Cyclic 2-amino-3-cyanothiophenes and derivatives for the treatment of cancer

Abstract

The present application encompasses compounds of formula (I) wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 to R 5 , A, p, U, V, W, L and E have the meanings given in the claims and the description, the use of said compounds as inhibitors of mutant Ras family proteins, pharmaceutical compositions and formulations containing such compounds, and the use of said pharmaceutical compositions and formulations as medicaments / medical, especially as medicaments for the treatment and / or prevention of oncogenic diseases.

Description

Technical Field

[0001] This invention relates to cyclic 2-amino-3-cyanothiophene of formula (I) and its derivatives.

[0002]

[0003] Where R 1a R 1b R 2a R 2b Z, R 3 To R 5 A, p, U, V, W, L, and E have the meanings given in the claims and specification, the use of the compound as an inhibitor of mutant Ras family proteins, pharmaceutical compositions and formulations containing such compounds, and the pharmaceutical compositions and formulations for pharmaceutical / medical use, particularly for the treatment and / or prevention of carcinogenic diseases, such as cancer. Background Technology

[0004] Ras family proteins, including KRAS (V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog), and HRAS (Harvey mouse sarcoma virus oncogene), and any mutants thereof, are small GTPases present in cells in GTP-bound or GDP-bound states (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Nimnual et al., Sci. STKE., 2002, 2002(145):pe36). Ras family proteins have weak intrinsic GTPase activity and express a slow nucleotide exchange rate (Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). The binding of GTPase-activating proteins (GAPs) (such as NF1) increases the GTPase activity of Ras family proteins. The binding of guanine nucleotide exchange factors (GEFs), such as the Son of Sevenless 1 (SOS1), promotes the release of GDP from Ras family proteins, enabling GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). When in the GTP-bound state, Ras family proteins are active and bind to effector proteins, including C-RAF and phosphoinositol 3-kinase (PI3K), to promote the RAF / mitogen or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian rapamycin target protein (mTOR) pathway, and the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6). These pathways influence various cellular processes, such as proliferation, survival, metabolism, activity, angiogenesis, immunity, and growth (Young et al., Adv. Cancer Res., 2009, 102: 1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3): 205-6).

[0005] Cancer-associated mutations in Ras family proteins suppress their intrinsic and GAP-induced GTPase activity, leading to an increase in the population of GTP-binding / active mutant Ras family proteins (McCormick et al., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). This, in turn, leads to the sustained activation of downstream effector pathways (e.g., RAF / MEK / ERK, PI3K / AKT / mTOR, RalGDS pathway) of mutant Ras family proteins. KRAS mutations (e.g., amino acids G12, G13, Q61, A146) have been found in various human cancers, including lung cancer, colorectal cancer, and pancreatic cancer (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Mutations in HRAS (e.g., amino acids G12, G13, Q61) and NRAS (e.g., amino acids G12, G13, Q61, A146) have also been found in various human cancer types, but the frequency is generally lower than that of KRAS mutations (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11): 828-51). Alterations in Ras family proteins / Ras genes (e.g., mutations, overexpression, gene amplification) have also been described as mechanisms of resistance to cancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 July; 92(7):709-22) and the EGFR tyrosine kinase inhibitors osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 7 5(12):2489-500).

[0006] Glycine-to-cysteine ​​substitutions at residue 12 of Ras family proteins (G12C mutations, such as KRAS G12C, NRAS G12C, and HRAS G12C) result from a GC-to-TA base substitution at codon 12. These are common mutations in the RAS gene, accounting for 14% of all KRAS mutations, 2% of all NRAS mutations, and 2% of all HRAS mutations across cancer types. G12C mutations are particularly prevalent in KRAS-mutant non-small cell lung cancer, affecting approximately half of cases, and are associated with DNA adducts formed through tobacco smoke. G12C mutations are not only associated with lung cancer but are also found in other RAS-mutant cancer types, including, for example, 3-5% of all KRAS-mutant colorectal cancers.

[0007] Inhibitors of these G12C mutant Ras family proteins that can covalently bind to these proteins, such as covalent binders to KRAS G12C, NRAS G12C, and HRAS G12C, are expected to inhibit signaling (e.g., ERK phosphorylation) in downstream cells of Ras family proteins. In cancer cells associated with dependence on mutant Ras family proteins (e.g., KRAS mutant cancer cell lines), such binders / inhibitors are expected to provide anti-cancer efficacy (e.g., inhibition of proliferation, survival, and metastasis).

[0008] To date, there are no approved inhibitors of G12C mutant Ras family proteins for therapeutic use. Recently, the first selective drugs targeting KRAS G12C have entered clinical development, with sotorasib and adagrasib already in late-stage trials for the treatment of KRAS G12C-driven lung cancer (see corresponding patent applications WO 2018 / 217651, WO 2017 / 201161, WO 2019 / 099524, and WO 2020 / 102730). There is a need for new or even improved inhibitors of G12C mutant Ras family proteins suitable for clinical use. Summary of the Invention

[0009] compound

[0010] It has now been unexpectedly discovered that R 1a R 1b R 2a R 2b Z, R 3 To R 5Compounds of formula (I), having the meanings given below, A, p, U, V, W, L, and E, act as inhibitors of G12C mutant Ras family proteins involved in controlling cell proliferation and possess antitumor activity, suitable for inhibiting uncontrolled cell proliferation caused by malignant diseases. It is believed that this antitumor activity derives from the inhibition of G12C mutant Ras family proteins, particularly KRAS G12C, which are key mediators of proliferation and survival in certain tumor cells. It is also believed that the compounds of the present invention interact with G12C mutant Ras family proteins, particularly KRAS G12C, via an electrophilic portion (e.g., a MICHAEL receptor) present in the compounds of formula (I) and subsequently covalently bind to them (confirmed by crystallography of KRAS G12C). Upon covalent binding to G12C mutant Ras family proteins, particularly KRAS G12C, it is most likely to occur at position 12 of the Ras family protein, and the compounds weaken or substantially eliminate the ability of G12C Ras family proteins to acquire their activity, pro-proliferative / pro-survival conformation.

[0011] In fact, the binding of compounds of formula (I) according to the invention can induce selectivity and extremely strong anti-proliferative cell activity in G12C mutant KRAS cell lines compared to wild-type KRAS cells, as well as a large selectivity window. This excellent potency can potentially result in lower systemic exposure and / or doses required for full efficacy in humans, and thus lead to good / preferred tolerability (e.g., a lower risk of idiosyncratic toxicity), making it more difficult to hit pathways when necessary, and can also prove beneficial and provide greater flexibility in combination therapy. The compounds express strong biomarker regulation, such as pERK in G12C mutant KRAS cell lines. Selected compounds were tested in the selectivity group and expressed good selectivity against other human targets, such as kinases. Last but not least, the selected compounds disclosed herein were tested and expressed good permeability, excellent solubility, and finely tuned PK properties.

[0012] Therefore, in a first aspect, the present invention relates to a compound of formula (I).

[0013]

[0014] or its salt, wherein

[0015] [A0]

[0016] R 1a and R 1b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0017] R 2a and R 2b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0018] And / or optionally R 1a Or R 1b One of them and R 2a Or R 2b One of them, together with the carbon atoms they are attached to, forms a cyclopropane ring;

[0019] [B0]

[0020] Z is -(CR) 6a R 6b ) n -;

[0021] Each R 6a and R 6b Independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0022] n is selected from 0, 1, and 2;

[0023] [C0]

[0024] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -CN, C3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0025] [D0]

[0026] Ring A is selected from the following rings: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, and triazole;

[0027] [E0]

[0028] If they exist, each R 4 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -CN, C 3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0029] p is selected from 0, 1, 2, and 3;

[0030] [F0]

[0031] U is selected from nitrogen (=N-) and nitrogen derived from R. A (=C(R A )-) replaced carbon;

[0032] V is selected from nitrogen (=N-) and R. B (=C(R B )-) replaced carbon;

[0033] W is selected from nitrogen (=N-) and R. C (=C(R C )-) replaced carbon;

[0034] R A R B and R C Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optional C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, -SC 1-6Alkyl group, -S(=O)2-C 1-6 Alkyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C-membered groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl groups and -C(=O)N(C 1-4 Alkyl)2;

[0035] [G0]

[0036] R 5 Selected from R a1 and R b1 ;

[0037] 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, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone 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, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. b1 and / or R c1 replace;

[0038] Each R b1 Independently selected from -OR c1 -NR c1 R c1 Halogens, -CN, -C(=O)R c1 -C(=O)OR c1 -C(=O)NR c1 R c1 -S(=O)2R c1 -S(=O)2NR c1 R c1 -NHC(=O)R c1 -N(C 1-4 Alkyl)C(=O)R c1-NHS(=O)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 -NHC(=O)OR c1 -N(C 1-4 Alkyl)C(=O)OR c1 and divalent substituent = O;

[0039] 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, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone 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, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. d1 and / or R e1 replace;

[0040] Each R d1 Independently selected from -OR e1 -NR e1 R e1 Halogens, -CN, -C(=O)R e1 -C(=O)OR e1 -C(=O)NR e1 R e1 -S(=O)2R e1 -S(=O)2NR e1 R e1 -NHC(=O)R e1 -N(C 1-4 Alkyl)C(=O)R e1 -NHS(=O)2R c1 -N(C 1-4 Alkyl)S(=O)2R c1 -NHC(=O)OR e1 -N(C 1-4 Alkyl)C(=O)OR e1 and divalent substituents = O;

[0041] Each R e1Independently 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, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone 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, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, optionally via one or more of the same or different C 1-4 Alkyl-substituted 3-11 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O;

[0042] [H0]

[0043] L is -L 1 -L 2 -L 3 -, where L 1 Connect to E;

[0044] L 1 Selected from bonds, -NH-, -N(C 1-4 Alkyl group, -O group, -C(=O) group, -NH-C(=O) group, -N(C) group 1-4 Alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C 1-4 Alkyl)-, -C(=O)-, C 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroaryl alkylene;

[0045] L 2 Selected from C1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroaryl alkylene;

[0046] L 3 Selected from bonds, -NH-, -N(C 1-4 Alkyl group, -O group, -C(=O) group, -NH-C(=O) group, -N(C) group 1-4 Alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C 1-4 Alkyl)-, -C(=O)-, C 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroaryl alkylene;

[0047] Where L 1 L 2 and L 3 Each C in 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12-membered heterocyclic and 5-10-membered heteroaryl groups are optionally and independently substituted by one or more of the same or different substituents selected from the following: C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -OH, -CN, C 1-6 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl group 2, divalent substituent =O, and C substituted with one or more of the same or different substituents selected from the following. 1-6 Alkyl groups: halogens, -OH, -CN, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl groups and -C(=O)N(C 1-4 Alkyl)2;

[0048] [I0]

[0049] E is

[0050]

[0051] Indicates a double or triple bond;

[0052] Q 1 Selected from bonds, -CH2-, -CH(OH)-, -C(=O)-, -C(=O)N(R) G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 )- and -C(=NR H1 )-;

[0053] Each R G1 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3-11 membered heterocyclic groups;

[0054] Each R H1 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0055] like To represent a double bond, then

[0056] R D Selected from hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, -CN, C 1-6 Alkoxy group, -C(=O)OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and C14 groups optionally substituted with one or more of the same or different substituents selected from the following 1-6 Alkyl groups: phenyl, 3-11 membered heterocyclic groups, C 1-6 Alkoxy, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)NH(C 1-6 Alkyl), -NHC(=O)-C 1-6 Alkyl group, -OC(=O)-C1-6 Alkyl and phenyl-C 1-6 Alkoxy;

[0057] R E and R F Each independently selected from R a2 and R b2 ;

[0058] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0059] Each R b2 Independently selected from -OR c2 -NR c2 R c2 Halogens, -CN, -C(=O)R c2 -C(=O)OR c2 -C(=O)NR c2 R c2 -S(=O)2R c2 -S(=O)2NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 -N(C 1-4 Alkyl)C(=O)OR c2 and divalent substituents = O;

[0060] 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, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, -OH, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl group 2, and divalent substituent = O;

[0061] or

[0062] R D and R E Together with the carbon atoms they are attached to, they form 4-7 membered unsaturated alicyclic rings or 4-7 membered unsaturated heterocyclic rings, wherein the 4-7 membered unsaturated alicyclic rings or 4-7 membered unsaturated heterocyclic rings optionally exclude R. F In addition, it may be substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -NH2, -CN, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, halogen, -C(=O)OC 1-6 Halogen and divalent substituent = O;

[0063] or

[0064] If Q 1 -C(=O)N(R) G1 )-, then -C(=O)N(R G1 )- of R G1 and R F Together they form a connector selected from the following: -C(=O)-, -CH2-, -CH2-C(=O)-, -C(=O)-CH2- and -C2H4-;

[0065] like To represent a triple bond, then

[0066] R D and R E None of them exist;

[0067] R F For R a2 ;

[0068] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0069] Each R b2 Independently selected from -OR c2 -NR c2 R c2 Halogens, -CN, -C(=O)R c2 -C(=O)OR c2 -C(=O)NR c2 R c2 -S(=O)2R c2 -S(=O)2NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 -N(C 1-4 Alkyl)C(=O)OR c2 and divalent substituents = O;

[0070] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0071] or

[0072] E is

[0073]

[0074] Q 2 Selected from bonds, -CH2-, -CH(OH)-, -C(=O)-, -C(=O)N(R)G2 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G2 )- and -C(=NR H2 )-;

[0075] Each R G2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 (alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3-11 membered heterocyclic groups;

[0076] Each R H2 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0077] R I Selected from hydrogen and halogens;

[0078] R J It is hydrogen; or

[0079] R I and R J Together with the carbon atoms they are attached to, they form cyclopropane or ethylene oxide rings;

[0080] R K Selected from hydrogen, C 1-6 Alkyl groups, -CN groups, and halogens;

[0081] R L Selected from hydrogen, C 1-6 Alkyl groups, -CN, halogens, and -C(=O)-C 1-6 alkyl;

[0082] or

[0083] E is

[0084]

[0085] Q 3 Selected from -C(=O)-, -C(=O)N(R) G3 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G3)- and -C(=NR H3 )-;

[0086] Each R G3 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3-11 membered heterocyclic groups;

[0087] Each R H3 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0088] R M Selected from halogens, -CN and -OC (=O)-C 1-6 alkyl;

[0089] or

[0090] E is

[0091]

[0092] Q 4 Selected from bonds, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C 1-4 Alkyl group, -S(=O)2- and -S(=O)2NH-;

[0093] Ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and 5-membered heteroaryl;

[0094] q is selected from 1, 2, 3, and 4;

[0095] Each R N Selected independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl, vinyl, ethynyl, halogen, -CN, nitro and C 1-4 Alkyl group.

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

[0097] in

[0098] R 1a R 1b R 2a R 2b Z, R 3 Ring A, R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0099] In a third aspect, the present invention relates to a compound of formula (Ib) or a salt thereof.

[0100] in

[0101] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0102] In a fourth aspect, the present invention relates to a compound of formula (Ib*) or a salt thereof.

[0103] in

[0104] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0105] In a fifth aspect, the present invention relates to a compound of formula (Ic) or a salt thereof.

[0106] in

[0107] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0108] In a sixth aspect, the present invention relates to a compound of formula (Ic*) or a salt thereof.

[0109] in

[0110] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0111] In a seventh aspect, the present invention relates to a compound of formula (Id) or a salt thereof.

[0112] in

[0113] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0114] In an eighth aspect, the present invention relates to a compound of formula (Id*) or a salt thereof.

[0115] in

[0116] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0117] In a ninth aspect, the present invention relates to a compound of formula (Ie) or a salt thereof.

[0118] in

[0119] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0120] In a tenth aspect, the present invention relates to a compound of formula (Ie*) or a salt thereof.

[0121] in

[0122] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 L and E are as defined in formula (I) of the first aspect.

[0123] It should be understood that, unless otherwise stated, compounds (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) and (Ie*) are each subsets of compound (I), and whenever they refer to compound (I), they are also intended to refer to and include compounds (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) and (Ie*).

[0124] It should be understood that, unless otherwise stated, compounds (Ib*), (Ic*), (Id*) and (Ie*) are each subsets of their respective compounds (Ib), (Ic), (Id) and (Ie), and are intended to refer to and include compounds (Ib*), (Ic*), (Id*) and / or (Ie*) whenever they are mentioned.

[0125] The following structural aspects represent preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0], [H0] and [I0], namely [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] to [D6], [E1] to [E4], [F1] to [F9], [G1] to [G8], [H1] to [H3] and [I1] to [I8].

[0126] In one aspect [A1], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0127] R 1a and R 1b All are independently selected from hydrogen and C 1-4 alkyl;

[0128] R 2a and R 2b Each is independently selected from hydrogen and halogens.

[0129] In another aspect [A2], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0130] R 1a and R 1b Each is independently selected from hydrogen and methyl;

[0131] R 2a and R 2b They are all independently selected from hydrogen and fluorine.

[0132] In another aspect [A3], the present invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0133] R 1a R 1b R 2a and R 2b It is hydrogen.

[0134] In another aspect [B1], the present invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0135] Z is -(CR) 6a R 6b ) n -;

[0136] n is 0.

[0137] In another aspect [B2], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0138] Z is -(CR) 6a R 6b ) n -;

[0139] n is 1;

[0140] R 6a and R 6b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups.

[0141] In another aspect [B3], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0142] Z stands for -CH2-.

[0143] In another aspect [B4], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0144] Z is -(CR) 6a R 6b ) n -;

[0145] n is 2;

[0146] Each R 6a and R 6b Independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups.

[0147] In another aspect [B5], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0148] Z stands for -CH2-CH2-.

[0149] In another aspect [C1], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0150] R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, cyano-C 1-4 Alkyl, halogen, -OH, -NH2, -NH(C)1-4 alkyl), -N(C) 1-4 Alkyl)2 and -CN.

[0151] In another aspect [C2], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0152] R 3 Selected from hydrogen, methyl, ethyl, -CF3, -CHF2, methoxy, trifluoromethoxy, cyanomethyl, -OH and -CN.

[0153] In another aspect [C3], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0154] R 3 It is hydrogen.

[0155] In another aspect [C4], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0156] R 3 C 1-4 alkyl.

[0157] In another aspect [C5], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0158] R 3 It is a methyl group.

[0159] In another aspect [D1], the present invention relates to a compound of formula (I) or (I*) or a salt thereof, wherein...

[0160] Ring A is selected from

[0161]

[0162]

[0163] In another aspect [D2], the invention relates to compounds of formula (I) or (I*) or salts thereof, wherein...

[0164] Ring A is selected from

[0165]

[0166] In another aspect [D3], the invention relates to compounds of formula (I) or (I*) or salts thereof, wherein...

[0167] Ring A is

[0168] In another aspect [D4], the invention relates to compounds of formula (I) or (I*) or salts thereof, wherein...

[0169] Ring A is

[0170] In another aspect [D5], the invention relates to a compound of formula (I) or (I*) or a salt thereof, wherein

[0171] Ring A is

[0172] In another aspect [D6], the invention relates to compounds of formula (I) or (I*) or salts thereof, wherein...

[0173] Ring A is

[0174] In another aspect [E1], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0175] p is 0.

[0176] In another aspect [E2], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0177] R 4 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -CN, C 3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0178] p is 1.

[0179] In another aspect [E3], the present invention relates to compounds of formula (I), (I*), (Ie) or (Ie*) or salts thereof, wherein

[0180] Each R 4 Selected independently from C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -CN, C 3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0181] p = 2.

[0182] In another aspect [E4], the present invention relates to a compound of formula (I) or (I*) or a salt thereof, wherein

[0183] Each R 4 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -CN, C 3-5 cycloalkyl groups and 3-5 membered heterocyclic groups;

[0184] p is 3.

[0185] In another aspect [F1], the present invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0186] U is via R A (=C(R A )-) replaced carbon;

[0187] V is the result of R B (=C(R B )-) replaced carbon;

[0188] W represents nitrogen (=N-);

[0189] R A and R B Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optional C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C-membered groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl groups and -C(=O)N(C 1-4 Alkyl)2.

[0190] In another aspect [F2], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0191] U is =CH-;

[0192] V is =CH-;

[0193] W stands for nitrogen (=N-).

[0194] In another aspect [F3], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0195] U is via R A (=C(R A )-) replaced carbon;

[0196] V is the result of R B (=C(R B )-) replaced carbon;

[0197] W is the time R C (=C(R C )-) replaced carbon;

[0198] R A R B and R C Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optional C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C)1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C-membered groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl groups and -C(=O)N(C 1-4 Alkyl)2.

[0199] In another aspect [F4], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0200] U is =CH-;

[0201] V is =CH-;

[0202] W = CH-.

[0203] In another aspect [F5], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0204] U stands for nitrogen (=N-);

[0205] V is the result of R B (=C(R B )-) replaced carbon;

[0206] W represents nitrogen (=N-);

[0207] R B Selected from hydrogen, C 1-6 Halogenated alkyl, optional C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C-membered groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl groups and -C(=O)N(C 1-4 Alkyl)2.

[0208] In another aspect [F6], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0209] U stands for nitrogen (=N-);

[0210] V is =CH-;

[0211] W stands for nitrogen (=N-).

[0212] In another aspect [F7], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0213] U is via R A (=C(R A )-) replaced carbon;

[0214] V represents nitrogen (=N-);

[0215] W represents nitrogen (=N-);

[0216] R A Selected from hydrogen, C 1-6 Halogenated alkyl, optional C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C-membered groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl groups and -C(=O)N(C 1-4 Alkyl)2.

[0217] In another aspect [F8], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0218] U is via R A (=C(R A )-) replaced carbon;

[0219] V represents nitrogen (=N-);

[0220] W represents nitrogen (=N-);

[0221] R A Selected from hydrogen and halogens.

[0222] In another aspect [F9], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0223] U stands for nitrogen (=N-);

[0224] V represents nitrogen (=N-);

[0225] W stands for nitrogen (=N-).

[0226] In another aspect [G1], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0227] R 5 Selected from R a1 and R b1 ;

[0228] R a1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6alkynyl group, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. b1 and / or R c1 replace;

[0229] Each R b1 Independently selected from -OR c1 -NR c1 R c1 Halogens, -CN, -C(=O)R c1 -C(=O)OR c1 -C(=O)NR c1 R c1 -S(=O)2R c1 -S(=O)2NR c1 R c1 -NHC(=O)R c1 -N(C 1-4 Alkyl)C(=O)R c1 and divalent substituents = O;

[0230] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. d1 and / or R e1 replace;

[0231] Each R d1 Independently selected from -OR e1 -NR e1 R e1 Halogens, -CN, -C(=O)R e1 -C(=O)NR e1 R e1 and divalent substituents = O;

[0232] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, optionally via one or more of the same or different C 1-4 Alkyl-substituted 3-11 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O.

[0233] In another aspect [G2], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0234] R 5 For R a1 ;

[0235] R a1 Selected from 3-11-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein all of the 3-11-membered heterocyclic groups and 5-10-membered heteroaryl groups are optionally derived from one or more identical or different R groups. b1 and / or R c1 replace;

[0236] Each R b1 Independently selected from -OR c1 -NR c1 R c1 Halogen, -C(=O)OR c1 and divalent substituents = O;

[0237] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10All cycloalkyl groups and 3-11 membered heterocyclic groups are optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0238] Each R d1 Independently selected from -OR e1 -NR e1 R e1 and halogens;

[0239] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3-11 membered heterocyclic groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl groups and optionally those with one or more identical or different C atoms 1-4 Alkyl-substituted 3-11 membered heterocyclic groups.

[0240] In another aspect [G3], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0241] R 5 For R selected from the following a1 :

[0242]

[0243] in

[0244] Each R a1 Optional via one or more identical or different R b1 and / or R c1 replace;

[0245] Each R b1 Independently selected from -OR c1 -NR c1 R c1 Halogen, -C(=O)OR c1 and divalent substituents = O;

[0246] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C1-6 Haloalkyl, C 3-10 All cycloalkyl groups and 3-11 membered heterocyclic groups are optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0247] Each R d1 Independently selected from -OR e1 -NR e1 R e1 and halogens;

[0248] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3-11 membered heterocyclic groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl groups and optionally those with one or more identical or different C atoms 1-4 Alkyl-substituted 3-11 membered heterocyclic groups.

[0249] In another aspect [G4], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0250] R 5 For R selected from the following a1 :

[0251]

[0252] in

[0253] Each R a1 Choose one or more of the following substitutions, either the same or different:

[0254] • C100 substituted with one or more of the same or different substituents selected from the following 1-6 Alkyl: C 3-6 Cycloalkyl, hydroxyl, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkoxy and optional C 1-4 Alkyl-substituted 3- to 7-membered heterocyclic groups;

[0255] • C substituted with one or more of the same or different halogens 3-6 cycloalkyl;

[0256] • Optional 3-11 membered heterocyclic groups substituted with one or more of the same or different substituents selected from the following: C 1-4 Alkyl, C 3-6 cycloalkyl groups and halogens; and

[0257] • Selected from the following substituents: halogen, -C(=O)-OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OH, -NH2,

[0258] -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl group 2 and divalent substituent = O.

[0259] In another aspect [G5], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0260] R 5 Selected from

[0261]

[0262]

[0263]

[0264] In another aspect [G6], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0265] R 5 For R b1 ;

[0266] R b1 Independently selected from -OR c1 and -NR c1 R c1 ;

[0267] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. d1 and / or Re1 replace;

[0268] Each R d1 Independently selected from -OR e1 -NR e1 R e1 Halogen, -C(=O)R e1 and -C(=O)NR e1 R e1 ;

[0269] Each R e1 Independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, optionally via one or more identical or different C16 groups. 1-4 Alkyl-substituted 3-11 membered heterocyclic groups, C 1-6 Alkoxy groups, halogens, and divalent substituents = O.

[0270] In another aspect [G7], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0271] R 5 For R b1 ;

[0272] R b1 For -OR c1 ;

[0273] Each R c1 Selected independently from C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 All cycloalkyl groups and 3-11 membered heterocyclic groups are optionally derived from one or more identical or different R groups. d1 and / or R e1 replace;

[0274] Each R d1 Independently selected from -NR e1 R e1 and halogens;

[0275] Each Re1 Independently selected from hydrogen and C 1-6 Alkyl groups and 3-11 membered heterocyclic groups, wherein the C 1-6 All alkyl groups and 3-11 membered heterocyclic groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl groups and optionally those with one or more identical or different C atoms 1-4 Alkyl-substituted 3-11 membered heterocyclic groups.

[0276] In another aspect [G8], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0277] R 5 Selected from

[0278]

[0279] In another aspect [H1], the present invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0280] L is -L 1 -L 2 -L 3 -, where L 1 Connect to E;

[0281] L 1 Selected from key, C 1-6 Alkyl groups and 4-12 membered heterocyclic groups;

[0282] L 2 Selected from C 1-6 Alkylenes, phenylenes, and 4-12 membered heterocyclic groups;

[0283] L 3 Selected from bonds, -NH-, -N(C 1-4 Alkyl)- and -O-;

[0284] Where L 1 and L 2 Each C in 1-6 The alkylene, phenylene, and 4-12 membered heterocyclic groups are optionally and independently substituted by one or more of the same or different substituents selected from the following: C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -OH, -CN, C 1-6 Alkoxy, -NH2, -NH(C) 1-4alkyl), -N(C) 1-4 Alkyl)2,

[0285] -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl group 2, divalent substituent =O, and C substituted with one or more of the same or different substituents selected from the following. 1-6 Alkyl groups: halogen, -OH, -CN, -NH2, C 1-4 Alkyl groups, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl groups and -C(=O)N(C 1-4 Alkyl)2.

[0286] In another aspect [H2], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0287] L is -L 1 -L 2 -L 3 -, where L 1 Connect to E;

[0288] L 1 Selected from key, C 1-6 Alkyl groups and 4-12 membered heterocyclic groups;

[0289] L 2 Selected from C 1-6 Alkylenes, phenylenes, and 4-12 membered heterocyclic groups;

[0290] L 3 Selected from bonds, -NH-, -N(C 1-4 Alkyl)- and -O-;

[0291] Where L 1 and L 2 Each C in 1-6 Alkylene, phenylene, and 4-12 membered heterocyclic groups optionally and independently undergo one or more identical or different C-terminal reactions. 1-6 Alkyl substitution.

[0292] In another aspect [H3], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0293] L is selected from

[0294]

[0295]

[0296]

[0297] In another aspect [I1], the present invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0298] E is

[0299]

[0300] Q 1 Selected from -CH2-, -C(=O)-, -C(=O)N(R) G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 )- and -C(=NR H1 )-;

[0301] Each R G1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and hydroxyl-C 1-6 alkyl;

[0302] Each R H1 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0303] R D Selected from hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, -CN, C 1-6 Alkoxy group, -C(=O)OC 1-6 Alkyl groups and C groups optionally substituted with one or more of the same or different substituents selected from the following 1-6 Alkyl groups: phenyl, 3-11 membered heterocyclic groups, C 1-6 Alkoxy, halogen, -OH, -N(C) 1-6 Alkyl)2, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)NH(C1-6 Alkyl), -NHC(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl and phenyl-C 1-6 Alkoxy;

[0304] R E and R F Each independently selected from R a2 and R b2 ;

[0305] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 All aryl and 5-10 heteroaryl groups are selected from one or more identical or different R groups. b2 and / or R c2 replace;

[0306] Each R b2 Independently selected from -OR c2 -NR c2 R c2 Halogen, -CN, -C (=O)OR c2 -C(=O)NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 and -N(C 1-4 Alkyl)C(=O)OR c2 ;

[0307] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, 3-11 membered heterocyclic, C 6-10 Aryl and 5-10 quinone heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3-11 membered heterocyclic, C 6-10 All aryl and 5-10 heteroaryl groups are optionally substituted with one or more of the same or different substituents selected from the following: C 1-6 Alkyl, C 1-6Alkyl groups, halogens, -OH, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl group 2 and divalent substituent = O.

[0308] In another aspect [I2], the present invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0309] E is

[0310]

[0311] Q 1 Selected from -CH2-, -C(=O)-, -C(=O)NH- and -C(=O)N(C 1-4 alkyl)-;

[0312] R D Selected from hydrogen, halogens and C 1-6 alkyl;

[0313] R E and R F Each independently selected from R a2 and R b2 ;

[0314] R a2 Selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be esterified by one or more identical or different R groups. b2 and / or R c2 replace;

[0315] Each R b2 Independently selected from -OR c2 and -C(=O)NR c2 R c2 ;

[0316] Each R c2 Selected independently from C 1-6 Alkyl groups and 3-11 membered heterocyclic groups.

[0317] In another aspect [I3], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0318] E is selected from

[0319]

[0320]

[0321]

[0322]

[0323]

[0324] In another aspect [I4], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0325] E is selected from

[0326]

[0327] In another aspect [I5], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0328] E is

[0329]

[0330] Q 1 Selected from -CH2-, -C(=O)-, -C(=O)N(R) G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 )- and -C(=NR H1 )-;

[0331] Each R G1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and hydroxyl-C 1-6 alkyl;

[0332] Each R H1 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0333] R F C selected from hydrogen and optionally substituted with substituents selected from the following 1-6 Alkyl groups: -OH, C 1-6 Alkoxy, -NH2, -NH(C) 1-4alkyl) and -N(C) 1-4 Alkyl)2.

[0334] In another aspect [I6], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0335] E is

[0336]

[0337] Q 1 Selected from -C(=O)-, -C(=O)N(R) G1 -, -S(=O)2- and -S(=O)2N(R) G1 )-;

[0338] Each R G1 Independently selected from hydrogen and C 1-6 alkyl;

[0339] R F C selected from hydrogen and optionally substituted with substituents selected from the following 1-6 Alkyl groups: -OH, C 1-6 Alkoxy, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 Alkyl)2.

[0340] In another aspect [I7], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0341] E is selected from

[0342]

[0343] In another aspect [I8], the invention relates to compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or salts thereof, wherein

[0344] E is selected from

[0345]

[0346] All of the above structural aspects [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] to [D6], [E1] to [E4], [F1] to [F9], [G1] to [G8], [H1] to [H3] and [I1] to [I8] are preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0], [H0] and [I0]. Structural aspects [A0] to [A3], [B0] to [B5], [C0] to [C5], [D0] to [D6], [E0] to [E4], [F0] to [F9], [G0] to [G8], [H0] to [H3] and [I0] to [I8] associated with different molecular portions of compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Id*), (Ie) and (Ie*) according to the invention may be combined as needed [A][B][ The combinations of [A][B][C][D][E][F][G][H][I] (for compounds of formula (I) and (I*)) and [A][B][C][E][F][G][H][I] (for compounds of formulas (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*)) yield preferred compounds (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*). Each such combination [A][B][C][D][E][F][G][H][I] represents and defines an individual embodiment or a general subset of compounds (I) and (I*) according to the invention. Each of these combinations [A][B][C][E][F][G][H][I] represents and defines an individual embodiment or a general subset of the compounds (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*) according to the invention.

[0347] The preferred embodiments of the present invention of formula (Ib) are example compounds Ib-1 to Ib-16 and any subset thereof.

[0348] The preferred embodiments of the present invention of formula (Ic) are example compounds Ic-1 to Ic-9 and any subset thereof.

[0349] The preferred embodiments of the present invention of formula (Id) are example compounds Id-1 to Id-9 and any subset thereof.

[0350] The preferred embodiment of the present invention of formula (Ie) is example compound Ie-1.

[0351] The present invention also relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) and (Ie*) (including all embodiments thereof).

[0352] The present invention also relates to hydrates of compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) and (Ie*) (including all embodiments thereof).

[0353] The present invention also relates to solvates of compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) and (Ie*) (including all embodiments thereof).

[0354] For example, compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*) carrying ester groups (including all embodiments thereof) are potential prodrugs for the cleavage of esters under physiological conditions and are also part of this invention.

[0355] The present invention also relates to pharmaceutically acceptable salts of compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*) (including all embodiments thereof).

[0356] The present invention also relates to compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*) (including all embodiments thereof) and pharmaceutically acceptable salts of inorganic or organic acids or bases.

[0357] intermediate

[0358] In the eleventh aspect, the present invention relates to a compound of formula (II) or a salt thereof.

[0359] in

[0360] R 1a R 1b R 2a R 2b Z, R 3 Ring A, R 4 p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3- in L 1 Hydrogen (H) attached to residue HL-.

[0361] Compound (II) is an intermediate in the synthesis of compound (I) (in the final synthetic step, the hydrogen in residue HL- is replaced / substituted by group E).

[0362] In a twelfth aspect, the present invention relates to a compound of formula (II*) or a salt thereof.

[0363] in

[0364] R 1a R 1b R 2a R 2b Z, R 3 Ring A, R 4 p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0365] In a thirteenth aspect, the present invention relates to a compound of formula (C-4) or a salt thereof.

[0366] in

[0367] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0368] In the fourteenth aspect, the present invention relates to a compound of formula (C-4*) or a salt thereof.

[0369] in

[0370] R 1a R 1b R 2a R 2b Z, R 3 R 4p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0371] In the fifteenth aspect, the present invention relates to a compound of formula (C-5) or a salt thereof.

[0372] in

[0373] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0374] In a sixteenth aspect, the present invention relates to a compound of formula (C-5*) or a salt thereof.

[0375] in

[0376] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0377] In the seventeenth aspect, the present invention relates to a compound of formula (C-7) or a salt thereof.

[0378] in

[0379] R 1a R 1b R 2a R 2b Z, R 3 R 4p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0380] In the eighteenth aspect, the present invention relates to a compound of formula (C-7*) or a salt thereof.

[0381] in

[0382] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0383] In a nineteenth aspect, the present invention relates to a compound of formula (D-7) or a salt thereof.

[0384] in

[0385] R 1a R 1b R 2a R 2b Z, R 3 R 4 p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0386] In a twentieth aspect, the present invention relates to a compound of formula (D-7*) or a salt thereof.

[0387] in

[0388] R 1a R 1b R 2a R 2b Z, R 3 R 4p, U, V, W, R 5 and L as defined in formula (I) of the first aspect, where -L 1 -L 2 -L 3 - in L 1 Hydrogen (H) attached to residue HL-.

[0389] It should be understood that, unless otherwise stated, compounds (II*), (C-4), (C-4*), (C-5), (C-5*), (C-7), (C-7*), (D-7) and (D-7*) are each subsets of compound (II), and whenever compound (II) is mentioned, it is also intended to refer to and include compounds (II*), (C-4), (C-4*), (C-5), (C-5*), (C-7), (C-7*), (D-7) and (D-7*).

[0390] It should be understood that, unless otherwise stated, compounds (C-4*), (C-5*), (C-7*) and (D-7*) are each subsets of their respective compounds (C-4), (C-5), (C-7) and (D-7), and whenever they refer to compounds (C-4), (C-5), (C-7) and / or (D-7), this is also intended to refer to and include compounds (C-4*), (C-5*), (C-7*) and / or (D-7*).

[0391] All the aforementioned structural aspects [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] to [D6] disclosed in the preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [E0], [F0], [G0] and [H0] of compounds of formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*) are disclosed. [E1] to [E4], [F1] to [F9], [G1] to [G8] and [H1] to [H3] are also preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0] and [H0] of compounds of formulas (II), (II*), (C-4), (C-4*), (C-5), (C-5*), (C-7), (C-7*), (D-7) and (D-7*).

[0392] Therefore, these structural aspects [A0] to [A3], [B0] to [B5], [C0] to [C5], [D0] to [D6], [E0] to [E4], [F0] to [F9], [G0] to [G8], and [H0] to [H3] associated with different molecular parts of compounds of formulas (II), (II*), (C-4), (C-4*), (C-4), (C-5*), (C-5*), (C-7), (C-7*), (D-7), and (D-7*) can be combined as needed to form [A][B][C][D][E][C][C][D][C ... F][G][H] (for compounds of formula (II) and (II*) and combinations [A][B][C][E][F][G][H] (for compounds of formula (C-4), (C-4*), (C-5), (C-5*), (C-7), (C-7*), (D-7) and (D-7*)) are combined with each other to obtain preferred compounds of formula (II), (II*), (C-4), (C-4*), (C-5), (C-5*), (C-7), (C-7*), (D-7) and (D-7*). Each such combination [A][B][C][D][E][F][G][H] represents and defines an individual embodiment or a general subset of compounds of formula (II) and (II*). Each of these combinations [A][B][C][E][F][G][H] represents and defines individual embodiments or general subsets of compounds of formulas (C-4), (C-4*), (C-5), (C-5*), (C-7), (C-7*), (D-7), and (D-7*).

[0393] Pharmaceutical Composition

[0394] Suitable pharmaceutical compositions for administering compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) 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 solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injectable)), elixirs, syrups, capsules, emulsions, inhalers, or dispersible powders. The content of compound (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the total composition, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dose may be administered several times a day.

[0395] Suitable tablets can be obtained, for example, by mixing the compound (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) with known pharmaceutically acceptable excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants. Tablets may also comprise several layers.

[0396] Therefore, coated tablets can be prepared by coating a core similar to that produced in tablets 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 can also consist of multiple layers. Similarly, using the excipients mentioned above regarding tablets, tablet coatings can consist of multiple layers to achieve delayed release.

[0397] Syrups or elixirs containing one or more compounds (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) may additionally contain excipients, such as sweeteners like saccharin, saccharin, glycerol, or sugar; and flavor enhancers, such as flavoring agents like 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.

[0398] Solutions for injection and infusion are prepared in common methods, such as by adding excipients such as isotonic reagents, preservatives such as p-hydroxybenzoic acid esters, 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 an organic solvent may optionally be used as a solubilizing agent or dissolving aid, and the solution is transferred to a vial or ampoule or infusion bottle.

[0399] Capsules containing one or more compounds (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*), 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.

[0400] Suitable suppositories can be manufactured, for example, by mixing with excipients provided for this purpose, such as neutral fats or polyethylene glycol or their derivatives.

[0401] 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).

[0402] The pharmaceutical composition is administered by common methods, preferably orally or dermally, with oral administration being the most preferred route. For oral administration, the tablets may contain additional excipients besides those described above, such as sodium citrate, calcium carbonate, and dicalcium 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.

[0403] For non-enteric use, a solution of the active substance with a suitable liquid excipient can be used.

[0404] The daily applicable dose range of compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) is typically 1 mg to 2000 mg, preferably 250 to 1250 mg.

[0405] However, depending on weight, age, route of administration, severity of the 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 lower 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, dividing it into several smaller doses throughout the day may be preferable.

[0406] Therefore, in another aspect, the present invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0407] Compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or their pharmaceutically acceptable salts, and pharmaceutical compositions comprising 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).

[0408] The elements of such combinations can be administered (whether dependently or independently) by methods customary to those skilled in the art, such as via oral, enteric, 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 with suitable dosage units of conventional, non-toxic, pharmaceutically acceptable excipients suitable for each route of administration.

[0409] 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.

[0410] 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 applied 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.

[0411] Therefore, in another aspect, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0412] In another aspect, the present invention also relates to a pharmaceutical preparation comprising a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0413] Pharmaceutical compositions intended for co-administration or combination use may also be provided in kit form.

[0414] Therefore, in another aspect, the present invention also relates to a kit comprising:

[0415] • A first pharmaceutical composition or dosage form comprising a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*), and optionally one or more pharmaceutically acceptable excipients, and

[0416] • A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0417] In one aspect, such a kit comprises a third pharmaceutical composition or dosage form, which contains another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0418] Medical Uses - Treatment Methods

[0419] Disease - Patient Group

[0420] This invention is primarily aimed at RAS G12C inhibitors, especially compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) (including all embodiments thereof), which are potentially suitable for the treatment and / or prevention of diseases and / or symptoms mediated by RAS G12C mutations, such as and preferably KRAS G12C, NRAS G12C and HRAS G12C.

[0421] Therefore, in another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable as a pharmaceutical agent.

[0422] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for use in methods of treating human or animal bodies.

[0423] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for the treatment and / or prevention of diseases and / or symptoms mediated by RAS G12C mutations.

[0424] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating and / or preventing diseases and / or symptoms mediated by RAS G12C mutations.

[0425] In another aspect, the present invention relates to a method for treating and / or preventing diseases and / or symptoms mediated by RAS G12C mutations, comprising administering to a human a therapeutically effective amount of a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof.

[0426] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for the treatment and / or prevention of cancer.

[0427] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for use in methods of treating and / or preventing cancer in human or animal bodies.

[0428] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating and / or preventing cancer.

[0429] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a human a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof.

[0430] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for providing inhibition of the G12C mutant RAS.

[0431] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical agent for providing inhibition of the G12C mutant RAS.

[0432] In another aspect, the present invention relates to a method for providing inhibition of the G12C mutant RAS, comprising administering to a human a therapeutically effective amount of a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof.

[0433] On the other hand, this involves identifying the link between a patient's G12C mutation status and their potential susceptibility to treatment with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*). RAS G12C inhibitors, such as compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*), can subsequently be advantageously used to treat patients with KRAS G12C, HRAS G12C, or NRAS G12C mutations who are resistant to other therapies. Therefore, this provides opportunities, methods, and tools for selecting patients, particularly cancer patients, for treatment with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*). This selection is based on whether the tumor cells to be treated possess wild-type or G12C mutant KRAS, HRAS, or NRAS genes. Therefore, the G12C KRAS, HRAS, or NRAS gene status can serve as a biomarker indicating that treatment with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) may be advantageous.

[0434] According to one aspect, a method is provided for selecting a patient to be treated with a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*), the method comprising...

[0435] • Provide samples containing tumor cells from the patient;

[0436] • Determine whether the RAS gene in the patient's tumor cell sample encodes wild-type (glycine at position 12) or mutant (cysteine ​​at position 12) KRAS, HRAS, or NRAS proteins; and

[0437] Based on the above, patients were selected to be treated with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*).

[0438] The method may or may not include the actual patient sample separation step.

[0439] In one aspect, if the tumor cell DNA carries the G12C mutant KRAS gene, the patient is selected for treatment with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*).

[0440] In another case, if the tumor cell DNA has the G12C mutant HRAS gene, the patient is selected to be treated with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*).

[0441] In another aspect, if the tumor cell DNA carries the G12C mutant NRAS gene, the patient is selected to be treated with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*).

[0442] According to another aspect, a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof is provided for treating cancer with tumor cells carrying the G12C mutant RAS gene.

[0443] According to another aspect, a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof is provided for treating cancer with tumor cells carrying the G12C mutant KRAS gene.

[0444] According to another aspect, a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof is provided for treating cancer with tumor cells carrying the G12C mutant HRAS gene.

[0445] According to another aspect, a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof is provided for treating cancer with tumor cells carrying the G12C mutant NRAS gene.

[0446] According to another aspect, a method for treating cancer with tumor cells carrying the G12C mutant RAS gene is provided, comprising administering to a human an effective amount of a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof.

[0447] According to another aspect, a method for treating cancer with tumor cells carrying G12C mutant KRAS, HRAS, or NRAS genes is provided, comprising administering an effective amount of a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof.

[0448] Determining whether a tumor or cancer contains G12C KRAS, HRAS, or NRAS mutations can be done by evaluating the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein, by evaluating the amino acid sequence of the KRAS, HRAS, or NRAS protein, or by evaluating the characteristics of the inferred KRAS, HRAS, or NRAS mutant protein. Wild-type human KRAS, HRAS, or NRAS sequences are known in the art. Methods for detecting mutations in the KRAS, HRAS, or NRAS nucleotide sequences are known to those skilled in the art. These methods include (but are not limited to) polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) 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, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide conjugation analysis, hybridization analysis, TaqMan assay, SNP genotyping analysis, high-resolution unwinding analysis, and microarray analysis. In some embodiments, G12CKRAS, HRAS, or NRAS mutations in a sample are assessed by real-time PCR. In real-time PCR, a fluorescent probe specific for KRAS, HRAS, or NRAS G12C mutations is used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, direct sequencing methods are used to identify KRAS, HRAS, or NRAS G12C mutations in specific regions (e.g., exon 2 and / or exon 3) of the KRAS, HRAS, or NRAS genes. This technique will identify all possible mutations in the sequenced region. Methods for detecting mutations in KRAS, HRAS, or NRAS proteins are known to those skilled in the art. These methods include (but are not limited to) detection of KRAS, HRAS, or NRAS mutants using binding agents (e.g., antibodies) specific to mutant proteins, protein electrophoresis, Western blotting, and direct peptide sequencing.

[0449] Methods for determining whether a tumor or cancer contains G12C KRAS, HRAS, or NRAS mutations can utilize a variety of samples. In some embodiments, the sample is obtained 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 cell lysate. In some embodiments, the sample is processed into DNA or RNA. In some embodiments, the sample is a liquid section, and blood samples are tested to look for cancer cells in a tumor circulating in the blood or DNA fragments in tumor cells in the blood.

[0450] The intended formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) compounds or their pharmaceutically acceptable salts, as defined and disclosed herein (above and below), are used to treat / prevent diseases / symptoms / cancers / tumors / cancer cells selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0451] In another respect, the disease / symptom / cancer / tumor / cancer cell of the compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, as defined and disclosed herein (above and below), is selected from pancreatic cancer, lung cancer (preferably non-small cell lung cancer (NSCLC)), cholangiocarcinoma and colorectal cancer.

[0452] Particularly preferred are compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or their pharmaceutically acceptable salts selected for the treatment / prevention of cancer according to the methods and uses defined and disclosed herein (above and below).

[0453] • Lung adenocarcinoma carrying the KRAS G12C mutation (preferably non-small cell lung cancer (NSCLC));

[0454] • Colorectal adenocarcinoma carrying the KRAS G12C mutation;

[0455] • Pancreatic adenocarcinoma carrying the KRAS G12C mutation (preferably pancreatic duct adenocarcinoma (PDAC)).

[0456] Additionally, the following cancers, tumors, and other proliferative diseases may be treated with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or their pharmaceutically acceptable salts (but not limited thereto). Preferably, the treatment methods, approaches, uses, compounds for use, and pharmaceutical compositions for use disclosed herein (above and below) are applied to treat diseases / symptoms / cancers / tumors (i.e., corresponding cells) carrying RAS G12C mutations (preferably KRAS G12C mutations) or have been identified as carrying RAS G12C mutations (preferably KRAS G12C mutations) as described and / or mentioned herein:

[0457] Cancers / tumors / carcinomas of the head and neck: such as tumors / carcinomas / cancers of the nasal cavity, sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar triangle, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsils, tonsillar arch, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including superior glottis, glottis, inferior glottis, vocal cords), laryngopharynx, and salivary glands (including minor salivary glands);

[0458] Lung cancers / tumors / carcinomas: such as non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma);

[0459] Mediastinal tumors: such as neurofibromas (including neurofibromas, schwannomas, malignant schwannomas, neurosarcomas, ganglioblastomas, gangliocytomas, neuroblastomas, pheochromocytomas, paragangliomas), germ cell tumors (including seminomas, teratomas, non-seminomas), thymic tumors (including thymomas, thymic lipomas, thymic carcinomas, thymic carcinoids), and mesenchymal tumors (including fibromas, fibrosarcomas, lipomas, liposarcomas, myxomas, mesotheliomas, leiomyomas, leiomyosarcomas, rhabdomyosarcomas, xanthogranulomas, mesenchymal tumors, hemangiomas, hemangioendotheliomas, hemangiopericytomas, lymphangiomas, perilymphatic cell tumors, and lymphangiomyomas);

[0460] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: Examples include the following tumors / carcinomas / cancers: esophagus, stomach (gastric cancer), pancreas, liver, and bile ducts (including hepatocellular carcinoma (HCC), such as childhood HCC, fibrolamellar HCC, complex HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC); hepatoblastoma; cholangiocarcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor. Tumors), gallbladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (including kidneys, such as renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenoid tumor, Grawitz tumor; ureter; bladder, such as urachal carcinoma, urethral epithelial carcinoma; urethra, such as distal, bulbar, prostate; prostate (androgen-dependent, non-androgen-dependent, castration-resistant, hormone-independent, hormone-refractory), penis);

[0461] Testicular cancer / tumor / cancer: such as seminoma, non-seminomatous tumor,

[0462] Gynecological cancers / tumors / carcinomas: such as tumors / carcinomas / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine body (including endometrium and fundus);

[0463] Breast cancers / tumors / carcinomas: such as breast cancer (invasive ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, ductal carcinoma, adenocystic carcinoma, papillary carcinoma, medullary carcinoma, mucinous carcinoma), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), Her2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast;

[0464] Cancers / tumors / carcinomas of the endocrine system: such as tumors / carcinomas / cancers of the following endocrine glands: thyroid gland (thyroid carcinoma / tumor; papillary carcinoma, follicular carcinoma, degenerative carcinoma, medullary carcinoma), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (adrenal cortex carcinoma / tumor), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, paraganglioma, pancreatic endocrine tumors (PET; non-functional PET, pancreatic polypeptide tumor (PPoma), gastrinoma, insulinoma, vasoactive intestinal peptide tumor (VIPoma), glucagonoma, somatostatinoma, growth hormone releasing factor tumor (GRFoma), adrenocorticotropic hormone tumor (ACTHoma)), carcinoid tumors;

[0465] Soft tissue sarcomas include: fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral schwannoma (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexus sarcoma, neuroblastoma, ganglioblastoma, neuroepithelial Ewing's sarcoma, paraganglioma, extraosseous chondrosarcoma, extraosseous osteosarcoma, mesenchymal tumor, soft tissue alveolar sarcoma, epithelioid sarcoma, extrarenal rhabdomyosarcoma, and connective tissue proliferative small cell tumor.

[0466] Sarcomas of the skeleton: such as myeloma, reticulum cell sarcoma, chondrosarcoma (including centrifugal chondrosarcoma, peripheral cell chondrosarcoma, clear cell chondrosarcoma, mesenchymal chondrosarcoma), osteosarcoma (including paraosteal osteosarcoma, periosteal osteosarcoma, highly malignant superficial osteosarcoma, small cell osteosarcoma, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, ameloblastoma, (fibro) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0467] Mesothelioma: such as pleural mesothelioma and peritoneal mesothelioma;

[0468] Skin cancers: such as basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous melanoma, superficial diffuse melanoma, malignant lentigines melanoma, acral lentigines melanoma, nodular melanoma, intraocular melanoma), actinic keratosis, and eyelid cancer;

[0469] Tumors of the central nervous system and brain: such as astrocytomas (cerebral astrocytoma, cerebellar astrocytoma, diffuse astrocytoma, myofibril astrocytoma, pleomorphic astrocytoma, pilocytic astrocytoma, protoplasmic large round cell astrocytoma), glioblastoma, glioma, oligodendroglioma, oligodendroastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, neuroblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, gangliocytoma, neuroblastoma, retinoblastoma, neuroma (e.g., acoustic neuroma), spinal cord tumors;

[0470] Lymphomas and leukemias: such as B-cell non-Hodgkin's lymphoma (NHL) (including small lymphoglobulin lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma). lymphoma (BL), T-cell non-Hodgkin's lymphoma (including degenerative large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytomas, chronic B-cell lymphoglobulin leukemia (B-CLL), chronic T-cell lymphoglobulin leukemia (T-CLL), B-cell small lymphoglobulin lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphoma) The following are types of leukemia: predominantly lymphocytic leukemia (NLPHD), tuberous sclerosis leukemia (NSHD), mixed cellularity leukemia (MCHD), lymphocyte-rich typical leukemia, lymphocyte-depleted leukemia (LDHD), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myeloid leukemia (AML), acute lymphoblastic / lymphoblastic leukemia (ALL), acute premyeloid leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), and chronic myeloid monocytic leukemia (CMML).

[0471] Cancer of unknown origin (CUP);

[0472] The characteristic is that all the cancers / tumors / carcinomas mentioned above, including both primary tumors and metastatic tumors derived from them, are located in a specific location / origin in the body.

[0473] All the cancers / tumors / carcinomas mentioned above can be further distinguished by their histopathological classification:

[0474] Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive carcinoma, verrucous carcinoma, pseudosarcoma, degenerative carcinoma, metastatic cell carcinoma, lymphoepithelial carcinoma), adenocarcinoma (AC) (well-differentiated adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, pleomorphic giant cell adenocarcinoma, mammary duct adenocarcinoma, small cell adenocarcinoma, signet ring cell adenocarcinoma, spindle cell adenocarcinoma, clear cell adenocarcinoma, oat cell adenocarcinoma, glial adenocarcinoma, adenosquamous adenocarcinoma, mucoepidermoid adenocarcinoma, adenoid cystic adenocarcinoma), mucinous cyst adenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); eosinophilic cell carcinoma;

[0475] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematologic neoplasms, mixed and undifferentiated carcinomas;

[0476] The compounds of the present invention can be used in treatment regimens in the context of first-line, second-line, or any other line of treatment.

[0477] The compounds of the present invention can be used for the prevention, short-term or long-term treatment of the above-mentioned diseases / symptoms / cancer / tumors, optionally in combination with radiotherapy and / or surgery.

[0478] The treatment methods, approaches, uses, and compounds disclosed herein (above and below) may be performed using any pharmaceutical composition or kit comprising any compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, as disclosed or defined herein, and using any pharmaceutical composition or kit comprising any individual embodiment or common subset thereof of compound (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof (each comprising all individual embodiments or common subsets of compound (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*).

[0479] Combination therapy

[0480] Compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts, may also be used as preoperative or postoperative adjuvants in combination 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. Preferably, the pharmacologically active substance used for co-administration is an anti-regenerative compound.

[0481] Therefore, in another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for use as defined above, wherein the compound is administered before, after or together with one or more other pharmacologically active substances.

[0482] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for use as defined above, wherein the compound is administered in combination with one or more other pharmacologically active substances.

[0483] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) as defined above, or pharmaceutically acceptable salts thereof, wherein the compound is administered before, after, or together with one or more other pharmacologically active substances.

[0484] In another aspect, the present invention relates to a method as defined above (e.g., a method for treatment and / or prevention), wherein the compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof is administered before, after or together with a therapeutically effective amount of one or more other pharmacologically active substances.

[0485] In another aspect, the present invention relates to a method as defined above (e.g., a method for treatment and / or prevention), wherein a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substances.

[0486] 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), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof is administered simultaneously, concurrently, sequentially, continuously, alternately, or separately from one or more other pharmacologically active substances.

[0487] 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 RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0488] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, which is suitable for treating and / or preventing cancer, wherein the compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof is administered simultaneously, concurrently, sequentially, continuously, alternately, or separately with one or more other pharmacologically active substances.

[0489] In another aspect, the present invention relates to a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof, the compound or a pharmaceutically acceptable salt thereof being suitable for the treatment and / or prevention of cancer, wherein the RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0490] In another aspect, the present invention relates to a kit comprising the following

[0491] A first pharmaceutical composition or dosage form comprising a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, and

[0492] • A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0493] This kit is intended for the treatment and / or prevention of cancer, wherein the first pharmaceutical composition is intended to be administered simultaneously, concurrently, sequentially, continuously, alternately, or separately with the second pharmaceutical composition and / or additional pharmaceutical compositions or dosage forms.

[0494] 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.

[0495] In another embodiment of the invention, the components (i.e., combination compounds), kits, uses, methods, and compounds for use according to the invention (including all embodiments) are administered simultaneously.

[0496] In another embodiment of the invention, the components (i.e., combination compounds), kits, uses, methods, and compounds for use according to the invention (including all embodiments) are administered in parallel.

[0497] In another embodiment of the invention, the components (i.e., combination compounds), kits, uses, methods, and compounds for use according to the invention (including all embodiments) are applied sequentially.

[0498] In another embodiment of the invention, the components (i.e., combination compounds), kits, uses, methods, and compounds for use according to the invention (including all embodiments) are administered sequentially.

[0499] In another embodiment of the invention, the components (i.e., combination compounds), kits, uses, methods, and compounds supplied for use according to the invention (including all embodiments) are administered alternately.

[0500] In another embodiment of the invention, the components (i.e., combination compounds), kits, uses, methods, and compounds for use according to the invention (including all embodiments) are applied separately.

[0501] The pharmacologically active substance to be used / in combination with a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) and / or to be used / in combination with a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof (including all individual embodiments or a common subset of compounds (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or in a medical use, application, treatment and / or prophylactic method as defined herein (above and below) may be selected from any one or more of the following (preferably one or two other pharmacologically active substances in all such embodiments):

[0502] 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutant thereof.

[0503] a. Irreversible inhibitors: such as afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV412, PF-6274484, HKI 357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib;

[0504] b. Reversible inhibitors: such as erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340;

[0505] c. Anti-EGFR antibodies: such as necitumumab, panitumumab, cetirizine.

[0506] Cetuximab and amivantamab;

[0507] d. Anti-HER2 antibodies: such as pertuzumab, trastuzumab, and trastuzumab emtansine;

[0508] e. Inhibitors of mutant EGFR;

[0509] f. HER2 inhibitors with exon 20 mutations;

[0510] g. Afatinib is the preferred irreversible inhibitor;

[0511] h. The preferred anti-EGFR antibody is cetuximab.

[0512] 2. Inhibitors of MEK and / or its mutants

[0513] a. For example, trametinib, cobimetinib, binimetinib, selumetinib, refametinib, BI 3011441;

[0514] b. Trametinib and BI 3011441 are preferred;

[0515] c. The optimal value is BI 3011441;

[0516] d. MEK inhibitors, such as those disclosed in WO 2013 / 136249;

[0517] e. MEK inhibitors as disclosed in WO 2013 / 136254

[0518] 3. Inhibitors of SOS1 and / or any mutant thereof (i.e., compounds that regulate / inhibit the GEF functional group of SOS1 by binding to SOS1 and preventing protein-protein interactions between SOS1 and (mutant) Ras proteins, such as KRAS).

[0519] a. For example, BAY-293, BI-3406, BI 1701963;

[0520] b. BI-3406 and BI 1701963 are preferred;

[0521] c. The optimal value is BI 1701963;

[0522] d. SOS1 inhibitors as disclosed in WO 2018 / 115380;

[0523] e. SOS1 inhibitors, such as those disclosed in WO 2019 / 122129;

[0524] f. SOS1 inhibitors disclosed in WO 2020 / 180768, WO 2020 / 180770, WO 2018 / 172250 and WO 2019 / 201848.

[0525] 4. Oncolytic virus

[0526] 5. RAS vaccine

[0527] a. For example, TG02 (Targovax).

[0528] 6. Cell cycle inhibitors

[0529] a. Inhibitors of CDK4 / 6 and / or any mutant thereof, for example.

[0530] i. For example, palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600;

[0531] ii. Preferably, peroxibuprofen and amaxibuprofen;

[0532] iii. Amaxibuprofen is the best option.

[0533] b. For example, periwinkle alkaloids

[0534] i. For example, Changchun Ruibin.

[0535] c. Inhibitors of, for example, aurora kinase and / or any mutant thereof.

[0536] i. For example, alisertib and barasertib.

[0537] 7. Inhibitors of PTK2 (=FAK) and / or any of its mutants

[0538] a. For example, TAE226, BI 853520.

[0539] 8. Inhibitors of SHP2 and / or any of its mutants

[0540] a. For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0541] 9. Inhibitors of PI3 kinase (=PI3K) and / or any mutant thereof

[0542] a. Inhibitors of PI3Kα and / or any mutant thereof, for example.

[0543] i. For example, alpelisib, serabelisib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactolisib, pictilisib, taselisib.

[0544] 10. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutant thereof

[0545] a. For example, ponatinib, infigratinib, and nintedanib.

[0546] 11. Inhibitors of AXL and / or any of its mutants

[0547] 12. Taxane

[0548] a. For example, paclitaxel, nab-paclitaxel, and docetaxel;

[0549] b. Pacific paclitaxel is preferred.

[0550] 13. Platinum-containing compounds

[0551] a. For example, cisplatin, carboplatin, oxaliplatin

[0552] b. Oxaliplatin is preferred.

[0553] 14. Antimetabolites

[0554] a. For example, combinations of 5-fluorouracil, capecitabine, fluorouracil, cytarabine, gemcitabine, pemetrexed, trifluridine, and tilpyrimidine (=TAS102);

[0555] b. Preferably, it is 5-fluorouracil.

[0556] 15. Immunotherapy agents

[0557] a. For example, immune checkpoint inhibitors

[0558] i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, and anti-TIM3 mAb;

[0559] ii. Preferably, it is resistant to PD1 mAb;

[0560] iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab;

[0561] iv. Nivolumab, pelizumab, izabenlimab and PDR-001 (= spartalizumab) are preferred;

[0562] v. The best options are izabenzimab, pelizumab, and nivolumab.

[0563] 16. Topoisomerase inhibitors

[0564] a. For example, irinotecan, lipo-irinotecan (nal-IRI), topotecan, etoposide;

[0565] b. Irinotecan and lipid-based irinotecan (nal-IRI) are the best choices.

[0566] 17. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutant thereof

[0567] 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.

[0568] 18. mTOR inhibitors

[0569] a. For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin 1, dactolisib, GDC-0349, VS-5584, vistusertib, AZD8055.

[0570] 19. Epigenetic regulators

[0571] a. For example, BET inhibitors

[0572] i. For example, JQ-1, GSK 525762, OTX-015, CPI-0610, TEN-010, OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601, CC-90010, AZD5153, I-BET151, BI 894999;

[0573] ii. Preferably BI 894999.

[0574] 20. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutant thereof

[0575] a. For example, xentuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (=dusigitumab), and linsitinib.

[0576] 21. Inhibitors of Src family kinases and / or any mutants thereof

[0577] 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;

[0578] 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;

[0579] c. For example, inhibitors of Frk subfamily kinases and / or any mutants thereof, i.e., inhibitors of Frk and / or any mutants thereof;

[0580] d. For example, dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU 6656, WH-4-023.

[0581] 22. Apoptosis regulators

[0582] a. For example, MDM2 inhibitors, such as p53 (preferably functional p53, optimal wt p53) inhibitors of the interaction between MDM2 and / or any mutant thereof;

[0583] i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115, BI 907828;

[0584] ii. Preferably, HDM-201, RG-7388, AMG-232 and BI 907828;

[0585] iii. The optimal value is BI 907828;

[0586] iv. MDM2 inhibitors as disclosed in WO 2015 / 155332;

[0587] v. MDM2 inhibitors as disclosed in WO 2016 / 001376;

[0588] vi. MDM2 inhibitors as disclosed in WO 2016 / 026937;

[0589] vii. MDM2 inhibitors as disclosed in WO 2017 / 060431;

[0590] b. For example, PARP inhibitors;

[0591] c. For example, MCL-1 inhibitors;

[0592] i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0593] 23. Inhibitors of c-MET and / or any of its mutants

[0594] a. For example, savolitinib, cabozantinib, and foretinib;

[0595] b. MET antibodies, such as emibetuzumab and amivantamab;

[0596] 24. Inhibitors of ERK and / or any of its mutants

[0597] a. For example, ulixertinib, LTT462;

[0598] 25. Inhibitors of farnesyltransferase and / or any mutant thereof

[0599] a. For example, tipifarnib;

[0600] In another embodiment of the (combination) use and method described above (e.g., methods of treatment and / or prevention), another pharmacologically active substance is administered before, after, or together with a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, wherein the other pharmacologically active substance is

[0601] • SOS1 inhibitors; or

[0602] ·BI 1701963; or

[0603] MEK inhibitors; or

[0604] Trametinib, or

[0605] ·BI 3011441; or

[0606] • Anti-PD-1 antibody; or

[0607] • Izabenlimab; or

[0608] • Cetuximab; or

[0609] Afatinib; or

[0610] • Standard System of Care (SoC) for a given condition; or

[0611] • PI3 kinase inhibitor.

[0612] In another embodiment of the (combination) use and method described above (e.g., methods of treatment and / or prevention), another pharmacologically active substance is administered in combination with a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, wherein the other pharmacologically active substance is

[0613] • SOS1 inhibitors; or

[0614] ·BI 1701963; or

[0615] MEK inhibitors; or

[0616] Trametinib; or

[0617] ·BI 3011441; or

[0618] • Anti-PD-1 antibody; or

[0619] • Izabenlimab; or

[0620] • Cetuximab; or

[0621] Afatinib; or

[0622] • Standard System of Care (SoC) for a given condition; or

[0623] • PI3 kinase inhibitor.

[0624] In another aspect of the (combination) uses and methods described above (e.g., methods of treatment and / or prevention), two additional pharmacologically active substances are administered before, after, or together with a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, wherein said two additional pharmacologically active substances are

[0625] • MEK inhibitors (preferably BI 3011441) and SOS1 inhibitors (preferably BI 1701963); or

[0626] Trametinib and SOS1 inhibitors (preferred BI 1701963); or

[0627] • Anti-PD-1 antibody (preferably izabenlimab) and anti-LAG-3 antibody; or

[0628] • Anti-PD-1 antibody (preferably izabenlimab) and SOS1 inhibitor (preferably BI 1701963); or

[0629] • MEK inhibitors (preferably BI 3011441) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0630] • SOS1 inhibitors (preferably BI 1701963) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0631] • MEK inhibitors (preferably BI 3011441) and afatinib; or

[0632] • MEK inhibitors (preferably BI 3011441) and cetuximab; or

[0633] Trametinib and afatinib; or

[0634] Trametinib and cetuximab; or

[0635] • SOS1 inhibitors (preferably BI 1701963) and afatinib; or

[0636] • SOS1 inhibitors (preferably BI 1701963) and cetuximab.

[0637] In another aspect of the (combination) uses and methods described above (e.g., methods of treatment and / or prevention), two additional pharmacologically active substances are administered in combination with a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or a pharmaceutically acceptable salt thereof, wherein the other two pharmacologically active substances are

[0638] • MEK inhibitors (preferably BI 3011441) and SOS1 inhibitors (preferably BI 1701963); or

[0639] Trametinib and SOS1 inhibitors (preferred BI 1701963); or

[0640] • Anti-PD-1 antibody (preferably izabenlimab) and anti-LAG-3 antibody; or

[0641] • Anti-PD-1 antibody (preferably izabenlimab) and SOS1 inhibitor (preferably BI 1701963); or

[0642] • MEK inhibitors (preferably BI 3011441) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0643] • SOS1 inhibitors (preferably BI 1701963) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0644] • MEK inhibitors (preferably BI 3011441) and afatinib; or

[0645] • MEK inhibitors (preferably BI 3011441) and cetuximab; or

[0646] Trametinib and afatinib; or

[0647] Trametinib and cetuximab; or

[0648] • SOS1 inhibitors (preferably BI 1701963) and afatinib; or

[0649] • SOS1 inhibitors (preferably BI 1701963) and cetuximab.

[0650] It may also be used / in combination with or in combination with compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or their pharmaceutically acceptable salts (including all individual embodiments or common subsets of compounds (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or additional pharmacologically active substances in medical uses, applications, treatments, and / or preventive methods as defined herein (above and below), including (but not limited to): hormones, hormone analogs, and anti-hormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate). Acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide, aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin) Acetate), luprolide), inhibitors of growth factors and / or 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), and inhibitors such as (anti) growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors, such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab);Antimetabolites (e.g., antifolate agents such as methotrexate and raltitrexed); pyrimidine analogs such as 5-fluorouracil (5-FU); nucleoside and deoxynucleoside analogs, capecitabine and gemcitabine; purine and adenosine analogs such as mecaptopurine, thioguanine, cladribine, pentostatin, and cytarabine). C) Fludarabine; antitumor antibiotics (e.g., anthracyclins, such as doxorubicin, doxil (polyethylene glycol-modified doxorubicin hydrochloride, myocet (non-polyethylene glycol-modified doxorubicin), daunorubicin, epirubicin, idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); 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 (such as vinblastine, vindesin, vincristine, and vinocrine; and taxanes, such as paclitaxel and docetaxel); angiogenesis inhibitors (such as tasquinimod), and tubulin inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxin, such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors). 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, temsirol) Immunomodulatory agents include: irofolimus, sirolimus, 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, pembrolizumab), antibody-dependent cell-mediated cytotoxicity (ADCC) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, 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, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer).

[0651] It should be understood that the combinations, compositions, kits, methods, uses, or compounds used according to the present invention are contemplated for simultaneous, parallel, sequential, continuous, alternating, or individual administration of the active ingredient or component. It should be understood that compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or their pharmaceutically acceptable salts, and one or more other pharmacologically active substances, can be formulated and administered in a dependent or independent manner. Compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), or (Ie*) or their pharmaceutically acceptable salts, and one or more other pharmacologically active substances, can be administered as part of the same pharmaceutical composition / dosage form or preferably as a separate pharmaceutical composition / dosage form.

[0652] In this context, the term "combination" or "combined" 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, for example, the simultaneous, parallel, sequential, continuous, alternating, or individual use of components or ingredients. The term "fixed combination" refers to the simultaneous administration of an active ingredient to a patient in the form of a single entity or dose. The term "non-fixed combination" refers to the simultaneous, parallel, or sequential administration of an active ingredient to a patient in the form of a single entity without a specific time limit, wherein such administration provides a therapeutically effective amount of the compound in the patient's body.

[0653] The administration of a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be carried out by co-administering the active components or ingredients, such as by simultaneously or concurrently administering the active components or ingredients in a single or two or more separate formulations or dosage forms. Alternatively, the administration of a compound of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) or (Ie*) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be carried out by sequential or alternating administration, such as by administering the active components or ingredients in two or more separate formulations or dosage forms.

[0654] For example, simultaneous administration includes administration at substantially the same time. This form of administration may also be referred to as "concomitant" administration. Concurrent administration includes administering the active agent within the same general period (e.g., on the same day but not necessarily at the same time). Alternating administration includes administering one agent during one period (e.g., within a course of several days or a week), then administering another agent during a subsequent period (e.g., within a course of several days or a week), and then repeating the pattern for one or more cycles. Sequential or consecutive administration includes administering one agent using one or more doses during a first period (e.g., within a course of several days or a week), then administering another agent using one or more doses during a second and / or additional period (e.g., within a course of several days or a week). An overlapping schedule may also be employed, which includes administering the active agent on different days during the treatment period, not necessarily according to a regular sequence. Variations of these general guidelines may also be used, e.g., depending on the agents to be used and the condition of the individual.

[0655] Definitions

[0656] Terms not specifically defined herein should be given the meaning that would be ascribed to them by one of ordinary skill in the art in light 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:

[0657] The prefix C x-y in the use of, 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 carbon atoms and a minimum of x carbon atoms.

[0658] 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.

[0659] The indication of the number of carbon atoms in a group consisting of a combination of carbon chains and carbon rings (e.g., cycloalkylalkyl, arylalkyl) involves the total number of carbon atoms in all carbon ring and carbon chain members. Clearly, ring structures have at least three members.

[0660] Generally, for groups containing two or more subunits (e.g., heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, arylalkyl), the last named subunit is the radical linker, for example, substituent aryl -C. 1-6 Alkyl refers to aryl groups bonded to C. 1-6 Alkyl groups, which are bonded to the core or to a substituent.

[0661] In groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or similar groups, those skilled in the art can see the group connection points of the molecule from the free valence of the group itself.

[0662] alkyl This indicates a monovalent saturated hydrocarbon chain, which can exist in straight (unbranched) or branched form. If the alkyl group is substituted, the substitution can occur independently of each other on all hydrogen-carrying carbon atoms, either monosubstituted or polysubstituted in each case.

[0663] Term "C" 1-5 Alkyl 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)-.

[0664] Other examples of alkyl groups are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (iso-Pr; isopropyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl; isoBu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH3)3), 1-pentyl (n-pentyl; - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-1-butyl (iso-pentyl; -CH2CH2CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neo-pentyl; -CH2C(CH3)3), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl;-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3), 2,3-di Methyl-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.

[0665] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., without any other definition, refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomer forms.

[0666] If the alkyl group is another (combination) group (such as, for example, C), x-y Alkylamino or C x-y If it is part of an alkyloxy group, then the definition of alkyl above also applies.

[0667] the term Alkylene It can also be derived from alkyl groups. Unlike alkyl groups, alkylene groups are divalent and require two coupling agents. 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.

[0668] Term "C" 1-4Alkyl 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)-.

[0669] 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.

[0670] The general terms propylidene, butylidene, pentylene, hexylidene, etc., without any other definition, refer to all possible isomers having the corresponding number of carbon atoms. That is, propylidene includes 1-methylethylidene, and butylidene includes 1-methylpropylidene, 2-methylpropylidene, 1,1-dimethylethylidene, and 1,2-dimethylethylidene.

[0671] If the alkylene group is another (combined) group (such as HO-C) x-y alkylene amino or H2N-C x-y If it is part of an alkylene group, then the above definition of alkylene also applies.

[0672] Unlike alkyl groups, alkenyl groups consist of at least two carbon atoms, where 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. In an alkyl group having at least two carbon atoms as defined above, if two hydrogen atoms from adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, the corresponding alkenyl group is formed.

[0673] alkenylExamples include vinyl, propenyl, allyl (propenyl-2-enyl), isopropenyl, butenyl, butenyl, butenyl, butenyl, 2-methyl-propenyl, 2-methyl-propenyl, 1-methyl-propenyl, 1-methyl-propenyl, 1-methylenepropyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, 3-methyl-butenyl, 3-methyl-butenyl, and 3-methyl-butenyl. Hexyl, 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, penta-1,4-dienyl, penta-1,3-dienyl, but-1,3-dienyl, 2,3-dimethylbut-1,3-diene, etc.

[0674] The general terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, pentadienyl, octadienyl, nonadienyl, decanadienyl, etc., without any other definition, refer to all possible isomers with 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.

[0675] The alkenyl group may be optionally present in cis or trans or E or Z orientation relative to the double bond.

[0676] When the alkenyl group is another (combined) group (such as C... x-y alkenylamino or C x-y When it is part of an alkenyloxy group, the above definition of alkenyl also applies.

[0677] Unlike alkylene, imide 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. In an alkylene group having at least two carbon atoms as defined above, if two hydrogen atoms on adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, the corresponding alkenyl group is formed.

[0678] Examples of alkenyl groups include vinylidene, propenylidene, 1-methylvinylidene, butenylidene, 1-methylpropenylidene, 1,1-dimethylvinylidene, 1,2-dimethylvinylidene, pentenylidene, 1,1-dimethylpropenylidene, 2,2-dimethylpropenylidene, 1,2-dimethylpropenylidene, 1,3-dimethylpropenylidene, hexenylidene, etc.

[0679] The generic terms propene, butene, pentenene, hexene, etc., without any other definition, refer to all conceivable isomers having the corresponding number of carbon atoms. That is, propene includes 1-methylvinylene, and butene includes 1-methylpropene, 2-methylpropene, 1,1-dimethylvinylene, and 1,2-dimethylvinylene.

[0680] The alkenyl group may optionally exist in a cis or trans or E or Z orientation relative to the double bond.

[0681] If the imide group is another (combined) group (such as HO-C) x-y imide-amino or H2N-C x-y If it is part of the alkenyloxy group, then the above definition of alkenyl also applies.

[0682] Unlike alkyl groups, acetylin It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a C-C triple bond. In an alkyl group having at least two carbon atoms as defined above, if two hydrogen atoms on adjacent carbon atoms are formally removed and the free valence is saturated to form two more bonds, the corresponding alkynyl group is formed.

[0683] 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.

[0684] The general terms propynyl, butynyl, pentylyl, hexynyl, heptynyl, octylyl, nonynyl, decynyl, etc., 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.

[0685] If a hydrocarbon chain carries at least one double bond and at least one triple bond, then by definition it belongs to an alkynyl subunit.

[0686] If the alkynyl group is part of another (combined) group (e.g., in C...), x-y alkynyl amino or C x-y If the alkynyl group is in the oxygen group, then the definition of alkynyl group above also applies.

[0687] Unlike alkylene, EthyneIt consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a C-C triple bond. In an alkylene group having at least two carbon atoms as defined above, if two hydrogen atoms on adjacent carbon atoms are formally removed and the free valence is saturated to form two more bonds, the corresponding ynylene group is formed.

[0688] Examples of ynyl groups include ethynyl, propynyl, 1-methylethynyl, butynyl, 1-methylpropynyl, 1,1-dimethylethynyl, 1,2-dimethylethynyl, pentyynyl, 1,1-dimethylpropynyl, 2,2-dimethylpropynyl, 1,2-dimethylpropynyl, 1,3-dimethylpropynyl, and hexynyl.

[0689] The general terms propynyl, butynyl, pentylyl, hexynyl, etc., without any other definition, refer to all conceivable isomers with the corresponding number of carbon atoms. That is, propynyl includes 1-methylethynyl, and butynyl includes 1-methylpropynyl, 2-methylpropynyl, 1,1-dimethylethynyl, and 1,2-dimethylethynyl.

[0690] If the ynylene group is part of another (combined) group (e.g., in HO-C...), x-y Imynylamino or H2N-C x-y If the alkynyl group is in the alkynyl group (in the alkynyl group), then the above definition of alkynyl group also applies.

[0691] heteroatoms It refers to oxygen, nitrogen, and sulfur atoms.

[0692] Haloalkyl (haloalkenyl, haloynyl) Alkyl (alkenyl, ynyl) compounds are derived from previously defined alkyl groups by the independent substitution of one or more hydrogen atoms in the hydrocarbon chain with the same or different halogen atoms. If the alkyl (alkenyl, ynyl) haloalkyl group is further substituted, the substitution can be monosubstituted or polysubstituted in each case, and can occur independently of each other on all hydrogen-carrying carbon atoms.

[0693] Examples of haloalkyl groups (haloalkenyl groups, 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.

[0694] The previously defined haloalkyl (haloalkenyl, haloynyl) also gave rise to the term. Haloalkylene (haloalkenyl, (halogenated acetylenic)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 formed by removing a hydrogen atom from the alkyl halogen (alkenyl halogen, alkynyl halogen).

[0695] The corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F, etc.

[0696] The above definition also applies if the corresponding halogen-containing group is part of another (combined) group.

[0697] halogen It involves fluorine, chlorine, bromine and / or iodine atoms.

[0698] cycloalkyl Composed of monocyclic, bicyclic, and spirocyclic alkyl groups. The ring system is saturated and formed by the attached carbon atoms. In bicyclic alkyl groups, two rings are joined together such that they share at least two carbon atoms. In spirocyclic alkyl groups, one carbon atom (the spiro atom) belongs to both rings.

[0699] If the cycloalkyl group is substituted, the substitution can occur in mono- or poly-substituted forms in each case, independently of each other on all hydrogen-carrying carbon atoms. The cycloalkyl group itself can act as a substituent and be bonded to the molecule at each suitable position in the ring system.

[0700] 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), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcareyl), bicyclo[3.1.1]heptyl (pinel), spiro[2.5]octyl, spiro[3.3]heptyl, etc.

[0701] If the cycloalkyl group is another (combination) group (such as C... x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y If a part of a cycloalkyl group is included, then the above definition of cycloalkyl also applies.

[0702] If the free valence of the cycloalkyl group is saturated, then the following is obtained: Alicyclic .

[0703] Therefore, terminology CycloalkyleneIt can be derived from the previously defined cycloalkyl group. Unlike cycloalkyl groups, cyclohexane groups are divalent and require two conjugates. Formally, the divalent form is obtained by removing a hydrogen atom from the cycloalkyl group. Corresponding groups are, for example:

[0704] Cyclohexyl and (Cyclohexylene)

[0705] If the cycloalkylene group is another (combined) group (such as HO-C) x-y Cycloalkylamino or H2N-C x-y If it is part of a cycloalkyl group, then the above definition of cycloalkyl also applies.

[0706] Cycloalkenyl It consists of subunits of monocyclic, bicyclic, and spirocyclic alkenyl groups. However, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. In cycloalkyl groups as defined above, if two hydrogen atoms are formally removed from adjacent ring carbon atoms, and the free valence is saturated to form a second bond, the corresponding cycloalkenyl group is obtained.

[0707] If the cycloalkenyl group is substituted, the substitution can occur in mono- or poly-substituted forms in each case, independently of each other on all hydrogen-carrying carbon atoms. The cycloalkenyl group itself can act as a substituent and be bonded to the molecule at each suitable position in the ring system.

[0708] 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, and cyclo... Pentyl-1,3-dienyl, cyclopentyl-2,4-dienyl, cyclohexyl-1,3-dienyl, cyclohexyl-1,5-dienyl, cyclohexyl-2,4-dienyl, cyclohexyl-1,4-dienyl, cyclohexyl-2,5-dienyl, bicyclo[2.2.1]heptyl-2,5-dienyl (norcamphenyl), bicyclo[2.2.1]heptyl-2-enyl (norcamphenyl), spiro[4,5]decyl-2-enyl, etc.

[0709] If the cycloalkenyl group is another (combined) group (such as C... x-y Cycloalkenylamino, C x-y cycloalkenyloxy or C x-y If it is part of a cycloalkenylalkyl group, then the above definition of cycloalkenyl also applies.

[0710] If the free valence of the cycloalkenyl group is saturated, then we obtain unsaturated alicyclic ring .

[0711] Therefore, terminology Cycloalkenyl It can be derived from the previously defined cycloalkenyl group. Unlike cycloalkenyl groups, deoxycycloalkenyl groups are divalent and require two binding complexes. Formally, the divalent group is obtained by removing a hydrogen atom from the cycloalkenyl group. Corresponding groups are, for example:

[0712] cyclopentenyl and (cyclopentenyl) etc.

[0713] If the cycloene group is another (combined) group (such as HO-C) x-y cycloene-enylamino or H2N-C x-y If it is part of a cycloalkylene group, then the above definition of cycloalkylene also applies.

[0714] Aryl It 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, however, partially saturated.

[0715] If the aryl group is substituted, the substitution can occur in mono- or poly-substituted forms in each case, independently of each other on all hydrogen-carrying carbon atoms. The aryl group itself can act as a substituent and be bonded to the molecule at every suitable position in the ring system.

[0716] Examples of aryl groups include phenyl, naphthyl, dihydroindenyl (2,3-dihydroindenyl), indenyl, anthraceneyl, phenanthryl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetrahydronaphthyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorene, etc. Phenyl is the most preferred.

[0717] The above definition of aryl also applies if the aryl group is part of another (combined) group (such as, for example, in arylamino, aryloxy, or arylalkyl).

[0718] If the free valence of the aryl group is saturated, then we obtain Fangzuji .

[0719] the term Aspartic It can also be derived from the previously defined aryl group. Unlike aryl, aryl derivatives are divalent and require two covalent groups. Formally, the second valence is obtained by removing a hydrogen atom from the aryl group. Corresponding groups are, for example:

[0720] Phenyl and (o-phenylene, m-phenylene, p-phenylene)

[0721] Naphthyl and wait.

[0722] 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.

[0723] heterocyclic group This indicates a cyclic system derived from previously defined cycloalkyl, cycloalkenyl, and aryl groups by independently replacing one or more -CH2- groups in a hydrocarbon ring with -O-, -S-, or -NH- groups, or by replacing one or more =CH- groups with =N- groups. A total of no more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and two sulfur atoms, or between one oxygen atom and one sulfur atom, 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.

[0724] The direct result of cycloalkyl, cycloalkenyl and aryl groups is that heterocyclic groups are composed of subunit monocyclic heterocyclic groups, bicyclic heterocyclic groups, tricyclic heterocyclic groups and spirocyclic groups, which can exist in saturated or unsaturated forms.

[0725] Unsaturation refers to the presence of at least one double bond in the ring system under discussion, but without forming a heteroaromatic system. In bicyclic heterocyclic groups, the two rings are linked together, resulting in at least two shared (hetero) atoms. In spiroheterocyclic groups, a single carbon atom (spiro atom) belongs to both rings.

[0726] If the heterocyclic group is substituted, the substitution can occur in mono- or poly-substituted forms in each case, independently of each other on all hydrogen-carrying carbon atoms and / or nitrogen atoms. The heterocyclic group itself can act as a substituent and be bonded to the molecule via each suitable position in the ring system. Substituents on the heterocyclic group are not counted in the number of heterocyclic group members.

[0727] Examples of heterocyclic groups include tetrahydrofuranyl, pyrrolylyl, pyrrolinyl, tetrahydroimidazolyl, thiazolidinyl, dihydroimidazolyl, pyrazolinyl, pyrazolinyl, piperidinyl, piperazinyl, epoxyethyl, aziridinyl, azircyclic butyl, 1,4-dioxanehexyl, azircyclic heptyl, diazircyclic heptyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3 -dioxolane, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazonylheptanyl, tetrahydrothiophene, high-thiomorpholinyl-S,S-dioxide, oxazolidinone, dihydropyrazolyl, dihydropyrroleyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophene-S-oxide, tetrahydrothiophene-S,S-dioxide, high-thiomorpholinyl-S-oxide, 2,3-dihydroazonyl, 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-diaza-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4,5]decyl, etc.

[0728] Other examples are the structures described below, which can be linked via hydrogen-carrying atoms (exchanged with hydrogen):

[0729]

[0730]

[0731]

[0732] The preferred monocyclic heterocyclic group is 4 to 7 members and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0733] Preferred monocyclic heterocyclic groups are piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and nitrogen-containing heterocyclic butyl groups.

[0734] The preferred bicyclic heterocyclic group is 6 to 10 members and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0735] The preferred tricyclic heterocyclic group is 9-membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0736] The preferred spirocyclic group is 7 to 11 members and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0737] The above definition of a heterocyclic group also applies if the heterocyclic group is part of another (combination) group (such as, for example, a heterocyclic amino, heterocyclic oxygen, or heterocyclic alkyl group).

[0738] If the free valence of the cycloalkyl group is saturated, then the following is obtained: Heterocyclic .

[0739] the term Sub-heterocyclic 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:

[0740] Piperidinyl and

[0741] 2,3-Dihydro-1H-pyrrole and wait.

[0742] The above definition of a heterocyclic group also applies if the heterocyclic group is part of another (combined) group (such as, for example, in HO-heterocyclic amino or H2N-heterocyclic oxygen).

[0743] heteroaryl A heteroaryl group represents a monocyclic heteroaromatic ring or a polycyclic ring having at least one heteroaromatic ring, which, compared to the corresponding aryl or cycloalkyl (cycloalkenyl) group, contains one or more heteroatoms, independently selected from nitrogen, sulfur, and oxygen, replacing one or more carbon atoms, wherein the resulting group must be chemically stable. The existence of a heteroaryl group presupposes a heteroatom and a heteroaromatic system.

[0744] If the heteroaryl group is substituted, the substitution can occur in mono- or poly-substituted forms in each case, independently of each other on all hydrogen-carrying carbon atoms and / or nitrogen atoms. The heteroaryl group itself can act as a substituent and be bonded to the molecule at each suitable position (carbon and nitrogen) in the ring system. Substituents on the heteroaryl group are not counted in the heteroaryl group membership count.

[0745] heteroarylExamples 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, isindoleyl, benzofuranyl, benzothiopheneyl, benzooxazolyl, benzyl The following are listed: benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolyl, indazole, isoquinolinyl, quinolinyl, quinoxalinyl, cinolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indoleazinyl, oxazolopyridyl, imidazopyridyl, naphthidyl, benzooxazolyl, pyridinylpyridyl, pyrimidinylpyridyl, purine, pteridyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indole-N-oxide, isoquinolinyl-N-oxide, quinazololyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indoleazinyl-N-oxide, indazole-N-oxide, benzothiazolyl-N-oxide, benzoimidazolyl-N-oxide, etc.

[0746] Other examples are the structures described below, which can be linked via hydrogen-carrying atoms (exchanged with hydrogen):

[0747]

[0748]

[0749] Preferably, the heteroaryl group is a 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring, each having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0750] The above definition of a heteroaryl group also applies if the heteroaryl group is part of another (combined) group (such as, for example, a heteroarylamino, heteroaryloxy, or heteroarylalkyl group).

[0751] If the free valence of the heteroaryl group is saturated, a heteroaryl group is obtained.

[0752] the term Hybrid aryl It also derives from the previously defined heteroaryl group. Unlike heteroaryl groups, hypoaryl groups are divalent and require two co-orienting elements. Formally, the second valence is obtained by removing a hydrogen atom from the heteroaryl group. Corresponding groups are, for example:

[0753] pyrrole and wait.

[0754] The above definition of a heteroaryl group also applies if the heteroaryl group is part of another (combined) group (such as, for example, in HO-heteroarylamino or H2N-heteroaryloxy).

[0755] Replaced This refers to the replacement of a hydrogen atom directly bonded to the atom under study by another atom or another atomic group (substituent). Depending on the starting conditions (number of hydrogen atoms), mono- or poly-substituent substitution can occur on a single atom. Specific substituent substitution is only feasible if the permitted valence of the substituent corresponds to the permitted valence of the atom to be substituted and the substitution produces a stable compound (i.e., the compound cannot spontaneously transform, such as rearrangement, cyclization, or elimination).

[0756] Divalent substituents (such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, or similar) can be substituents only on carbon atoms, while the divalent substituents =O and =NR can also be substituents on sulfur. Generally, substitution can occur only on the ring system via divalent substituents 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 only possible at the -CH2- group or sulfur atom in the ring system (only the =O group or the =NR group, possibly one or two =O groups, or for example, one =O group and one =NR group, each group replacing a free electron pair).

[0757] Stereochemicals / sols / hydrates: Unless specifically instructed otherwise, 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 racemates, as well as mixtures of individual mirror-image isomers in different proportions, mixtures of non-mirror-image isomers, or mixtures containing any of the aforementioned forms of such isomers and mirror-image isomers, 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.

[0758] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example by separating corresponding mixtures, by 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 (e.g., starting from optically active starting materials and / or by using chiral reagents).

[0759] 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-image isomers 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).

[0760] 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 derivatizing the corresponding racemic compound with an optically active chiral auxiliary agent, 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 (partial) crystallization from a suitable solvent in the presence of an optically active chiral auxiliaries.

[0761] Salt: The phrase “pharmaceutically acceptable” in this article refers to compounds, substances, compositions, and / or dosage forms that, within the scope 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 in proportion to a reasonable benefit / risk ratio.

[0762] As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound in which the symbiotic compound is modified by producing its acidic or basic 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 the like.

[0763] For example, the salt includes salts formed from the following: 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.

[0764] 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.

[0765] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from philic compounds containing a basic or acidic moiety. 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).

[0766] In addition to the salts mentioned above, salts of other acids suitable for purifying or separating the compounds of the present invention (e.g., trifluoroacetates) are also included as part of the present invention.

[0767] In diagrams such as the following

[0768]

[0769] The letter A has a cyclical referential function to easily indicate, for example, that the cyclic in question is connected to other cyclics.

[0770] For divalent groups, it is crucial to determine the adjacent groups they are bonded to and their valence. For clarity, the corresponding combination may be indicated in parentheses, as shown in the following representation:

[0771] or (R) 2 )-C(=O)NH- or (R 2 )-NHC(=O)-.

[0772] If such a description is missing, the divalent group can combine in two directions, that is, for example, -C(=O)NH- also includes -NHC(=O)- (and vice versa).

[0773] Groups or substituents are typically selected from those with corresponding group names (e.g., R). a R b Many 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 is considered to be completely independent of each other.

[0774] For the purposes of this invention, a therapeutically effective amount refers to the amount of a substance capable of eliminating disease symptoms or preventing or alleviating these symptoms or prolonging the survival of the treated patient.

[0775] As used in this article, Ras family proteins refer to V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog (KRAS), neuroblastoma RAS virus oncogene homolog (NRAS), and Harvey mouse sarcoma virus oncogene (HRAS) and any of their mutants.

[0776] As used herein, RAS G12C inhibitors refer to compounds that bind to one or more of the G12C mutant RAS proteins KRAS G12C (=KRAS G12C inhibitor), NRAS G12C (=NRAS G12C inhibitor), and / or HRAS G12C (=HRAS G12C inhibitor), especially KRAS G12C, and are able to adversely regulate or inhibit all or part of the enzymatic activity of KRAS G12C and / or NRAS G12C and / or HRAS G12C, especially KRAS G12C. While not wishing to be bound by theory, it is believed that the compounds of the present invention can selectively react with KRAS G12C and / or HRAS G12C and / or NRAAS G12C proteins (preferably KRAS G12C) by forming a covalent bond with the cysteine ​​residue at position 12 of KRAS G12C and / or HRAS G12C and / or NRAAS G12C (preferably KRASG12C), thereby causing regulation / inhibition of the enzymatic activity of these mutant RAS proteins.

[0777] List of abbreviations

[0778]

[0779]

[0780]

[0781] Example

[0782] 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:

[0783] Preparation of compounds according to the present invention

[0784] General

[0785] Unless otherwise stated, all reactions are carried out using methods commonly used in chemical laboratories on 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).

[0786] If a compound is represented by both its structural formula and its nomenclature, and there is a conflict, the structural formula is the determining factor.

[0787] 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).

[0788] Chromatography

[0789] Thin-layer chromatography was performed on ready-made silica gel 60 TLC plates on glass (with fluorescent indicator F-254) manufactured by Merck.

[0790] Preparative high-performance liquid chromatography (RP-HPLC) of the example compounds of the present invention was performed using a column manufactured by Waters (name: SunFire). TM Prep C18, OBD TM 10μm, 50×150mm or SunFire TM Prep C18 OBD TM 5μm, 30×50mm or XBridge TM Prep C18, OBD TM 10μm, 50×150mm or XBridge TM Prep C18, OBD TM 5μm, 30×150mm or XBridge TM Prep C18, OBD TM The assay was performed on Agilent or Gilson systems with 5μm (30×50mm) and YMC (name: Actus-Triart Prep C18, 5μm, 30×50mm).

[0791] The compounds were eluted using different gradients of H2O / acetonitrile. For the Agilent system, 5% acid modifier (20 mL HCOOH to 1 L H2O / acetonitrile (1 / 1)) was added to the water (acidic conditions). For the Gilson system, 0.1% HCOOH was added to the water.

[0792] For chromatography on the Agilent system under alkaline conditions, an H2O / acetonitrile gradient is used, and the water is made alkaline by adding 5% alkaline modifier (50g NH4HCO3 + 50mL NH3 (25% in H2O) to a final volume of 1L). For the Gilson system, the water is made alkaline as follows: 5mL NH4HCO3 solution (158g in 1L H2O) and 2mL NH3 (28% in H2O) are added to a final volume of 1L with H2O.

[0793] Supercritical fluid chromatography (SFC) of the intermediates and example 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).

[0794] Analytical HPLC (reaction control) of intermediates and final compounds was performed using a Waters (name: XBridge) system. TM C18, 2.5μm, 2.1×20mm or XBridge TM The analysis is performed using columns manufactured by C18 (2.5 μm, 2.1 × 30 mm) or Aquity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm), YMC (Triart C18, 3.0 μm, 2.0 × 30 mm), and Phenomenex (Luna C18, 5.0 μm, 2.0 × 30 mm). In all cases, the analytical instrument is also equipped with a mass detector.

[0795] HPLC-mass spectrometry / UV-spectroscopy determination

[0796] Retention times / MS-ESI values ​​for characterizing the example compounds according to the present invention were generated using an HPLC-MS apparatus (high performance liquid chromatography with a mass detector). + The specified retention time t is the time of the compound eluted at the injection peak. Ret. =0.00.

[0797] SFC-method (preparative)

[0798] Preparative SFC was performed on the Waters Thar SFC 80 system.

[0799] Column: Chiralpak AD-H (21 x 250 mm), 5 μm

[0800] Flow rate: 25g / min

[0801] Mobile phase: 75% CO2 + 25% MeOH (0.5% isopropylamine)

[0802] ABPR: 120 bar

[0803] Temperature: 35℃

[0804] UV: 220nm

[0805] Stacking time: 8min

[0806] HPLC - Methods (Analysis)

[0807] Method A

[0808] Samples were analyzed on an Agilent 1200 Series LC system coupled to an Agilent 6140 mass spectrometer. Purity was determined via...

[0809] UV detection was determined within a 170nm bandwidth in the 230-400nm range. LC parameters are as follows:

[0810]

[0811]

[0812] Method B

[0813]

[0814] Method C

[0815]

[0816] Method D

[0817]

[0818]

[0819] Method E

[0820]

[0821] Method F

[0822]

[0823]

[0824] Method G

[0825]

[0826] 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 not as limiting of 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 in a manner similar to known background art compounds or the methods described herein, i.e., the synthesis of these compounds is within the skill of an organic chemist. The substances described in the literature can be prepared according to the disclosed synthetic methods. If the exact configuration of the following chemical structure is depicted without a stereocenter (e.g., an asymmetrically substituted carbon atom), then both configurations should be considered to be included and disclosed in the representation. The representation of a stereocenter in racemic form should always be considered to include and disclose two mirror-image isomers (if no other defined stereocenter is present) or all other potential non-mirror-image isomers and mirror-image isomers (if additionally defined or non-defined stereocenters are present).

[0827] A general reaction flow and overview of the synthetic route for compound (I) according to the present invention.

[0828] Process 1:

[0829]

[0830] Experimental procedure for the synthesis of A-2a

[0831]

[0832] A-1a (93.46 mL, 587.5 mmol, 1.0 equivalent) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 25.85 g, 646.3 mmol, 1.1 equivalent) in THF (2.0 L) at 0–10 °C. The mixture was stirred at 10 °C for 30 min, followed by dropwise addition of methyl iodide (55.11 mL, 881.3 mmol, 1.5 equivalent) at 10 °C. The mixture was allowed to reach room temperature overnight. After complete conversion, the reaction mixture was cooled to 0 °C and quenched with a saturated ammonium chloride aqueous solution. The product was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give A-2a, which was used in the next step without further purification.

[0833] The following intermediate A-2 (Table 1) can be obtained in a similar manner using different cyclic β-keto esters A-1. If necessary, the crude product A-2 can be purified by chromatography.

[0834] Table 1

[0835]

[0836] Experimental procedure for the synthesis of A-3a

[0837]

[0838] At room temperature, malononitrile (58.04 g, 879.3 mmol, 1.5 equivalents) was added to a solution of A-2a (108.00 g, 586.2 mmol) in toluene (1.03 L), followed by ammonium acetate (9.04 g, 117.2 mmol, 0.2 equivalents) and acetic acid (13.41 mL, 234.5 mmol, 0.4 equivalents). The mixture was stirred at 110 °C for 16 hours. After complete conversion, the mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude product A-3a. This crude product was used in the next step without further purification (see also Naumann et al., Pharmazie 51 (1996), 4).

[0839] The following intermediate A-3 (Table 2) can be obtained in a similar manner using different intermediates A-2. If necessary, the crude product A-3 can be purified by chromatography.

[0840] Table 2

[0841]

[0842] Experimental procedure for the synthesis of A-4a

[0843]

[0844] Sulfur (68.9 g, 2.2 mol, 2.0 equivalent) and L-proline (24.8 g, 0.22 mol, 0.2 equivalent) were added to a solution of A-3a (250.0 g, 1.1 mol) in DMF (3.0 L), and the resulting mixture was stirred at 80 °C for 12 hours. After complete conversion, the mixture was partitioned between EtOAc and water, and the organic layer was collected. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give A-4a.

[0845] The following intermediate A-4 (Table 3) can be obtained in a similar manner using different intermediates A-3. If necessary, the crude product A-4 can be purified by chromatography.

[0846] Table 3:

[0847]

[0848] Experimental procedure for A-4d synthesis

[0849]

[0850] A stirred solution of A-1a (12.00 g, 70.5 mmol) in EtOH (60.0 mL) was treated with sulfur (2.26 g, 70.5 mmol, 1.00 equivalent), morpholine (6.14 g, 70.5 mmol, 1.0 equivalent), and malononitrile (4.66 g, 70.5 mmol, 1.0 equivalent). The reaction mixture was then stirred at 55 °C for 1 hour. After complete conversion, the reaction mixture was concentrated, diluted with water, extracted with EtOAc, dried, filtered, and concentrated under reduced pressure to give a crude product. This crude product was purified by column chromatography (20-30% EtOH / hexane) to give A-4d. (HPLC method A; t) ret = 1.10 min; [M+H] + =251).

[0851] Experimental procedure for the synthesis of A-5a

[0852]

[0853] A-4a (78.0 mg, 0.3 mmol, 1.0 equivalent) was dissolved in EtOH (1.5 mL), and potassium hydroxide (4 M in water, 0.37 mL, 1.5 mmol, 5.0 equivalent) was added. The mixture was stirred at 78 °C for 16 hours. After complete conversion, water and EtOAc were added to the mixture, and the pH of the aqueous phase was adjusted to pH 4 using KHSO4 solution (10% in water), and the product was extracted using EtOAc. The combined organic layers were dried, filtered, and concentrated. The crude product was purified by acid reversed-phase chromatography (gradient elution: 20% to 90% acetonitrile / water) to give A-5a.

[0854] The following intermediates A-5 (Table 4) can be obtained in a similar manner using different esters A-4. If necessary, crude product A-5 can be purified by chromatography, and mirror isomers can be separated using preparative SFC chromatography as described herein, for example, separating A-5a into A-5b and its mirror isomers.

[0855] Table 4

[0856]

[0857]

[0858] Process 2a:

[0859]

[0860] Process 2b:

[0861]

[0862] Experimental Procedure for E-2a Synthesis

[0863]

[0864] DIPEA (2.882 g, 22.3 mmol, 2.0 equivalence) was added to a solution of (S)-1-((S)-1-methylpyrrolidone-2-yl)-ethanol-1-ol (1.441 g, 11.15 mmol, 1.0 equivalence) in DMSO, and the mixture was cooled to 10 °C. E-1a (2.0 g, 11.15 mmol, 97% purity, 1.0 equivalence) was added, and the mixture was stirred at 10 °C for 45 min. The mixture was filtered, and the filtrate was purified by alkaline reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile / water) to give E-2a. (HPLC method A; t) ret = 1.36 min; [M+H] + =267).

[0865] Additional intermediate E-2 can be obtained in a similar manner. If necessary, crude product E-2 can be purified by chromatography.

[0866] Experimental Procedure for E-2b Synthesis

[0867]

[0868] E-3a (3.50 g, 15.9 mmol) was dissolved in DMF (10 mL). 2-Dimethylaminoethyl chloride HCl salt (6.87 g, 47.72 mmol) was added, and the mixture was stirred at 150 °C for 25 min. The mixture was cooled to room temperature and filtered through glass powder, followed by washing with EtOAc. The solvent was removed by lyophilization. The residue was purified by normal-phase chromatography (gradient elution: 0% to 20% MeOH / DCM) to give E-2b.

[0869] The intermediate E-2 (Table 5) can be obtained in a similar manner. If necessary, the crude product E-2 can be purified by chromatography.

[0870] Table 5

[0871]

[0872] Experimental procedure for the synthesis of E-4a (Method A)

[0873]

[0874] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.76 g, 13.73 mmol) and cesium carbonate (2.76 g, 13.73 mmol) were dissolved in DMA (10 mL). E-1b (2.50 g, 13.73 mmol) was added, and the mixture was stirred at 90 °C for 1 hour. The reaction mixture was extracted from water into EtOAc, and the organic phase was dried over magnesium sulfate. The solvent was removed under vacuum, and the residue was purified by basic reversed-phase chromatography (gradient elution: 45% to 98% acetonitrile / water) to give E-4a.

[0875] Experimental procedure for E-4b synthesis (Method B)

[0876]

[0877] Piperazine-1-carboxylic acid tert-butyl ester (5.92 g, 31.79 mmol, 1.1 equivalents) was added to a stirred solution of E-1b (5.00 g, 28.90 mmol) in DMSO (50.0 mL). DIPEA (11.21 g, 86.71 mmol, 3.0 equivalents) was then added, and the reaction mixture was stirred at 60 °C for 1 hour. After complete conversion, the mixture was dissolved in EtOAc and washed with water (3×). The organic phase was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc / hexane) to give E-4b.

[0878] Experimental procedure for E-4c synthesis (Method C)

[0879]

[0880] Piperazine-1-carboxylic acid tert-butyl ester (11.22 g, 57.22 mmol, 1.0 equivalent) was added to a stirred solution of E-1c (10.20 g, 57.22 mmol) in DCM (60.0 mL). DIPEA (20.71 g, 160.21 mmol, 2.8 equivalent) was then added, and the reaction mixture was stirred at 60 °C for 1 hour. After complete conversion, the mixture was dissolved in EtOAc and washed with water (3×). The organic phase was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH) to give E-4c.

[0881] Experimental procedure for E-4d synthesis (Method D)

[0882]

[0883] N-(2-hydroxyethyl)-N-methylcarbamate tert-butyl ester (171 mg, 0.95 mmol, 1.1 equivalents) was added to a stirred mixture of sodium hydride (22.8 mg, 0.95 mmol, 1.1 equivalents) and THF (2 mL) under argon atmosphere, and the mixture was stirred for 5 minutes. E-1c (150 mg, 0.86 mmol, 1.0 equivalents) was added, and the mixture was stirred for 1 hour. The reactants were quenched by adding a few drops of water, and the solvent was removed under vacuum. The crude product was dissolved in DCM and purified by column chromatography (DCM / MeOH) to give E-4d.

[0884] Experimental procedure for the synthesis of E-4e (Method E)

[0885]

[0886] E-1d (1.00 g, 6.62 mmol), piperazine-1-carboxylic acid tert-butyl ester (724.6 mg, 3.70 mmol, 0.8 equivalents), sodium tert-butoxide (915.4 mg, 9.24 mmol, 2.0 equivalents), 2-(di-tert-butylphosphine)biphenyl (275.7 mg, 0.92 mmol, 0.20 equivalents), and tris(diphenylmethylacetone)dipalladium(0) (211.5 mg, 0.23 mmol, 0.05 equivalents) were added to anhydrous dioxane (9.00 mL), and the mixture was stirred at room temperature for 1 hour. After complete conversion, the mixture was concentrated, diluted with water, extracted with DCM, dried, and the combined organic layers were filtered and concentrated. The crude product was purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile / water) to give E-4e.

[0887] The following (additional) intermediate E-4 (Table 6) can be obtained in a similar manner according to methods A to E using different amines PG-LH and intermediate E-1. If necessary, crude product E-4 can be purified by chromatography.

[0888] Table 6

[0889]

[0890]

[0891]

[0892]

[0893]

[0894] Experimental Procedure for E-6a Synthesis

[0895]

[0896] E-1b (500 mg, 2.83 mmol, 1.0 equivalent) and cesium fluoride (1.72 g, 11.33 mmol, 4.0 equivalent) were dissolved in DMA (5 ml) and heated to 110 °C by microwave irradiation. The mixture was filtered and the solid was washed with a small amount of DMA to obtain a crude product solution of E-5a in DMA.

[0897] Sodium hydride (158 mg, 3.97 mmol, 1.4 equivalents) was added to a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (531 mg, 187.24 mmol, 1.0 equivalent) in THF (5 mL), and the mixture was stirred for 30 min. This mixture was then slowly added to a freshly prepared solution of E-5a (397 mg, 140.09 mmol, 1.0 equivalent) in DMA and stirred for 5 min, followed by the addition of water and EtOAc. The phases were separated, and the aqueous phase was extracted twice with EtOAc (30 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated. The mixture was dissolved in acetonitrile and water and purified by acidic reversed-phase chromatography to give the desired product E-6a.

[0898] The intermediate E-6 (Table 7) can be obtained in a similar manner. If necessary, the crude product E-7 can be purified by chromatography.

[0899] Table 7

[0900]

[0901] Experimental Procedure for E-6d Synthesis

[0902]

[0903] E-1b (267 mg, 1.54 mmol, 1.0 equivalent) and cesium fluoride (937 mg, 6.17 mmol, 4.0 equivalent) were dissolved in DMA (3 mL) and heated to 110 °C by microwave irradiation. The mixture was filtered and the solid was washed with a small amount of DMA to obtain a crude product solution of E-5a in DMA. 5,8-diazaspiro[3.5]nonane-4-carboxylic acid tert-butyl ester (349 mg, 1.54 mmol, 1.0 equivalent) and DIPEA (0.667 mL, 3.86 mmol, 2.5 equivalent) were added to the mixture, and the mixture was stirred at 60 °C for 30 min. The mixture was filtered and the filtrate was purified by alkaline reversed-phase chromatography to obtain the desired product E-6d.

[0904] The intermediate E-6 (Table 8) can be obtained in a similar manner. If necessary, the crude product E-6 can be purified by chromatography.

[0905] Table 8

[0906]

[0907] Experimental Procedure for E-6f Synthesis

[0908]

[0909] Intermediate E-4ap (60 mg, 0.19 mmol, 1.0 equivalent) and cesium fluoride (56 mg, 0.37 mmol, 2.0 equivalent) were dissolved in DMSO (2 mL) and stirred overnight at 80 °C, then cooled to room temperature. Additional cesium fluoride (56 mg, 0.37 mmol, 2.0 equivalent) was added, and the mixture was stirred at 110 °C to complete the reaction. Water and acetonitrile were added, and the mixture was purified by acid reversed-phase chromatography to give the desired product E-6f.

[0910] The following intermediate E-6 (Table 9) can be obtained from other intermediates E-4 in a similar manner. If necessary, crude product E-6 can be purified by chromatography.

[0911] Table 9

[0912]

[0913] Synthesize various building blocks HR 5

[0914]

[0915] Experimental Procedure for G-2a Synthesis

[0916] G-1a (500 mg, 2.33 mmol) was dissolved together with anhydrous THF (5.00 mL) in triethylamine (485 μL, 3.5 mmol, 1.5 equivalences), and the mixture was cooled to 0 °C. Benzyl chloroformate (519 μL, 3.5 mmol, 1.5 equivalences) was added fractionally, and the mixture was stirred for 2 hours and allowed to reach room temperature overnight. After complete conversion, water was added to the mixture, and the product was extracted with DCM. The extracted extracts were dried, combined, filtered, and concentrated. The crude product was used in the next step without further purification. (HPLC Method B, t) ret = 0.766 min, [M+H] + =249 / 293).

[0917] Experimental Procedure for G-3a Synthesis

[0918] G-2a (813 mg, 2.33 mmol) was dissolved in DCM (25.00 mL) and treated with HCl (4 M in dioxane, 11.67 mL, 46.66 mmol, 20.0 equivalent). The mixture was stirred at room temperature for 2 hours. After complete conversion, the mixture was concentrated and the product was separated by basic reversed-phase chromatography (gradient elution: 10% to 70% acetonitrile / water). (HPLC Method B, t) ret = 0.478 min, [M+H] + =249).

[0919] Experimental procedure for the synthesis of G-4a (Method F)

[0920]

[0921] G-3a (4.0 g, 16.12 mmol) was dissolved in anhydrous DCM (50.00 mL) and treated with formaldehyde (37% in water, 1.21 mL, 16.12 mmol, 1.00 equivalent) and acetic acid (92 μL, 1.61 mmol, 0.10 equivalent). The mixture was stirred for 15 min, and then sodium triacetoxyborohydride (6.335 g, 29.00 mmol, 1.80 equivalent) was added, and the mixture was stirred at room temperature for 1 h. After complete conversion, water was added to the mixture, and the product was extracted with DCM. The combined extracts were dried, filtered, and concentrated. The crude product was purified by normal-phase chromatography (DCM / MeOH).

[0922] Experimental procedure for the synthesis of G-4b (Method G)

[0923]

[0924] K₂CO₃ (0.303 g, 2.51 mmol, 2.50 equivalence) was added to a stirred solution of G-3a (250.0 mg, 1.00 mmol) in anhydrous DMF (5.00 mL), followed by the addition of 1-bromo-2-methoxy-ethane (0.122 g, 1.00 mmol, 1.00 equivalence). The reaction mixture was stirred at 80 °C for 16 hours. After complete conversion, water was added to the mixture, and the product was extracted with EtOAc. The combined extracts were dried, filtered, and concentrated. The crude product was purified by normal-phase chromatography (DCM / MeOH).

[0925] The following (additional) intermediate G-4 (Table 10) can be obtained in a similar manner according to method F or G using G-3a and different aldehydes or ketones as alkylating agents. If necessary, the crude product G-4 can be purified by chromatography.

[0926] Table 10

[0927]

[0928] Experimental Procedure for G-5a Synthesis

[0929]

[0930] G-5a (3.00 g, 11.44 mmol) was dissolved in MeOH (20.0 mL) and palladium (10% / carbon, 360 mg) was added. The mixture was stirred in a hydrogenation reactor at 5 bar hydrogen pressure for 16 hours at room temperature. After complete conversion, the catalyst was filtered off and the residue was concentrated. The crude product was used in the following steps without purification.

[0931] The following intermediate G-5 ( Building Unit HR 5 (Table 11) can be obtained in a similar manner using analogues G-4 with different substitutions.

[0932] Table 11

[0933]

[0934]

[0935] Experimental Procedure for G-7a Synthesis

[0936]

[0937] G-6a (590.0 mg, 2.49 mmol) was dissolved in anhydrous THF (1.50 mL) and the mixture was cooled to 0 °C. LiAlH4 (2 M in THF, 6.22 mL, 12.44 mmol, 5.00 equivalent) was added dropwise, and the mixture was stirred at 70 °C in a sealed container for 1.5 hours. After complete conversion, the mixture was diluted with THF (15 mL), and potassium sodium tartrate tetrahydrate was slowly added while stirring at room temperature for 1.5 hours. The mixture was filtered, and the filtrate was concentrated. The crude product, unpurified, was used in the following steps.

[0938] The following intermediate G-7 ( Building Unit HR 5 (Table 12) can be obtained in a similar manner using the corresponding N-Boc-aminoketone G-6 as the starting material.

[0939] Table 12

[0940]

[0941]

[0942] Experimental Procedure for E-10a Synthesis

[0943]

[0944] A solution of piperazine-1-carboxylic acid tert-butyl ester (505 mg, 2.71 mmol; 1.0 equivalent) in acetone (11 mL) was added to E-9a (500 mg, 2.71 mmol; 1.0 equivalent) in acetone (6 mL) at 0 °C. An aqueous solution of sodium bicarbonate (225.00 mg, 2.12 mmol; 0.78 equivalent) in water (5 mL) was added, and the reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was filtered, and the solid was washed with water and dried to give the desired compound E-10a (HPLC method A, t). ret = 1.47 min, [M+H] + =334).

[0945] Experimental Procedure for E-11a Synthesis

[0946]

[0947] E-10a (1.04 g, 3.11 mmol, 1.0 equivalent), (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (561.41 mg, 4.05 mmol, 1.3 equivalent), and DIPEA (808.47 mg, 6.22 mmol, 2.0 equivalent) were dissolved in anhydrous THF (12 mL) and stirred at room temperature for 3 hours, followed by stirring at 40 °C for 1 hour. The solvent was removed under vacuum, and the residue was purified by normal-phase chromatography (cyclohexane:EtOAc 10:90 to 80:20) to obtain E-11a (HPLC method A, t ret = 1.54 min, [M+H] + =427).

[0948] Experimental Procedure for E-8a Synthesis

[0949]

[0950] E-11a (898 mg, 1.68 mmol, 1.0 equivalent) and sodium cyanide (329.85 mg, 6.73 mmol, 4.0 equivalent) were dissolved in DMSO (5 mL) and stirred at 60 °C for 3 hours. The solvent was removed and the residue was purified by reversed-phase chromatography to obtain the desired compound E-8a (HPLC method A, t). ret = 1.53 min, [M+H] + =418).

[0951] Experimental Procedure for E-8b Synthesis

[0952]

[0953] E-1a (1000 mg, 97% purity, 5.58 mmol, 1.0 equivalent) was slowly added to a solution of (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (792 mg, 6.13 mmol, 1.1 equivalent) and DIPEA (1.94 mL, 11.15 mmol, 2 equivalent) in DMSO (3 mL). The mixture was stirred at room temperature for 30 min. After complete conversion of the starting material was observed, (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.50 mg, 97% purity, 7.25 mmol, 1.3 equivalent) and DIPEA (0.97 mL, 5.58 mmol, 1 equivalent) were added to the mixture. The mixture was stirred at 60 °C for 60 min, and DIPEA (0.97 mL, 5.58 mmol, 1 equivalent) was added. The mixture was stirred at 70°C for 50 min and then stirred overnight at room temperature. After complete conversion was observed, the reactants were diluted with water and DCM and the phases were separated. The aqueous phase was extracted with DCM (3×) and the organic phases were combined. The solvent was removed under vacuum to give crude product E-8a. The crude product was dissolved in acetonitrile and water, filtered, and purified by alkaline reversed-phase chromatography (gradient elution: 35% to 95% acetonitrile / water) to give the desired purified product E-8b.

[0954] The following intermediate E-8 (Table 13) can be obtained in a similar manner without separating the corresponding intermediate E-2. If necessary, the crude product E-8 can be purified by chromatography.

[0955] Table 13

[0956]

[0957] Experimental procedure for E-8d synthesis

[0958]

[0959] Cesium fluoride (1.218 g, 8.02 mmol, 2.5 equivalents) was added to a solution of E-1a (600 mg, 3.21 mmol, 93% purity, 1.0 equivalent) in anhydrous DMSO (6 mL), and the resulting mixture was stirred at room temperature for 1 hour until complete conversion of the starting material was observed. The resulting suspension was filtered, and the filtered solid was washed with anhydrous DMSO (2 mL). The filtrate (8 mL) was added to (S)-1-((S)-1-methylpyrrolid-2-yl)ethanol-1-ol (453 mg, 3.51 mmol, 1.1 equivalents), and DIPEA (1.085 mL, 6.38 mmol, 2 equivalents) was added. The mixture was stirred at room temperature for 1 hour. After observing complete conversion of the starting material, a solution of piperazine-1-carboxylic acid tert-butyl ester (674 mg, 3.51 mmol, 97% purity, 1.1 equivalents) in anhydrous DMSO (3 mL) and DIPEA (1.085 mL, 6.38 mmol, 2 equivalents) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. After observing complete conversion, the reactants were diluted with acetonitrile and water, filtered, and purified by alkaline reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile / water) to give the desired product E-8d.

[0960] The following intermediate E-8 (Table 14) can be obtained in a similar manner without separating the corresponding intermediates E-5 and E-7 separately. If necessary, the crude product E-8 can be purified by chromatography.

[0961] Table 14

[0962]

[0963] Experimental procedure for the synthesis of E-8g (Method A)

[0964]

[0965] E-4f (50.0 mg, 0.148 mmol), G-5a (115 mg, 0.740 mmol, 5.0 equivalent), and DIPEA (25.78 μL, 0.15 mmol, 1.0 equivalent) were combined with anhydrous NMP (10 μL) and stirred in a sealed container at 120 °C for 1 hour. The product was separated by alkaline reversed-phase chromatography (gradient elution: 40% to 98% acetonitrile / water) to give E-8 g.

[0966] Intermediate E-8, labeled “A” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0967] Experimental procedure for E-8h synthesis (Method B)

[0968]

[0969] E-4e (400.0 g, 1.24 mmol), N-methylpiperazine (352.1 mg, 3.48 mmol, 2.8 equivalences), sodium tert-butoxide (246.3 mg, 2.49 mmol, 2.0 equivalences), 2-(di-tert-butylphosphine)biphenyl (74.18 mg, 0.25 mmol, 0.20 equivalences), and tris(diphenylmethylacetone)palladium(0) (56.9 mg, 0.062 mmol, 0.05 equivalences) were added to anhydrous dioxane (2.50 mL), and the mixture was stirred at 110 °C for 1 hour. After complete conversion, the mixture was concentrated, diluted with water, extracted with DCM, dried, and the combined organic layers were filtered and concentrated. The crude product was purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile / water) to give E-8h.

[0970] Intermediate E-8, labeled “B” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0971] Experimental procedure for E-8i synthesis (Method C)

[0972]

[0973] E-4b (1.00 g, 3.10 mmol), (S)-1,3-dimethylpiperazine (0.99 g, 8.67 mmol, 2.80 equivalents), tris(diphenylmethylacetone)palladium(0) (141.85 mg, 0.154 mmol, 0.05 equivalents), xantphos (184.80 mg, 0.31 mmol, 0.10 equivalents), cesium carbonate (2.019 g, 6.196 mmol, 2.00 equivalents), and anhydrous dioxane (8.00 mL) were combined and stirred at 110 °C in a sealed container under an argon atmosphere for 16 hours. After complete conversion, brine was added to the mixture and the product was extracted with DCM. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by basic reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile / water) to give E-8i.

[0974] Intermediate E-8, labeled “C” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0975] Experimental procedure for the synthesis of E-8j (Method D)

[0976]

[0977] E-4 g (3.035 g, 8.51 mmol), (S)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester (3.645 g, 17.01 mmol, 2.00 equivalents), tris(diphenylmethylacetone)palladium(0) (778.82 mg, 0.850 mmol, 0.10 equivalents), 1,3-bis(2,6-di-isopropylphenyl)imidazolium chloride (723.0 mg, 1.701 mmol, 0.20 equivalents), cesium carbonate (8.313 g, 25.514 mmol, 3.00 equivalents), and anhydrous dioxane (32.00 mL) were combined and stirred at 110 °C in a sealed container under argon atmosphere for 16 hours. After complete conversion, brine was added to the mixture and the product was extracted with DCM. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by alkaline reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile / water) to obtain E-8j.

[0978] Intermediate E-8, labeled “D” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0979] Experimental procedure for E-8k synthesis (Method E)

[0980]

[0981] E-4b (400 mg, 1.239 mmol), 1-(1-methylpiperidin-4-yl)piperazine (273.0 mg, 1.49 mmol, 1.20 equivalents), RuPhos Pd G3 (106.0 mg, 0.120 mmol, 0.10 equivalents), tripotassium phosphate (553.0 mg, 2.605 mmol, 2.10 equivalents), and anhydrous dioxane (3.10 mL) were combined and stirred at 85 °C in a sealed container under an argon atmosphere for 2 hours. After complete conversion, the mixture was diluted with DCM and filtered. The crude mixture was purified by normal-phase chromatography (DCM / MeOH / NH3) to give E-8k.

[0982] Intermediate E-8, labeled “E” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0983] Experimental procedure for the synthesis of E-8l (Method F)

[0984]

[0985] E-4b (100 mg, 0.31 mmol), pyridine-4-boronic acid (45.70 mg, 0.37 mmol, 1.20 equivalents), RuPhosPd G3 (27.3 mg, 0.031 mmol, 0.10 equivalents), tripotassium phosphate (138.1 mg, 0.65 mmol, 2.10 equivalents), and anhydrous dioxane (0.9 mL) were combined and stirred in a sealed container at 80 °C under an argon atmosphere for 1 hour. After complete conversion, the mixture was concentrated. The crude product was purified by basic reversed-phase chromatography to give E-8l.

[0986] Intermediate E-8, labeled “F” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0987] Experimental procedure for the synthesis of E-8m (Method G)

[0988]

[0989] Add (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (922 mg, 5.64 mmol, 79% purity, 4.0 equivalent) to a mixture of DIPEA (736.3 μL, 4.23 mmol, 3 equivalents) and E-4i (560 mg, 1.41 mmol, 85% purity, 1 equivalent) in DMSO (1 mL) and stir the mixture at 100 °C for 16 h. Cool the mixture to room temperature, dilute with acetonitrile and water, filter, and purify by acid reversed-phase chromatography (gradient elution: 10% to 98% acetonitrile / water) to give the desired product E-8m.

[0990] Intermediate E-8, labeled “G” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0991] Experimental procedure for E-8n synthesis (Method H)

[0992]

[0993] A mixture of E-4k (1.50 g, 4.44 mmol, 1.0 equivalent) and (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (688 mg, 5.33 mmol, 1.2 equivalent) in THF (45 mL) was cooled to 0 °C. Sodium tert-butoxide (854 mg, 8.88 mmol, 2.0 equivalent) was added to the mixture at 0 °C. The mixture was slowly heated to room temperature and stirred at room temperature for 2 hours. The reactants were quenched by adding cold water and EtOAc. The phases were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and concentrated under vacuum. The crude product was purified by normal-phase chromatography (2% MeOH / DCM) to give the desired product E-8n.

[0994] Intermediate E-8, labeled “H” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0995] Experimental procedure for the synthesis of E-8o (Method I)

[0996]

[0997] A solution of (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (312 mg, 2.42 mmol, 1.7 equivalents) in THF (3 mL) was cooled to 0 °C, and sodium hydride (74 mg, 1.85 mmol, 1.3 equivalents) was added fractionally over 10 min. A solution of E-4l (500 mg, 1.42 mmol, 1.0 equivalents) in THF (5 mL) was slowly added to the mixture, and the mixture was stirred for 18 h. The reactants were quenched by adding a saturated aqueous solution of ammonium chloride. The mixture was extracted with a mixture of DCM and MeOH (9:1). The phases were separated, and the organic layer was concentrated under vacuum. The crude product was purified by normal-phase chromatography (2% MeOH / DCM) to give the desired product E-8o.

[0998] Intermediate E-8, labeled “I” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[0999] Experimental procedure for E-8p synthesis (Method J)

[1000]

[1001] Trimethylamine (149.8 mg, 1.48 mmol, 2.5 equivalents) was added to a mixture of E-4r (200 mg, 0.59 mmol, 1.0 equivalents) and (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (91.8 mg, 0.71 mmol, 1.2 equivalents) in acetonitrile (1.5 mL). The mixture was stirred at 40 °C for 2 hours. The mixture was then stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure, and the crude product was purified by normal-phase chromatography (gradient elution: 0% to 90% MeOH in DCM + ammonia) to give the desired product E-8p.

[1002] Intermediate E-8, labeled “J” (Table 15), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[1003] Table 15

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013] Experimental procedure for synthesizing intermediate E-8cc

[1014]

[1015] E-2b (3.94 g, 20.93 mmol, 4.0 equivalents), piperazine-1-carboxylic acid tert-butyl ester (1.76 g, 5.23 mmol, 1.0 equivalents), sodium tert-butoxide (2.01 g, 20.93 mmol, 4.0 equivalents), 2-(di-tert-butylphosphine)-biphenyl (624.45 mg, 0.21 mmol, 0.4 equivalents), and tris-(diphenylmethylacetone)-dipalladium (479.05 mg, 0.052 mmol, 0.1 equivalents) were added to a sealed tube in dioxane (10 mL) and shaken overnight at 45 °C under nitrogen. The reaction mixture was mixed with EtOAc and water and extracted into EtOAc. The organic phase was dried over magnesium sulfate and purified by silica gel normal-phase chromatography (DCM:MeOH, 100:0 to 80:20).

[1016] The following intermediate E-8 (Table 16) can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[1017] Table 16

[1018]

[1019] Experimental procedure for the synthesis of E-8cf (Method K)

[1020]

[1021] Sodium hydride (60% dispersion in mineral oil, 652.8 mg, 16.32 mmol, 5.0 equivalent) was added to a solution of (S)-1-((S)-1-methylpyrrolid-2-yl)ethanol-1-ol (1.335 g, 8.16 mmol, 2.5 equivalents) in DMF (50 mL) at room temperature. The mixture was stirred for 10 min at room temperature, and E-6 g (1.00 g, 3.26 mmol, 1.0 equivalent) was added. The mixture was stirred for 3 h at room temperature. The reactants were quenched by adding water and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried, filtered, and the solvent was removed under vacuum. The crude product was purified by basic reversed-phase chromatography to give E-8cf.

[1022] Intermediate E-8, labeled “K” (Table 17), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[1023] Experimental procedure for the synthesis of E-8cg (Method L)

[1024]

[1025] Potassium tert-butoxide (45.6 mg, 0.41 mmol, 5.0 equivalents) was added to a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethanol-1-ol (52.6 mg, 0.41 mmol, 5.0 equivalents) in 2 mL of THF at room temperature. The mixture was stirred at room temperature for 30 min, and E-6b (25.0 mg, 0.081 mmol, 1.0 equivalents) was added. The mixture was stirred at room temperature for 15 min. The reactants were quenched by adding water and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, and the solvent was removed under vacuum. The crude product was purified by acid reversed-phase chromatography to give E-8cg.

[1026] Intermediate E-8, labeled “L” (Table 17), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[1027] Experimental procedure for the synthesis of E-8ch (Method M)

[1028]

[1029] E-6h (100.0 mg, 0.31 mmol, 1.0 equivalent) and (S)-1,3-dimethylpiperazine (42.5 mg, 0.37 mmol, 1.2 equivalent) were dissolved in DMSO (1 mL) at room temperature, and DIPEA (115.0 μL, 0.62 mmol, 2.0 equivalent) was added. The mixture was stirred for 1 hour. The mixture was diluted with acetonitrile and water and purified by acid reversed-phase chromatography to obtain E-8ch.

[1030] Intermediate E-8, labeled “M” (Table 17), can be obtained in a similar manner. If necessary, crude product E-8 can be purified by chromatography.

[1031] Table 17

[1032]

[1033]

[1034] Experimental procedure for E-8cn synthesis

[1035]

[1036] DCM (41 mL) containing E-8j (2.404 g, 4.50 mmol) was treated with HCl (4 M in dioxane, 8.33 mL, 33.31 mmol, 7.4 equivalences) and the mixture was stirred at room temperature for 5 hours. After complete conversion, the mixture was concentrated and the crude product was purified by basic reversed-phase chromatography (gradient elution: 25% to 100% acetonitrile / water) to give E-8cn.

[1037] The following intermediate E-8 (Table 18) can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[1038] Table 18

[1039]

[1040]

[1041] Experimental Procedure for E-8CQ Synthesis

[1042]

[1043] DCM (10.72 mL) containing E-8cn (231 mg, 0.532 mmol) was treated with formaldehyde (37% in water, 79.89 μL, 1.06 mmol, 2.0 equivalent), acetic acid (304.0 μL, 5.32 mmol, 10.0 equivalent), and a small amount of molecular sieve, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (232.3 mg, 1.06 mmol, 2.0 equivalent) was added, and the mixture was stirred at room temperature for 2 hours. After complete conversion, the mixture was diluted with brine, and the product was extracted with DCM. The combined organic extracts were dried, filtered, and concentrated, and the crude product was purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile / water) to give E-8cq.

[1044] The following intermediate E-8 (Table 19) can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[1045] Table 19

[1046]

[1047] Process 3:

[1048]

[1049] Experimental Procedure for E-12a Synthesis

[1050]

[1051] A solution of sodium hydroxide in water (16 mL, 4 M, 63.96 mmol, 1 equivalent) was added to a solution of E-8aq (1.776 g, 4.26 mmol, 1 equivalent) in MeOH (35 mL), and the resulting mixture was stirred at 65 °C for 1.5 h. The reaction volume was reduced under reduced pressure to remove most of the MeOH, and the remaining aqueous solution was carefully neutralized with an aqueous solution of HCl (8 M). The mixture was diluted with acetonitrile and purified by acid reversed-phase chromatography (gradient elution: 10% to 85% acetonitrile / water) to give the desired product E-12a.

[1052] The following intermediate E-12 (Table 20) can be obtained in a similar manner using different intermediates E-8 as starting materials. If necessary, the crude product E-8 can be purified by chromatography.

[1053] Table 20

[1054]

[1055]

[1056] Experimental Procedure for E-13a Synthesis

[1057]

[1058] N,O-dimethylhydroxylamine hydrochloride (725 mg, 7.43 mmol, 2.0 equivalents) was suspended in THF (10 mL), and DIPEA (3.236 mL, 18.58 mmol, 5.0 equivalents) was added. The mixture was stirred at room temperature for 15 minutes. A solution of THF (10 mL) containing intermediate E-12a (1.618 g, 3.72 mmol, 1.0 equivalents) and HATU (1.586 g, 4.09 mmol, 1.1 equivalents) was added to the mixture, and the mixture was stirred for 45 minutes. Water was added to the mixture, which was then diluted with acetonitrile and filtered. The filtrate was purified by alkaline reversed-phase chromatography (gradient elution: 20% to 90% acetonitrile / water) to give the desired product E-13a.

[1059] The following intermediate E-13 (Table 21) can be obtained in a similar manner using different intermediates E-12 as starting materials. If necessary, the crude product E-13 can be purified by chromatography.

[1060] Table 21

[1061]

[1062]

[1063] Process 4:

[1064]

[1065] Experimental procedure for the synthesis of A-6a

[1066]

[1067] CDI (17.12 g, 102.42 mmol, 1.1 equivalent) was added to a solution of A-5b (22.00 g, 93.11 mmol, 1.0 equivalent) in THF (300 mL), and the mixture was stirred at 50 °C for 1 hour. The mixture was cooled to room temperature, and sodium borohydride (10.78 g, 279.32 mmol, 3.0 equivalent) suspended in 5 mL of water was slowly added to the reaction mixture (exothermic reaction). After the addition, the mixture was stirred for 1 hour, and then quenched by the slow addition of water (250 mL). THF was removed under vacuum, and the resulting mixture was extracted with EtOAc (3 × 120 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over MgSO4. The solvent was removed under vacuum, and the crude product was used for the next step without further purification.

[1068] The following intermediate A-6 (Table 22) can be obtained in a similar manner using different intermediates A-5 as starting materials. If necessary, the crude product A-6 can be purified by chromatography.

[1069] Table 22

[1070]

[1071] Experimental procedure for the synthesis of A-7a

[1072]

[1073] A-6a (21.10 g, 75.93 mmol, 80% purity, 1.0 equivalent) was mixed with N,N-dimethylformamide dimethyl acetal (57.6 g, 454.37 mmol, 94% purity, 6.0 equivalent) and irradiated in an ultrasonic bath for 15 min until the mixture was a clear solution. Water (200 mL) was added and the reaction mixture was stirred at room temperature for 30 min until a precipitate formed. The precipitate was filtered and water (100 mL) was added. The mixture was irradiated in an ultrasonic bath for 15 min and the precipitate was filtered. The precipitate was washed with isopropanol (25 mL) and dried under vacuum at 45 °C overnight to give A-7a, which was used in the next step without further purification.

[1074] The following intermediate A-7 (Table 23) can be obtained in a similar manner using different intermediates A-6 as starting materials. If necessary, the crude product A-7 can be purified by chromatography.

[1075] Table 23

[1076]

[1077] Experimental procedure for the synthesis of A-8a

[1078]

[1079] A solution of oxaloyl chloride (12.2 mL, 144.20 mmol, 2.5 equivalents) in DCM (120 mL) was cooled to -78 °C. Anhydrous DMSO (18.44 mL, 259.57 mmol, 4.5 equivalents) in DCM (60 mL) was added dropwise to the reaction mixture (exothermic reaction). The mixture was stirred at -78 °C for 30 min. A-7a (16.00 g, 57.68 mmol, 1.0 equivalents) was slowly added to the reaction mixture. The mixture was stirred at -78 °C for 30 min, and trimethylamine (71.96 mL, 519.32 mmol, 9.0 equivalents) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for another 2 h. Water and DCM were added to the mixture, and the phases were separated. The aqueous layer was extracted twice with DCM, and the combined organic layers were washed three times with water. The organic layer was dried with MgSO4 and the solvent was removed under vacuum to obtain crude intermediate A-8a, which was used in the next step without further purification.

[1080] The following intermediate A-8 (Table 24) can be obtained in a similar manner using different intermediates A-7 as starting materials. If necessary, the crude product A-8 can be purified by chromatography.

[1081] Table 24

[1082]

[1083] Experimental procedure for the synthesis of A-9a

[1084]

[1085] A mixture of A-8a (15.90 g, 57.75 mmol, 1.0 equivalent), Cs₂CO₃ (22.58 g, 69.26 mmol, 1.2 equivalent), and MeOH (120 mL) was cooled to 0 °C, and a solution of BESTMANN-OHIRA reagent (dimethyl(1-diazo-2-oxopropyl)phosphonate; 12.20 g, 63.52 mmol, 1.1 equivalent) in MeOH (5 mL) was added dropwise to the reaction mixture. After 3 hours at 0 °C, the reaction mixture was slowly heated to room temperature. After complete conversion, MeOH was removed under vacuum, and water (500 mL) and EtOAc (500 mL) were added to the mixture. The phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed three times with water, dried over MgSO₄, and the solvent was removed under vacuum. The residue was mixed with diethyl ether and stirred at room temperature for 30 minutes. The mixture was cooled to 0°C and stirred for another 30 min, then filtered and washed with a small amount of cold diethyl ether. The precipitate was dried under vacuum at 45°C to give intermediate A-9a, which was used in the next step without further purification.

[1086] The following intermediate A-9 (Table 25) can be obtained in a similar manner using different intermediates A-8 as starting materials. If necessary, the crude product A-9 can be purified by chromatography.

[1087] Table 25

[1088]

[1089] Experimental Procedure for C-1a Synthesis

[1090]

[1091] LiHMDS (1.123 mL, 1.123 mmol, 2.4 equivalents, 1 M in THF) was added dropwise to a solution of A-9a (132 mg, 0.47 mmol, 1.01 equivalents) in 1 mL of THF at -78 °C. E-13a (224 mg, 0.47 mmol, 1.00 equivalents) in 2 mL of THF was added to the mixture at -78 °C, and the mixture was stirred at -78 °C for 30 min. The mixture was then slowly heated to room temperature and stirred for 5 min. The reaction was monitored by HPLC-MS to reveal the formed products and some remaining starting materials A-9A and E-13a. The mixture was cooled to -78 °C, and additional LiHMDS (0.56 mmol, 0.56 mmol, 1.2 equivalents, 1 M in THF) was added dropwise to the mixture. The mixture was stirred at -78°C for 25 min, and then slowly heated to room temperature, stirring at this temperature for 10 min. Afterward, the reactants were quenched with water and diluted with EtOAc. The phases were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile and water and purified by alkaline reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile / water) to give the desired product C-1a.

[1092] The following intermediate C-1 (Table 26) can be obtained in a similar manner using different intermediates E-13 and A-9 as starting materials. If necessary, the crude product C-1 can be purified by chromatography.

[1093] Table 26

[1094]

[1095]

[1096]

[1097] Alternative synthesis of building block A-9

[1098] Process 5:

[1099]

[1100] The alternative synthesis of building block A-9 began with TMS-protected alkyne A-15, which underwent asymmetric epoxidation (→ A-14) using a SHI catalyst, followed by treatment with an organometallic nucleophile, such as a Grinner reagent, to introduce the residue R. 3(→A-13). Deprotection with TMS in the presence of a base such as K2CO3 yields the hydroxyl intermediate A-12, which is subsequently oxidized to give the cyclic ketone A-11. Bicyclic closure with malononitrile and sulfur finally yields aminocycanothiothene A-10. Subsequent protection with an amino group yields A-9 as formamidin.

[1101] Experimental Procedure for A-14a Synthesis

[1102]

[1103] K₂CO₃ (48.37 g, 350.00 mmol, 2.5 equivalents) and ETDA (ethylenediaminetetraacetic acid; 20.5 mg, 0.07 mmol, 4.99 × 10⁻⁶) were added to a solution of A-15a (25.0 g, 140.18 mmol, 1.0 equivalent) and Shi catalyst ((3a'R,4S,7a'R)-2,2,2',2'-tetramethyldihydrospiro[[1,3]dioxacyclopentane-4,6'-[1,3]dioxacyclopenta[4,5-c]pyran]-7'(4'H)-one; 7.24 g, 28.04 mmol, 0.2 equivalents) in acetonitrile (175 mL) at 0 °C. -4 A solution of H₂O₂ (56.1 mL, 560.71 mmol, 30%, 4.0 equivalent) in water (175 mL) was added slowly over 0.5–1 hour to a vigorously stirred reaction mixture. Upon completion of the addition, the reaction mixture was stirred at 0 °C for 2.5 hours. The reaction mixture was quenched with heptane (125 mL). The phases were separated, and the aqueous layer was extracted three times with heptane (125 mL). The combined organic layers were washed with a saturated aqueous solution of Na₂SO₃ (50 mL), dried over Na₂SO₄, and concentrated under vacuum to give the desired product A-14a. 1 H-NMR (CDCl3, 400mHz): δ3.34-3.32(m,1H),2.10-2.09(m,1H),2.03-2.00(m ,1H),1.91-1.87(m,2H),1.41-1.37(m,2H),1.32-1.22(m,2H),0.16(m,9H).

[1104] Experimental procedure for the synthesis of A-13a

[1105]

[1106] LiCl (0.5 M in THF; 12.35 mL, 61.75 mmol, 1.2 equivalents) was added to a dry flask under N2 atmosphere. The solution was cooled to -5 to 0 °C, and LaCl3·2LiCl (0.6 M in THF; 1.03 mL, 0.62 mmol, 0.012 equivalents) and MeMgCl (3 M in THF; 20.58 mL, 61.75 mmol, 1.2 equivalents) were added sequentially to the cooled solution. The mixture was stirred for 10–15 min, during which time A-14a (10.00 g, 51.45 mmol, 1.0 equivalents) was added dropwise. The reaction mixture was heated to room temperature. When the reaction was complete, the reaction mixture was cooled to -5 to 0 °C and quenched with a saturated aqueous solution of NH4Cl (40 mL). Gas escape was observed, and the cooled batch was removed. The phases were separated. The aqueous layer was extracted three times with MTBE (50 mL). The combined organic layers were dried over Na2SO4 and then concentrated under vacuum. The crude product was purified by rapid column chromatography (10% MTBE / hexane) to give the desired product A-13a. 1 H-NMR (DMSO-d6, 400mHz): δ4.56 (d, J = 5.0Hz, 1H), 3.03-2.98 (m, 1H), 1.62-1.58 ( m,3H),1.50-1.42(m,3H),1.19-1.18(m,2H),1.14(s,3H),0.12(t,J=3.5Hz,9H).

[1107] Experimental procedure for the synthesis of A-12a

[1108]

[1109] K₂CO₃ (6.21 g, 44.95 mmol, 1.4 equivalents) was added to a solution of A-13a (6.76 g, 32.13 mmol, 1.0 equivalents) in MeOH (87.5 mL). The reaction mixture was stirred at room temperature for 2 hours. When the reaction was complete, the reaction mixture was filtered. The filtered solid was washed with MeOH (20 mL). The filtrate was concentrated under vacuum and then diluted with MTBE (100 mL). A precipitate was observed and the solid was filtered. The filtered solid was washed twice with MTBE (25 mL). The collected filtrate was washed with a 14% wt% NH₄Cl aqueous solution. The aqueous layer was back-extracted with MTBE (25 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by distillation (25–30 mbar, bath temperature 125–150 °C, head temperature 85–87 °C) to give the desired product A-12a. 1H-NMR (DMSO-d6, 400mHz): δ4.59 (d, J = 5.0Hz, 1H), 3.03-2.99 (m, 1H), 1.63-1.61 (m, 3H), 1.49-1.42 (m, 3H), 1.20-1.16 (m, 2H), 1.18 (s, 3H).

[1110] Experimental procedure for the synthesis of A-11a

[1111]

[1112] Add A-12a (10.0 g, 68.67 mmol, 94% purity, 1 equivalent) to a solution of Na₂SO₄ (20.0 g), 2-iodobenzenesulfonic acid (0.78 g, 2.75 mmol, 0.04 equivalent), and potassium persulfate (35.90 g, 116.7 mmol, 1.7 equivalent) in acetonitrile (100 mL). Stir the reaction mixture vigorously and heat to 70–75 °C. After 20–24 hours, cool the reaction mixture to 20–25 °C, at which point add MTBE (100 mL). Filter the resulting slurry; wash the solids with MTBE (20 mL). Concentrate the filtrate at ≥35 Torr. Purify the crude substance by fractional distillation (30–35 Torr, 110–120 °C) to obtain the desired product A-11a. 1 H-NMR (CDCl3, 500mHz): δ3.02-2.95 (td, J=13.6, 6.0Hz, 1H), 2.36 (s, 1H), 2.34-2.31 (d, J=13.2H z,1H),2.16-2.08(m,3H),1.76-1.74(m,1H),1.69-1.63(m,1H),1.61-1.54(m,2H),1.33(s,3H).

[1113] Experimental Procedure for A-10b Synthesis

[1114]

[1115] A solution of malononitrile (5.02 g, 71.37 mmol, 1.00 equivalent), sulfur (2.42 g, 74.94 mmol, 1.05 equivalent), and NH4OAc (5.5 g, 71.37 mmol, 1.00 equivalent) in EtOH (9.7 mL) was slowly added at 50 °C. After 2 hours, the conversion to A-10b was completed, and the reaction mixture was used for the next step without separation.

[1116] Experimental procedure for the synthesis of A-9a

[1117]

[1118] DMF-DMA (47.41 mL, 357 mmol, 5.0 equivalence) was added to the reaction mixture containing A-10b in EtOH at 50 °C. The reaction mixture was stirred for 5–6 hours, during which time the reaction mixture was quenched with H₂O (97.2 mL) and stirred at room temperature, then cooled to room temperature overnight. The crude material was filtered, and the filtered wet solid was dissolved in EtOH (48.6 mL). The resulting slurry was stirred at 70 °C for 3 hours, and then stirred overnight at room temperature. The solid was filtered and washed with heptane (29.2 mL). The solid was recrystallized from EtOH (29.2 mL); the resulting slurry was stirred at 70 °C for 3 hours, and then stirred at room temperature for 10–12 hours. The solid was filtered, washed with heptane (29.2 mL), and further dried under vacuum at 60 °C to give A-9a.

[1119] Step 6:

[1120]

[1121] Experimental procedure for the synthesis of A-23a

[1122]

[1123] Add K₂CO₃ (0.056 g, 0.41 mmol, 0.01 equivalent) to a solution of A-14a (10.0 g, 40.2 mmol, 78.1% purity, 1.00 equivalent) in MeOH (100 mL). Stir the reaction mixture at room temperature for 3–5 hours. When the reaction is complete, add heptane (50 mL) and H₂O (20 mL) to the stirred reaction mixture. Separate the phases and extract the aqueous layer with heptane (25 mL). The combined organic layers containing A-23a are used in the next step without solvent concentration to avoid product loss due to product volatilization.

[1124] Experimental Procedure for A-20a Synthesis

[1125]

[1126] THF (15 mL) was added to a solution of A-23a (15 g, 8.72 mmol, 7.1% purity, 1.00 equivalence) in heptane from the previous operation. The solution mixture was cooled to -25 °C, at which point n-BuLi (2.5 M in hexane, 6.97 mL, 17.44 mmol, 2.00 equivalence) was added via an additional funnel. After stirring for 10–15 min, TESCl (1.83 mL, 10.90 mmol, 1.25 equivalence) was slowly added. After another 30 min, A-23a was exhausted, and the reaction mixture was heated to -5 °C, at which point it was quenched with 20 wt% NH4Cl aqueous solution (14 mL). The solution mixture was further heated to room temperature. The phases were separated. The organic layer was washed with 18 wt% NH4Cl aqueous solution (7 mL) and subsequently concentrated under vacuum to give A-20a. 1 H-NMR (CDCl3, 500mHz): δ3.30 (s, 1H), 2.25-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.95 -1.85(m,1H),1.45-1.20(m,3H),0.96(t,J=7.88Hz,9H),0.57(q,J=7.88Hz,6H).

[1127] The corresponding intermediate A-20b (tert-butyldimethylsilyl protecting group (TBS) replacing the triethylsilyl protecting group (TES)) can be obtained in a similar manner using TBSCl:

[1128]

[1129] Experimental Procedure for A-21a Synthesis

[1130]

[1131] After 30–40 min, n-BuLi (2.5 M in hexane, 95.0 mL, 237.50 mmol, 1.02 equivalent) was added to a solution of A-22a (25 g, 233.83 mmol, 1.00 equivalent) in THF (250 mL) at -25 °C via an additional funnel. After stirring for 10–15 min, TESCl (40.65 mL, 241.43 mmol, 1.03 equivalent) was slowly added. After another 30 min, the reaction mixture was heated to -5 °C, at which point it was quenched with a 20% wt% NH4Cl aqueous solution (200 mL). The solution mixture was further heated to room temperature. The phases were separated. The organic layer was concentrated under vacuum to obtain A-21a. 1H-NMR (CDCl3, 500mHz): δ6.25-6.20 (m, 1H), 2.20-2.05 (m, 4H), 1.70-1.50 (m, 4H), 0.95 (t, J = 7.84Hz, 9H), 0.60 (q, J = 7.84Hz, 9H).

[1132] The corresponding intermediate A-21b (tert-butyldimethylsilyl protecting group (TBS) replacing the triethylsilyl protecting group (TES)) can be obtained in a similar manner using TBSCl:

[1133]

[1134] Experimental Procedure for A-20a Synthesis

[1135]

[1136] K₂CO₃ (28.3 g, 205.06 mmol, 2.5 equivalents) and ETDA (ethylenediaminetetraacetic acid; 11.98 mg, 0.04 mmol, 4.99 x 10⁻⁶ ppm) were added to a solution of A-21a (20.0 g, 82.03 mmol, 90.4% purity, 1.0 equivalent) and SHI catalyst ((3a'R,4S,7a'R)-2,2,2',2'-tetramethyldihydrospiro[[1,3]dioxane-4,6'-[1,3]dioxanepentan[4,5-c]pyran]-7'(4'H)-one; 4.39 g, 16.43 mmol, 0.2 equivalents) in acetonitrile (160 mL) at 0 °C. -4 A solution of H₂O₂ (33.5 mL, 328.09 mmol, 30%, 4.0 equivalent) in water (102.5 mL) was added slowly over 1.5–2 hours to the vigorously stirred reaction mixture. Upon completion of the addition, the reaction mixture was stirred at 0 °C for 14–16 hours. The reaction mixture was quenched with heptane (100 mL). The phases were separated, and the aqueous layer was extracted three times with heptane (100 mL). The combined organic layers were washed with a saturated aqueous solution of Na₂SO₃ (40 mL), dried over Na₂SO₄, and concentrated under vacuum to give the desired product A-20a.

[1137] The corresponding intermediate A-20b (tert-butyldimethylsilyl protecting group (TBS) replacing the triethylsilyl protecting group (TES)) can be obtained from A-21b in a similar manner:

[1138]

[1139] Experimental Procedure for A-19a Synthesis

[1140]

[1141] Add A-20a (10.00 g, 34.43 mmol, 81.4% purity, 1.0 equivalent), LiCl (0.5 M in THF; 82.6 mL, 61.75 mmol, 1.2 equivalent), and LaCl3·2LiCl (0.6 M in THF; 1.72 mmol, 2.9 mL, 0.05 equivalent) to a dry flask under N2 atmosphere. Cool the solution to -5 to 0 °C, and add MeMgCl (3 M in THF; 20.0 mL, 60.25 mmol, 1.75 equivalent) over 20–30 min. Stir the resulting mixture at 0 °C for 30 min, and then at room temperature for 14–16 h. When the reaction is complete, add MTBE (105 mL) and cool the reaction mixture to -5 to 0 °C. Quench the reactants dropwise with 1 N HCl (69.0 mL, 69.0 mmol, 2 equivalent). After stirring for another 15-20 min, the phases were separated. The aqueous layer was extracted with MTBE (52.5 mL). The combined organic layers were dried over Na2SO4 and then concentrated under vacuum to give the desired product A-19a. 1 H-NMR (CDCl3, 500mHz): δ3.20-3.10(m,1H),1.90-1.80(m,2H),1.75-1.65(m,1H),1.60-1. 55(m,5H),1.35(s,3H),1.30-1.10(m,2H),0.97(t,J=7.85Hz,9H),0.60(q,J=7.85Hz,6H).

[1142] The corresponding intermediate A-19b (tert-butyldimethylsilyl protecting group (TBS) replacing the triethylsilyl protecting group (TES)) can be obtained from A-20b in a similar manner:

[1143]

[1144] Experimental Procedure for A-18a Synthesis

[1145]

[1146] H₂O (0.51 mL, 28.06 mmol, 1 equivalent) was added to a vigorously stirred solution of potassium persulfate (23.72 g, 77.16 mmol, 2.75 equivalents), 2-iodobenzenesulfonic acid (407 mg, 1.40 mmol, 0.05 equivalents), and A-19a (10.7 g, 28.06 mmol, 66.2% purity, 1.0 equivalent) in acetonitrile (71 mL). The reaction mixture was heated at 70–75 °C for 16–18 hours. After the reaction was complete, the reaction mixture was cooled to 20–25 °C and diluted with MTBE (71 mL). The resulting slurry was stirred for 10–15 min and then filtered under vacuum. The filtered solids were washed with MTBE (71 mL). The filtrate was concentrated under vacuum at 40 °C to give A-18a. 1 H-NMR (CDCl3, 500mHz): δ3.10-2.95(m,1H),2.35-2.25(m,1H),2.20-2.00(m,3H),1.75-1. 65(m,1H),1.60-1.50(m,3H),1.30(s,3H),0.95(t,J=7.85Hz,9H),0.57(q,J=7.85Hz,6H).

[1147] The corresponding intermediate A-18b (tert-butyldimethylsilyl protecting group (TBS) replacing the triethylsilyl protecting group (TES)) can be obtained from A-19b in a similar manner:

[1148]

[1149] Experimental Procedure for A-17a Synthesis

[1150]

[1151] A solution of malononitrile (2.85 g, 42.34 mmol, 1.5 equivalent) in EtOH was slowly added to a solution of A-18a (10.0 g, 28.23 mmol, 70.7% purity, 1.0 equivalent), sulfur (1.36 g, 42.34 mmol, 1.5 equivalent), and NH4OAc (3.26 g, 42.34 mmol, 1.5 equivalent) in EtOH (50 mL) at 50–55 °C. After 14–18 hours, the conversion to A-17a was completed, and the reaction mixture was used for the next step without separation.

[1152] The corresponding intermediate A-17b (tert-butyldimethylsilyl protecting group (TBS) replacing the triethylsilyl protecting group (TES)) can be obtained from A-18b in a similar manner:

[1153]

[1154] Experimental Procedure for A-16a Synthesis

[1155]

[1156] DMF-DMA (19.9 mL, 141.14 mmol, 5.0 equivalents) was added to the reaction mixture containing A-17a in EtOH at 50-55 °C. The reaction mixture was stirred for 5-6 hours, during which time it was cooled to approximately 40 °C, and H2O (71 mL) was added dropwise over 1 hour. The resulting slurry was then cooled to 15-20 °C over 1 hour. After stirring for another 30 min, the solid was filtered and washed with cold EtOH / H2O (1:1 v / v, 100 mL). The solid was then dried under vacuum at 40-45 °C overnight to obtain A-16a. 1 H-NMR(CDCl3,500mHz): δ7.65(s,1H),3.09(s,3H),3.06(s,3H),2.65-2.50(m,2H),2.10-2.03(m,1H ),1.97-1.90(m,1H),1.85-1.70(m,2H),1.65(s,3H),1.00(t,J=7.90Hz,9H),0.58(q,J=7.90Hz,6H).

[1157] The corresponding intermediate A-16b (tert-butyldimethylsilyl protecting group (TBS) replacing the triethylsilyl protecting group (TES)) can be obtained from A-17b in a similar manner:

[1158]

[1159] Experimental procedure for the synthesis of A-9a

[1160]

[1161] Cool the solution of A-16a (8.0 g, 16.53 mmol, 79.7% purity, 1.0 equivalent) in THF (32 mL) to 0–5 °C. Slowly add TBAF (1.0 M in THF; 19.85 mL, 19.85 mmol, 1.2 equivalent) to the stirred mixture. Stir the reaction mixture for another 30 min, then add MTBE (52 mL), followed by H₂O. Heat the resulting mixture to room temperature and stir for another 10 min. Filter the solids by vacuum filtration as the first batch. Separate the phase of the filtrate. Concentrate the organic layer under vacuum at 40 °C. Dissolve the oily residue in isopropanol (20 mL). Add heptane (20 mL) dropwise to the stirred solution to obtain a slurry. After stirring for another 1–2 h, filter the solids by vacuum filtration as the second batch. The first and second batches of product were combined and washed with isopropanol / heptane (1:1 v / v, 40 mL), followed by washing with heptane (40 mL). The solid was then dried under vacuum at 40-45 °C to give A-9a.

[1162] A-9a can also be obtained from A-16b in a similar manner.

[1163] Process 7

[1164]

[1165] Experimental procedures for the synthesis of C-2a and C-3a

[1166]

[1167] Hydroxylamine hydrochloride (133.6 mg, 1.92 mmol, 3.0 equivalent) was added to a solution of C-1c (450 mg, 0.64 mmol, 1.0 equivalent) in MeOH (6 mL), and the reaction mixture was stirred at room temperature for 1 hour. Additional hydroxyamine hydrochloride (44.5 mg, 0.64 mmol, 1.0 equivalent) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with acetonitrile and water, filtered, and purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile / water) to give the desired intermediates C-2a (second elution, major product) and C-3a (first elution, minor product).

[1168] The following intermediates C-2 and C-3 (Table 27) can be obtained in a similar manner using different intermediates C-1 as starting materials. If necessary, crude products C-2 and C-3 can be purified by chromatography.

[1169] Table 27

[1170]

[1171]

[1172]

[1173]

[1174] Experimental Procedure for C-4a Synthesis

[1175] To a solution of C-2a (286 mg, 0.398 mmol, 1.0 equivalent) in THF (3 mL), an aqueous HCl solution (1 mL, 2.00 mmol, 2 M) was added, and the mixture was stirred at 65 °C for 1 hour. Additional aqueous HCl solution (0.3 mL, 0.60 mmol, 2 M) was added to the mixture, and stirring was continued for another 3.5 hours. The reactants were carefully neutralized and alkalized with a saturated aqueous sodium bicarbonate solution, and diluted with EtOAc and water. The phases were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile and water and purified by basic reversed-phase chromatography (gradient elution: 20% to 95% acetonitrile / water) to give the desired product C-4a.

[1176] The following intermediate C-4 (Table 28) can be obtained in a similar manner using different intermediates C-2 as starting materials. If necessary, the crude product C-4 can be purified by chromatography.

[1177] Table 28

[1178]

[1179]

[1180]

[1181] Experimental Procedure for C-5a Synthesis

[1182]

[1183] To a solution of C-3a (65 mg, 0.09 mmol, 1.0 equivalent) in THF (1 mL), an aqueous HCl solution (135 mL, 0.54 mmol, 4 M) was added, and the mixture was stirred at 65 °C for 75 min. The mixture was stirred overnight at room temperature and then stirred at 65 °C for 1 h. The reactants were carefully neutralized and alkalized with a saturated aqueous sodium bicarbonate solution, and diluted with EtOAc and water. The phases were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile and water and purified by basic reversed-phase chromatography (gradient elution: 10% to 90% acetonitrile / water) to give the desired product C-5a.

[1184] (Note: In this single-step method, under acidic conditions, there is the formation of the aromatic isoxazole system, the cleavage of the Boc protecting group and the amidine protecting group, that is, depending on the order of the sub-steps, certain additional intermediates not described above can be generated without separation.)

[1185] The following intermediate C-5 (Table 29) can be obtained in a similar manner from different intermediates C-3 as starting materials. If necessary, the crude product C-5 can be purified by chromatography.

[1186] Table 29

[1187]

[1188]

[1189] Experimental Procedure for C-6a Synthesis

[1190]

[1191] A solution of C-1a (188 mg, 0.27 mg, 1.0 mg, 1.0 mg, 1 mL) in MeOH was added to a solution of hydroxylamine-O-sulfonic acid (52.5 mg, 0.47 mmol, 1.7 equivalents) in MeOH (0.2 mL), and the mixture was stirred at room temperature for 5 hours. Sodium bicarbonate (25.2 mg, 0.30 mmol, 1.1 equivalents) and sodium hydrosulfide (38.2 mg, 0.68 mmol, 2.5 equivalents) were added to the reaction mixture, and the mixture was stirred at 50 °C for 1.5 hours. The reaction mixture was diluted with water and EtOAc. The phases were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile and water and purified by alkaline reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile / water) to give the desired product C-6a.

[1192] The following intermediate C-6 (Table 30) can be obtained in a similar manner using different intermediates C-1 as starting materials. If necessary, the crude product C-6 can be purified by chromatography.

[1193] Table 30

[1194]

[1195]

[1196] Experimental Procedure for C-7a Synthesis

[1197]

[1198] A solution of C-6a (69 mg, 0.096 mmol, 1.0 equivalent) in THF (1.5 mL) was added to an aqueous solution of HCl (0.500 mL, 1.00 mmol, 2 M), and the mixture was stirred at 65 °C for 3 hours. The reactants were carefully neutralized and alkalized with a saturated aqueous sodium bicarbonate solution, and diluted with EtOAc and water. The phases were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile and water and purified by basic reversed-phase chromatography (gradient elution: 10% to 95% acetonitrile / water) to give the desired product C-7a.

[1199] The following intermediate C-7 (Table 31) can be obtained in a similar manner from different intermediates C-6 as starting materials. If necessary, the crude product C-7 can be purified by chromatography.

[1200] Table 31

[1201]

[1202]

[1203] Synthesis of the final compound (I) according to the present invention:

[1204] Experimental procedure for the synthesis of compound Ib-1

[1205]

[1206] A freshly prepared solution of acryloyl chloride in acetone (120 μL, 0.12 mmol, 1 M, 1.5 equivalents) was added to a solution of potassium carbonate (22.1 mg, 0.16 mmol, 2.0 equivalents) in acetone (0.3 mL) and water (70 μL). The mixture was stirred for 5 min, followed by the addition of intermediate C-4a (45 mg, 0.08 mmol, 1.0 equivalents) in acetone (1 mL), and the reaction mixture was stirred for 10 min. After the reaction was complete, the mixture was diluted with acetonitrile and water, filtered, and purified by alkaline reversed-phase chromatography (gradient elution: 10% to 98% acetonitrile / water) to give the desired compound Ib-1.

[1207] The following compounds Ib, Ic, and Id (Table 32) can be obtained in a similar manner using different intermediates C-4, C5, and C-7 as starting materials. If necessary, the crude products Ib, Ic, and Id can be purified by chromatography.

[1208] Table 32

[1209]

[1210]

[1211]

[1212]

[1213]

[1214] Experimental procedure for the synthesis of compound Ib-10

[1215]

[1216] Trimethylamine (27.7 μL, 0.19 mmol, 6.0 equivalents) was added to a solution of 2-fluoroacrylic acid (7.5 mg, 0.083 mmol, 2.6 equivalents) and HATU (30.4 mg, 0.08 mmol, 2.5 equivalents) in DMF (0.5 mL). The mixture was stirred at room temperature for 1 min, followed by the addition of intermediate C-4a (18 mg, 0.03 mmol, 1.0 equivalents) to a solution of DMF (0.5 mL). The reaction mixture was stirred for another 1 min. After the reaction was complete, the mixture was diluted with acetonitrile and water, filtered, and purified by alkaline reversed-phase chromatography (gradient elution: 10% to 98% acetonitrile / water) to give the desired compound Ib-10.

[1217] The following compounds Ib, Ic, and Id (Table 33) can be obtained in a similar manner using different intermediates C-4, C5, and C-7 as starting materials. If necessary, the crude products Ib, Ic, and Id can be purified by chromatography.

[1218] Table 33

[1219]

[1220]

[1221] Experimental procedure for the synthesis of compound Ib-14

[1222]

[1223] DIPEA (54.2 μL, 0.31 mmol, 5 equivalents) and HATU (26.0 mg, 0.07 mmol, 1.1 equivalents) were added to a solution of 4-methoxy-2-enoic acid (10.8 mg, 0.09 mmol, 1.5 equivalents) in anhydrous DMF (0.2 mL), and the mixture was stirred for 10 min. Intermediate C-4a (35.0 mg, 0.06 mmol, 1.0 equivalents) was added to a solution of DMF (0.3 mL), and the reaction mixture was stirred for 10 min. After the reaction was complete, the mixture was diluted with acetonitrile and water, filtered, and purified by alkaline reversed-phase chromatography (gradient elution: 10% to 95% acetonitrile / water) to give the desired compound Ib-14.

[1224] The following compounds Ib, Ic, and Id (Table 34) can be obtained in a similar manner using different intermediates C-4, C5, and C-7 as starting materials. If necessary, the crude products Ib, Ic, and Id can be purified by chromatography.

[1225] Table 34

[1226]

[1227]

[1228] Step 8:

[1229]

[1230] Experimental Procedure for the Synthesis of D-2a

[1231]

[1232] DIPEA (1.58 mL, 9.18 mmol, 2.5 equivalents) was added to a solution of D-1a (712.0 mg, 3.67 mmol) and methyl 2-aminoacetate hydrochloride (553.0 mg, 4.41 mmol, 1.2 equivalents) in DMSO (10 mL), and the mixture was stirred in a sealed container at 100 °C for 16 hours. After complete conversion, a few drops of water were added to the reaction mixture, and the product was separated by alkaline reversed-phase chromatography (gradient elution: 20% to 90% acetonitrile / water) to give D-2a (HPLC method B; t ret = 0.58 min; [M+H] + =263).

[1233] Experimental Procedure for D-3a Synthesis

[1234]

[1235] D-2a (795.0 mg, 3.02 mmol) was dissolved in THF (15.0 mL), and 1 M NaOH aqueous solution (4.53 mL, 4.53 mmol, 1.5 equivalents) was added. The mixture was stirred at room temperature for 1 hour. After complete conversion, the reaction mixture was concentrated and the residue was acidified to pH 3 using 6 M HCl aqueous solution. The precipitate formed was collected by filtration, dissolved in DMSO, and purified by acid reversed-phase chromatography (gradient elution: 10% to 70% acetonitrile / water) to give D-3a. Acid reversed-phase chromatography (gradient elution: 10% to 70% acetonitrile / water) of the filtrate from water treatment gave another product eluent (HPLC method C; t) ret = 0.42 min; [M+H] + =249).

[1236] Experimental Procedure for D-4a Synthesis

[1237]

[1238] D-3a (570.0 mg, 2.29 mmol) was treated with tert-butyl nitrite (298.4 μL, 2.52 mmol, 1.1 equivalents) and stirred vigorously at room temperature for 0.5 h. Trifluoroacetic anhydride (795.4 μL, 5.72 mmol, 2.5 equivalents) was added and the mixture was stirred at room temperature for 0.5 h. A solution of t-BuOH (13.0 mL), TEA (1903.6 μL, 13.73 mmol, 6.0 equivalents), disodium 4,7-diphenyl-1,10-phenanthroline-3,8-disulfonic acid trihydrate (270.3 mg, 0.46 mmol, 0.20 equivalents) in water (6.5 mL), a solution of copper(II) sulfate pentahydrate (114.30 mg, 0.46 mmol, 0.20 equivalents) in water (6.5 mL), A-10a (495.08 mg, 2.29 mmol, 1.0 equivalents), and sodium ascorbate (906.86 mg, 4.58 mmol, 2.0 equivalents) was added, and the mixture was stirred at room temperature for 16 hours. After complete conversion, the mixture was diluted with DCM and brine, the layers were separated, and the aqueous phase was extracted with DCM. The organic layers were combined, dried, filtered, concentrated, and the crude product was purified by alkaline reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile / water) to obtain D-4a (HPLC method B; t ret = 0.87 min; [M+H] + =432).

[1239] Experimental Procedure for D-5a Synthesis

[1240]

[1241] D-4a (480.7 mg, 1.11 mmol) was treated with 1-methylpiperazine (616.7 μL, 5.56 mmol, 5.0 equivalent) and DIPEA (286.96 μL, 1.67 mmol, 1.5 equivalent) and stirred at room temperature for 0.5 h, then stirred at 40 °C for 16 h. After complete conversion, water was added to the mixture and the resulting suspension was stirred at room temperature for 15 min. The precipitate was collected by filtration, washed with water, and dried to obtain D-5a, which was used in the following steps (HPLC method A; t ret = 1.46 min; [M+H] + =512 / 514).

[1242] Experimental Procedure for D-6a Synthesis

[1243]

[1244] D-5a (518.0 mg, 1.01 mmol) was combined with piperazine-1-carboxylic acid tert-butyl ester (3.77 g, 20.22 mmol, 20.0 equivalents) and DIPEA (695.6 μL, 4.04 mmol, 4.0 equivalents), and the mixture was stirred at 120 °C for 6 days in a sealed container. After complete conversion, the mixture was diluted with DCM and brine, the layers were separated, and the aqueous phase was extracted with DCM. The organic layers were combined, dried, filtered, and concentrated under reduced pressure to give D-6a, which was used in the following steps (HPLC method B; t ret = 0.86 min; [M+H] + =618).

[1245] Experimental Procedure for D-7a Synthesis

[1246]

[1247] A mixture of D-6a (624.5 mg, 1.01 mmol) and dioxane (8 mL) was treated with HCl (4 N in dioxane, 5.05 mL, 20.22 mmol, 20.0 equivalent) and stirred at 70 °C for 30 min, followed by stirring at 80 °C for 20 min. After complete conversion, the mixture was concentrated under reduced pressure, and the crude product was purified by alkaline reversed-phase chromatography (gradient elution: 20% to 98% acetonitrile / water) to obtain D-7a (HPLC method B; t ret = 0.62 min; [M+H] + =518).

[1248] Experimental Procedure for the Synthesis of Ie-1

[1249]

[1250] Ie-1 was synthesized according to the procedure described for Ib-1.

[1251] Table 35

[1252]

[1253] The following examples describe the biological activities of the compounds according to the present invention, but the present invention is not limited to these examples.

[1254] KRAS::SOS1 Alpha screening combined with analysis

[1255] This analysis can be used to examine the efficacy of the compound bound to KRAS G12C according to the present invention in inhibiting the protein-protein interaction between SOS1 and KRAS G12C. This inhibits the GEF function of SOS1 and locks KRAS G12C into its inactive GDP-binding state. The lower IC50 value in this analytical setting... 50 The value indicates strong inhibition of protein-protein interactions between SOS1 and KRAS:

[1256] Reagents:

[1257] • Homemade GST-marked SOS1 (564_1049_GST_TEV_ECO)

[1258] • GST-TEV-SOS1 (564-1049) purchased from Viva Biotech Ltd.

[1259] The expression construct containing the C-terminal avi-tag KRAS G12C (amino acids 1-169 (uniprot) of reference sequence P01116-2, with additional mutations: C51S, C80L, and C118S) was obtained through gene synthesis (GeneArt, Thermo Fisher) in the donor vector (pDONR-221) and transferred via recombinant cloning into the pDEST17 vector carrying the N-terminal His6-tag. The protein was expressed in *E. coli*, and the purified protein was biotinylated with *E. coli* biotinylate (BirA) before use.

[1260] GDP (Sigma catalog number G7127)

[1261] • AlphaLISA glutathione receptor beads (PerkinElmer, catalog number AL109)

[1262] • AlphaScreen antibiotic streptavidin donor beads (PerkinElmer catalog number 6760002)

[1263] • Analysis disk: Proxiplate-384PLUS, white (PerkinElmer, catalog number 6008289)

[1264] Analysis buffer:

[1265] 1x PBS

[1266] 0.1% BSA

[1267] ·0.05% Tween 20

[1268] KRAS::SOS1 GDP mixture:

[1269] Before use, mix 7.5 nM (final analytical concentration) KRAS G12C, 10 μM (final analytical concentration) GDP and 5 nM (final analytical concentration) GST-SOS1 in analytical buffer and keep at room temperature.

[1270] Bead mixture:

[1271] Before use, mix AlphaLISA glutathione receptor beads and AlphaScreen antibiotic streptavidin donor beads in the analysis buffer at a concentration of 10 μg / mL (final analytical concentration) and keep at room temperature.

[1272] Analysis plan:

[1273] Dilute the compound to a final starting concentration of 100 μM and test in duplicate. Generate an analysis ready-to-use disk (ARP) using an Access Labcyte workstation equipped with a Labcyte Echo 550 or 555 acoustic distributor. For compounds with a starting concentration of 100 μM, serially dilute 150 nL of the compound solution 1:5 and transfer in duplicate at 11 concentrations per well.

[1274] The analysis was performed in a dark room at less than 100 lux using a fully automated robotic system. 10 μL of the KRAS::SOS1 GDP mixture was added to column 1-24 to give 150 nL of the compound solution (final dilution for analysis 1:100, final DMSO concentration 1%).

[1275] After a 30-minute incubation period, 5 μL of the bead mixture was added to column 1-23. The trays were kept at room temperature in a dark incubator. After a further 60-minute incubation, the signal was measured using a PerkinElmer Envision HTS multi-label reader with an AlphaScreen specification from PerkinElmer. Each tray contained the following controls:

[1276] • Diluted DMSO + KRAS::SOS1 GDP mixture + bead mixture

[1277] • Diluted DMSO + KRAS::SOS1 GDP mixture

[1278] Result calculation:

[1279] IC is calculated and analyzed using a 4-parameter logarithmic model. 50 value.

[1280] The example compounds disclosed herein contain ICs determined using the analysis described above. 50value.

[1281] Ba / F3 cell model generation and proliferation analysis

[1282] Ba / F3 cells 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 KRASG12 mutant were obtained from GeneScript. To generate a KRASG12-dependent Ba / F3 model, Ba / F3 cells were transduced with a retrovirus containing a vector carrying the KRASG12 isotype. Platinum-E cells (Cell Biolabs) were used for retrovirus 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 KRASG12 mutation, IL-3 was no longer supplemented in the growth medium. Ba / F3 cells carrying the empty vector were used as a control. Puromycin was not used approximately ten days prior to the experiment.

[1283] For proliferation analysis, Ba / F3 cells were cultured in growth medium (RPMI-1640 + 10% FCS) at a concentration of 1×10⁻⁶. 3 60 μl cells / cell were seeded into 384-well plates. Compounds were added using an AccessLabcyte workstation equipped with a Labcyte Echo 550 or 555 acoustic dispenser. All treatments were technically reproducible. Analyses were performed using a fully automated robotic system. Treated cells were cultured at 37°C for 72 hours in 5% CO2. AlamarBlue was added. TM (ThermoFisher), a viable staining agent, was used to measure fluorescence in a PerkinElmer Envision HTS multi-label reader. Raw data were imported into and analyzed using Boehringer Ingelheim's proprietary software MegaLab (based on curve fitting of the PRISM program, GraphPad Inc.).

[1284] The IC50 of the representative compound (I) according to the present invention was measured using this analysis. 50 The values ​​are presented in Table 36.

[1285] Plasma protein binding (PPB)

[1286] The binding of the test compound to plasma was determined using balanced dialysis (ED) and quantitative mass spectrometry mediated by liquid chromatography (LC-MS). Briefly, ED was performed using a dialysis apparatus consisting of two chambers separated by a semipermeable membrane with a molecular weight cutoff of 5-10 kg / mol. One chamber was filled with commercially available plasma (mouse and human plasma, respectively) or serum (10% FCS in PBS) containing 1-10 μmol / L of the test compound, and the other chamber was filled with phosphate-buffered saline (PBS) with or without polydextrose. The dialysis chambers were incubated at 37°C for 3-5 hours. After incubation, proteins were precipitated from aliquots of each chamber, and the plasma-containing compartments (c) were identified by LC-MS. 血浆 ) and buffer-containing compartments (c 缓冲液 The concentration of the test compound in the supernatant of the plasma was determined. The fraction (f) of unbound test compound (unbound to plasma) was calculated according to the following equation. u ):

[1287]

[1288] The data in Table 36 show that the compounds of the present invention measured in these analyses exhibited excellent antiproliferative potency against Ba / F3 cells with the G12C mutation, typically in the single-digit nanomolar range, despite showing high plasma protein binding to the FCS used in this analysis (i.e., in reality, they existed only in free form, with much lower inhibitory effects). This is the IC50 of this analysis. 50 The values ​​have been corrected for plasma protein binding of compounds within 10% of the FCS (unbound fraction (f)). u (See the last row of Table 36 for the reason). Data also show that many of the compounds of this invention have lower IC50 values ​​at similar protein binding levels in human plasma compared to the most advanced clinically available G12C inhibitors, namely sotorasirb and adagrasirb. 50 / Higher power (see uncorrected and especially corrected IC) 50 Such compounds may achieve the same therapeutic efficacy at lower doses, or allow for higher therapeutic efficacy at the same doses in humans. The same correction principle can also be applied to the IC50 of the proliferation analysis described below. 50 (See the results in Table 37.)

[1289] Table 36

[1290]

[1291]

[1292] Additional proliferation analysis using the G12C mutant cancer cell line

[1293] • SW 837CTG proliferation analysis (CRC)

[1294] SW837 cells (ATCC#CCL-235) were cultured in a 175 cm³ cell culture flask using L-15-10% FCS, 1% L-Glu, 1xNEAA, and 1x Na-Pyrovat. 2 Cultures were grown in a humid environment at 37°C and 0% CO2, with the medium changed or subcultured 2-3 times per week. Materials used for analysis included CulturPlate-384, white opaque 384-well microplates, sterile and pre-treated for tissue culture (Perkin Elmer #6007680); Leibovitz L15 medium; and FBS #SH30071.03 (HyClone).

[1295] Proliferation analysis began on day 1 with cell seeding at a density of 500 cells / well in 90 μL of L-15-10% FCS, 1% L-Glu, 1xNEAA, and 1x Na-Pyrovat in a flat-bottomed 384-well microtiter dish. Any other luminescence-compatible culture dish type was acceptable. On day 2, 10 μL dilutions of the test compounds covering approximately 0, 1, and 10,000 nM concentrations were added to the cells. Cells were incubated for 5 days at 37°C in a humidified CO2-controlled (CO2-free) incubator. On day 7, 100 μL of Cell Titer Glow reagent (Cell titer Glo Luminescent, catalog number G7571, Promega) was added to each well and the cells were incubated for another 10 minutes at room temperature (with stirring). Luminescence was measured on a WallacVictor using standard luminescence readings. IC50 was calculated using the standard Levenberg Marquard algorithm (GraphPad Prism). 50 value.

[1296] The IC50 of the representative compound (I) according to the present invention was measured using this analysis. 50 The values ​​are presented in Table 37.

[1297] • MiaPaCa-2 CTG proliferation analysis (pancreatic cancer)

[1298] MiaPaCa-2 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum. CRM-CRL-1420 TM In cell culture flasks (175cm) 2Cultures were grown in a humid environment at 37°C and 5% CO2, with the medium changed or subcultured 2-3 times per week. Materials used for analysis included CulturPlate-384, white opaque 384-well microplates, sterile and pre-treated for tissue culture (Perkin Elmer #6007680); DMEM medium; and FBS #SH30071.03 (HyClone).

[1299] Proliferation analysis began on day 1 with cell seeding at a density of 500 cells / well in 90 μL of DMEM medium supplemented with 10% FBS in flat-bottomed 384-well microtiter dishes. Any other luminescence-compatible culture dish type was acceptable. On day 2, 10 μL dilutions of the test compounds covering approximately 0, 1, and 10,000 nM concentrations were added to the cells. Cells were incubated for 5 days at 37°C in a humidified incubator with 5% CO2. On day 7, 100 μL of Cell TiterGlow reagent (Cell titer Glo Luminescent, catalog number G7571, Promega) was added to each well and the cells were incubated for another 10 minutes at room temperature (with stirring). Luminescence was measured on a Wallac Victor using standard luminescence readings. IC50 was calculated using the standard Levenberg Marquard algorithm (GraphPad Prism). 50 value.

[1300] The IC50 of the representative compound (I) according to the present invention was measured using this analysis. 50 The values ​​are presented in Table 37.

[1301] • NCI-H358 CTG proliferation analysis (120h) (NSCLC)

[1302] NCI-H358 cells (ATCC code CRL-5807) were dispensed at a density of 2000 cells / well into opaque white 96-well plates (Perkin Elmer catalog number 5680) in 100 μL of RPMI-1640ATCC-prepared solution (Gibco#A10491) + 10% FCS. Cells were incubated overnight at 37°C in a humidified tissue culture incubator at 5% CO2. Compounds (in 10 mM stock solution in DMSO) were added logarithmically using an HP digital dispenser D300 (Tecan), normalized to the amount of DMSO added. For measurements at time point T0, untreated cells were analyzed at the time of compound addition. Cell viability was measured using the CellTiter-Glo luminescent cell viability assay (Promega product code G7570) after 120 hours of incubation. Cell viability (stated as a percentage of control) was defined as the relative luminescence units (RLU) per well divided by the RLU of cells in the DMSO control. IC50 was determined based on cell viability measurements using a four-parameter model via nonlinear regression. 50 value.

[1303] The IC50 of the representative compound (I) according to the present invention was measured using this analysis. 50 The values ​​are presented in Table 37.

[1304] • NCI-H2122 CTG proliferation analysis (120h) (NSCLC)

[1305] CTG analysis was designed to quantitatively measure the proliferation of NCI-H2122 cells (ATCC CRL-5985) using the CellTiter Glow assay kit (Promega G7571). Cells were grown in RPMI medium (ATCC) supplemented with fetal bovine serum (LifeTechnologies, Gibco BRL, catalog number 10270-106). On Day 0, 1000 NCI-H2122 cells were seeded in 60 μL of RPMI ATCC + 10% FCS + penicillin-streptomycin in 384-well flat-bottomed dishes. Cells were then incubated overnight in a CO2 incubator at 37°C. On Day 1, compounds, including a DMSO control, were added to the ECHO acoustic liquid handling system (Beckman Coulter). The dishes were incubated for 120 hours, and cell viability was measured using the CellTiter-Glo luminescent cell viability assay kit (Promega product code G7570). Cell viability (stated as a percentage of control) was defined as the relative luminescence units (RLU) per well divided by the RLU of cells in the DMSO control. IC50 was determined based on cell viability measurements using a four-parameter model via nonlinear regression. 50 value.

[1306] Table 37

[1307]

[1308]

[1309] ERK phosphorylation analysis

[1310] ERK phosphorylation assay was used to examine the efficacy of the compound in in vitro inhibiting KRAS G12C-mediated signal transduction in KRAS G12C mutant human cancer cell lines. This confirms the molecular mechanism of action of the compound according to the invention by interfering with the RAS G12C protein signal transduction cascade. The lower IC50 value in this assay setting... 50 The value indicates the higher potency of the compound according to the invention. The compound according to the invention was observed to exhibit inhibitory activity against ERK phosphorylation in KRAS G12C mutant human cancer cell lines, thus confirming the molecular mode of action of the compound on RAS G12C protein signaling transduction.

[1311] ERK phosphorylation analysis was performed using the following human cell lines:

[1312] NCI-H358 (ATCC (ATCC CRL-5807): Human lung cancer with a KRAS G12C mutation (→Analysis 1) and NCI-H358_Cas9_SOS2 (i.e., the same cell line where SOS2 is blocked) (→Analysis 2). The vector containing the designed DNA sequence for generating the SOS2 protein gene knockout gRNA was obtained from Sigma-Aldrich. To generate the NCI-H358 SOS2 gene knockout cell line, NCI-H358 cells expressing the Cas9 endonuclease were transfected with XtremeGene9 reagent and corresponding plastids. Transfection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. GFP-positive cells were collected and further expanded. These GFP-positive cell pools were diluted by single-cell analysis, and the SOS2 gene knockout clones were identified by Western ink dot assay and genomic DNA sequencing.

[1313] Materials used for analysis:

[1314] RPMI-1640 medium ( 30-2001 TM )

[1315] Fetal bovine serum (FBS) from HyClone (SH30071.03)

[1316] Non-essential amino acids (11140035) from Thermo Fischer Scientific

[1317] Pyruvate (11360039) from Thermo Fischer Scientific

[1318] Glutamax (35050061) from Thermo Fischer Scientific

[1319] 384 disks (781182) from Greiner Bio-One

[1320] Proxiplate from PerkinElmer TM 384(6008280)

[1321] AlphaLISA SureFire Ultra p-ERK1 / 2 (Thr202 / Tyr204) Analytical Kit (ALSU-PERK-A500)

[1322] EGF (E4127) from Sigma

[1323] Receptor mixture: Protein A receptor beads (6760137M) from PerkinElmer.

[1324] Donor mixture: AlphaScreen antibiotic streptavidin-coated donor beads (6760002) from PerkinElmer.

[1325] trametinib

[1326] Staurosporine (S6942) from Sigma Aldrich

[1327] Analysis settings:

[1328] Cells were seeded at 40,000 cells / well in 60 μL of RPMI containing 10% FBS, non-essential amino acids, pyruvate, and glutamax in Greiner TC 384 trays. Cells were incubated at room temperature for 1 hour, followed by overnight incubation at 37°C and 5% CO2 under humidified conditions. Then, 60 nL of compound solution (10 mM DMSO stock solution) was added using a Labcyte Echo 550 device. After incubation for 1 hour in the aforementioned incubator, the medium was removed after centrifugation, and cells were lysed with 20 μL of 1.6x lysis buffer containing protease inhibitors, 100 nM trametinib + 100 nM astrococcus, from the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) assay kit. After incubating with shaking at room temperature for 20 minutes, 6 μL of each lysate sample was transferred to a 384-well Proxiplate, and pERK (Thr202 / Tyr204) was analyzed using the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) assay kit. 3 μL of acceptor mixture and 3 μL of donor mixture were added under soft light and incubated in the dark at room temperature for 2 hours, followed by signal measurement on a PerkinElmer Envision HTS multi-label reader. The raw data were imported into Boehringer Ingelheim's proprietary software MegaLab (based on curve fitting of the PRISM program, GraphPad Inc.) for analysis.

[1329] The IC50 of the representative compound (I) according to the present invention was measured using this analysis. 50 The values ​​are presented in Table 38 (IC from Analysis 2). 50 Marked with *, all others are from analysis 1).

[1330] Table 38

[1331]

[1332] The following examples of formulations illustrate the invention but do not limit its scope:

[1333] Examples of drug formulations

[1334]

[1335] The finely powdered active ingredient, lactose, and some corn starch are mixed together. The mixture is sieved, then moistened with a polyvinylpyrrolidone solution in water, kneaded, wet-granulated, and dried. The granules, remaining corn starch, and magnesium stearate are sieved and mixed together. The mixture is then pressed to produce tablets of appropriate shape and size.

[1336]

[1337]

[1338] 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 dried and sieved granules. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of suitable size.

[1339]

[1340] The active ingredient, lactose, and cellulose are mixed together. The mixture is screened, then moistened with water, kneaded, wet-granulated and dried, or dry-granulated, or directly blended with magnesium stearate, 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.

[1341]

[1342] The active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5, with sodium chloride added to make it isotonic. The resulting solution is filtered to remove pyrogens, and the filtrate is transferred to ampoules under aseptic conditions, which are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg, and 50 mg of active ingredient.

Claims

1. A compound or a salt thereof, wherein the compound is selected from:

2. A compound or a salt thereof, wherein the compound is selected from:

3. Use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of cancers having tumor cells carrying the G12C mutant KRAS gene, said cancer being selected from pancreatic cancer, lung cancer, and colorectal cancer.

4. The use according to claim 3, wherein the compound or salt is administered before, after, or together with one or more other pharmacologically active substances.

5. The use according to claim 3, wherein the compound or salt is administered in combination with one or more other pharmacologically active substances.

6. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and One or more pharmaceutically acceptable excipients.

7. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and One or more other pharmacologically active substances.

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