independently

[0381]

[0382]

[0383]

[0384] In another sub-aspect [J7], the invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0385] Each R 7 For R b2 ;

[0386] Each R b2 Independently selected from -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 ;

[0387] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups.d2 and / or R e2 replace;

[0388] Each R d2 Independently selected from -OR e2 -N(R) e2 )R e2 Halogen, -C(=O)R e2 -C(=O)OR e2 and divalent substituent = O;

[0389] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 The alkyl group and the 3- to 11-membered heterocyclic group are all optionally substituted with one or more of the same or different halogens.

[0390] In another sub-aspect [J8], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0391] Each R 7 For R b2 ;

[0392] Each R b2 Independently selected from -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 ;

[0393] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups are all optionally derived from one or more identical or different R groups. d2 and / or R e2 replace;

[0394] Each R d2 Independently selected from -OR e2 Halogen, -C(=O)R e2 and divalent substituent = O;

[0395] Each R e2 Independently selected from hydrogen and C 1-6 Alkyl groups and 3- to 11-membered heterocyclic groups.

[0396] In another sub-aspect [J9], the present invention relates to a compound of formula (I) according to aspects [D0], [D1], [D2], [D3], [D4], [D5] and [D6], or a salt thereof, wherein

[0397] Each R 7 Selected independently

[0398]

[0399]

[0400] In another aspect [L1], the present invention relates to a compound of formula (I) or a salt thereof according to a combination of aspect [D2] and aspect [A5] or [A6].

[0401] In another aspect [L2], the present invention relates to a compound of formula (I) according to aspect [D2] or according to aspect [L1], wherein each aspect is combined with aspect [B3] or [B4].

[0402] In another aspect [L3], the present invention relates to a compound of formula (I) or a salt thereof according to aspect [D2] or according to aspect [L1] or [L2], each aspect being combined with aspect [I2] or [I3].

[0403] In another aspect [L4], the present invention relates to a compound of formula (I) according to aspect [D2] or any of [L1] to [L3], or a salt thereof, each aspect being combined with any of aspects [C5] to [C8].

[0404] In another aspect [L5], the present invention relates to a compound of formula (I) according to aspect [D2] or any of [L1] to [L4], or a salt thereof, each aspect being combined with any of aspects [J1] to [J7], [J3a], [J4a], [J6a] and [J6b].

[0405] In another aspect [L6], the invention relates to a compound of formula (I) or a salt thereof according to any one of aspects [D2] or [L1] to [L5], each aspect relating to R 4 It is a 3- to 11-membered heterocyclic group or R 4 It is a 7-membered heterocyclic group combination.

[0406] It should be understood that all sub-aspects [E1] to [E3] (regarding residue R) 5 [F1] to [F3] (regarding residue R) 6 [G1] and [G2] (regarding residue R) 8 [H1] to [H3] (regarding residue R) 9[I1] to [I3] (regarding residue R) 10 ) and [J1] to [J9] (regarding residue R) 7 Additional aspects [D] may be formed by combining aspects [D0] to [D9] as appropriate, and all of them will be included.

[0407] All the structural aspects [A1] to [A9], [B1] to [B4], [C1] to [C16] and [D1] to [D9] mentioned above (including, where appropriate, additional aspects based on combinations of [D1] to [D9] and sub-aspects [E1] to [E3], [F1] to [F3], [G1] and [G2], [H1] to [H3], [I1] to [I3] and [J1] to [J9] as described above) are preferred embodiments of the corresponding structural aspects [A0], [B0], [C0] and [D0]. The structural aspects [A0] to [A9], [B0] to [B4], [C0] to [C16] and [D0] to [D9] (including additional aspects [D] as described above) associated with different molecular portions of the compound (I) according to the invention may be combined with each other in combinations [A][B][C][D] as needed to obtain the preferred compound (I). Each of these combinations [A][B][C][D] represents and defines a separate embodiment or a general subset of the compound (I) according to the invention.

[0408] The preferred embodiments of the present invention having structure (I) are compounds I-1 to I-225 and any subset thereof.

[0409] All synthetic intermediates and their salts, as generally defined and specifically disclosed herein, are also part of this invention.

[0410] All individual synthetic reaction steps, as generally defined or specifically disclosed herein, and the reaction sequence comprising these individual synthetic reaction steps, are also part of this invention.

[0411] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of compounds of formula (I) (including all individual embodiments and common subsets disclosed herein).

[0412] The present invention further relates to a hydrate of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein).

[0413] The present invention further relates to a solvate of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein).

[0414] For example, compounds of formula (I) with an ester group (including all individual embodiments and general subsets disclosed herein) are possible prodrugs that cleave under physiological conditions and are also part of this invention.

[0415] The present invention further relates to a pharmaceutically acceptable salt of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein).

[0416] The present invention further relates to a pharmaceutically acceptable salt of a compound of formula (I) and a non-organic or organic acid or base (including all individual embodiments and general subsets disclosed herein).

[0417] Pharmaceutical Composition

[0418] Suitable pharmaceutical compositions for administering compounds of formula (I) according to the invention will be apparent to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar-coated tablets, solutions (especially for injection (subcutaneous, intravenous, intramuscular) and infusion (injectable)), elixirs, syrups, capsules, emulsions, inhalers, or dispersible powders. The content of compound (I) should be in the range of 0.1 to 90 wt%, preferably 0.5 to 50 wt%, of the total composition, i.e., an amount sufficient to achieve the specified dosage range below. Where necessary, the specified dosage may be administered several times a day, for example, twice daily.

[0419] 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. Tablets may also comprise several layers.

[0420] Therefore, coated tablets can be prepared by coating a core produced in a tablet-like manner with excipients commonly used for tablet coating (such as collidone, shellac, gum arabic, talc, titanium dioxide, or sugar). To achieve delayed release or prevent incompatibility, the core may also consist of multiple layers. Similarly, tablet coatings can consist of multiple layers to achieve delayed release, possibly using the excipients mentioned above regarding tablets.

[0421] Syrups or elixirs containing one or more compounds (I) or in combination with one or more other pharmaceutically active substances may additionally contain excipients, such as sweeteners, such as saccharin, cyclohexylamine sulfonate, glycerol, or sugar; and flavoring agents, such as flavoring agents, such as vanilla extract or orange extract. They may also contain excipients, such as suspending adjuvants or thickeners, such as sodium carboxymethyl cellulose; humectants, such as condensation products of fatty alcohols and ethylene oxide; or preservatives, such as parabens.

[0422] The solutions for injection and infusion are prepared in a conventional manner, for example, by adding excipients such as isotonic reagents, preservatives such as parabens or stabilizers such as alkali metal salts such as ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, and if water is used as a diluent, then organic solvents may optionally be used as solubilizing agents or dissolving aids, and are transferred to injection vials or ampoules or infusion bottles.

[0423] Capsules containing one or more compounds (I) or combinations thereof with one or more other pharmaceutically active substances can be prepared, for example, by mixing the compound / active substance with an inert excipient such as lactose or sorbitol and filling it into a gelatin capsule.

[0424] Suitable suppositories can be prepared, for example, by mixing with excipients provided for this purpose, such as neutral fats or polyethylene glycol or their derivatives.

[0425] Excipients that may 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), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol); carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersible silicates and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, waste sulfurous liquid, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0426] The pharmaceutical composition is administered by conventional methods, preferably orally or dermally, with oral administration being the most preferred route. For oral administration, the tablets may contain, in addition to the excipients mentioned above, additional excipients such as sodium citrate, calcium carbonate, and calcium hydrogen phosphate, as well as various excipients such as starch (preferably potato starch), gelatin, and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used simultaneously in the tableting process. In the case of an aqueous suspension, the active ingredient may be combined with various flavoring or coloring agents other than those mentioned above.

[0427] For non-enteric use, a solution of the active substance with a suitable liquid excipient can be used.

[0428] The daily dose range of the compound of formula (I) is typically from 1 mg to 2000 mg, preferably from 250 mg to 2000 mg.

[0429] However, depending on weight, age, route of administration, severity of disease, individual response to the drug, the nature of its formulation, and the time or interval between administrations (continuous or intermittent treatment with one or more doses daily), deviations from the prescribed dosage may sometimes be necessary. Therefore, in some cases, using a dose smaller than the minimum given above may be sufficient, while in others it may be necessary to exceed the upper limit. When administering a larger dose, it may be advisable to divide it into several smaller doses throughout the day.

[0430] Therefore, in another 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.

[0431] Compounds of formula (I) or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing such compounds and salts, may also be used in combination with other pharmacologically active substances, such as other anti-proliferative compounds (e.g., chemotherapy) (see further combination therapy below).

[0432] The elements of such combinations can be administered by methods conventional to those skilled in the art and as they are used in monotherapy (whether dependently or independently), for example by oral, enteral, non-enteric (e.g., intramuscular, intraperitoneal, intravenous, percutaneous or subcutaneous injection or implantation), nasal, vaginal, rectal or local administration routes, and can be formulated alone or together in suitable dosage units containing conventional, non-toxic, pharmaceutically acceptable excipients suitable for each route of administration.

[0433] A combination of therapeutically effective single or fractionated daily doses can be administered. Such doses, which are therapeutically effective in monotherapy or at doses lower than those used in monotherapy, can be administered to produce the desired (combined) therapeutically effective amount when combined.

[0434] However, when the combined use of two or more active substances or ingredients produces a synergistic effect, the amount of one, more, or all of the substances or ingredients to be administered can be reduced while still achieving the desired therapeutic effect. This can, for example, be applied to avoid, limit, or reduce any unwanted side effects associated with the use of one or more of the substances or ingredients when used at their usual amounts, while still obtaining the desired pharmacological or therapeutic effect.

[0435] Therefore, in another aspect, the present invention also relates to a pharmaceutical composition 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.

[0436] In another aspect, the present invention also relates to a pharmaceutical formulation 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.

[0437] Pharmaceutical compositions intended for co-administration or combination use may also be provided in kit form.

[0438] Therefore, in another aspect, the present invention also relates to a kit comprising:

[0439] • A first pharmaceutical composition or dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and common subsets disclosed herein) and optionally one or more pharmaceutically acceptable excipients, and

[0440] • A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0441] In one aspect, such a kit comprises a third pharmaceutical composition or dosage form containing another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0442] Medical Uses - Treatment Methods

[0443] Indications - patient population

[0444] This invention is primarily aimed at EGFR inhibitors, particularly compounds of formula (I) (including all individual embodiments and general subsets disclosed herein), which are potentially applicable to the treatment and / or prevention of diseases and / or conditions associated with or regulated / mediated by mutant EGFR, especially wherein inhibition of mutant EGFR has therapeutic benefits, including but not limited to the treatment and / or prevention of cancer.

[0445] 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, which is used as a medicine.

[0446] 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 treating a human or animal body.

[0447] 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 the treatment and / or prevention of diseases and / or conditions mediated by mutant EGFR.

[0448] 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 for the manufacture of a medicament for the treatment and / or prevention of diseases and / or conditions mediated by mutant EGFR.

[0449] 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.

[0450] 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 the treatment and / or prevention of cancer.

[0451] 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, in a method of treating and / or preventing cancer in a human or animal body.

[0452] 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 for the manufacture of a medicament for treating and / or preventing cancer.

[0453] 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.

[0454] 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 providing inhibition of mutant EGFR.

[0455] 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 for the manufacture of a medicament for providing inhibition against mutant EGFR.

[0456] In another aspect, the present invention relates to a method for providing inhibition of 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.

[0457] On the other hand, this relates to identifying the association between a patient's EGFR mutation status and their potential sensitivity to treatment with compounds of formula (I), including all individual embodiments and the general subset disclosed herein. EGFR inhibitors, such as compounds of formula (I), including all individual embodiments and the general subset disclosed herein, can be advantageously used to treat patients with EGFR mutations who may be resistant to other therapies. Therefore, this provides opportunities, methods, and tools for selecting patients, particularly cancer patients, to be treated with compounds of formula (I), including all individual embodiments and the general subset disclosed herein. This selection is based on whether the tumor cells to be treated have a wild-type or mutant EGFR gene. Therefore, EGFR gene status can be used as a biomarker indicating potentially advantageous selection for treatment with compounds of formula (I), including all individual embodiments and the general subset disclosed herein.

[0458] According to one aspect, a method is provided for treating a patient with a compound of formula (I) (including all individual embodiments and a common subset disclosed herein), the method comprising:

[0459] • Provide a tumor cell sample from the patient, preferably a tumor DNA sample;

[0460] • Determine whether the EGFR gene in the patient's sample encodes wild-type or mutant EGFR protein; and

[0461] • Patients treated with compounds of formula (I) (including all individual embodiments and general subsets disclosed herein) based on the above selection.

[0462] The method may or may not include the actual patient sample separation step.

[0463] As used herein in disclosing and defining aspects of the invention, "mutant EGFR" refers to the mutant EGFR gene and / or the corresponding protein derived from said mutant EGFR gene, and includes, but is not limited to:

[0464] [K1]

[0465] • EGFR containing deletions in exon 19 (=del 19)

[0466] For example

[0467] -delE746_A750 (most common),

[0468] -delE746_S752insV,

[0469] -delL747_A750insP,

[0470] -delL747_P753insS,

[0471] -delS752_I759;

[0472] • EGFR containing the mutation L858R (=L858R) in exon 21;

[0473] • EGFR containing the mutation T790M (=T790M) in exon 20

[0474] ● EGFRs containing a mutation (=C797mut) at residue C797 in exon 20, for example

[0475] -C797S,

[0476] -C797G,

[0477] -C797N,

[0478] • EGFR containing a mutation (=L792mut) in exon 20, such as

[0479] -L792F,

[0480] -L792H,

[0481] -L792Y,

[0482] Or any mutant EGFR containing a combination of two or more mutations, such as del19 T790M

[0483] ·del19 C797mut

[0484] -del19 C797S

[0485] -del19 C797G

[0486] -del19 C797N

[0487] ·del19 T790M C797mut

[0488] -del19 T790M C797S

[0489] -del19 T790M C797G

[0490] -del19 T790M C797N

[0491] ·del19 L792mut

[0492] -del19 L792F

[0493] -del19 L792H

[0494] -del19 L792Y

[0495] ·del19 T790M L792mut

[0496] -del19 T790M L792F

[0497] -del19 T790M L792H

[0498] -del19 T790M L792Y

[0499] L858R T790M

[0500] ·L858R C797mut

[0501] -L858R C797S

[0502] -L858R C797G

[0503] -L858R C797N

[0504] ·L858R T790M C797mut

[0505] -L858R T790M C797S

[0506] -L858R T790M C797G

[0507] -L858R T790M C797N

[0508] ·L858R L792mut

[0509] -L858R L792F

[0510] -L858R L792H

[0511] -L858R L792Y

[0512] ·L858R T790M L792mut

[0513] -L858R T790M L792F

[0514] -L858R T790M L792H

[0515] -L858R T790M L792Y

[0516] Therefore, in one aspect of the invention [K2], the mutant EGFR contains a deletion (=del19) in exon 19.

[0517] In another aspect of the invention [K3], the mutant EGFR includes the mutation L858R (=L858R) in exon 21.

[0518] In another aspect of the invention [K4], the mutant EGFR contains the mutation T790M (=T790M) in exon 20.

[0519] In another aspect of the invention [K5], the mutant EGFR contains a mutation (=C797mut) in residue C797 of exon 20.

[0520] In another aspect of the invention [K6], the mutant EGFR contains the mutation C797S (=C797S) in exon 20.

[0521] In another aspect of the invention [K7], the mutant EGFR contains the mutation C797G (=C797G) in exon 20.

[0522] In another aspect of the invention [K8], the mutant EGFR contains the mutation C797N (=C797N) in exon 20.

[0523] In another aspect of the invention [K9], the mutant EGFR contains a mutation (=L792mut) in residue L792 in exon 20.

[0524] In another aspect of the invention [K10], the mutant EGFR contains the mutation L792F (=L792F) in exon 20.

[0525] In another aspect of the invention [K11], the mutant EGFR contains the mutation L792H (=L792H) in exon 20.

[0526] In another aspect of the invention [K12], the mutant EGFR contains the mutation L792Y (=L792Y) in exon 20.

[0527] In another aspect of the invention [K13], the mutant EGFR contains the mutation del19 T790M.

[0528] In another aspect of the invention [K14], the mutant EGFR contains the mutation del19 C797mut.

[0529] In another aspect of the invention [K15], the mutant EGFR contains the mutation del19 C797S.

[0530] In another aspect of the invention [K16], the mutant EGFR contains the mutation del19 C797G.

[0531] In another aspect of the invention [K17], the mutant EGFR contains the mutation del19 C797N.

[0532] In another aspect of the invention [K18], the mutant EGFR contains the mutation del19 T790M C797mut.

[0533] In another aspect of the invention [K19], the mutant EGFR contains the mutation del19 T790M C797S.

[0534] In another aspect of the invention [K20], the mutant EGFR contains the mutation del19 T790M C797G.

[0535] In another aspect of the invention [K21], the mutant EGFR contains the mutation del19 T790M C797N.

[0536] In another aspect of the invention [K22], the mutant EGFR contains the mutation del19 L792mut.

[0537] In another aspect of the invention [K23], the mutant EGFR includes the mutation del19 L792F.

[0538] In another aspect of the invention [K24], the mutant EGFR contains the mutation del19 L792H.

[0539] In another aspect of the invention [K25], the mutant EGFR includes the mutation del19 L792Y.

[0540] In another aspect of the invention [K26], the mutant EGFR contains the mutation del19 T790M L792mut.

[0541] In another aspect of the invention [K27], the mutant EGFR includes the mutation del19 T790M L792F.

[0542] In another aspect of the invention [K28], the mutant EGFR contains the mutation del19 T790M L792H.

[0543] In another aspect of the invention [K29], the mutant EGFR includes the mutation del19 T790M L792Y.

[0544] In another aspect of the invention [K30], the mutant EGFR includes EGFR L858R T790M.

[0545] In another aspect of the invention [K31], the mutant EGFR includes EGFR L858R C797mut.

[0546] In another aspect of the invention [K32], the mutant EGFR includes the mutation L858R C797S.

[0547] In another aspect of the invention [K33], the mutant EGFR includes the mutation L858R C797G.

[0548] In another aspect of the invention [K34], the mutant EGFR includes the mutation L858R C797N.

[0549] In another aspect of the invention [K35], the mutant EGFR contains the mutation L858R T790M C797mut.

[0550] In another aspect of the invention [K36], the mutant EGFR includes the mutation L858R T790M C797S.

[0551] In another aspect of the invention [K37], the mutant EGFR includes the mutation L858R T790M C797G.

[0552] In another aspect of the invention [K38], the mutant EGFR includes the mutation L858R T790M C797N.

[0553] In another aspect of the invention [K39], the mutant EGFR includes the mutation L858R L792mut.

[0554] In another aspect of the invention [K40], the mutant EGFR includes the mutations L858R and L792F.

[0555] In another aspect of the invention [K41], the mutant EGFR includes the mutations L858R and L792H.

[0556] In another aspect of the invention [K42], the mutant EGFR includes the mutations L858R and L792Y.

[0557] In another aspect of the invention [K43], the mutant EGFR includes the mutation L858R T790M L792mut.

[0558] In another aspect of the invention [K44], the mutant EGFR includes the mutations L858R T790M L792F.

[0559] In another aspect of the invention [K45], the mutant EGFR includes the mutations L858R T790M L792H.

[0560] In another aspect of the invention [K46], the mutant EGFR includes the mutations L858R T790M L792Y.

[0561] In one aspect, if the tumor cell DNA carries a mutant EGFR gene, the patient is selected for treatment with a compound of formula (I) (including all individual embodiments and a general subset disclosed herein), wherein the mutant EGFR gene is preferably selected from any one of [K1] to [K46].

[0562] In another aspect, a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) or a pharmaceutically acceptable salt thereof is provided for treating cancers with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene is preferably selected from any one of [K1] to [K46].

[0563] In another aspect, a method for treating cancer with tumor cells carrying a mutant EGFR gene is provided, 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 mutant EGFR gene is preferably selected from any one of [K1] to [K46].

[0564] 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 for the manufacture of a medicament for treating cancers having tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene is preferably selected from any one of [K1] to [K46].

[0565] Determining whether a tumor or cancer contains mutant EGFR can be done by assessing the nucleotide sequence encoding the EGFR protein at the DNA or RNA level, by assessing the amino acid sequence of the EGFR protein, or by assessing the characteristics of a probable EGFR mutant protein. The sequence of wild-type human EGFR is known in the art. Methods for detecting mutations in the EGFR nucleotide sequence 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) analysis, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis, real-time PCR analysis, PCR sequencing, mutation-pair gene-specific PCR amplification (MASA) analysis, digital droplet PCR, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide conjugation analysis, hybridization analysis, TaqMan assay, SNP genotyping analysis, high-resolution melting analysis, microarray analysis, and next-generation sequencing. In some embodiments, EGFR mutations in a sample are assessed by real-time PCR. In real-time PCR, fluorescent probes specific for EGFR mutations are used. When a mutation is present, the probe binds and fluorescence is detected. In some implementations, direct sequencing of a specific region in the EGFR gene is used to identify EGFR mutations. This technique identifies all possible mutations in the sequenced region. Methods for detecting mutations in the EGFR protein are known to those skilled in the art. These methods include, but are not limited to, detecting EGFR mutants using binding agents (e.g., antibodies) specific to the mutant protein, protein electrophoresis, Western blotting, and direct peptide sequencing.

[0566] Methods for determining whether a tumor or cancer contains EGFR mutations can utilize various sample types. In some embodiments, the sample is taken from an individual 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 section, and blood, urine, sputum, or other bodily fluid samples are tested to look for cancer cells from the tumor or DNA fragments from tumor cells within these samples.

[0567] In another aspect, the use of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) to treat / prevent or as disclosed herein in medical uses, applications, treatments and / or preventive methods for diseases / conditions / cancers selected from lung cancer, brain cancer, colorectal cancer, bladder cancer, urethral cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelioma, including metastases of all listed cancers (particularly brain metastases).

[0568] In another aspect, the treatment / prevention of a disease / condition / cancer as disclosed herein, using a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), is lung cancer. Preferably, the lung cancer to be treated is non-small cell lung cancer (NSCLC), including, for example, locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology. Most preferably, the lung cancer to be treated is NSCLC adenocarcinoma.

[0569] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains a deletion (=del19) in exon 19. Preferably, the cancer patient to be treated and suffering from this cancer is treated with a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as first-line treatment (in respect of EGFR TKI treatment), i.e., the patient is untreated with respect to EGFR TKI.

[0570] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutant del19 T790M. Preferably, the cancer patient to be treated and suffering from this cancer is treated as a second-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior 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).

[0571] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation del19 C797S. Preferably, the cancer patient to be treated and suffering from this cancer is given a compound of formula (I) (including all individual embodiments and the general subset disclosed herein) as second-line treatment (in terms of EGFR TKI treatment), i.e., the patient has progressed after prior treatment with a third-generation EGFR TKI (i.e., the patient has progressed after prior treatment with, for example, osimertinib, olmutinib, nazartinib, lazertinib, almortinib, or avitinib).

[0572] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation del19 C797mut (preferably C797G or C797N). Preferably, the cancer patient to be treated and suffering from this cancer is treated as a second-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior treatment with a third-generation EGFR TKI (i.e., the patient has progressed after prior treatment with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0573] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutant del19 T790M C797S. Preferably, the cancer patient to be treated and suffering from this cancer is treated as a third-line therapy (in terms of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior therapy with a first- or second-generation EGFR TKI following T790M acquisition (i.e., the patient has progressed after prior therapy with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib) and has progressed after additional therapy with a third-generation EGFR TKI following C797S acquisition (i.e., the patient has progressed after additional therapy with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0574] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation del19 T790M C797mut (preferably C797G or C797N). Preferably, the cancer patient seeking treatment and suffering from this cancer is treated as a third-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior therapy with a first or second-generation EGFR TKI following T790M acquisition (i.e., the patient has progressed after prior therapy with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib) and has progressed after additional therapy with a third-generation EGFR TKI following C797mut (preferably C797G or C797N) acquisition (i.e., the patient has progressed after additional therapy with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0575] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation del19 L792mut (preferably L792F, L792H, or L792Y). Preferably, the cancer patient to be treated and suffering from this cancer is treated as a second-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior treatment with a third-generation EGFR TKI (i.e., the patient has progressed after prior treatment with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0576] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation del19 T790M L792mut (preferably L792F, L792H or L792Y). Preferably, the cancer patient seeking treatment and suffering from this cancer is treated as a third-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior therapy with a first or second-generation EGFR TKI following T790M acquisition (i.e., the patient has progressed after prior therapy with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib) and has progressed after additional therapy with a third-generation EGFR TKI following L792mut (preferably L792F, L792H, or L792Y) acquisition (i.e., the patient has progressed after additional therapy with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0577] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains an L858R mutation. Preferably, the cancer patient to be treated and suffering from this cancer is treated with a compound of formula (I) (including all individual embodiments and general subsets disclosed herein) as first-line therapy (in respect of EGFR TKI therapy), i.e., the patient is untreated with respect to EGFR TKIs.

[0578] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation L858R T790M. Preferably, the cancer patient to be treated and suffering from this cancer is treated as a second-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior 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).

[0579] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation L858R C797S. Preferably, the cancer patient to be treated and suffering from this cancer is treated as a second-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior treatment with a third-generation EGFR TKI (i.e., the patient has progressed after treatment with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0580] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation L858R C797mut (preferably C797G or C797N). Preferably, the cancer patient to be treated and suffering from this cancer is treated as a second-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior treatment with a third-generation EGFR TKI (i.e., the patient has progressed after prior treatment with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0581] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene comprises the mutant L858R T790M C797S. Preferably, the cancer patient to be treated and suffering from this cancer is treated as a third-line therapy (in terms of EGFR TKI therapy) with a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior therapy with a first- or second-generation EGFR TKI following T790M acquisition (i.e., the patient has progressed after prior therapy with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib) and has progressed after additional therapy with a third-generation EGFR TKI following C797S acquisition (i.e., the patient has progressed after additional therapy with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0582] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation L858R T790M C797mut (preferably C797G or C797N). Preferably, the cancer patient seeking treatment and suffering from this cancer is treated as a third-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior therapy with a first or second-generation EGFR TKI following T790M acquisition (i.e., the patient has progressed after prior therapy with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib) and has progressed after additional therapy with a third-generation EGFR TKI following C797mut (preferably C797G or C797N) acquisition (i.e., the patient has progressed after additional therapy with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0583] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutation L858R L792mut (preferably L792F, L792H, or L792Y). Preferably, the cancer patient to be treated and suffering from this cancer is treated as a second-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior treatment with a third-generation EGFR TKI (i.e., the patient has progressed after prior treatment with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0584] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is a cancer with tumor cells carrying a mutant EGFR gene, wherein the mutant EGFR gene contains the mutant L858R T790M L792mut (preferably L792F, L792H or L792Y). Preferably, the cancer patient seeking treatment and suffering from this cancer is treated as a third-line therapy (in respect of EGFR TKI therapy) by administration of a compound of formula (I) (including all individual embodiments and general subsets disclosed herein), i.e., the patient has progressed after prior therapy with a first or second-generation EGFR TKI following T790M acquisition (i.e., the patient has progressed after prior therapy with gefitinib, erlotinib, icotinib, afatinib, or dacomitinib) and has progressed after additional therapy with a third-generation EGFR TKI following L792mut (preferably L792F, L792H, or L792Y) acquisition (i.e., the patient has progressed after additional therapy with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib).

[0585] In another aspect, the cancer to be treated (including all embodiments disclosed herein) is cancer that has progressed after prior treatment with a third-generation EGFR TKI (i.e., the cancer has progressed after prior treatment with, for example, osimertinib, omamotinib, nazatinib, lazatinib, ametinib, or avitinib). In one aspect, a cancer patient to be treated with this cancer is given a compound of formula (I) (including all individual embodiments and the general subset disclosed herein) as second-line treatment (in terms of EGFR TKI treatment). In another aspect, a cancer patient to be treated with this cancer is given a compound of formula (I) (including all individual embodiments and the general subset disclosed herein) as third-line treatment (in terms of EGFR TKI treatment). The preferred treatment in these cases is treatment following prior treatment with osimertinib.

[0586] The compounds of the present invention can be used for the prevention, short-term or long-term treatment of the diseases / conditions / cancers / tumors mentioned above, optionally in combination with radiotherapy and / or surgery.

[0587] The treatments, methods, uses, and compounds disclosed herein (above and below) may be used with any compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and common subsets disclosed herein) and with any pharmaceutical composition or kit containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and common subsets disclosed herein).

[0588] Combination therapy

[0589] Compounds of formula (I) or pharmaceutically acceptable salts thereof (including all individual embodiments and general subsets disclosed herein) and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other pharmacologically active substances, such as other anti-regenerative compounds (e.g., chemotherapy) or in combination with other treatments, such as radiation or surgical interventions (in the form of pre- or post-operative adjuvant therapy). Preferably, the pharmacologically active substance for co-administration is an anti-regenerative compound.

[0590] Therefore, in another aspect, the present invention relates to a compound of formula (I) as disclosed above or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), wherein the compound is administered before, after or together with one or more other pharmacologically active substances.

[0591] In another aspect, the present invention relates to a compound of formula (I) as disclosed above or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), wherein the compound is administered in combination with one or more other pharmacologically active substances.

[0592] In another aspect, the present invention relates to the use of a compound of formula (I) as disclosed above or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), wherein the compound is administered before, after or together with one or more other pharmacologically active substances.

[0593] In another aspect, the present invention relates to a method as disclosed above (e.g., a treatment and / or prevention method) 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.

[0594] In another aspect, the present invention relates to a method as disclosed above (e.g., a treatment and / or prevention method) 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.

[0595] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need a therapeutically effective amount of 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, in parallel, sequentially, continuously, alternately, or separately from one or more other pharmacologically active substances.

[0596] In another 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 the treatment and / or prevention of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, in parallel, sequentially, continuously, alternately or separately with one or more other pharmacologically active substances.

[0597] In another aspect, the present invention relates to a kit comprising...

[0598] • A first pharmaceutical composition or dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and common subsets disclosed herein) and optionally one or more pharmaceutically acceptable excipients, and

[0599] • A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients for the treatment and / or prevention of cancer, wherein the first pharmaceutical composition is administered simultaneously, concurrently, sequentially, continuously, alternately, or separately from the second and / or additional pharmaceutical compositions or dosage forms.

[0600] In one aspect, such a kit for this purpose comprises a third pharmaceutical composition or dosage form containing another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0601] In another embodiment of the invention, the combination, kit, use, method and components of the compound (i.e., combination) used according to the invention (including all embodiments) are administered simultaneously.

[0602] In another embodiment of the invention, the combinations, kits, uses, methods, and components of compounds (i.e., combination formulations) used according to the invention (including all embodiments) are administered in parallel.

[0603] In another embodiment of the invention, the combination, kit, use, method and components of the compound (i.e., combination) used according to the invention (including all embodiments) are applied sequentially.

[0604] In another embodiment of the invention, the combination, kit, use, method and components of the compound (i.e., combination) used according to the invention (including all embodiments) are administered continuously.

[0605] In another embodiment of the invention, the combinations, kits, uses, methods, and components of compounds (i.e., combination formulations) used according to the invention (including all embodiments) are applied alternately.

[0606] In another embodiment of the invention, the combinations, kits, uses, methods, and components of the compounds (i.e., combination formulations) used according to the invention (including all embodiments) are administered separately.

[0607] The pharmacologically active substance used together or in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments or a common subset of compound (I)) or used in the medical uses, applications, treatments and / or preventive methods disclosed herein (above and below) may be selected from any one or more of the following (preferably, one or two additional pharmacologically active substances are present for all of these embodiments):

[0608] 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutant thereof.

[0609] a. Irreversible inhibitors: such as afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, omamotinib, osimertinib, ametinib, nazatinib, lagetinib, pelitinib;

[0610] b. Reversible inhibitors: such as erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340;

[0611] c. Anti-EGFR antibodies: such as necitumumab, panitumumab, cetuximab

[0612] Monoclonal antibodies (cetuximab) and amivantanab;

[0613] d. Anti-HER2 antibodies: such as pertuzumab, trastuzumab, etc.

[0614] Trastuzumab emtansine;

[0615] e. Inhibitors of mutant EGFR;

[0616] f. Inhibitors of HER2 with exon 20 mutations;

[0617] g. Afatinib is the preferred irreversible inhibitor;

[0618] h. Cetuximab is the preferred anti-EGFR antibody;

[0619] 2. Inhibitors of MEK and / or its mutants

[0620] a. For example, trametinib, cobimetinib, binimetinib, and so on.

[0621] Selumetinib, Refametinib, BI 3011441;

[0622] b. Trametinib and BI 3011441 are preferred;

[0623] c. The optimal value is BI 3011441;

[0624] 3. Inhibitors of c-MET and / or its mutants

[0625] a. For example, savolitinib, cabozantinib, and foretinib;

[0626] b. MET antibodies, such as emibetuzumab and amivantanab;

[0627] 4. Inhibitors of SOS1 and / or any mutant thereof (i.e., compounds that regulate / inhibit the GEF function of SOS1 by binding to SOS1 and preventing protein-protein interactions between SOS1 and (mutant) Ras proteins, such as KRAS)

[0628] a. For example, BAY-293, BI-3406, BI 1701963;

[0629] b. The optimal value is BI 1701963;

[0630] 5. Inhibitors of GDP-loaded or GTP-loaded RAS and / or any mutant thereof (i.e., compounds that regulate / inhibit the function of (mutant) RAS proteins, for example, by binding to GDP-loaded or GTP-loaded (mutant) RAS proteins, such as KRAS, NRAS, and / or HRAS, preferably KRAS).

[0631] a. Irreversible inhibitors of KRAS G12C;

[0632] i. For example, AMG-510, MRTX849, ARS-324, GDC-6036;

[0633] b. Reversible or irreversible GDP-loaded (mutant) KRAS binders;

[0634] c. Reversible or irreversible GTP-loaded (mutant) KRAS binders;

[0635] 6. Immunotherapy agents

[0636] a. For example, immune checkpoint inhibitors

[0637] i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb

[0638] mAb, anti-TIM3 mAb;

[0639] ii. Preferably, it is resistant to PD1 mAb;

[0640] iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001

[0641] (=spartalizumab), AMG-404, ezabenlimab;

[0642] iv. Nivolumab, pembrolizumab, PDR-001 (=spartazumab) and ebbenlimumab are preferred;

[0643] v. The best options are pembrolizumab, nivolumab, and ebbenlimumab.

[0644] b. For example, immunomodulators

[0645] i. For example, CD73 inhibitors or CD73 inhibitory antibodies

[0646] 7. Inhibitors of ALK and / or any of its mutants

[0647] a. For example, crizotinib, alectinib, entrectinib, brigatinib, and ceritinib;

[0648] b. Crizotinib and alectinib are preferred;

[0649] c. Crizotinib is the best option;

[0650] 8. Taxane

[0651] a. For example, paclitaxel, albumin-bound paclitaxel, and docetaxel;

[0652] b. Pacific paclitaxel is preferred;

[0653] 9. Platinum-containing compounds

[0654] a. For example, cisplatin, carboplatin, and oxaliplatin.

[0655] b. Carboplatin is preferred;

[0656] 10. Antimetabolites

[0657] a. For example, combinations of 5-fluorouracil, capecitabine, fluorouridine, cytarabine, gemcitabine, pemetrexed, trifluridine, and tipyrimidine (=TAS102);

[0658] b. Pemetrexed is preferred;

[0659] 11. Cell cycle inhibitors

[0660] a. Inhibitors of CDK4 / 6 and / or any mutant thereof, for example.

[0661] i. For example, palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600;

[0662] ii. Preferably, peroxibuxib and abemaxibuxib;

[0663] iii. The best option is abemacib.

[0664] b. For example, periwinkle alkaloids

[0665] i. For example, Changchun Ruibin.

[0666] c. For example, inhibitors of Aurora kinase and / or any mutant thereof.

[0667] i. For example, alisertib and barasertib.

[0668] 12. mTOR inhibitors

[0669] a. For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin 1, dactolisib, GDC-0349, VS-5584, vistusertib, AZD8055.

[0670] 13. Inhibitors of Src family kinases and / or any mutants thereof

[0671] a. For example, inhibitors of SrcA subfamily kinases and / or any mutants thereof, i.e., inhibitors of Src, Yes, Fyn, Fgr and / or any mutants thereof;

[0672] b. For example, inhibitors of SrcB subfamily kinases and / or any mutants thereof, i.e., inhibitors of Lck, Hck, Blk, Lyn and / or any mutants thereof;

[0673] c. For example, inhibitors of Frk subfamily kinases and / or any mutants thereof, i.e., inhibitors of Frk and / or any mutants thereof;

[0674] d. For example, dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU 6656, WH-4-023.

[0675] 14. Apoptosis inducers

[0676] a. For example, MCL-1 inhibitors;

[0677] i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0678] b. For example, Bcl-2 inhibitors;

[0679] i. For example, venetoclax, obatoclax, navitoclax, oblimersen;

[0680] c. For example, Bcl-xL inhibitors

[0681] 15. Anti-angiogenic agents

[0682] a. For example, bevacizumab and nintedanib;

[0683] b. Bevacizumab is the best option;

[0684] c. For example, anti-VEGF / Ang2 bispecific antibodies

[0685] i. For example, bispecific binding molecules disclosed and described in WO 2012 / 131078 and WO 2018 / 220169;

[0686] 16. Inhibitors of PI3 kinase (=PI3K) and / or any mutant thereof

[0687] a. Inhibitors of PI3Kα and / or any mutant thereof, for example.

[0688] i. For example, alpelisib, serabelisib, GDC-0077, HH-CYH33, AMG511, buparlisib, dactolisib, pictilisib, taselisib.

[0689] 17. Histone deacetylase inhibitors

[0690] 18. IL6 inhibitors

[0691] 19. Inhibitors of JAK and / or any mutant thereof

[0692] 20. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutant thereof

[0693] a. For example, encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (Example 131 in WO 2014 / 151616), LXH254, sorafenib, LY-3009120 (Example 1 in WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265;

[0694] 21. Inhibitors of receptor tyrosine kinase (RTK) and / or any mutant thereof

[0695] 22. Inhibitors of SHP2 and / or any of its mutants

[0696] a. For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0697] In another embodiment of the (combination) uses and methods described above (e.g., treatment and / or prevention methods), an additional pharmacologically active substance is administered before, after, or together with the compound of formula (I) or its pharmaceutically acceptable salt (including all individual embodiments and general subsets disclosed herein), wherein the additional pharmacologically active substance is

[0698] • SOS1 inhibitors; or

[0699] ·BI 1701963; or

[0700] MEK inhibitors; or

[0701] Trametinib, or

[0702] ·BI 3011441, or

[0703] • Anti-PD-1 antibody; or

[0704] • Ebenolimab, or

[0705] • Cetuximab; or

[0706] Afatinib; or

[0707] • Inhibitors of GDP- or GTP-loaded mutant KRAS; or

[0708] MCL1 inhibitors; or

[0709] • PI3K inhibitors.

[0710] In another embodiment of the (combination) use and methods (e.g., treatment and / or prevention methods) as described above, an additional pharmacologically active substance is administered in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), wherein the additional pharmacologically active substance is

[0711] • SOS1 inhibitors; or

[0712] ·BI 1701963

[0713] MEK inhibitors; or

[0714] Trametinib, or

[0715] ·BI 3011441, or

[0716] • Anti-PD-1 antibody; or

[0717] • Ebenolimab, or

[0718] • Cetuximab; or

[0719] Afatinib; or

[0720] • Inhibitors of GDP- or GTP-loaded mutant KRAS; or

[0721] MCL1 inhibitors; or

[0722] • PI3K inhibitors.

[0723] In another aspect of the (combination) uses and methods described above (e.g., treatment and / or prevention methods), two other pharmacologically active substances are administered before, after, or together with the compound of formula (I) or its pharmaceutically acceptable salts (including all individual embodiments and general subsets disclosed herein), wherein the two other pharmacologically active substances are

[0724] • MEK inhibitors and SOS1 inhibitors; or

[0725] Trametinib and SOS1 inhibitors; or

[0726] Trametinib and BI 1701963, or

[0727] ·BI 3011441 and BI 1701963, or

[0728] • Anti-PD-1 antibody and anti-LAG-3 antibody; or

[0729] • Anti-PD-1 antibody and anti-CTLA-4 antibody; or

[0730] • Anti-PD-1 antibodies and SOS1 inhibitors; or

[0731] • Ebenemlimab and BI 1701963; or

[0732] • MEK inhibitors and inhibitors selected from the following: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0733] • BI 3011441 and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0734] • SOS1 inhibitors and inhibitors selected from the following: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0735] • BI 1701963 and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0736] MEK inhibitors and afatinib; or

[0737] • BI 3011441 and afatinib; or

[0738] MEK inhibitors and cetuximab; or

[0739] • BI 3011441 and cetuximab; or

[0740] Trametinib and afatinib; or

[0741] Trametinib and cetuximab; or

[0742] • SOS1 inhibitors and afatinib; or

[0743] • BI 1701963 and afatinib; or

[0744] • SOS1 inhibitors and cetuximab; or

[0745] • BI 1701963 and cetuximab; or

[0746] • SOS1 inhibitors and inhibitors of GDP- or GTP-loaded mutant KRAS; or

[0747] • Inhibitors of BI 1701963 and GDP- or GTP-loaded mutant KRAS; or

[0748] • Cisplatin and Pemetrexed; or

[0749] Carboplatin and Pemetrexed.

[0750] In another aspect of the (combination) uses and methods described above (e.g., treatment and / or prevention methods), two other pharmacologically active substances are administered in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including all individual embodiments and general subsets disclosed herein), wherein the two other pharmacologically active substances are

[0751] • MEK inhibitors and SOS1 inhibitors; or

[0752] Trametinib and SOS1 inhibitors; or

[0753] Trametinib and BI 1701963, or

[0754] ·BI 3011441 and BI 1701963, or

[0755] • Anti-PD-1 antibody and anti-LAG-3 antibody; or

[0756] • Anti-PD-1 antibody and anti-CTLA-4 antibody; or

[0757] • Anti-PD-1 antibodies and SOS1 inhibitors; or

[0758] • Ebenemlimab and BI 1701963; or

[0759] • MEK inhibitors and inhibitors selected from the following: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0760] • BI 3011441 and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0761] • SOS1 inhibitors and inhibitors selected from the following: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0762] • BI 1701963 and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0763] MEK inhibitors and afatinib; or

[0764] • BI 3011441 and afatinib; or

[0765] MEK inhibitors and cetuximab; or

[0766] • BI 3011441 and cetuximab; or

[0767] Trametinib and afatinib; or

[0768] Trametinib and cetuximab; or

[0769] • SOS1 inhibitors and afatinib; or

[0770] • BI 1701963 and afatinib; or

[0771] • SOS1 inhibitors and cetuximab; or

[0772] • BI 1701963 and cetuximab; or

[0773] • SOS1 inhibitors and inhibitors of GDP- or GTP-loaded mutant KRAS; or

[0774] • Inhibitors of BI 1701963 and GDP- or GTP-loaded mutant KRAS; or

[0775] • Cisplatin and Pemetrexed; or

[0776] Carboplatin and Pemetrexed.

[0777] It may also be used, together with or in combination with compounds of formula (I) or pharmaceutically acceptable salts thereof (including all individual embodiments or common subsets of compound (I)) or with additional pharmacologically active substances used in medical uses, applications, treatments and / or preventive methods as disclosed herein (above and below), including but not limited to: hormones, hormone analogs and anti-hormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate). Acetate), fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide; aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane); LHRH agonists and antagonists (e.g., goserelin acetate). Acetate), luprolide; inhibitors of growth factors and / or their corresponding receptors (growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, such as HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors); such as (anti) growth factor antibodies, (anti) growth factor receptor antibodies and inhibitors of tyrosine kinase inhibitors, such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bevacizumab, and trastuzumab);Antimetabolites (such as antifolates like methotrexate, raltitrexed, pyrimidine analogs like 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs like mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine) C) Fludarabine; antitumor antibiotics (such as anthracyclines, such as doxorubicin, doxil (polyethylene glycol-modified doxorubicin hydrochloride, myocet (non-polyethylene glycol-modified doxorubicin), daunorubicin, epirubicin, and idarubicin), mitomycin-C, bleomycin, dactinomycin, plicamycin, and streptozotocin). zocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustin and lomustin, thiotepa); antimitotic agents (e.g., vinca alkaloids). Alkaloids, such as vinblastine, vindesin, vicorelbin, and vincristine; and taxanes, such as paclitaxel and docetaxel; angiogenesis inhibitors (e.g., tasquinimod); tubulin inhibitors; DNA synthesis inhibitors; PARP inhibitors; and topoisomerase inhibitors (e.g., epipodophyllotoxin, such as etoposide, etopophos, teniposide, amsacrin, topotecan, irinotecan, and 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, STK33 inhibitors, AKT inhibitors, PLK inhibitors) 1. Inhibitors: CDK inhibitors, Aurora kinase inhibitors; tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors); protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimics, 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 analogs (e.g., everolimus, tanciolimus, stilbene). Ingredients include: sirolimus (lime); androgen synthesis inhibitors; androgen receptor inhibitors; DNMT inhibitors; HDAC inhibitors; ANG1 / 2 inhibitors; CYP17 inhibitors; radiopharmaceuticals; proteasome inhibitors (e.g., carfilzomib); immunotherapeutic agents, such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, such as ipilimumab, nivolumab, and pembrolizumab); ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, and anti-CD20 antibodies); and T-cell conjugates (e.g., bispecific T-cell conjugates). Examples include CD3×BCMA, CD3×CD33, CD3×CD19, PSMA×CD3; tumor vaccines; and various chemotherapy agents, such as amifostin, anagrelor, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer.

[0778] It should be understood that the combinations, compositions, kits, methods, uses, or compounds used according to the present invention are conceivable to be administered simultaneously, in parallel, sequentially, continuously, alternately, or separately. It should be understood that compounds of formula (I) or their pharmaceutically acceptable salts and one or more other pharmacologically active substances can be administered dependently or independently, such as compounds of formula (I) or their pharmaceutically acceptable salts and one or more other pharmacologically active substances, as part of the same pharmaceutical composition / dosage form or preferably as separate pharmaceutical compositions / dosage forms.

[0779] In this context, the term "combination" or "in combination" as used in the sense of this invention includes, but is not limited to, products resulting from mixing or combining more than one active ingredient, and includes fixed and non-fixed (e.g., free) combinations (including kits) and uses, such as simultaneous, parallel, sequential, continuous, alternating, or separate use of components or ingredients. The term "fixed combination" means simultaneous administration of the active ingredient to a patient in a single entity or dose form. The term "non-fixed combination" means simultaneous, parallel, or sequential administration of the active ingredient to a patient in separate entities without a specific time limit, wherein such administration provides a therapeutically effective amount of the compound in the patient's body.

[0780] The application 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 co-application of the active ingredient or component, such as by simultaneous or concurrent application of a single formulation or dosage form or of two or more separate formulations or dosage forms. Alternatively, the application 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 sequential or alternating application of the active ingredient or component, such as of two or more separate formulations or dosage forms.

[0781] For example, simultaneous administration includes administration at essentially the same time. This form of administration may also be referred to as "concomitant" administration. Parallel administration includes administration of the active agent within the same general time period (e.g., on the same day but not necessarily at the same time). Alternating administration includes administration of one agent during a time period (e.g., over a period of several days or a week), followed by administration of another agent during a subsequent time period (e.g., over a period of several days or a week), and then repeating this pattern one or more cycles. Sequential or continuous administration includes administration of one agent using one or more doses during a first time period (e.g., over a period of several days or a week), followed by administration of another agent using one or more doses during a second and / or additional time period (e.g., over a period of several days or a week). Overlapping schedules may also be used, which include administration of the active agent on different dates within the treatment period, not necessarily in a regular order. Variations of these general guidelines may also be used, for example, depending on the agent used and the individual's condition.

[0782] definition

[0783] Terms not specifically defined herein shall be given the meanings that would be ascribed to them by one of ordinary skill in the art in view of the present invention and the context. However, as used in this specification, unless stated to the contrary, the following terms have the designated meanings and will follow the following conventions:

[0784] The prefix C x-y used, where x and y each represent positive integers (x < y), indicates that the directly associated specified and mentioned chain or ring structure or combination of chain and ring structures as a whole can consist of a maximum of y and a minimum of x carbon atoms.

[0785] The indication of the number of members in a group containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl) refers to the total number of atoms in all ring members or the total number of all ring and carbon chain members.

[0786] 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) refers to the total number of carbon atoms in all carbon ring and carbon chain members. Obviously, the ring structure has at least three members.

[0787] Generally, for a group containing two or more sub - groups (e.g., heteroarylalkyl, heterocyclicalkyl, cycloalkylalkyl, arylalkyl or similar groups), the last - named sub - group is the group attachment point. For example, the substituent arylC 1-6 alkyl means that the aryl is bonded to C 1-6 alkyl, which in turn is bonded to the core or the group to which the substituent is attached.

[0788] In groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, one of ordinary skill in the art can see the group attachment point of the molecule from the free valence of the group itself.

[0789] alkyl represents a monovalent saturated hydrocarbon chain, which can exist in straight - chain (unbranched) and branched - chain forms. If the alkyl is substituted, in each case it can be substituted by monosubstitution or polysubstitution independently of each other on all hydrogen - bearing carbon atoms.

[0790] The term "C 1-5Alkyl groups include, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0791] Other examples of alkyl groups include 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 (secondary 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, -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl 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.

[0792] The general terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, or similar groups, without any other definition, refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms.

[0793] If the alkyl group is another (combined) group (such as C... x-y Alkylamino or C x-y If it is part of an alkyloxy group, then the above definition of alkyl also applies.

[0794] the term alkylene Derived from alkyl groups. Unlike alkyl groups, alkylene groups are divalent and require two covalent groups. Formally, the second valence is generated by removing a hydrogen atom from the alkyl group. Corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2-, or >CHCH3, etc.

[0795] Term "C" 1-4 Alkyl groups include, for example, -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2 -CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2 -CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3))2)-, and -C(CH3)(CH2CH3)-.

[0796] Other examples of alkylene compounds include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene, etc.

[0797] The generic terms propylidene, butylidene, pentylene, hexylidene, or similar groups without any other definition mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e., propylidene includes 1-methylethylidene, and butylidene includes 1-methylpropylidene, 2-methylpropylidene, 1,1-dimethylethylidene, and 1,2-dimethylethylidene.

[0798] If the alkylene group is part of another (combined) group (such as in HO-C) x-y alkylene amino or H2N-C x-y If (in alkylene oxide), then the above definition of alkylene also applies.

[0799] Unlike alkyl groups, alkenyl It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a C-C double bond and each carbon atom can be part of only one C-C double bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, the corresponding alkenyl group is formed.

[0800] Examples of alkenyl groups include vinyl, propyl-1-enyl, allyl (propyl-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-propyl-2-enyl, 2-methyl-propyl-1-enyl, 1-methyl-propyl-2-enyl, 1-methyl-propyl-1-enyl, 1-methylenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, and 3-methyl-but-2-enyl. -alkenyl, 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-methylene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hex-1,3-dienyl, hex-1,4-dienyl, pent-1,4-dienyl, pent-1,3-dienyl, but-1,3-dienyl, 2,3-dimethylbut-1,3-diene, etc.

[0801] The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, hepadienyl, octadienyl, nonadienyl, decanadienyl, or similar groups without any other definition refer to all conceivable isomers having the corresponding number of carbon atoms. That is, propenyl includes prop-1-enyl and prop-2-enyl, and butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, etc.

[0802] The alkenyl group may be optionally oriented in cis or trans or E or Z relative to the double bond.

[0803] If the alkenyl group is part of another (combined) group (such as in C... x-y alkenyl amino or C x-y (In alkenyloxy group), the above definition of alkenyl also applies.

[0804] Unlike alkylene, alkenylene It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a C-C double bond, and each carbon atom may be part of only one C-C double bond. If, in an alkylene group having at least two carbon atoms as defined above, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, the corresponding alkenyl group is formed.

[0805] Examples of alkenyl groups include vinylidene, propenyl, 1-methylvinylidene, butenyl, 1-methylpropenyl, 1,1-dimethylvinylidene, 1,2-dimethylvinylidene, pentenyl, 1,1-dimethylpropenyl, 2,2-dimethylpropenyl, 1,2-dimethylpropenyl, 1,3-dimethylpropenyl, hexenyl, etc.

[0806] The generic terms propene, butene, pentenene, hexene, or similar groups without any other definition refer to all conceivable isomers having the corresponding number of carbon atoms, i.e., propene includes 1-methylvinylene, and butene includes 1-methylpropene, 2-methylpropene, 1,1-dimethylvinylene, and 1,2-dimethylvinylene.

[0807] The alkenyl group may optionally exist in cis or trans or E or Z orientation relative to the double bond.

[0808] If the imide group is part of another (combined) group (such as in HO-C) x-y imide-amino or H2N-C x-y (In the case of alkenyloxy group), the above definition of alkenyl also applies.

[0809] Unlike alkyl groups, alkynyl It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a C-C triple bond. If, in each case, two hydrogen atoms at adjacent carbon atoms are formally removed from an alkyl group having at least two carbon atoms as defined above, and the free valence is saturated to form two additional bonds, the corresponding alkynyl group is formed.

[0810] Examples of alkynyl groups include ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, 1-methyl-prop-2-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, 3-methyl-but-1-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, etc.

[0811] The general terms propynyl, butynyl, penynyl, hexynyl, heptynyl, octyynyl, nonynyl, decynyl, or similar groups without any other definition refer to all conceivable isomers having the corresponding number of carbon atoms. That is, propynyl includes prop-1-ynyl and prop-2-ynyl, and butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

[0812] If a hydrocarbon chain carries at least one double bond and at least one triple bond, then by definition it belongs to an alkynyl group.

[0813] If the alkynyl group is part of another (combined) group (such as in C... x-y alkynyl amino or C x-y If the alkynyl group is an alkynyl group (in the case of an alkynyl group), then the above definition of alkynyl group also applies.

[0814] Unlike alkylene, alkynylene It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a C-C triple bond. If, in each case, two hydrogen atoms at adjacent carbon atoms are formally removed from an alkylene group having at least two carbon atoms as defined above, and the free valence is saturated to form two additional bonds, then the corresponding alkynylene group is formed.

[0815] Examples of ynyl groups include ynylene, propynylene, 1-methylynylene, butynylene, 1-methylpropynylene, 1,1-dimethylynylene, 1,2-dimethylynylene, pentyryne, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, and hexynylene.

[0816] The general terms propynyl, butynyl, pentylyl, hexynyl, or similar groups without any other definition refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e., propynyl includes 1-methylethynyl, and butynyl includes 1-methylpropynyl, 2-methylpropynyl, 1,1-dimethylethynyl, and 1,2-dimethylethynyl.

[0817] If the ynylene group is part of another (combined) group (such as in HO-C) x-y Imynylamino or H2N-C x-yIf the alkynyl group is in the alkynyl group (in the alkynyl group), then the above definition of alkynyl group also applies.

[0818] heteroatom This refers to oxygen, nitrogen, phosphorus, and sulfur atoms. Preferably, the heteroatoms are selected from oxygen, nitrogen, and sulfur.

[0819] haloalkyl (haloalkenyl, haloalkynyl) Alkyl (alkenyl, ynyl) compounds are derived from previously defined alkyl groups by the independent substitution of one or more hydrogen atoms in a hydrocarbon chain with the same or different halogen atoms. If the alkyl (alkenyl, ynyl) haloalkyl group is further substituted, the substitution can occur independently of each other in the form of mono- or poly-substituted substitutions on all hydrogen-carrying carbon atoms in each case.

[0820] Examples of haloalkyl (haloalkenyl, haloalkynyl) groups include -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0821] The previously defined haloalkyl (haloalkenyl, haloynyl) also gave rise to the term. haloalkylene (haloalkenylene, haloalkynylene) Unlike alkyl halogens (alkenyl halogens, alkynyl halogens), alkylene halogens (alkenylene halogens, alkynyl halogens) are divalent and require two co-conjugated compounds. Formally, the second valence is achieved by removing a hydrogen atom from the alkyl halogen (alkenyl halogen, alkynyl halogen).

[0822] The corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F, etc.

[0823] The above definition also applies if the corresponding halogen-containing group is part of another (combined) group.

[0824] halogen It refers to fluorine, chlorine, bromine and / or iodine atoms.

[0825] cycloalkyl It is composed of monocyclic cycloalkyl (= monocyclic hydrocarbon ring), bicyclic cycloalkyl (= bicyclic hydrocarbon ring), and spirocyclic alkyl (= spirohydrocarbon ring) daughter groups. The ring system is saturated. In a bicyclic hydrocarbon ring, the two rings are bonded together such that they together have at least two carbon atoms. In a spirohydrocarbon ring, one carbon atom (spiro atom) belongs to both rings.

[0826] If the cycloalkyl group is substituted, the substitution can occur independently of each other on all hydrogen-carrying carbon atoms in either mono- or poly-substituted form. The cycloalkyl group itself can act as a substituent and be bonded to the molecule at every suitable position in the ring system.

[0827] Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindene), bicyclo[4.4.0]decyl (decahydronaphthyl), and bicyclo[2.2.1]heptyl (norphinyl). (4.1.0) heptyl (norcarel), (3.1.1) heptyl (pinel), spiro[2.5] octyl, spiro[3.3] heptyl, etc.

[0828] If the cycloalkyl group is part of another (combination) group (such as in C... x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y If the cycloalkyl group is an alkyl group, then the above definition of cycloalkyl also applies.

[0829] If the free valence of the cycloalkyl group is saturated, an alicyclic group is obtained (where all the definitions of cycloalkyl groups apply to alicyclic groups accordingly).

[0830] the term cycloalkylene Derived from the previously defined cycloalkyl group. Unlike cycloalkyl groups, cyclohexene alkyl groups are divalent and require two conjugates. Formally, the second valence is obtained by removing a hydrogen atom from the cycloalkyl group. Corresponding groups are, for example:

[0831] Cyclohexyl and (Cyclohexylene)

[0832] If the cycloalkylene group is part of another (combined) group (such as in HO-C) x-y Cycloalkylamino or H2N-C x-y In the case of cycloalkylene oxides, the above definition of cycloalkylene oxides also applies.

[0833] cycloalkenyl It is also composed of monocyclic cycloalkenyl (= monocyclic hydrocarbon ring), bicyclic cycloalkenyl (= bicyclic hydrocarbon ring), and spirocyclic alkenyl (= spirohydrocarbon ring) daughter groups. However, the system is unsaturated, that is, there is at least one C-C double bond, but no aromatic system. If two hydrogen atoms at adjacent ring carbon atoms are formally removed from the cycloalkyl group as defined above, and the free valence is saturated to form a second bond, the corresponding cycloalkenyl group is obtained.

[0834] If the cycloalkenyl group is substituted, the substitution can occur independently of each other in the form of mono- or poly-substituted substitutions on all hydrogen-carrying carbon atoms in each case. The cycloalkenyl group itself can act as a substituent and be bonded to the molecule at each suitable position in the ring system.

[0835] Examples of cycloalkenyl groups 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, cyclopent-1,4-dienyl, cyclopent-1,3-dienyl, cyclopent-2,4-dienyl, cyclohex-1,3-dienyl, cyclohex-1,5-dienyl, cyclohex-2,4-dienyl, cyclohex-1,4-dienyl, cyclohex-2,5-dienyl, and bicyclo[2.2.1]hept-2,5-dienyl (decyl) -2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (decyl) Alkenyl), spiro[4,5]dec-2-alkenyl, etc.

[0836] When the cycloalkenyl group is part of another (combined) group (such as in C... x-y cycloalkenylamino, C x-y cycloalkenyloxy or C x-y The above definition of cycloalkenyl also applies when it is in cycloalkenyl alkyl groups.

[0837] If the free valence of the cycloalkenyl group is saturated, then we obtain unsaturated alicyclyl (All definitions of cycloalkenyl groups apply to unsaturated alicyclic groups accordingly).

[0838] Therefore, terminology cycloalkenylene It can be derived from the previously defined cycloalkenyl group. Unlike cycloalkenyl groups, deoxycycloalkenyl groups are divalent and require two binding complexes. Formally, the second valence is obtained by removing a hydrogen atom from the cycloalkenyl group. Corresponding groups are, for example:

[0839] cyclopentenyl and (cyclopentenyl) etc.

[0840] If the cycloene group is part of another (combined) group (such as in HO-C) x-y cycloene-enylamino or H2N-C x-y In the case of cycloalkylene oxides, the above definition of cycloalkylene also applies.

[0841] arylIt represents a monocyclic, bicyclic, or tricyclic carbon ring having at least one aromatic carbon ring. Preferably, it represents a monocyclic group (phenyl) having six carbon atoms or a bicyclic group having nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or partially saturated.

[0842] If the aryl group is substituted, the substitution can occur independently of each other in the form of mono- or poly-substituted substitutions on all hydrogen-carrying carbon atoms in each case. The aryl group itself can act as a substituent and be bonded to the molecule at every suitable position in the ring system.

[0843] Examples of aryl compounds include phenyl, naphthyl, indanyl (2,3-dihydroindanyl), indanyl, anthracene, phenanthryl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorene, etc. Phenyl is preferred.

[0844] The above definition of aryl also applies if the aryl group is part of another (combined) group (such as in arylamino, aryloxy, or arylalkyl).

[0845] If the free valence of the aryl group is saturated, then we obtain aromatic (All definitions of aryl apply to aryl groups accordingly).

[0846] the term arylene It can also be derived from the previously defined aryl group. Unlike aryl, aryl derivatives are divalent and require two co-orienting compounds. Formally, the second valence is formed by removing a hydrogen atom from the aryl group. Corresponding groups are, for example:

[0847] Phenyl and (o-phenylene, m-phenylene, p-phenylene),

[0848] Naphthyl and wait.

[0849] If the arylene is part of another (combined) group (such as in HO-aryleneamino or H2N-aryleneoxy), then the above definition of the arylene also applies.

[0850] heterocyclylThis indicates a cyclic system derived from previously defined cycloalkyl, cycloalkenyl, and aryl groups through the substitution of one or more carbon atoms with heteroatoms. For example, the -CH2- group in a hydrocarbon ring may be independently substituted with groups such as -O-, -S-, -NH-, or -PH-, or through the substitution of one or more =CH- groups with groups =N-, wherein a total of no more than five heteroatoms may be present, at least one carbon atom must be between two oxygen atoms and two sulfur atoms or between oxygen and sulfur atoms, and the ring as a whole must be chemically stable. Heteroatoms may optionally be present in all possible oxidation stages (sulfur → sulfoxide-SO-, sulfone-SO2-; nitrogen → N-oxide). In heterocyclic groups, there is no heteroaromatic ring, i.e., no heteroatom is part of the aromatic system.

[0851] The direct result of cycloalkyl, cycloalkenyl and aryl groups is that heterocyclic groups are composed of monocyclic heterocyclic groups (=monocyclic heterocycle), bicyclic heterocyclic groups (=bicyclic heterocycle), tricyclic heterocyclic groups (=tricyclic heterocycle) and spirocyclic groups (=spirocyclic heterocycle), which can exist in saturated or unsaturated forms.

[0852] Unsaturation means that the ring system under discussion contains at least one double bond, but does not form a heteroaromatic system. In bicyclic heterocycles, the two ring bonds are linked together such that they share at least two (hetero) atoms. In spiroheterocycles, a single carbon atom (spiro atom) belongs to both rings.

[0853] If the heterocyclic group is substituted, the substitution can occur independently of each other in the form of mono- or poly-substituted substitutions on all hydrogen-carrying carbon and / or nitrogen atoms. The heterocyclic group itself can act as a substituent and be bonded to the molecule at each suitable position in the ring system. Substituents on the heterocyclic group do not count the number of members of the heterocyclic group; that is, a given number of members of the heterocyclic group refers only to the number of atoms in the ring / ring system that forms the heterocyclic group.

[0854] Examples of heterocyclic groups include tetrahydrofuranyl, pyrrolylyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolyl, pyrazolyl, piperidinyl, piperazinyl, epoxyethyl, aziridinyl, azircyclic butyl, 1,4-dioxane, azircyclic heptyl, diazacyclic heptyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanecycloyl, tetrahydropyranyl, tetrahydrothiopyranyl [1,4]-oxazolidinyl heptyl, tetrahydrothiopheneyl, high-thiomorpholinyl-S,S-dioxide, oxazolidinyl, dihydropyrazolyl, dihydropyrroleyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiopheneyl-S-oxide, tetrahydrothiopheneyl-S,S-dioxide, high-thiomorpholinyl-S-oxide, 2,3-dihydroazolidinyl, 2H-pyrroleyl, 4H-pyranyl, 1,4-dihydropyridyl, 8-aza-bicyclo[3.2.1]octyl, 8- Aza-bicyclo[5.1.0]octyl, 2-oxa-5-aza-bicyclo[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, etc.

[0855] Other embodiments are structures described below, which can be linked via individual hydrogen-carrying atoms (exchanged with hydrogen):

[0856]

[0857]

[0858]

[0859]

[0860] Preferably, the heterocyclic group is a 4- to 8-membered monocyclic heterocyclic group and has one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0861] Preferred heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, homomorpholinyl, pyrrolidinyl, azirrobutyl, oxacyclobutyl, 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, and 2,5-diazabicyclo[2.2.1]heptyl.

[0862] The preferred monocyclic heterocyclic group is a 4- to 7-membered monocyclic heterocyclic group and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0863] Preferred monocyclic heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azacyclic butyl.

[0864] The preferred bicyclic heterocyclic group is a 6- to 10-membered bicyclic heterocyclic group and has one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0865] The preferred tricyclic heterocyclic group is a 9-membered tricyclic heterocyclic group and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0866] The preferred spiroheterocyclic group is a 7- to 11-membered spiroheterocyclic group and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0867] The above definition of a heterocyclic group also applies if the heterocyclic group is part of another (combined) group (such as in a heterocyclic amino, heterocyclic oxygen, or heterocyclic alkyl group).

[0868] If the free valence of the heterocyclic group is saturated, then we obtain heterocycle (All definitions of heterocyclic groups apply to heterocycles accordingly).

[0869] the term heterocyclylene It also derives from the previously defined heterocyclic groups. Unlike heterocyclic groups, subheterocyclic groups are divalent and require two binding complexes. Formally, the second valence is obtained by removing a hydrogen atom from the heterocyclic group. Corresponding groups are, for example:

[0870] Piperidinyl and

[0871] 2,3-Dihydro-1H-pyrrole and wait.

[0872] The above definition of a heterocyclic group also applies if the heterocyclic group is part of another (combined) group (such as in HO-heterocyclic amino or H2N-heterocyclic oxygen).

[0873] heteroarylThis refers to a monocyclic or polycyclic heteroaromatic ring having at least one heteroaromatic ring, which contains one or more heteroatoms, selected independently from nitrogen, sulfur, and oxygen, rather than one or more carbon atoms, relative to the corresponding aryl or cycloalkyl (cycloalkenyl) group, wherein the resulting group must be chemically stable. The prerequisites for the existence of a heteroaryl group are heteroatoms and a heteroaromatic system.

[0874] If a heteroaryl group is substituted, the substitution can occur independently of each other in the form of mono- or poly-substituted substitutions on all hydrogen-carrying carbon and / or nitrogen atoms. The heteroaryl group itself can act as a substituent and be bonded to the molecule via suitable positions (both carbon and nitrogen) in the ring system. Substituents on the heteroaryl group do not count the number of members of the heteroaryl group; that is, a given number of members of the heteroaryl group refers only to the number of atoms in the ring / ring system that forms the heteroaryl group.

[0875] Examples of heteroaryl groups include furanyl, thiopheneyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyrazinyl-N-oxide, imidazoleyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indoleyl, isoyndoleyl, benzofuranyl, benzothiopheneyl, and benzoxazole. The following are listed: benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolyl, indazole, isoquinolinyl, quinolinyl, quinoxolinyl, cinolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indazinyl, oxazolopyridyl, imidazopyridyl, naphthidyl, benzooxazolyl, pyridopyridyl, pyrimidinyl, purine, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indole-N-oxide, isoquinolinyl-N-oxide, quinazololyl-N-oxide, quinoxolinyl-N-oxide, phthalazinyl-N-oxide, indazinyl-N-oxide, indazole-N-oxide, benzothiazolyl-N-oxide, benzoimidazolyl-N-oxide, etc.

[0876] Other embodiments are structures described below, which can be linked via individual hydrogen-carrying atoms (exchanged with hydrogen):

[0877]

[0878]

[0879] Preferably, the heteroaryl group is a 5- to 6-membered monocyclic or a 9- to 10-membered bicyclic heteroaryl group, each having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0880] The above definition of a heteroaryl group also applies if the heteroaryl group is part of another (combined) group (such as in a heteroarylamino, heteroaryloxy, or heteroarylalkyl group).

[0881] If the free valence of the heteroaryl group is saturated, then we obtain heteroaromatic ring (All definitions of heteroaryl groups apply to heteroaryl rings accordingly).

[0882] the term heteroarylene It also derives from the previously defined heteroaryl group. Unlike heteroaryl groups, hypoaryl groups are divalent and require two conjugates. Formally, the second valence is obtained by removing a hydrogen atom from the heteroaryl group. Corresponding groups are, for example:

[0883] pyrrole and wait.

[0884] The above definition of a heteroaryl group also applies if the heteroaryl group is part of another (combined) group (such as in HO-heteroarylamino or H2N-heteroaryloxy).

[0885] substituted This refers to the substitution of a hydrogen atom directly bonded to the atom in question by another atom or another group of atoms (substituents). Depending on the starting conditions (number of hydrogen atoms), mono- or poly-substitution can occur on a single atom. Substitution with a specific substituent is only feasible if the permitted valences of the substituents and atoms correspond to each other and the substitution produces a stable compound (i.e., a compound that does not spontaneously transform, for example, through rearrangement, cyclization, or elimination).

[0886] Divalent substituents, such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, or similar groups, can only be substituents on carbon atoms, while the divalent substituents =O and =NR can also be substituents on sulfur and phosphorus. Generally, substitution can be carried out by divalent substituents only in the ring system and requires the replacement of two homologous hydrogen atoms (i.e., hydrogen atoms bonded to the same carbon atom that was saturated before substitution). Therefore, substitution by divalent substituents is possible only at the -CH2-, sulfur, and phosphorus atoms in the ring system (only =O or =NR groups, possibly one or two =O groups or, for example, one =O group and one =NR group, each group replacing a free pair of electrons).

[0887] stereochemistry / solvate / hydrateUnless otherwise specified, throughout this specification and the accompanying claims, the given chemical formula or name will cover tautomers and all stereo, optical and geometric isomers (e.g., mirror-image isomers, non-mirror-image isomers, E / Z isomers, etc.) and their racemic derivatives, as well as mixtures of individual mirror-image isomers in different proportions, mixtures of non-mirror-image isomers, or any mixture of such isomers and mirror-image isomers in any of the foregoing forms, and their salts (including pharmaceutically acceptable salts) and their solvates (such as hydrates), including solvates and hydrates of the free compound or solvates and hydrates of salts of the compound.

[0888] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example by separating corresponding mixtures, using stereochemically pure starting materials, and / or by stereoselective synthesis. Optically active forms are known in the art, such as by analysis of racemic forms or by synthesis, for example by starting with optically active starting materials and / or by using chiral reagents.

[0889] The mirror-isomer pure compounds or intermediates of the present invention can be prepared via asymmetric synthesis, for example by preparation and subsequent separation of suitable non-mirror-isomer compounds or intermediates that can be separated by known methods (e.g., by chromatographic separation or crystallization), and / or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.

[0890] Furthermore, those skilled in the art know how to prepare mirror-isomerically pure compounds from corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase, or by resolving the racemic mixture using a suitable eluent, for example by forming a non-mirror-image isomer salt with the racemic compound and an optically active acid or base, followed by eluenting the salt and releasing the desired compound from the salt, or by deriving the corresponding racemic compound with an optically active chiral auxiliary reagent, followed by non-mirror-image isomer separation and removal of the chiral auxiliary group, or by kinetic resolving of the racemic mixture (e.g., by enzymatic resolving); by enantioselective crystallization from aggregates of isomorphic crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary agent.

[0891] salt: The phrase “pharmaceutically acceptable” is used in this article to refer to compounds, materials, compositions, and / or dosage forms that, within the bounds of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0892] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by producing its acid or salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkali metal or organic salts of acidic residues (such as carboxylic acids); and similar salts.

[0893] For example, such salts include those derived from: benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentian acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0894] It can form other pharmaceutically acceptable salts with cations from ammonia, L-arginine, calcium, 2,2'-iminodiethanol, L-lysine, magnesium, N-methyl-D-glucosamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0895] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of a suitable base or acid in water or an organic diluent (such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or mixtures thereof).

[0896] In addition to the salts mentioned above, salts of other acids suitable for purifying or separating the compounds of the present invention (e.g., trifluoroacetate) are also part of the present invention.

[0897] In representations such as the following

[0898]

[0899] The letter A has a circular reference function to easily indicate, for example, the connection between the circular in question and other circulars.

[0900] In representations such as the following

[0901]

[0902] The dotted lines and circles in ring A indicate that the bonds between ring members in ring A can be independently selected from single bonds, double bonds, or (hetero)aromatic bonds. A (hetero)aromatic bond is a bond containing non-locally bound electrons with a bond order between single and double bonds. Preferably, ring A is a (hetero)aromatic ring.

[0903] Groups or substituents are typically selected from those with corresponding group names (e.g., R). a R bMany alternative groups / substituents (etc.). If such groups are used repeatedly in different parts of the molecule to define the compounds of the present invention, it should be noted that each use should be considered completely independent of each other.

[0904] For the purposes of this invention, a therapeutically effective amount means the amount of a substance that can eliminate disease symptoms or prevent or alleviate these symptoms or prolong the survival of the treated patient.

[0905] Abbreviation list

[0906]

[0907]

[0908]

[0909] The features and advantages of the present invention will become apparent from the following detailed description of embodiments, which illustrate the principles of the invention but do not limit its scope:

[0910] Preparation of compounds according to the invention

[0911] Overview

[0912] Unless otherwise stated, all reactions are carried out using methods commonly used in chemical laboratories in commercially available equipment. Starting materials sensitive to air and / or moisture are stored under a protective gas atmosphere, and the corresponding reactions and operations are carried out under a protective gas atmosphere (nitrogen or argon).

[0913] The compounds of this invention are named using the software ChemDraw according to IUPAC rules. If a compound is represented by a structural formula and its name, the structural formula shall prevail in the event of a conflict.

[0914] The microwave reaction is carried out, preferably under stirring, in an initiator / reactor manufactured by Biotage, or in an Explorer manufactured by CEM, or in a Synthos 3000 or Monowave 3000 manufactured by Anton Paar, in a sealed container (preferably 2, 5 or 20 mL).

[0915] Chromatography

[0916] Thin-layer chromatography was performed on off-the-shelf silica 60 TLC plates on glass (with fluorescent indicator F-254) manufactured by Merck.

[0917] Preparative high-performance liquid chromatography (HPLC) of the compounds according to embodiments of the present invention was performed using columns manufactured by Waters (name: Sunfire C18 OBD, 10 μm, 30 × 100 mm, part number 186003971; X-Bridge C18 OBD, 10 μm, 30 × 100 mm, part number 186003930). The compounds were eluted using, for example, different gradients of H2O / AcCN, wherein 0.2% HCOOH was added to water (acidic conditions). For chromatography under alkaline conditions, the water was made alkaline, for example, according to the following formulation: 5 mL of ammonium bicarbonate solution (158 g to 1 L H2O) and 2 mL of 32% ammonia were added to H2O. (aq) Add to 1L.

[0918] Supercritical fluid chromatography (SFC) of the intermediates and compounds of the present invention was performed on a JASCOSFC system having 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), and PhenomenexLux C2 (250 × 20 mm, 5 μm).

[0919] Analytical HPLC (reaction monitoring) of intermediate compounds is performed using columns, for example, those manufactured by Waters and Phenomenex. In each case, the analytical equipment also includes a mass detector.

[0920] HPLC mass spectrometry / UV spectroscopy

[0921] Retention times / MS-ESI values ​​for the compounds according to embodiments of the present invention were generated using an HPLC-MS apparatus (high performance liquid chromatography with a mass detector) manufactured by Agilent. + Retention time t of compounds eluted at injection peak Ret. =0.00.

[0922] HPLC Method (Preparative)

[0923] NP 1

[0924] NP purification: glass column

[0925] Column: 100-200 mesh size silicone

[0926] Solvents: A: DCM; B: MeOH

[0927] Detection: KMnO4

[0928] Flow rate: 100 mL / min

[0929] Gradient: 0-60 min: 1% B

[0930] 60-100 min: variable; 100-200 min: 10% B

[0931] Preparative HPLC 1

[0932] HPLC: 333 and 334 pumps

[0933] Column: Waters XBridge C18 OBD, 10μm, 30×100mm, part number 186003930

[0934] Solvents: A: 10mM NH4HCO3 in H2O; B: AcCN (HPLC grade)

[0935] Testing: UV / Vis-155

[0936] Flow rate: 50 mL / min

[0937] Gradient: 0.00-1.50 min: 1.5% B

[0938] 1.50-7.50 min: variable; 7.50-9.00 min: 100% B

[0939] Preparative HPLC 3

[0940] HPLC / MS: Semi-preparative HPLC (Agilent)

[0941] Column: Triart Prep C18, 10μm, 30×100mm, part number 3010000120

[0942] Solvents: A: H₂O + 0.2% HCOOH; B: AcCN (HPLC grade) + 0.2% HCOOH

[0943] Testing: UV / Vis-155

[0944] Quality: Agilent G6120B MSD-API-ES, positive mode range 120-820

[0945] Flow rate: 50 mL / min

[0946] Gradient: 0.00-0.80 min: 28% B

[0947] 0.80–6.80 min: variable; 6.80–9.00 min: 98% B

[0948] HPLC Method (Analytical)

[0949] LCMS3,basisch_1

[0950] HPLC: Agilent 1100 series

[0951] MS: Agilent LC / MSD (API-ES+ / -3000V, quadrupole, G6140)

[0952] Column: Waters, XBridge C18, 2.5μm, 2.1×20mm column

[0953] Solvents: A: 20mM NH4HCO3 / NH3 in H2O, pH 9; B: AcCN (HPLC grade)

[0954] Detection: MS: Positive and Negative Modes

[0955] Mass range: 120-900m / z

[0956] Flow rate: 1.00 mL / min

[0957] Column temperature: 60℃

[0958] Gradient: 0.00-1.50 min: 10% → 95% B

[0959] 1.50-2.00 min: 95% B

[0960] 2.00-2.10 min: 95% → 10% B

[0961] VAB

[0962] HPLC: Agilent 1100 / 1200 series

[0963] MS: Agilent LC / MSD SL

[0964] Column: Waters XBridge BEH C18, 2.5μm, 2.1×30mm XP

[0965] Solvents: A: 5mM NH4HCO3 / 19mM NH3 in H2O; B: AcCN (HPLC grade)

[0966] Detection: MS: Positive and Negative Modes

[0967] Mass range: 100-1200m / z

[0968] Flow rate: 1.40 mL / min

[0969] Column temperature: 45℃

[0970] Gradient: 0.00-1.00 min: 5% B → 100% B

[0971] 1.00-1.37 min: 100% B

[0972] 1.37-1.40 min: 100% → 5% B

[0973] VAS

[0974] HPLC: Agilent 1100 / 1200 series

[0975] MS: Agilent LC / MSD SL

[0976] Column: YMC TriART C18 2.0×30mm, 3μm

[0977] Solvents: A: H₂O + 0.2% formic acid; B: AcCN (HPLC grade)

[0978] Detection: MS: Positive and Negative Modes

[0979] Mass range: 105-1200m / z

[0980] Flow rate: 1.40 mL / min

[0981] Column temperature: 35℃

[0982] Gradient: 0.0 min: 5% B

[0983] 0.0-1.00 min: 5% B → 100% B

[0984] 1.00-1.37 min: 100% B

[0985] 1.37-1.40 min: 100% B → 5% B

[0986] TCG_LCMS,basisch_1

[0987] HPLC: Waters ACQUITY UPLC

[0988] MS: ACQUITY SQD mass spectrometer from Waters

[0989] Column: YMC triart Waters, 1.8μm, 2.1×33mm

[0990] Solvents: A: 10mM NH4OAc, pH 6.5; B: AcCN (HPLC grade)

[0991] Detection: MS: Positive and Negative Modes

[0992] Mass range: 100-1000 m / z

[0993] Flow rate: 1.00 mL / min

[0994] Column temperature: 50℃

[0995] Gradient: 0.00-0.75 min: 2% B

[0996] 0.75-1.00 min: 2% → 10% B

[0997] 1.00-2.00 min: 10% → 98% B

[0998] 2.00-2.50 min: 98% B

[0999] 2.50-2.90 min: 98% B

[1000] 2.90-3.00 min: 98% → 2% B

[1001] TCG_LCMS,basisch_2

[1002] HPLC: Shimadzu Prominence

[1003] MS:LCMS / MS-API Q trap

[1004] Column: Waters XBridge C18; 4.6×50mm, 5μm

[1005] Solvents: A: 10mM NH4OAc, pH 6.5; B: AcCN (HPLC grade)

[1006] Detection: MS: Positive and Negative Modes

[1007] Mass range: 100-800m / z

[1008] Flow rate: 1.20 mL / min

[1009] Column temperature: 25℃

[1010] Gradient: 0.00-0.01 min: 0% → 10% B

[1011] 0.01-1.50 min: 10% → 30% B

[1012] 1.50-3.00 min: 30% → 90% B

[1013] 3.00-4.00 min: 90% B

[1014] 4.00-5.00 min: 90% → 10% B

[1015] GVK_LCMS_19

[1016] HPLC: Agilent RRLC

[1017] MS: Agilent Technologies-6130 Quadrupole LC / MS

[1018] Column: Waters XBridge C18, 4.6×75mm, 3.5μm

[1019] Solvents: A: 10mM NH4OAc; B: AcCN (HPLC grade)

[1020] Detection: MS: Positive and Negative Modes

[1021] Mass range: 70-1200m / z

[1022] Flow rate: 2.0 mL / min

[1023] Column temperature: 35℃

[1024] Gradient: 0.00-0.20 min: 10% B

[1025] 0.20-2.50 min: 10% → 75% B

[1026] 2.50-3.00min: 75%→100%B

[1027] 3.00-4.80 min: 100% B

[1028] 4.80-5.00 min: 100% → 5% B

[1029] GVK_LCMS_41

[1030] UPLC / MS: Waters Acquity-UPLC-SQ Detector-2

[1031] Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm

[1032] Solvents: A: 0.07% formic acid / AcCN; B: 0.07% formic acid / water

[1033] Detection: MS: Positive and Negative Modes

[1034] Mass range: 100-1500 m / z

[1035] Flow rate: 0.6 mL / min

[1036] Column temperature: 35℃

[1037] Gradient: 0.00-0.30 min: 97% B

[1038] 0.30-2.20 min: 97% → 2% B

[1039] 2.20-3.30 min: 2% B

[1040] 3.30-4.50 min: 2% → 97% B

[1041] 4.50-4.51 min: 97% B

[1042] GVK_LCMS_61

[1043] UPLC / MS: Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2

[1044] Column: AQUITY UPLC BEH C18 1.7μm, 2.1×50mm

[1045] Solvents: A: 0.07% formic acid / AcCN; B: 0.07% formic acid / water

[1046] Detection: MS: Positive and Negative Modes

[1047] Mass range: 100-1500 m / z

[1048] Flow rate: 0.6 mL / min

[1049] Column temperature: 35℃

[1050] Gradient: 0.00-0.40 min: 97% B

[1051] 0.40-2.50 min: 97% → 2% B

[1052] 2.50-3.40 min: 2% B

[1053] 3.40-3.50 min: 2% → 97% B

[1054] 3.50-4.00 min: 97% B

[1055] XB5A

[1056] HPLC: Agilent HPLC 1100 / 1200

[1057] Column: Waters XBridge BEH C18, 4.6×50mm, p / n 186006037

[1058] Solvents: A: H₂O + 0.01% HClO₄; B: 100% AcCN (HPLC grade)

[1059] Flow rate: 1.50 mL / min

[1060] Column temperature: 30℃

[1061] Gradient: 0.00-3.50: 10% B

[1062] 3.50-4.50 min: 10% → 95% B

[1063] 4.50-5.00 min: 10% B

[1064] The compounds and intermediates according to the invention are prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. These methods are intended as illustrative of the invention and do not limit its subject matter or the scope of the compounds claimed in these examples. Where the preparation of a starting compound is not described, it is commercially available, or its synthesis is described in the background art, or it can be prepared similarly to known background art compounds or by the methods described herein, i.e., the synthesis of these compounds is within the skill of an organic chemist. Substances described in the literature can be prepared according to the published synthetic methods.

[1065] Overview of general reaction procedures and synthetic routes

[1066] The compound (I) according to the invention can be synthesized using a BUCHWALD-HARTWIG cross-coupling reaction (→ process 1), starting with 1H-pyrazolo[4,3-c]pyridine A-1 and different halogenated 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).

[1067] Process 1

[1068]

[1069] The desired A-1 block can be synthesized from pyridine derivative A-7 (→ Procedure 2). The ester group is reduced and then oxidized to give formaldehyde A-5. This is followed by a dead-cycle reaction with hydrazine monohydrate (see, for example, WO 2015 / 94929), and then protection of the indazole nitrogen in A-4 (e.g., with a Boc or THP group) to give protected indazole A-3. This is then coupled with boronic ester C-1 via Suzuki coupling (see, for example, J.Org.Chem.2007,72,4067-4072; Org.Lett.,2011,13,252-255; J.Org.Chem.2004,69,7779-7782) or with the corresponding stanane C-2 via Stiele coupling (see, for example, WO 2003 / 87037), followed by deprotection to give 1H-pyrazolo[4,3-c]pyridine A-1. Alternatively, formaldehyde A-5 can be obtained by using malonyl chloride and nitriles (D-4) as starting materials. The resulting dihydroxypyridine D-3 is then subjected to chlorination conditions to give dichloride D-2 (see, for example, WO 2018 / 93569, WO 2014 / 52563, J.Med.Chem.2009, 52, 7473-7487). The nitrile group is then reduced, followed by hydrolysis, to give aldehyde A-5.

[1070] Process 2

[1071]

[1072] The key building block B-1 can be obtained, for example, from B-3 using three different synthetic strategies (→ Procedure 3a):

[1073] R with N-linked residues 4 The constructive block B-1 can be obtained by nucleophilic aromatic substitution under pure conditions with an excess of the corresponding N-nucleophile / amine B-2.

[1074] R with O-linked residues 4 The constructive block B-1 can be obtained by nucleophilic aromatic substitution in a suitable solvent with an excess of O-nucleophile / alcohol B-2 and a strong base such as sodium hydride (see, for example, US 2016 / 207924).

[1075] R 4 CC coupling can be achieved using residues R 4 Suzuki coupling of the boric acid derivative B-2 was achieved using a palladium catalyst (e.g., [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)).

[1076] Process 3a

[1077]

[1078] A more specific exemplary implementation of constructing block B-1 is as follows (→ process 3b):

[1079] Process 3b

[1080]

[1081] Depending on the exact properties of the bicyclic system, there are different methods for synthesizing the key building block B-3:

[1082] Constructing segments B-3a It can be obtained in the following order (→ Process 4):

[1083] residue R 10 Introducing the starting material B-9-a (e.g., via alkylation or reductive amination with AcCN containing the corresponding iodide and potassium carbonate, → B-8), followed by reduction of the nitro group with iron, yields intermediate B-7. Subsequently, B-6a is obtained via a dead-cycle reaction with thiocarbonyl diimidazole (see, for example, WO 2016 / 196840). Chlorination with thionyl chloride (see, for example, WO2003 / 74515) yields B-5a. Finally, the constructed block B-3a can be obtained via nucleophilic aromatic substitution with a nucleophile / amine B-4 (e.g., using potassium carbonate and AcCN as solvents – see, for example, J. Med. Chem. 2007, Vol. 50, #26, pp. 6450-6453). Alternatively, starting with 2,4,6-trichloropyridine, it can be obtained via an amine via S... N Ar yields intermediate B-5a, which gives aminopyridine E-4 (see, for example, WO 2006 / 53166, WO 2008 / 92942, New J. Chem. 2016, Vol. 40, #11, pp. 9194-9204, WO2006 / 122137). E-4 is then iodinated to give E-3, which can subsequently react with chlorosulfonyl isocyanate to give urea E-2 (see, for example, Org. Lett. 2006, Vol. 8, #15, pp. 3311-3314). Ullman-Goldberg amination gives oxazabenzimidazole B-3f, which can ultimately be chlorinated to give trichloride B-5a.

[1084] Process 4

[1085]

[1086] In the alternative method (→process 5), intermediate B-7 is subjected to a dead cycle via amidation with formic acid B-11 to intermediate B-10 and cyclization under acidic conditions (see, for example, Bioorg. Med. Chem. Lett., 2011, Vol. 21, #14, pp. 4197-4202). In yet another variation, for example, formic acid B-11 is activated with polyphosphoric acid, and can be cyclized / condensed into B-3a in a single-step / one-pot reaction. In R 7 In the case of H, the capsid is subjected to a dead cycle using trimethyl orthoformate (TMOF) as the C1 acid equivalent.

[1087] Process 5

[1088]

[1089] Constructing segments B-3b It can be obtained in the following order (→ Process 6):

[1090] One possible reaction sequence begins with the reduction of the nitro group of the starting material B-13-a (e.g., with iron). A dead-cycle reaction of B-12 can be carried out, for example, with potassium ethyl xanthate (→ B-6b; see, for example, WO 2015 / 104688). Chlorination with thioyl chloride (see, for example, WO 2013 / 56679) yields B-5b. Subsequently, the constructive block B-3b can be obtained by nucleophilic aromatic substitution with a nucleophile / amine B-4 (e.g., using potassium carbonate and AcCN as solvents – see, for example, J. Med. Chem. 2007, Vol. 50, #26, pp. 6450-6453).

[1091] Process 6

[1092]

[1093] Constructing segments B-3c* It can be obtained in the following order (→ Process 7):

[1094] Starting material B-18 is alkylated onto a pyrrole ring to give B-17, which is then treated with hydrazine hydrate to give B-16. A dead-cycle reaction under acetic acid conditions yields B-15, which is subsequently treated with sodium nitrite and hydrochloric acid to give B-14 (see, for example, Monatshefte für Chemie 2016, Vol. 147, #4, pp. 783-789). In the final step, B-3c* can be obtained by chlorination with a mixture of phosphorus oxychloride and phosphorus pentachloride.

[1095] Process 7

[1096]

[1097] The block B-3d* can be constructed in the following order (→ process 8):

[1098] The reaction sequence for generating the constructive block B-3d* begins with the formylation of B-24 with, for example, n-BuLi and ethyl formate, to give formaldehyde B-23 (see, for example, WO 2015 / 25026). A GRIGNARD reaction is then carried out, followed by oxidation, to give intermediate B-21 (see, for example, WO 2017 / 42100). B-19 can be obtained by nucleophilic aromatic substitution of the corresponding glycine ester B-20 with, for example, EtOH containing DIPEA. A dead-cycle reaction is then carried out under basic conditions to give B-3d*.

[1099] Process 8

[1100]

[1101] Constructing segments B-3e* It can be obtained in the following order (→ Process 9):

[1102] The multi-step reaction sequence for constructing block B-3e* begins with the nitration of B-31, followed by the reaction of B-30 with the oxalate diester B-29 to give B-28 (see, for example, WO 2004 / 104001). Reduction of the nitro group results in a dead cycle for B-27 (see, for example, WO2012 / 80450). Iodization with a DCM containing N-iodosuccinimide yields B-26, followed by alkylation with the corresponding alkyl halide to give B-25. This sequence concludes with a Suzuki coupling to introduce R. 9 Partially, we obtain B-3e* (see, for example, US 2013 / 210818).

[1103] Process 9

[1104]

[1105] The construct blocks B-3c*, B-3d*, and B-3e* are implementations of the more general construct blocks B-3c, B-3d, and B-3e, respectively, where R 7 =-C(=O)OR*, which can be converted into intermediate B-1 and subsequently coupled with intermediate A-1. The resulting compound (I) according to the invention can then be further modified by saponification and derivatization / amidation of the free carboxyl group.

[1106] Constructing segments B-3f It can be obtained in the following order (→ Process 10):

[1107] Starting again with dichloropyridine B-7 (see processes 4 and 5), intermediate B-32 can be obtained via a dead cycle. Residue R can be introduced, for example, by alkylation with a solvent (such as DMF) containing the corresponding alkylating agent (e.g., alkyl iodide) and a base (e.g., sodium hydride). 6 We obtain B-3f.

[1108] Process 10

[1109]

[1110] Constructing segments B-3g It can be obtained in the following order (→ Process 11):

[1111] Starting with trichloropyridine compound B-34, dead cycles and residue R were achieved by using the corresponding hydrazine B-33, for example, in a solvent such as MeOH. 10 Introduction.

[1112] Process 11

[1113]

[1114] Constructing segments B-3h It can be obtained in the following order (→ Process 12):

[1115] Starting with the diazotization of B-36, followed by a dead cycle, intermediate B-3h can be obtained (see, for example, WO 2007 / 117778). Other residues R can be introduced, for example, by alkylation with a solvent (such as AcCN) containing the corresponding alkylating agent B-35 (e.g., dimethyl sulfate) and a base (e.g., potassium carbonate). 6 Other intermediates B-3h were obtained.

[1116] Process 12

[1117]

[1118] Synthetic intermediate A-1

[1119] Synthesis of A-1-a

[1120]

[1121] Experimental procedure for the synthesis of A-6-a

[1122] DIBAL-H (854.0 mL; 85.40 mmol) was added to a stirred solution of A-7-a (100.0 g; 42.70 mmol) in THF (100.0 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with Rochelle salt (1000 mL) and then EtOAc (1000 mL) was added. The reaction mixture was filtered through a diatomaceous earth mat and washed with EtOAc (1000 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was 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. =1.60min, method GVK_LCMS_41).

[1123] Experimental procedure for the synthesis of A-5-a

[1124] Dess-Martin periodinane (170.0 g; 40.1 mmol) was added to a stirred solution of A-6-a (70.0 g; 36.50 mmol) in DCM (100.0 mL) under reflux. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was quenched with saturated NaHCO3 solution (2000 mL) and stirred for 15 min. The reaction mixture was filtered through a diatomaceous earth mat and washed with DCM (1000 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was 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 min, method GVK_LCMS_41).

[1125] Experimental procedure for the synthesis of A-4-a

[1126] Hydrazine monohydrate (63.7 mL; 121.0 mmol) was added to a stirred solution of A-5-a (46.0 g, 24.2 mmol) in DMA (460.0 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into ice water (800 mL) and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was 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 min, method GVK_LCMS_19).

[1127] Experimental procedure for the synthesis of A-3-a

[1128] TEA (24.5 mL, 17.9 mmol) and Boc anhydride (41.11 mL, 17.9 mmol) were added to a stirred solution of A-4-a (25.0 g; 14.9 mmol) in THF (250.0 mL) under reflux. The reaction mixture was stirred under reflux for 16 h. The reaction mixture was poured into ice water (500 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by normal phase chromatography (EtOAc / petroleum ether 20:80) to obtain the desired product A-3-a (HPLC-MS: (M+H)). + =268,t Ret. =1.31min, method LCMS3, basisch_1).

[1129] Experimental procedure for the synthesis of A-2-a

[1130] C-1-a (35.83 g; 15.2 mmol), cesium carbonate (2.0 M in water; 124.14 g; 38.1 mmol), and PdCl2 (dppf) (10.37 g; 1.13 mmol, 0.1 equivalent) were added to a stirred solution of A-3-a (34.0 g; 12.7 mmol) in 1,4-dioxane (340.0 mL). The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with EtOAc (2 × 250 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the desired product A-2-a (HPLC-MS: (M+H)). + =341,t Ret .=1.14min, method LCMS3, basisch_1).

[1131] Experimental procedure for the synthesis of A-1-a

[1132] Dioxane (250.0 mL) containing 4.0 M was added to a stirred solution of A-2-a (50.0 g; 14.7 mmol) in 1,4-dioxane (500.0 mL) at 0 °C. The reaction mixture was stirred at rt for 6 h. The reaction mixture was filtered off and washed with EtOAc (2 × 200 mL). The obtained solid was dissolved in water (400 mL) and cooled to 0 °C, and the pH was adjusted to 9 using a 1 N NaOH aqueous solution. The precipitate was filtered off and washed with diethyl ether (2 × 250 mL) to give A-1-a (HPLC-MS: (M + H)).+ =241,t Ret. =0.59min, method LCMS3, basisch_1)

[1133] Substitutional Synthesis of Block A-4-a

[1134]

[1135] Experimental procedure for the synthesis of D-3-a

[1136] A solution of D-4-a (2.825 g, 34.409 mmol, 1.0 equivalent) in acetonitrile (21.0 mL) was added to a solution of malonyl chloride (5.00 g, 34.409 mmol, 1.0 equivalent) in acetonitrile (37.5 mL) at a rate controlled below 15 °C. The reaction mixture was stirred at 20 °C under nitrogen for 15 h, then filtered and washed with acetonitrile (19.5 mL). The resulting solid was dried under vacuum at 50 °C under nitrogen venting to give the desired product D-3-a. 1 H-NMR(500MHz,DMSO-d6)δ5.77(1H,s),2.37(3H,s)).

[1137] Experimental procedure for the synthesis of D-2-a

[1138] Phosphorus oxychloride (10.0 g, 65.181 mmol, 3.3 equivalents) was added to a suspension of D-3-a (6.61 g, 19.752 mmol, 1.0 equivalents) and benzyltriethylammonium chloride (4.50 g, 19.752 mmol, 1.0 equivalents) in acetonitrile (13.2 mL) at 20 °C. The mixture was stirred at 20 °C for 3 h, then heated to 78 °C and held for 8 h. The mixture was cooled to 22 °C and toluene (46.3 mL) was added. The mixture was cooled to 15 °C, and water (15.8 mL) was added at a rate that kept the internal temperature below 25 °C. A solution of sodium hydroxide (50% in water, 12.64 g, 158.015 mmol, 8.0 equivalents) in water (9.9 mL) was added at a rate that kept the temperature below 25 °C to achieve pH 7.4. The mixture was filtered through diatomaceous earth and washed with toluene (27.8 mL). The aqueous phase was removed, and the organic phase was washed with water (9.9 mL). The organic phase was recycled through a carbon filter, and then the toluene was removed by vacuum distillation. Methylcyclohexane (66 mL) was added, and vacuum distillation was continued. The mixture was heated to 70 °C until a clear solution was obtained, and then cooled to 20 °C. The mixture was filtered, and the solid was washed with heptane (13.2 mL) to give the desired product D-2-a( 1H-NMR(500MHz,DMSO-d6)δ8.01(1H,s),2.70(3H,s)).

[1139] Experimental procedure for the synthesis of A-3-a (via A-4-a and A-5-a)

[1140] A solution of D-2-a (3.04 g, 15.622 mmol, 1.0 equivalent) in heptane (30.4 mL) containing 1 M diisobutylaluminum hydrogenation was added at -30 °C at a rate maintained below -20 °C. The mixture was stirred at -25 °C for 50 min, followed by the addition of EtOAc (1.1 g, 12.497 mmol, 0.8 equivalent) at a rate maintained below -20 °C. The mixture was then heated to -10 °C and stirred for 15 min. A solution of tartaric acid (2.58 g, 17.184 mmol, 1.1 equivalent) in water (11.4 mL) was added at a rate maintained below 5 °C. The mixture was then heated to 5 °C and stirred for 15 min. A solution of sodium potassium tartrate tetrahydrate (4.41 g, 15.622 mmol, 1.0 equivalent) in water (11.4 mL) was added to adjust the pH to 6.5, and the mixture was heated to rt. Isopropyl acetate (18 mL) was added, and the mixture was stirred at rt for 1.5 h. The aqueous phase was removed, and heptane / isopropyl acetate was removed by vacuum distillation until approximately 9 mL remained. EtOH (30 mL) was then added, and distillation was continued until approximately 12 mL (→ A-5-a) remained. Hydrazine hydrate (55% in water, 4.24 g, 46.865 mmol, 3.0 equivalent) was added to this solution of A-5-a in EtOH, and the mixture was heated at 78 °C for 12 h. The mixture was cooled to rt, and 2-methyltetrahydrofuran (30 mL) and water (15 mL) were added. The mixture was stirred for 15 min, and then the aqueous phase was removed. 2-Methyltetrahydrofuran was removed by vacuum distillation until approximately 6 mL remained. Acetonitrile (30 mL) was then added, and distillation continued until approximately 6 mL remained (→ A-4-a). The mixture was cooled to rt, and then TEA (4.74 g, 46.865 mmol, 3.0 equivalent) was added, followed by acetonitrile (1.5 mL) containing DMAP (0.191 g, 1.562 mmol, 0.1 equivalent) and acetonitrile (6.0 mL) containing di-tert-butyl dicarbonate (4.43 g, 20.308 mmol, 1.3 equivalent). The mixture was aged at rt for 40 min, followed by the addition of water (24 mL) after 1 h. The mixture was stirred at rt for 1 h, followed by filtration to collect A-3-a. The solid was washed with water (6 mL) and then dried under vacuum at 40 °C. 1H-NMR (500MHz, CDCl3) δ8.22(s,1H),7.93(s,1H),2.83(s,3H),1.73(s,9H)).

[1141] Synthesis of A-1-b

[1142]

[1143] Experimental procedure for the synthesis of A-3-b

[1144] p-TsOH (0.3 g; 172.1 mmol) and 2,3-dihydro-4H-pyran (4.5 g; 84 mmol) were added to a suspension of A-4-a (3.0 g; 167.6 mmol) in EtOAc (70.0 mL), and the mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was 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. =0.850min, method VAB).

[1145] Experimental procedure for the synthesis of A-2-b

[1146] C-2-a (100.0 mg; 0.39 mmol), copper iodide (I) (3.0 mg; 0.02 mmol), cesium fluoride (120.7 mg; 0.80 mmol), and PdCl2 (dppf) (30.6 mg; 0.04 mmol) were added to a stirred solution of A-3-b (179.3 mg; 0.44 mmol) in DMF (4.0 mL). The reaction mixture was stirred at 100 °C under argon atmosphere for 3 h. The reaction mixture was poured into water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by reversed-phase chromatography (HPLC) to obtain the desired product A-2-b (HPLC-MS: (M+H)). + =337,t Ret. =0.852 min, method VAB).

[1147] Experimental procedure for the synthesis of A-1-b

[1148] Dioxane (0.8 mL) containing 4.0 M HCl was added to a stirred solution of A-2-b (54.0 mg; 0.16 mmol) in DCM (1.5 mL) under reflux. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was then concentrated under reduced pressure to give A-1-b (HPLC-MS: (M+H)). +=253.3, t Ret. =0.623min, method VAB).

[1149]

[1150] Hexabutyltin (4.7 g; 8.1 mmol), DIPEA (1.49 mL, 8.1 mmol), and Pd(PPh3)4 were added to a stirred solution of C-3-a (400.0 mg; 1.62 mmol) in degassed toluene under stirring conditions, and the mixture was stirred at 130 °C for 2 h in a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in EtOAc and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by normal-phase chromatography (hexane / EtOAc) to obtain the desired product C-2-a (HPLC-MS: (M+H)). + =412.2, t Ret = 2.33 min, method GVK_LCMS_41)

[1151] The following intermediate A-1 (Table 1) can be obtained in a similar manner using different structural blocks A-7, A-3, C-1 and C-2 as starting materials.

[1152] Table 1:

[1153]

[1154]

[1155] Synthetic intermediate B-1

[1156] Synthesis of B-1a-a

[1157]

[1158] B-2-a (3.84 mL, 43.6 mmol) was added to the starting material B-3a-a (1.5 g, 4.36 mmol). The reaction mixture was stirred at 140 °C for 1 h under microwave irradiation. The pure product B-1a-a was obtained by normal-phase chromatography using DCM / MeOH.

[1159] The following intermediates B-1a, B-1b, B-1c*, B-1d* and B-1e* (Table 2) can be obtained in a similar manner using different structural blocks B-3a, B-3b, B-3c*, B-3d* and B-3e* as starting materials.

[1160] Table 2:

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171] Synthesis of B-1a-s

[1172]

[1173] B-2-b (75.0 mg; 0.78 mmol) and Cs₂CO₃ (500 mg; 1.54 mmol) were added to a stirred solution of B-3a-d (100 mg; 0.44 mmol) in AcCN (0.50 mL). The mixture was stirred at 75 °C for 48 h. B-1a-s was obtained by preparative HPLC.

[1174] Synthesis of B-1b-g

[1175] NaH (32 mg; 0.80 mmol) was added to a solution of B-2-c (75 mg; 0.20 mmol) in DMSO. After stirring at ambient temperature for 5 min, B-3b-a was added to the reaction mixture and stirring continued for 3 days. The pure product B-1b-g was obtained by preparative HPLC 1 purification.

[1176] The following intermediates B-1a and B-1b (Table 3) can be obtained in a similar manner using different structural blocks B-3a and B-3b as starting materials.

[1177] Table 3:

[1178]

[1179]

[1180] Synthesis of B-1a-z

[1181]

[1182] B-3a-a (250 mg, 0.73 mmol), B-2-d (141 mg, 0.80 mmol), Pd(II)dppf Cl2*CH2Cl2 (61 mg, 0.07 mmol), and sodium carbonate (196 mg, 1.82 mmol) were suspended in dioxane (2.0 mL) and water (1.0 mL). The reaction mixture was stirred at 100 °C for 1 h under microwave irradiation. The unsaturated intermediate was purified by NP 1 and used directly in the next step.

[1183] An unsaturated intermediate (215 mg; 0.62 mmol), EtOH (5.0 mL), and tris(triphenylphosphine)rhodium(I) chloride (113 mg; 0.12 mmol) were charged into a BUCHI laboratory autoclave. The mixture was stirred at 5 bar H₂ pressure for 16 h. The reaction mixture was diluted with DCM and saturated NaHCO₃ aqueous solution and extracted. The organic phase was dried over MgSO₄, filtered, and the solvent was evaporated under reduced pressure to give B-1a-z.

[1184] Synthesis of B-1b-i

[1185]

[1186] Pd(II)dppfCl2*CH2Cl2 (61 mg; 0.07 mmol), sodium carbonate (196 mg; 1.82 mmol), and B-2-e (77 mg; 0.90 mmol) were added to a stirred solution of B-3b-a (130 mg; 0.37 mmol), and the mixture was stirred for 16 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic phase was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC to give B-1b-1.

[1187] The following intermediates B-1a, B-1b, B-1c*, B-1d* and B-1e* (Table 4) can be obtained in a similar manner using different structural blocks B-3a, B-3b, B-3c*, B-3d* and B-3e* as starting materials.

[1188] Table 4:

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196] Synthetic intermediate B-3

[1197] Synthesis of B-3a-a

[1198]

[1199] Starting materials B-5a-a (30.0 g, 126.9 mmol) and B-4-a (18.3 g, 126.9 mmol) were suspended in AcCN. The reaction mixture was stirred at 60 °C for 3 h under microwave irradiation. The reaction mixture was diluted with DCM, mixed with a semi-saturated aqueous NH4Cl solution, and extracted once. The organic phase was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure to give B-3a-a.

[1200] The following intermediates B-3a and B-3b (Table 5) can be obtained in a similar manner using different structural blocks B-5a and B-5b as starting materials.

[1201] Table 5:

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209] Synthesis of B-3c*-a

[1210]

[1211] Experimental procedure for the synthesis of B-17-a

[1212] NaH (32.46 mL; 814.98 mmol) was added dropwise to a stirred solution of B-18-a (65.0 g; 271.6 mmol) in DMF (650.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, followed by the addition of ethyl chloroacetate at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into ice water (2000 mL), the precipitate was filtered, and dried under vacuum to give B-17-a (HPLC-MS: (M+H)). + =326,t Ret .=1.41min, method LCMS3, basisch_1).

[1213] Experimental procedure for the synthesis of B-16-a

[1214] Hydrazine hydrate (500 mL) was added to a stirred solution of B-17-a (75.0 g; 230.52 mmol) in EtOH (1000 mL) under reflux. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was cooled to reflux, and the precipitate was filtered, washed with EtOAc, and dried under vacuum to give B-16-a.

[1215] Experimental procedure for the synthesis of B-15-a

[1216] B-16-a (160 g; 538.15 mmol) was dissolved in acetic acid (1500 mL), and the reaction mixture was stirred at rt for 16 h. Diethyl ether (2500 mL) was then added to the reaction mixture, and the precipitate was filtered and dried under vacuum to give B-15-a (HPLC-MS: (M+H)). + =266.1, t Ret = 0.775 min, method VAB).

[1217] Experimental procedure for the synthesis of B-14-a

[1218] A solution of sodium nitrite (45.52 g, 659.72 mmol) in water was added to a stirred solution of B-15-a (35.0 g; 131.65 mmol) in 1500 mL of 4N HCl aqueous solution. The reaction mixture was allowed to reach settling temperature (rt) over a period of 16 h. The precipitate was filtered, washed with water (500 mL), and dried under vacuum to obtain B-14-a (HPLC-MS: (M+H)). + =251.0, t Ret. =0.92min, method LCMS3, basisch_1).

[1219] Experimental procedure for the synthesis of B-3c*-a

[1220] POCl3 (400.0 mL), DIPEA (76.0 mL; 459.54 mmol), and PCl5 (19.1 g; 91.91 mmol) were added to a stirred solution of B-14-a (23.0 g; 91.91 mmol) in toluene (100.0 mL) at 0 °C. The reaction mixture was then stirred under reflux for 48 h. POCl3 and toluene were removed under reduced pressure, and the resulting residue was dissolved in EtOAc (1000 mL) and extracted with saturated NaHCO3 aqueous solution (2 × 1000 mL), followed by washing with brine (500 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was 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 min, method GVK_LCMS_61).

[1221] Synthesis of B-3d*-a

[1222]

[1223] Experimental procedure for the synthesis of B-23-a

[1224] The stirred solution of B-24-a (500.0 g; 2.74 mol) in THF (5.0 L) was cooled to -78 °C. Hexane (1.7 L; 2.74 mol) containing 1.6 M n-butyllithium was added under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 60 min, followed by dropwise addition of ethyl formate (220.45 mL; 2.74 mol) at -78 °C, and stirring of the reaction mixture at -78 °C for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (2 × 2.0 L). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by normal-phase chromatography (EtOAc / hexane 0:10) to obtain the desired product B-23-a (HPLC-MS: t...). Ret = 2.11 min, method GVK_LCMS_41).

[1225] Experimental procedure for the synthesis of B-22-a

[1226] The stirred solution of B-23-a (170 g; 807.8 mmol) in THF (1.7 L) was cooled to -78 °C. Then, THF containing 2 M methyl magnesium (807.8 mL, 1.62 mol) was added under nitrogen. The reaction mixture was stirred at -78 °C for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (1 × 2.0 L). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by normal-phase chromatography (EtOAc / hexane 5:20) to obtain the desired product B-22-a (HPLC-MS: t...). Ret = 1.75 min, method GVK_LCMS_61).

[1227] Experimental procedure for the synthesis of B-21-a

[1228] N-methylmorpholine (131.7 g, 1.13 mol, 1.5 equivalents) was added to a stirred solution of B-22-a (170 g, 0.76 mol) in DCM (1.7 L) under reflux. The reaction mixture was stirred under reflux for 30 min. Tetrapropaneperruthenium perruthenate (8.7 g, 24.7 mmol) was then added and the reaction mixture was stirred under reflux for 4 h. The reaction mixture was filtered through a diatomaceous earth filter and washed with DCM (3000 mL). The solvent was evaporated under reduced pressure. The crude product was purified by normal phase chromatography (EtOAc / hexane 10:50) to give the desired product B-21-a (HPLC-MS: t Ret = 2.02 min, method GVK_LCMS_61).

[1229] Experimental procedure for the synthesis of B-19-a

[1230] DIPEA (256.7 mL, 1.43 mol) was added to a stirred solution of B-21-a (268 g; 1.19 mol) and glycine tert-butyl methyl ester B-20-a (259.0 g; 1.43 mol) in EtOH (2.6 L) under stirring. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with water (200 mL) and the solvent was removed under reduced pressure, followed by extraction with EtOAc (2 × 200 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by normal-phase chromatography (EtOAc / hexane 2:5) to obtain the desired product B-19-a (HPLC-MS: (M+H)). + =333.0, t Ret .=1.39min, method LCMS3, basisch_1).

[1231] Experimental procedure for the synthesis of B-3d*-a

[1232] Potassium tert-butoxide (16.84 g; 0.15 mol) was added to a stirred solution of B-19-a (100 g, 0.30 mol) in DME (800 mL) at -15 °C. The reaction mixture was stirred at -15 °C for 6 h. The reaction mixture was quenched with ice water (2 L), and the precipitate was filtered off, washed with n-pentane, and dried under vacuum to give B-3d*-a (HPLC-MS: (M+H)). + =315.0, t Ret .=1.67min, method LCMS3, basisch_1).

[1233] Synthesis of B-3e*-a

[1234]

[1235] Experimental procedure for the synthesis of B-30-a

[1236] A stirred solution of B-31-a (350.0 g; 2.2 mol) in trifluoroacetic anhydride (1.7 L) was cooled to 0 °C. Nitric acid (285.8 g; 4.5 mol) was then added dropwise at 0 °C, allowing the reaction mixture to reach settling temperature (rt) over an 18-hour period. The reaction mixture was quenched with sodium metabisulfite and stirred at rt for 2 hours. The reaction mixture was neutralized to pH 7 using an 8N NaOH aqueous solution and extracted with DCM (2 × 600 mL), followed by washing with brine. The combined organic layers were dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give the desired product B-30-a (HPLC-MS: (M+H)). + =207.0, t Ret = 2.62 min, method GVK_LCMS_41).

[1237] Experimental procedure for the synthesis of B-28-a

[1238] B-30-a (70.5 g; 0.48 mol) was added 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, and the reaction mixture was stirred at rt for 30 min. A solution of B-29-a (100.0 g; 0.48 mol) in diethyl ether (150 mL) was added to the reactants. The reaction mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure, and the solution was acidified to pH 4 using acetic acid, followed by extraction with EtOAc (2 × 600 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give the desired product B-28-a (HPLC-MS: (M+H)). + =307.0, t Ret = 2.37 min, method GVK_LCMS_41).

[1239] Experimental procedure for the synthesis of B-27-a

[1240] Iron (54.7 g; 0.98 mol) and an aqueous solution of ammonium chloride (750.0 mL) were added to a stirred solution containing B-28-a (50.0 g; 0.16 mol) in 1.75 L of EtOH and 0.75 L of EtOH. The reaction mixture was stirred at 90 °C for 5 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with hot EtOH and THF. The solvent was diluted in water and extracted with EtOAc (2 × 1 L). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the desired product B-27-a (HPLC-MS: (M+H)). + =269,t Ret = 2.25 min, method GVK_LCMS_41).

[1241] Experimental procedure for the synthesis of B-26-a

[1242] NIS (69.5 g; 0.31 mol) was added to a stirred solution of DCM (400 mL) and DMF (200 mL) containing B-27-a (40.0 g; 0.15 mol) under reflux for 24 h. The reaction mixture was quenched with ice water and extracted with DCM (2 × 2 L). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by normal-phase chromatography (EtOAc / petroleum ether 50:70) to obtain the desired product B-26-a (HPLC-MS: (M+H)). + =273.38, t Ret. =3.12min, method GVK_LCMS_41).

[1243] Experimental procedure for the synthesis of B-25-a

[1244] A stirred solution of B-26-a (50.5 g; 0.13 mol) in DMF (500 mL) was cooled to 0 °C, followed by the addition of NaH (6.3 g; 0.26 mol), and the reaction mixture was stirred at rt for 30 min. The reaction mixture was then cooled to 0 °C, followed by the addition of iodomethane (37.25 g; 0.26 mol). The reaction mixture was stirred at rt for 3 h, followed by quenching with water. The precipitate was filtered, washed with diethyl ether, and dried under vacuum to give B-25-a (HPLC-MS: (M+H)). + =398.90, t Ret. =2.73min, method GVK_LCMS_41).

[1245] Experimental procedure for the synthesis of B-3e*-a

[1246] Fe(acac)3 (1.77 g; 0.005 mol) was added to a stirred solution of B-25-a (20.0 g; 0.05 mol) in THF (400 mL) under rt, and the reaction mixture was cooled to 0 °C. Subsequently, 1 N MeMgBr solution (100 mL) was added at 0 °C, and the reaction mixture was allowed to reach rt over a period of 8 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was 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 min, method GVK_LCMS_61).

[1247] Synthesis of B-3f-a and B-3f-b

[1248]

[1249] Experimental procedure for the synthesis of B-3f-a

[1250] CDI (350 mg, 2.16 mmol) was added to a stirred solution of B-7-a (336 mg, 1.66 mmol) in DCE (6 mL), and the reaction mixture was stirred overnight at 50 °C. The residue was treated with AcCN (4 mL), and the precipitate was filtered, washed with AcCN, and dried overnight in a vacuum drying oven at 45 °C to obtain B-3f-a (HPLC-MS: (M+H)). + =218,t Ret = 0.50 min, method VAB).

[1251] Experimental procedure for the synthesis of B-3f-b

[1252] Sodium hydride (6.47 g, 161.69 mmol) was added to a stirred solution of B-3f-a (29.38 g, 134.75 mmol) in DMF (293.4 mL) at -5 °C, and the mixture was stirred for 10 min. Iodomethane (10.07 mL, 161.69 mmol) was added, and the mixture was stirred at -5 °C for 45 min. The reaction mixture was quenched with saturated NH4Cl (300 mL) and diluted with saturated brine (200 mL). The precipitate was 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 min, method XB5A).

[1253] Synthesis of B-3g-a

[1254]

[1255] Experimental procedure for the synthesis of B-3g-a

[1256] Methylhydrazine (0.023 mL; 0.445 mmol) was added to a stirred solution of B-34-a (50.00 mg; 0.223 mmol) in MeOH (1 mL) and stirred overnight at 60 °C. The reaction mixture was filtered and purified by preparative HPLC 3 to give the desired product B-3g-a (20 mg, 0.093 mmol) (HPLC-MS: (M+H). + =216,t Ret. =1.24min, method LCMS3, basisch_1).

[1257] The following intermediate B-3g (Table 6) can be obtained in a similar manner by using the construction of block B-34 and the corresponding hydrazine derivative as starting materials.

[1258] Table 6:

[1259]

[1260]

[1261] Synthesis of B-3h-a

[1262]

[1263] Experimental procedure for the synthesis of B-3h-a

[1264] A solution of B-36-a (200.0 mg; 0.975 mmol) in concentrated HCl (2.0 mL) was stirred at rt for 10 min and cooled to 0 °C. Then, water containing NaNO2 (79.594 mg; 1.170 mmol) was added dropwise at -5 °C, and the mixture was stirred at 0 to -5 °C for 15 min. Concentrated HCl containing SnCl2*2H2O (511.507 mg; 2.243 mmol) was added dropwise, and the reaction mixture was stirred for 30 min. The reaction mixture was then filtered, washed with water and NaHCO3 aqueous solution, and air-dried. The crude substance was purified by rapid column chromatography using 0–30% EtOAc / PE as eluent to obtain the desired product B-3h-a (50.0 mg, 0.247 mmol) (HPLC-MS: (M+H). + =202,t Ret. =1.93min, method GVK_LCMS_41).

[1265] Experimental procedure for the synthesis of B-3h-b

[1266] Dimethyl sulfate (25.0 μL, 0.258 mmol) was added dropwise 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) while stirring at rt for 30 min. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give B-3h-b (22.00 mg, 0.102 mmol) (HPLC-MS: (M+H)). + =216,t Ret. =1.23min, method LCMS3, basisch_1).

[1267] Synthesis of B-3a-c

[1268]

[1269] Experimental procedure for the synthesis of B-10-a

[1270] The stirred solution of B-7-a (200 mg, 1.04 mmol) in DCM (10 mL) was cooled to -20 °C. B-11-a (120 mg, 1.25 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred at -20 °C for 2 h. The reaction mixture was alkalized with sodium carbonate (saturated aqueous solution). The aqueous phase was extracted with DCM. The organic layer was concentrated to dryness. The crude compound was purified (normal phase chromatography) to give the desired product B-10-a (HPLC-MS: (M+H)). + =248.0, t Ret. =1.46min, method TCG_LCMS, basisch_1).

[1271] Experimental procedure for the synthesis of B-3a-c

[1272] Add 1,4-dioxane (10 mL) and acetic acid (1.0 mL, 15.5 mmol, 8.7 equivalents) to B-10-a (500 mg, 2.0 mmol). Heat the reaction mixture to 110 °C. After complete conversion, evaporate the solvent. Basicilize the residue with sodium bicarbonate (saturated aqueous solution). Extract the aqueous layer with EtOAc. Evaporate the solvent and purify the residue (normal phase chromatography, mobile phase cyclohexane / EtOAc) to give B-3a-c.

[1273] The intermediate B-10 (Table 7) can also be obtained by synthesizing B-10-a similarly to the starting material of different structural blocks B-7 and B-11.

[1274] Table 7:

[1275]

[1276] Synthesis of B-3a-d

[1277]

[1278] Acetic acid (100 mL, 1740 mmol, 10 equivalents) and polyphosphoric acid (135 mL, 2320 mmol, 13.3 equivalents) were added to B-7-a (34.7 g, 174.8 mmol, 1 equivalent). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to rt, diluted with water, and alkalized to pH 8 with 6N sodium hydroxide aqueous solution. The aqueous phase was extracted with DCM. The organic layer was concentrated to dryness, and the residue was purified (normal phase chromatography, mobile phase cyclohexane / EtOAc 35% to 95%) to give B-3a-d.

[1279] Synthesis of B-3a-e

[1280]

[1281] B-7-a (2.8 g, 14.58 mmol, 1 equivalent), trimethyl orthoformate (30 mL, 274 mmol, 18.8 equivalent), and acetic acid (3 mL, 52 mmol, 3.6 equivalent) were charged into a pressure reactor. The reaction mixture was stirred at 100 °C for 16 h. After cooling, the reaction mixture was alkalized with an aqueous sodium bicarbonate solution. The aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by normal-phase chromatography (mobile phase cyclohexene / EtOAc) to give B-3a-e.

[1282] Synthesis of B-3a-g

[1283]

[1284] At 0 °C, a solution of B-3a-f (18.0 g, 77.56 mmol) in DCM (270.0 mL) was added with Dysmart reagent (39.46 g, 93.08 mmol, 1.2 equivalents) and stirred at rt for 12 h. The reaction mixture was diluted with saturated NaHCO3 solution (500.0 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude substance was 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 material B-3a-f can be obtained using glycolic acid as the carboxylic acid, similar to the synthesis described with respect to B-3a-d.

[1285] Synthesis of B-3a-h

[1286]

[1287] 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 for 10 min at rt. 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 and dissolved in DMF and water, filtered, and purified by preparative HPLC 1 to give B-3a-h (41.00 mg, 0.112 mmol).

[1288] The following intermediate B-3a (Table 8) can be obtained in a similar manner to that described for intermediates B-3a-c to B-3a-e, B-3a-g and B-3a-h.

[1289] The following intermediate B-3a (Table 8) can be obtained in a similar manner using different structural blocks B-7 and B-14 as starting materials.

[1290] Table 8:

[1291]

[1292]

[1293] Synthetic intermediate B-5

[1294] Synthesis of B-5a-a

[1295]

[1296] Experimental procedure for the synthesis of B-8-a

[1297] K₂CO₃ (165.9 g; 1.20 mol) was added to a stirred solution of B-9-a (100.0 g; 0.480 mol) in AcCN (1500 mL) at 0 °C and stirred for 15 min. Subsequently, MeI (186.2 mL; 2.90 mol) was added at the same temperature, and the reaction mixture was heated to 80 °C and maintained for 16 h. The solvent was removed under reduced pressure, and the crude product was partitioned between ice-cold water and EtOAc. The separated organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by rapid column chromatography using EtOAc / petroleum ether as eluent to obtain the desired product B-8-a (HPLC-MS: (M+H)). + =222.0; t Ret .=1.11min, method LCMS3, basisch_1).

[1298] Experimental procedure for the synthesis of B-7-a

[1299] NH4Cl (101.5 g; 1.91 mol) and water (100.0 mL) were added to a stirred solution of B-8-a (85.0 g; 0.383 mol) in EtOH (750 mL), and the mixture was stirred for 10 min. Then, iron (105.3 g; 1.91 mol) was added. The reaction mixture was stirred at 90 °C for 16 h. After complete conversion, the reaction mixture was evaporated under vacuum and dissolved in EtOAc and water, then filtered through a diatomaceous earth mat. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain a crude product. This crude product was wet-milled with 5% EtOAc / petroleum ether, stirred for 30 min, filtered, and dried under vacuum to obtain B-7-a (HPLC-MS: (M+H)). + =192.0; t Ret .=0.81min, method LCMS3, basisch_1).

[1300] Experimental procedure for the synthesis of B-6a-a

[1301] 1,1'-Thiocarbonyldiimidazole (139.0 g; 0.781 mol) was added to a stirred solution of B-7-a (75.0 g; 0.391 mol) in THF (600 mL). The reaction mixture was stirred at 80 °C for 24 h, then cooled to rt and evaporated to dryness. EtOAc was added to the residue and the mixture was extracted with water. The organic layer was washed with water, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give a crude product, which was wet-milled 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 min, method GVK_LCMS_41).

[1302] Experimental procedure for the synthesis of B-5a-a

[1303] A solution of B-6a-a (60.0 g; 0.256 mol) in thionyl chloride (600 mL) and DMF (120 mL) was stirred at 80 °C for 30 min. The reaction mixture was evaporated under vacuum, diluted with EtOAc, and extracted with saturated NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product. This crude product was purified by normal-phase chromatography using DCM / petroleum ether to give B-5a-a (HPLC-MS: (M+H)). + =236.0, t Ret = 2.03 min, method GVK_LCMS_41).

[1304] Alternative synthesis B-5a-a

[1305]

[1306] Experimental procedure for the synthesis of E-4-a

[1307] EtOH containing methylamine (33 wt%, 10.0 mL, 73.04 mmol, 5.33 equivalents) was added to a suspension of 2,4,6-trichloropyridine (2.5 g, 13.7 mmol, 1.0 equivalent) in EtOH (2.5 mL) at 80 °C for 4 h. The mixture was stirred at 80 °C for 4 h, followed by cooling to rt for 2 h. The mixture was stirred at rt for 1 h, followed by filtration. The solid was washed sequentially with water (5.0 mL), heptane (2.5 mL), and MTBE (2.5 mL). The solid was dried under vacuum at 50 °C, followed by slurrying with MTBE (10.0 mL) at rt for 1 h. The mixture was filtered, followed by washing with MTBE (2.5 mL). The solid was dried under vacuum at 55 °C to give E-4-a( 1 H-NMR (500MHz, DMSO-d6) δ7.35 (d, J = 5Hz, 1H), 6.51 (s, 2H), 2.72 (d, J = 5Hz, 3H)).

[1308] Experimental procedure for the synthesis of E-3-a

[1309] A suspension of E-4-a (5.0 g, 27.715 mmol, 1.0 equivalent) and N-iodosuccinimide (6.55 g, 29.101 mmol, 1.05 equivalent) in acetonitrile (30 mL) was heated to 80 °C and maintained for 8 h. The mixture was cooled to rt after 1 h, and then water (20 mL) was added after 1 h. The mixture was cooled to rt and stirred at rt for 1 h. The mixture was filtered, and the solid was then washed with water (13 mL). The solid was dried under vacuum at 55 °C to give E-3-a ( 1 H-NMR (500MHz, DMSO-d6) δ6.58 (d, J = 4Hz, 1H), 6.45 (s, 1H), 2.82 (d, J = 4Hz, 3H)).

[1310] Experimental procedure for the synthesis of E-2-a

[1311] A solution of chlorosulfonyl isocyanate (2.32 g, 25.107 mmol, 1.3 equivalents) in 2-methyltetrahydrofuran (6 mL) was added at -15 °C to 30 mL of 2-methyltetrahydrofuran containing E-3-a (5.97 g, 19.313 mmol, 1.0 equivalents) to maintain the temperature below -5 °C. The mixture was stirred at -10 °C for 1 h, followed by the addition of 2.0 M sodium hydroxide solution (3.92 equivalents) at a rate maintaining the temperature below 18 °C. The mixture was cooled to 0 °C and stirred at that temperature for 1 h, followed by filtration. The solid was washed with water (12 mL) and isopropyl acetate (12 mL). The solid was then dried under vacuum at 55 °C to give E-2-a ( 1 H-NMR (400MHz, DMSO-d6) δ7.58(s,1H),6.25(s,2H),3.05(s,3H)).

[1312] Experimental procedure for the synthesis of B-3f-a

[1313] N,N-diisopropylethylamine (9.37 mL, 53.765 mmol, 2.0 equivalent) was added to a suspension of E-2-a (10.0 g, 26.883 mmol, 1.0 equivalent), copper iodide (I) (57.5 mg, 0.5 mmol, 0.02 equivalent), and 1,10-phenanthroline (48.5 mg, 0.269 mmol, 0.01 equivalent) in acetonitrile (100 mL). The mixture was heated at 80 °C for 18 h, followed by cooling to rt. The mixture was filtered and washed with acetonitrile (10 mL). The filtrate was then vacuum distilled until 50 mL of solution remained. The mixture was then filtered to collect a second batch of solids. The combined batches of solids were treated at 40 °C with acetonitrile (5 mL) and 10 wt% ammonium chloride (aqueous solution, 10 mL). The mixture was stirred at 40 °C for 2 h, followed by cooling to rt and filtration. The solid was dried under vacuum at 55°C to obtain B-3f-a( 1 H-NMR (400MHz, DMSO-d6) δ11.86(br s,1H),7.40(s,1H),3.30(s,3H)).

[1314] Experimental procedure for the synthesis of B-5a-a

[1315] A suspension of B-3f-a (2.54 g, 11.16 mmol, 1.0 equivalent) and benzyltriethylammonium chloride (5.08 g, 22.32 mmol, 2.0 equivalent) in phosphorus oxychloride (9.41 g, 61.386 mmol, 5.5 equivalent) 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 maintaining the temperature below 50 °C. The mixture was cooled to 25 °C, and then 30 wt% sodium hydroxide (22 equivalents) was added to adjust the pH to 7.4. The mixture was then filtered and washed 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 toluene was removed by vacuum distillation until 7.5 mL remained. The mixture was cooled to rt, heptane (7.6 mL) was added, and the mixture was stirred at rt for 1 h, followed by filtration. The solid was washed with water (5 mL) and then dried at 50 °C to obtain B-5a-a( 1 H-NMR(500MHz,DMSO-d6)δ7.99(s,1H),3.82(s,3H)).

[1316] Synthesis of B-5b-a

[1317]

[1318] Experimental procedure for the synthesis of B-12-a

[1319] Water (300 mL) and NH4Cl (178.1 g; 3.30 mol) were added to a stirred solution of B-13-a (150.0 g; 0.66 mol) in EtOH (1200 mL). Iron powder (181.4 g; 3.30 mol) was then slowly added, and the reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was filtered through a diatomaceous earth mat, and the solvent was evaporated under vacuum. The remaining residue was dissolved in EtOAc and extracted with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain a crude substance. This crude substance was stirred with petroleum ether for 1 h, filtered, and washed with petroleum ether to obtain B-12-a (HPLC-MS: (M+H)). + =197.0, t Ret = 0.817 min, method VAB).

[1320] Experimental procedure for the synthesis of B-6b-a

[1321] O-ethyl dithiocarbonate (3.00 g; 18.7 mmol) was added to a stirred solution of B-12-a (2.46 g; 12.5 mmol) in AcCN (50 mL). The reaction mixture was stirred at 80 °C for 3 days. The mixture was diluted with water and extracted with DCM. The product containing the aqueous phase was acidified with 1 N HCl aqueous solution and extracted with DCM. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum to give B-6b-a (HPLC-MS: (M+H)). + =237.1, t Ret = 0.562 min, method VAB).

[1322] Experimental procedure for the synthesis of B-5b-a

[1323] Oxalate chloride (0.5 mL; 5.80 mmol) was added to a stirred solution of B-6b-a (1.10 g; 4.64 mmol) in 1,2-dichloroethane. DMF (0.36 mL; 4.64 mmol) was then added dropwise while the mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to rt, diluted with DCM and water, and extracted. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum to give B-5b-a (HPLC-MS: (M+H)). + =252.1, t Ret = 0.909 min (method VAB).

[1324] Synthesize compound (I) according to the present invention.

[1325] Synthetic I-001

[1326]

[1327] B-1b-b (80 mg, 0.2 mmol, 1 equivalent), A-1-a (50 mg, 0.2 mmol, 1 equivalent), tris(dibenzylidene-acetone)dipalladium(0) (18 mg, 0.02 mmol, 0.1 equivalent), and tert-butylXPhos (18 mg, 0.04 mmol, 0.2 equivalent) were placed in a pressure vessel. Toluene (1 mL) and 1,4-dioxane (1 mL) were added, and the reaction mixture was purged with argon. Sodium tert-butoxide (2 M in THF; 155 μL, 0.34 mmol, 1.75 equivalent) was added, and the reaction mixture was heated (microwave irradiated) to 125 °C and maintained for 20 min. The reaction mixture was purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-001.

[1328] Synthesis of I-002, I-003 and I-004

[1329]

[1330] Step 1

[1331] B-1b-d (180 mg, 0.4 mmol), A-1-a (100 mg, 0.4 mmol, 1 equivalent), tris(dibenzylidene-acetone)dipalladium(0) (36 mg, 0.04 mmol, 0.1 equivalent), and tert-butylXPhos (36 mg, 0.04 mmol, 0.2 equivalent) were placed in a pressure vessel. Toluene (1 mL) and 1,4-dioxane (1 mL) were added, and the reaction mixture was purged with argon. Sodium tert-butoxide (2 M in THF; 320 μL, 0.7 mmol, 1.75 equivalent) was added, and the reaction mixture was heated (microwave irradiated) to 125 °C and maintained for 20 min. The reaction mixture was purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-002.

[1332] Step 2

[1333] I-002 (140 mg, 0.21 mmol) was dissolved in DCM (2.5 mL). Trifluoroacetic acid (0.5 mL, 6.5 mmol, 30 equivalences) was added, and the reaction mixture was stirred at rt for 4 h. An aqueous solution of potassium bicarbonate was added, and the aqueous layer was alkalized by extraction with DCM. The organic phase was dried over sodium sulfate and filtered off. The filtrate was reduced to dryness to give I-003.

[1334] Step 3

[1335] I-003 (40 mg, 0.07 mmol) was dissolved in a mixture of DCM (1 mL) and MeOH (1 mL). Glacial acetic acid (8.3 μL, 0.14 mmol, 2 equivalents) and formaldehyde (37% in water; 16 μL, 0.21 mmol, 3 equivalents) were added, and the reaction mixture was stirred at rt for 10 min. Sodium cyanoborohydride (23.8 mg, 0.36 mmol, 5 equivalents) was added, and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water, and the aqueous phase was extracted with DCM. The solvent was evaporated, and the residue was purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-004.

[1336] Synthesis of I-069, I-070 and I-071

[1337]

[1338] Step 1

[1339] B-1c*-b (3.80 g; 12.63 mmol), A-1-1 (3.25 g; 12.85 mmol), tris-(dibenzylacetone)-dipalladium(0) (750 mg, 0.80 mmol), and tert-butylXPhos (750 mg, 1.68 mmol) were placed in a flask. Toluene (100 mL) was added, and the reaction mixture was purged with argon. Sodium tert-butoxide (2 M in THF; 12.5 mL, 25.0 mmol) was added, and the reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was purified (normal phase chromatography, mobile phase DCM / MeOH) to give I-069.

[1340] Step 2

[1341] I-069 (1.56 g; 2.97 mmol) was dissolved in EtOH (15.0 mL) and water (5 mL), and LiOH (0.5 g; 20.5 mmol) was added. The reaction mixture was stirred under reflux for 6.5 h. The mixture was evaporated to dryness, slurried with water, and acidified to pH 5 with 1 N HCl aqueous solution. The resulting residue was filtered, washed with water, and freeze-dried to give I-070.

[1342] Step 3

[1343] I-070 (1.10 g; 2.22 mmol) was dissolved in AcCN (15.0 mL) and DIPEA (1.00 mL; 5.70 mmol). HATU (1.50 g; 3.75 mmol) was added to the solution, and the mixture was stirred at rt for 30 min. Morpholine (0.35 mL; 4.05 mmol) was added, and stirring was continued at rt for 17 h. The reaction mixture was purified (normal phase chromatography, mobile phase DCM / MeOH / NH4OH) to give I-071.

[1344] Synthesis of I-082, I-083 and I-084

[1345]

[1346] Step 1

[1347] B-1d*-a (1.80 g, 4.67 mmol), A-1-a (1.40 g, 5.54 mmol), tris-(dibenzylacetone)-dipalladium(0) (350 mg, 0.38 mmol), and tert-butylXPhos (330 mg, 0.74 mmol) were placed in a flask. Toluene (45 mL) was added, and the reaction mixture was purged with argon. Sodium tert-butoxide (2 M in THF; 4.5 mL, 9.00 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was purified (preparative HPLC 1) to give I-082.

[1348] Step 2

[1349] I-082 (1.18 g; 2.07 mmol) was dissolved in 1,4-dioxane (16.0 mL), and 1,4-dioxane containing 4N hydrogen chloride (4.0 mL; 46.67 mmol) was added. The reaction mixture was stirred at 65 °C for 3.5 h and then cooled to rt. The resulting precipitate was filtered off, washed with 1,4-dioxane, and dried under vacuum to give I-083.

[1350] Step 3

[1351] I-083 (1.10 g; 1.90 mmol) was dissolved in NMP (10.0 mL) and DIPEA (1.75 mL; 10.24 mmol). HATU (1.00 g; 2.50 mmol) was added to the solution, and the mixture was stirred at 30 °C for 30 min. Pyrrolidine (0.20 mL; 2.32 mmol) was added, and stirring was continued at 30 °C for 1 h. The mixture was diluted with water and extracted with DCM. The solvent was evaporated, and the residue was purified (normal phase chromatography, mobile phase DCM / MeOH / NH4OH) to give I-084.

[1352] Synthetic I-126

[1353]

[1354] In a pressure vessel, I-107 (150 mg; 0.27 mmol), p-toluenesulfonic acid (467 mg; 2.71 mmol), and lithium chloride (115 mg; 2.71 mmol) were suspended in NMP and stirred at 180 °C for 25 min under microwave irradiation. The reaction mixture was purified by preparative HPLC 1 to obtain I-126.

[1355] The following compounds (I) (Tables 9 and 10) can be obtained in a manner similar to that described with respect to compounds I-001 to I-004, I-069 to I-071, I-082 to I-084 and I-126, or by further derivatizing the compounds (I) originally obtained in this manner.

[1356] Table 9:

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388] Table 10:

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403] The following examples describe the biological activity of the compounds according to the present invention, but the invention is not limited to these examples:

[1404] Ba / F3 cell model generation and proliferation analysis

[1405] Ba / F3 cell lines were ordered from DSMZ (ACC300, Lot 17) and grown at 37°C in a 5% CO2 atmosphere in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10 ng / mL IL-3. Plasmids containing the EGFR mutant were obtained from GeneScript. To generate an EGFR-dependent Ba / F3 model, Ba / F3 cells were transduced with a retrovirus containing a vector carrying an EGFR isoform. Platinum-E cells (Cell Biolabs) were used for retroviral encapsulation. The retrovirus was added to the Ba / F3 cells. To ensure infection, 4 μg / ml agglutinin was added and the cells were spin-fected. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10% to 20% were further cultured, and selection was initiated with 1 μg / ml puromycin. As a control, parental Ba / F3 cells were used to demonstrate the selection status. Selection was considered successful when the parental Ba / F3 cell culture died. To assess the transformation potential of the EGFR mutation, IL-3 was no longer supplemented in the growth medium. Ba / F3 cells carrying the blank vector were used as a control. Ba / F3 cells were converted from IL-3 to EGF using wild-type EGFR known to be dependent on the EGF ligand. Puromycin was not used approximately ten days prior to the experiments. For proliferation analysis (data in Table 13), Ba / F3 cells were cultured in growth medium at 5 × 10⁶ cells / day. 3 100 μl cells / cell were seeded into 96-well plates. Compound was added using an HP D3000 digital dispenser. All treatments were repeated three times. Treated cells were incubated at 37°C and 5% CO2 for 72 h. CellTiter- Chemiluminescence cell viability analysis (Promega) was performed, and chemiluminescence was measured using a multi-label disk reader, VICTOR X4. Raw data were imported into Boehringer-Ingelheim proprietary software MegaLab (based on curve fitting of the PRISM program, GraphPad Inc.) for analysis.

[1406] Table A: Viability IC50 of Ba / F3 cell lines driven by specified EGFR paired genes and treated with specified compounds, in nM. 50 Value (showing the average data from two independent biological experiments with three technical replicates).

[1407]

[1408]

[1409]

[1410] Ba / F3 EGFR del19 T790M C797S proliferation analysis

[1411] Other compounds measured using the analysis described above are indicated by (*).

[1412]

[1413] pEGFR analysis

[1414] This analysis quantifies EGFR phosphorylation at Tyr1068 and measures the inhibitory effect of compounds on the transgenic EGFR del19 T790MC797S protein in Ba / F3 cells. Mouse Ba / F3 cells were grown at 37°C in a 5% CO2 atmosphere in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10 ng / mL IL-3 and transduced using a retroviral vector encoding EGFR del19T790MC797S. Transduced cells were selected using puromycin. After selection, IL-3 was extracted, and IL-3-independent cells were cultured. p-EGFR Tyr1068 was measured using the AlphaScreen Surefire pEGF receptor (Tyr1068) assay (PerkinElmer, TGRERS). For analysis, Ba / F3 EGFR del19 T790MC797S cells were seeded in DMEM medium containing 10% FCS. Using the Echo platform, 60 nL of compound dilution was added to each well of a Greiner TC 384 dish. Subsequently, 60 μL of 60,000 cells / well was added. Cells and compound were incubated together at 37°C for 4 h. After centrifugation and removal of the culture supernatant, 20 μL of 1.6-fold dissolution buffer from the TGR / Perkin Elmer kit and protease inhibitor were added. The mixture was incubated at room temperature with shaking (700 rpm) for 20 min. After centrifugation, 4 μL of the dissolved mixture was transferred to Proxiplates. 5 μL of the receptor mixture (1:25 diluted in activation buffer from combined reaction buffer 1 and reaction buffer 2 (TGRERS assay kit, Perkin Elmer) plus 1:50 of protein A receptor beads 6760137) was added to each well. The dish was shaken for 1 min (1400 rpm) and incubated at room temperature in the dark for 2 h. Add 3 μL of donor mixture (donor beads coated with AlphaScreen streptavidin (6760002, PerkinElmer) diluted 1:50 in dilution buffer (TGRERS assay kit, PerkinElmer)) to each well. Shake the disc for 1 min (1400 rpm) and incubate in the dark at room temperature for 2 h. Then analyze the disc using an Envision reader platform. Calculate the results as a ratio of the test compound value to the negative control (DMSO) value. (MEGASTARIC) 50 The application uses a 4-parameter logic model to calculate the IC based on these values. 50 value.

[1415] This dose-response analysis of phospho-EGFR (pEGFR) compounds quantified EGFR phosphorylation at Tyr1068 in F3 cells expressing the EGFR variant del19T790MC797S. The results of the analysis are provided as IC50. 50 Values ​​(see Table 9). Reported pEGFR IC50 values ​​for a given compound. 50 The lower the value, the stronger the compound's ability to inhibit the EGFR del19T790MC797S target protein in Ba / F3 cells.

[1416] PC-9EGFR del19 T790M C797S proliferation analysis

[1417] This analysis quantifies the antiproliferative effects of the compounds in Table 10 in PC-9EGFR del19 T790M C797S cells. PC-9 is a non-small cell lung cancer cell line obtained from the European Certified Cell Culture Association (ECACC#90071810; Lot No.: 14A030) that expresses an oncogenic variant of EGFR called EGFR del19. To generate the PC-9_TMCS_10 clone expressing EGFR del19 T790MC797S, genome engineering was used to introduce the mutant T790M and C797S into exon 20 of the EGFR locus in the PC-9 parental cells. Successful mutation introduction was verified using sequencing. Cells were seeded in 96-well plates (150 μL) in growth medium (RPMI-1640 (Gibco#12633012) + 10% FCS (HyClone#SH30071)). One day after cell seeding on plates, the compound was added using an HP D3000 digital dispenser. All treatments were repeated three times. The treated cells were cultured at 37°C and 5% CO2 for 96 hours. CellTiter- Chemiluminescence cell viability analysis (Promega) was performed, with chemiluminescence measured using a multi-label disk reader, VICTOR X4. Raw data were imported into Boehringer Ingelheim's proprietary software MegaLab (curve fitting based on R (library DLC)) for analysis. Cell viability was quantified by normalizing compound-treated cells with DMSO. Dose-response curves were calculated using a 4-parameter logistic regression model. The relative IC50 value was defined as the drug concentration at the inflection point of the dose-response curve.

[1418] The analysis results are provided to IC 50 Values ​​(see Table 10). The reported IC50 values ​​of a given compound on the cells mentioned above. 50 The lower the value, the stronger the anti-proliferation effect of the compound.

[1419] The following examples of formulations illustrate the invention but do not limit its scope:

[1420] Examples of pharmaceutical formulations

[1421]

[1422]

[1423] The finely powdered active ingredient, lactose, and some corn starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated, and dried. The granules, remaining corn starch, and magnesium stearate are sieved and mixed together. The mixture is pressed to produce tablets of suitable shape and size.

[1424]

[1425] The finely powdered active ingredient, some corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together. The mixture is sieved and processed with the remaining corn starch and water to form granules, which are then dried and sieved again. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is pressed to form tablets of suitable size.

[1426]

[1427] The active ingredient, lactose, and cellulose are mixed together. The mixture is sieved, then moistened with water, kneaded, wet-granulated and dried, or dry-granulated, or directly blended with magnesium stearate as a final compound, and compressed into tablets of suitable shape and size. When wet-granulating, additional lactose or cellulose and magnesium stearate are added and the mixture is compressed to produce tablets of suitable shape and size.

[1428] D) Ampoule solution

[1429] 50 mg of the active substance according to formula (I)

[1430] 50mg sodium chloride

[1431] 5mL of water for injection

[1432] The active ingredient is dissolved in water with its inherent pH or optionally between pH 5.5 and 6.5, and sodium chloride is added to make it isotonic. The resulting solution is filtered to remove pyrogens, and the filtrate is transferred to ampoules under aseptic conditions, followed by sterilization and fusion sealing. The ampoules contain 5 mg, 25 mg, and 50 mg of active ingredient.

Claims

1. A compound selected from the group consisting of: Or its salt.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, used as a medicine.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of diseases and / or conditions mediated by mutant EGFR.

4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of cancer.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, for treating cancer with tumor cells carrying a mutant EGFR gene.

6. The compound or a pharmaceutically acceptable salt thereof for the purpose according to any one of claims 2 to 5, wherein the compound or salt is administered before, after, or together with one or more other pharmacologically active substances.

7. The compound or a pharmaceutically acceptable salt thereof for the purpose according to any one of claims 2 to 5, wherein the compound or salt is administered in combination with one or more other pharmacologically active substances.

8. Use of a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions mediated by mutant EGFR.

9. Use of a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of cancer.

10. Use of a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancers with tumor cells carrying a mutant EGFR gene.

11. The use according to any one of claims 9 to 10, wherein the cancer is selected from lung cancer, brain cancer, colorectal cancer, bladder cancer, urethral cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer, and mesothelioma, including metastases of all the listed cancers.

12. The use according to claim 11, wherein the transfer is a brain transfer.

13. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

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