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

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application relates to cyclic 2-amino-3-cyanothiophenes of formula (I) and derivatives thereof

[0002]

[0003] wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 , R 5 , A, 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 their use as medicaments / medical uses, especially as agents for the treatment and / or prevention of oncological diseases, such as cancer. BACKGROUND

[0004] Ras family proteins, including KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey rat sarcoma viral oncogene), and any mutants thereof, are small GTPases that exist in cells in either a GTP-bound or GDP-bound state (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 a slow rate of nucleotide exchange (Hunter et al., Mol. Cancer Res., 2015, 13(9): 1325-35). Binding of GTPase-activating proteins (GAPs), such as NF1, increases the GTPase activity of Ras family proteins. Guanine nucleotide exchange factors (GEFs), such as SOS1 (Son of Sevenless 1), promote release of GDP from Ras family proteins, allowing GTP binding (Chardin et al., Science, 1993, 260(5112): 1338-43). When in the GTP-bound state, Ras family proteins are active and engage effector proteins, including C-RAF and phosphoinositide 3-kinase (PI3K), to promote the RAF / mitogen or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian target of rapamycin (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 affect a variety of cellular processes, such as proliferation, survival, metabolism, motility, 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-bound / 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 effector pathways downstream of mutant Ras family proteins (e.g., RAF / MEK / ERK, PI3K / AKT / mTOR, RalGDS pathway). KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are found in a variety of human cancers, including lung, colorectal, and pancreatic cancers (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) are also found in a variety of human cancer types, but are generally less frequent than 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 Jul;92(7):709-22) and the EGFR tyrosine kinase inhibitor osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 75(12):2489-500).

[0006] Glycine to cysteine mutations at residue 12 of Ras family proteins (i.e., G12C mutations, e.g., KRAS G12C, NRAS G12C, and HRAS G12C) are common mutations in RAS genes, resulting from a G.C to T.A base transversion at codon 12, and account for 14% of all KRAS mutations, 2% of all NRAS mutations, and 2% of all HRAS mutations across cancer types. G12C mutations are particularly enriched in KRAS-mutant non-small cell lung cancer, with approximately half harboring this mutation, which has been linked to DNA adducts formed by tobacco smoke. G12C mutations are not only associated with lung cancer, but are also found in other RAS-mutant cancer types, e.g., 3-5% of all KRAS-mutant colorectal cancers.

[0007] Such inhibitors of G12C mutant Ras family proteins, e.g. covalent binders of KRAS G12C, NRAS G12C and HRAS G12C, capable of covalently binding to G12C mutant Ras family proteins, are expected to inhibit signaling downstream of Ras family proteins in cells (e.g. ERK phosphorylation). In cancer cells dependent on a mutant Ras family protein (e.g. KRAS mutant cancer cell lines), such binders / inhibitors are expected to produce anti-cancer efficacy (e.g. inhibition of proliferation, survival, metastasis, etc.).

[0008] To date, no G12C mutant Ras family protein inhibitor has been approved for therapeutic use. Recently, the first selective drugs against KRAS G12C have entered clinical development, with Sotorasib and Adagrasib having entered late stage for the treatment of lung cancer caused by KRAS G12C (see corresponding patent applications WO 2018 / 217651, WO 2017 / 201161, WO 2019 / 099524, WO 2020 / 102730). There is a need for new or even improved G12C mutant Ras family protein inhibitors suitable for clinical use. DETAILED DESCRIPTION

[0009] Compounds

[0010] It has now been found, surprisingly, that compounds of formula (I), wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 , R 5 , A, p, U, V, W, L and E have the meanings given below, act as inhibitors of G12C mutant Ras family proteins involved in the control of cell proliferation, have anti-tumor activity and can be used to inhibit uncontrolled cell proliferation caused by malignant diseases. This anti-tumor activity is believed to result from the inhibition of G12C mutant Ras family proteins, in particular KRAS G12C, which are key mediators of the proliferation and survival of certain tumor cells. It is further believed that the compounds according to the present application interact with G12C mutant Ras family proteins, in particular KRAS G12C, via the electrophilic moiety (e.g. Michael acceptor) present in the compound of formula (I) and then covalently bind (confirmed by crystallography of KRAS G12C). Upon covalent binding to G12C mutant Ras family proteins, in particular KRAS G12C (most likely occurring at position 12 of the Ras family proteins), the compounds impair or substantially eliminate the ability of the G12C Ras family proteins to access their active, pro-proliferative / pro-survival conformation.

[0011] In fact, the binding of the compounds of formula (I) according to the present application can lead to a selective and very strong anti-proliferative cellular effect in G12C mutant KRAS cell lines compared to KRAS wild-type cells and a greater selectivity window. This superior efficacy can potentially lead to lower systemic exposure and / or the dose required to fully exert efficacy in humans, thus having a good / better tolerability (e.g. less risk of idiosyncratic toxicity), can enable a more powerful hit on the pathway when necessary and is also beneficial in terms of results and increase flexibility in case of combination therapy. The compounds show a strong biomarker modulation, e.g. pERK in G12C mutant KRAS cell lines. Selected compounds were tested in a selective panel and these compounds show a good selectivity against other human targets (e.g. kinases). Last but not least, selected compounds disclosed herein were tested and show a good permeability, an excellent solubility and have just the right PK profile.

[0012] Thus, in a first aspect, the present application relates to a compound of formula (I)

[0013]

[0014] wherein

[0015] [A0]

[0016] R 1a and R 1b are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclyl;

[0017] R 2a and R 2b are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclyl;

[0018] and / or, optionally, one of R 1a or R 1b and R 2a or R2b One of them, together with the carbon atoms to which they are attached, 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 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, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups;

[0025] [D0]

[0026] Ring A is an oxadiazole or a thiadiazole;

[0027] [E0]

[0028] U is selected from nitrogen (=N-) and R. A Substituted carbon (=C(R) A )-);

[0029] V is selected from nitrogen (=N-) and R. B Substituted carbon (=C(R) B )-);

[0030] W is selected from nitrogen (=N-) and R. C Substituted carbon (=C(R) C )-);

[0031] RA R B and R C are each independently selected from the group consisting of hydrogen, C 1-6 haloalkyl, C 3-5 cycloalkyl substituted with C 2-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-4 haloalkoxy, halogen, -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 1-6 alkyl)2, -S-C 1-6 alkyl, C 3-5 cycloalkyl, 3-5 membered heterocyclyl, and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of 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), and -C(=O)N(C 1-4 alkyl)2;

[0032] R is selected from the group consisting of R

[0033] and R 5 ; a1 b1 ;

[0034] R a1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with one or more R b1 and / or R c1 ;

[0035] each R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -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 a bivalent substituent =O;

[0036] each R c1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R d1 and / or R e1 ;

[0037] each R d1 is independently selected from -OR e1 , -NR e1 R e1 , halogen, -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;

[0038] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, 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 The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl groups, 3-11 membered heterocyclic groups—which may optionally be substituted by one or more of the same or different of the following groups: C 1-4 Alkyl, 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;

[0039] [G0]

[0040] L is -L 1 -L2 -L 3 wherein L 1 is connected to E;

[0041] L 1 is selected from a bond, -NH-, -N(C 1-4 alkyl)-, -O-, -C(=O)-, -NH-C(=O)-, -N(C 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 heterocyclylene and 5-10 membered heteroarylene;

[0042] L 2 is selected from C 1-6 alkylene, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene;

[0043] L 3 is selected from a bond, -NH-, -N(C 1-4 alkyl)-, -O-, -C(=O)-, -NH-C(=O)-, -N(C 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 heterocyclylene and 5-10 membered heteroarylene;

[0044] wherein L 1 , L 2 and L 3 are each C 1-6 alkylene, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene are optionally and independently substituted with one or more substituents, which are the same or different, selected from the group consisting of C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, -OH, -CN, C 1-6 alkoxy, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -C(=O)OH, -C(=O)-OC 1-6 alkyl, -C(=O)NH2, -C(=O)NH(C 1-4alkyl, -C(=O)N(C 1-4 alkyl, -C(=O)N(C 1-6 alkyl, -C(=O)N(C 1-4 alkyl, -C(=O)N(C 1-4 alkyl, -C(=O)N(C 1-4 alkyl, -C(=O)N(C 1-6 alkyl, -C(=O)N(C 1-4 alkyl, -C(=O)N(C 1-4 alkyl, -C(=O)N(C

[0045] [HO] [HO]

[0046] E is E is

[0047] E is E is E is

[0048] E is represents a double or a triple bond;

[0049] Q 1 is selected from the group consisting of a bond, -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 )-;

[0050] each R G1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 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 and 3- to 1 1 -membered heterocyclyl;

[0051] each R H1 is independently selected from the group consisting of hydrogen, -OH, C 1-6 alkoxy, -CN and C 1-6 alkyl;

[0052] if represents a double bond, then

[0053] R D selected from hydrogen, C 3-7 cycloalkyl, phenyl, halogen, -CN, C 1-6 alkoxy, -C(=O)O-C 1-6 alkyl, -NHC(=O)-C 1-6 alkyl and C 1-6 alkyl: phenyl, 3- to 11-membered heterocyclyl, C 1-6 alkoxy, halogen, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -C(=O)OH, -C(=O)O-C 1-6 alkyl, -C(=O)NH(C 1-6 alkyl), -NHC(=O)-C 1-6 alkyl, -OC(=O)-C 1-6 alkyl and phenyl-C 1-6 alkoxy;

[0054] R E and R F are each independently selected from R a2 and R b2 ;

[0055] R a2 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R b2 and / or R c2 ;

[0056] each R b2 is independently selected from -OR c2 , -NR c2 R c2 , halogen, -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 bivalent substituent =O;

[0057] each R c2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents, identically or differently, selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, -OH, -C(=O)OH, -C(=O)O-C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)-NH2, -C(=O)-NH-(C 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2and bivalent substituent =O;

[0058] or

[0059] R D and R E together with the carbon atom to which they are attached form a 4-7 membered unsaturated aliphatic ring or a 4-7 membered unsaturated heterocyclic ring, wherein the 4-7 membered unsaturated aliphatic ring or the 4-7 membered unsaturated heterocyclic ring and R F are optionally substituted with one or more substituents, identically or differently, selected from the group consisting of 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 1-4alkyl)2, halogen, -C(=O)O-C 1-6 alkyl and bivalent substituent =O;

[0060] or

[0061] if Q 1 is -C(=O)N(R G1 )-, then R G1 of -C(=O)N(R G1 )2 is not hydrogen; F together form a linker selected from -C(=O)-, -CH2-, -CH2-C(=O)-, -C(=O)-CH2- and -C2H4-;

[0062] if represents a triple bond, then

[0063] R D and R E are both absent;

[0064] R F is R a2 ;

[0065] R a2 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R b2 and / or R c2 ;

[0066] each R b2 is independently selected from -OR c2 , -NR c2 R c2 , halogen, -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)ORc2 -N(C 1-4 alkyl)C(=O)OR c2 and divalent substituents =O;

[0067] each R c2 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0068] or

[0069] E is

[0070]

[0071] Q 2 is selected from a bond, -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 )-;

[0072] each R G2 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 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 and 3-11 membered heterocyclyl;

[0073] each R H2 is independently selected from hydrogen, -OH, C 1-6 alkoxy, -CN and C 1-6 alkyl;

[0074] R I is selected from hydrogen and halogen;

[0075] R J is hydrogen; or

[0076] R I and R J together with the carbon atom to which they are attached form a cyclopropane or a dioxirane ring;

[0077] R K selected from the group consisting of hydrogen, C 1-6 alkyl, -CN and halogen;

[0078] R L selected from the group consisting of hydrogen, C 1-6 alkyl, -CN, halogen and -C(=O)-C 1-6 alkyl;

[0079] or

[0080] E is

[0081]

[0082] Q 3 selected from the group consisting of -C(=O)-, -C(=O)N(R G3 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G3 )- and -C(=NR H3 )-;

[0083] each R G3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 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 and 3-11 membered heterocyclyl;

[0084] each R H3 is independently selected from the group consisting of hydrogen, -OH, C 1-6 alkoxy, -CN and C 1-6 alkyl;

[0085] R M is selected from the group consisting of halogen, -CN and -O-C(=O)-C 1-6 alkyl;

[0086] or

[0087] E is

[0088]

[0089] Q 4selected from the group consisting of a bond, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C 1-4 alkyl)-, -S(=O)2-, and -S(=O)2NH-;

[0090] Ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and 5-membered heteroaryl;

[0091] q is selected from 1, 2, 3, and 4;

[0092] each R N is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, vinyl, ethynyl, halogen, -CN, nitro, and C 1-4 alkoxy;

[0093] or a salt thereof.

[0094] In a second aspect, the present application relates to a compound of formula (I*), or a salt thereof

[0095] wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 , Ring A, U, V, W, R 5 , L, and E are as defined for formula (I) in the first aspect.

[0096] In a third aspect, the present application relates to a compound of formula (la), or a salt thereof

[0097] wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 , L, and E are as defined for formula (I) in the first aspect.

[0098] In a fourth aspect, the present application relates to a compound of formula (la*), or a salt thereof

[0099] wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 , L, and E are as defined for formula (I) in the first aspect.

[0100] It is to be understood that each of compounds (I*), (Ia) and (Ia*) is a subset of compounds (I) and that whenever reference is made to compounds (I), this is also intended to refer to and include compounds (I*), (Ia) and (Ia*) unless otherwise indicated.

[0101] It is to be understood that compound (Ia*) is a subset of the respective compound (Ia) and that whenever reference is made to compounds (Ia), this is also intended to refer to and include compound (Ia*) unless otherwise indicated.

[0102] The following structural aspects represent preferred embodiments [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] to [D2], [E1] to [E9], [F1] to [F8], [G1] to [G3], and [H1] to [H8] of the respective structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0], and [H0], respectively.

[0103] In one aspect [A1], the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a salt thereof, wherein

[0104] R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl;

[0105] R 2a and R 2b are each independently selected from hydrogen and halogen.

[0106] In another aspect [A2], the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a salt thereof, wherein

[0107] R 1a and R 1b are each independently selected from hydrogen and methyl;

[0108] R 2a and R 2b are each independently selected from hydrogen and fluorine.

[0109] In another aspect [A3], the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a salt thereof, wherein

[0110] R 1a , R 1b , R 2a and R 2b are hydrogen.

[0111] In another aspect [B1], the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0112] Z is -(CR 6a R 6b ) n -;

[0113] n is 0.

[0114] In another aspect [B2], the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0115] Z is -(CR 6a R 6b ) n -;

[0116] n is 1;

[0117] R 6a and R 6b are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclyl.

[0118] In another aspect [B3], the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0119] Z is -CH2-.

[0120] In another aspect [B4], the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0121] Z is -(CR 6a R 6b ) n -;

[0122] n is 2;

[0123] each R 6a and R 6b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, -NH2, -NH(C 1-4alkyl), -N(C 1-4 alkyl, C 3-5 cycloalkyl and 3-5 membered heterocyclyl.

[0124] In another aspect [B5] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0125] Z is -CH2-CH2-.

[0126] In another aspect [C1] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano-C 1-4 alkyl, halogen, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2and -CN.

[0127] In another aspect [C2] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0128] R 3 is selected from hydrogen, methyl, ethyl, -CF3, -CHF2, methoxy, trifluoroethoxy, cyanomethyl, -OH and -CN. In another aspect [C3] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein R 3 is hydrogen.

[0129] In another aspect [C4] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0130] R 3 is C 1-4 alkyl.

[0131] In another aspect [C5] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0132] R 3 is methyl.

[0133] In another aspect [D1] the application relates to a compound of formula (I) or (I*), or a salt thereof, wherein

[0134] Ring A is selected from

[0135]

[0136] In another aspect [D2] the application relates to a compound of formula (I) or (I*), or a salt thereof, wherein

[0137] Ring A is

[0138] In another aspect [E1] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0139] U is =CH-; A substituted carbon (=C(R A )-);

[0140] V is =CH-; B substituted carbon (=C(R B )-);

[0141] W is nitrogen (=N-);

[0142] R A and R B are each independently selected from the group consisting of hydrogen, C 1-6 haloalkyl, C 3-5 cycloalkyl-substituted C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -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 heterocyclyl, and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of 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), and -C(=O)N(C 1-4 alkyl)2.

[0143] In another aspect [E2] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0144] U is =CH-;

[0145] V is =CH-;

[0146] W stands for nitrogen (=N-).

[0147] On the other hand [E3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0148] U is R A Substituted carbon (=C(R) A )-);

[0149] V is R B Substituted carbon (=C(R) B )-);

[0150] W was R C Substituted carbon (=C(R) C )-);

[0151] R A R B and R C Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optionally 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 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.

[0152] On the other hand [E4], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0153] U is =CH-;

[0154] V is =CH-;

[0155] W is = CH-.

[0156] In another aspect [E5] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0157] U is nitrogen (=N-);

[0158] V is carbon (=C(R B )-) substituted by R B

[0159] W is nitrogen (=N-);

[0160] R B is selected from hydrogen, C 1-6 haloalkyl, optionally C 3-5 cycloalkyl-substituted C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -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 heterocyclyl and C 1-6 alkyl optionally substituted by a substituent selected from 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) and -C(=O)N(C 1-4 alkyl)2.

[0161] In another aspect [E6] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0162] U is nitrogen (=N-);

[0163] V is =CH-;

[0164] W is nitrogen (=N-).

[0165] In another aspect [E7] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0166] U is carbon (=C(R A )-) substituted by R A

[0167] V is nitrogen (=N-);​​

[0168] W is nitrogen (=N-);

[0169] R A selected from hydrogen, C 1-6 haloalkyl, optionally substituted with C 3-5 cycloalkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, -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 heterocycle and C 1-6 alkyl optionally substituted with a substituent selected from 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) and -C(=O)N(C 1-4 alkyl)2.

[0170] In another aspect [E8] the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein U is carbon (=C(R A )-) substituted with R A ;

[0171] V is nitrogen (=N-);

[0172] W is nitrogen (=N-);

[0173] R A selected from hydrogen and halogen.

[0174] In another aspect [E9] the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0175] U is nitrogen (=N-);

[0176] V is nitrogen (=N-);

[0177] W is nitrogen (=N-).

[0178] In another aspect [F1] the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0179] R 5 selected from R a1 and R b1 ;

[0180] R a1 selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R b1 and / or R c1 ;

[0181] each R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -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 a bivalent linking group =O;

[0182] each R c1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R d1 and / or R e1 ;

[0183] each R d1independently selected from -OR e1 , -NR e1 R e1 , halogen, -CN, -C(=O)R e1 , -C(=O)NR e1 R e1 and the bivalent substituent =O;

[0184] each R e1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents selected identically or differently from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, which are optionally substituted with one or more substituents selected identically or differently from C 1-4 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OH, C 1-6 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, hydroxy-C 1-4 alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 alkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2and the bivalent substituent =O.

[0185] In another aspect [F2] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0186] R 5 is R a1 ;

[0187] R a1 is selected from 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein said 3-11 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R b1 and / or R c1 identically or differently;

[0188] each R b1 is independently selected from -OR c1 , -NRc1 R c1 , halogen, -C(=O)OR c1 and bivalent substituents =O;

[0189] each R c1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are optionally substituted with one or more, identical or different, R d1 and / or R e1 ;

[0190] each R d1 is independently selected from -OR e1 , -NR e1 R e1 and halogen;

[0191] each R e1 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 11-membered heterocyclyl are optionally substituted with one or more, identical or different, substituents selected from C 1-6 alkyl and 3- to 11-membered heterocyclyl - which are optionally substituted with one or more, identical or different, C 1-4 alkyl.

[0192] In another aspect [F3] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein R 5 is R a1 selected from:

[0193]

[0194] wherein

[0195] each R a1 is optionally substituted with one or more, identical or different, R b1 and / or R c1 ;

[0196] each R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -C(=O)ORc1 and divalent substituents = O;

[0197] 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 3-10 Cycloalkyl groups and 3-11 membered heterocyclic groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace;

[0198] Each R d1 Independently selected from -OR e1 -NR e1 R e1 and halogens;

[0199] 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 The cycloalkyl and 3-11 membered heterocyclic groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl groups and 3-11 membered heterocyclic groups—which are optionally separated by one or more identical or different C groups. 1-4 Alkyl substitution.

[0200] On the other hand [F4], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein R 5 It is selected from the following R a1 :

[0201]

[0202]

[0203] Each R a1 Optionally substituted with one or more of the same or different of the following groups:

[0204] ·C 1-6 Alkyl group, optionally substituted with one or more identical or different substituents selected from the following: C 3-6 Cycloalkyl, hydroxyl, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4alkyl, C 1-4 alkyl, C

[0205] • C 3-6 alkyl, C

[0206] • 3-11 membered heterocyclyl, optionally substituted by one or more substituents, identical or different, selected from: C 1-4 alkyl, C 3-6 alkyl, C

[0207] • a substituent selected from: halogen, -C(=O)-OC 1-6 alkyl, C 1-6 haloalkyl, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2and a bivalent substituent =O.

[0208] In another aspect [F5] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein R 5 is selected from

[0209]

[0210]

[0211]

[0212] In another aspect [F6] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein R 5 is R b1 ;

[0213] R b1 is independently selected from -OR c1 and -NR c1 R c1 ;

[0214] each R c1 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by one or more R d1 and / or R e1 ;

[0215] each R d1 is independently selected from -OR e1 , -NR e1 R e1 , halogen, -C(=O)R e1 and -C(=O)NR e1 R e1 ;

[0216] each R e1 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl, which are optionally substituted with one or more identical or different C 1-4 alkyl, C 1-6 alkoxy, halogen and the bivalent substituent =O.

[0217] In another aspect [F7] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0218] R 5 is R b1 ;

[0219] R b1 is -OR c1 ;

[0220] each R c1 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl are optionally substituted with one or more identical or different R d1 and / or R e1 ;

[0221] each R d1 is independently selected from -NR e1 R e1 and halogen;

[0222] each R e1 is independently selected from hydrogen, C 1-6alkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl and 3-11 membered heterocyclyl are each optionally substituted with one or more substituents selected from C 1-6 alkyl and 3-11 membered heterocyclyl, which are optionally substituted with one or more identical or different C 1-4 alkyl.

[0223] In another aspect [F8] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein R 5 is selected from

[0224]

[0225] In another aspect [G1] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein

[0226] L is -L 1 -L 2 -L 3 -, wherein L 1 is connected to E;

[0227] L 1 is selected from a bond, C 1-6 alkylene and 4-12 membered heteroalkylene;

[0228] L 2 is selected from C 1-6 alkylene, phenylene and 4-12 membered heteroalkylene;

[0229] L 3 is selected from a bond, -NH-, -N(C 1-4 alkyl)- and -O-;

[0230] wherein L 1 and each C 2 in L 1-6 alkylene, phenylene and 4-12 membered heteroalkylene are optionally and independently substituted with one or more substituents selected from C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, -OH, -CN, C 1-6 alkoxy, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -C(=O)OH, -C(=O)-OC 1-6 alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl), -C(=O)N(C1-4 Alkyl group 2, divalent substituent =O, and C group optionally 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 Alkoxy, -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.

[0231] In another aspect [G2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0232] L is -L 1 -L 2 -L 3 -, where L 1 Connect to E;

[0233] L 1 Selected from key, C 1-6 Alkyl groups and 4-12 membered heterocyclic groups;

[0234] L 2 Selected from C 1-6 Alkylenes, phenylenes, and 4-12 membered heterocyclic groups;

[0235] L 3 Selected from bonds, -NH-, -N(C 1-4 Alkyl)- and -O-;

[0236] Where L 1 and L 2 Each C in 1-6 Alkylene, phenylene, and 4-12 membered heterocyclic groups are optionally and independently bound by one or more identical or different C16 groups. 1-6 Alkyl substitution.

[0237] In another aspect [G3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein L is selected from...

[0238]

[0239]

[0240] In another aspect [H1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein E is

[0241]

[0242] 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 )-;

[0243] each R G1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and hydroxy-C 1-6 alkyl;

[0244] each R H1 is independently selected from hydrogen, -OH, C 1-6 alkoxy, -CN and C 1-6 alkyl;

[0245] R D is selected from hydrogen, C 3-7 cycloalkyl, phenyl, halogen, -CN, C 1-6 alkoxy, -C(=O)O-C 1-6 alkyl and C 1-6 alkyl optionally substituted by one or more substituents identical or different selected from phenyl, 3-11 membered heterocyclyl, C 1-6 alkoxy, halogen, -OH, -N(C 1-6 alkyl)2, -C(=O)OH, -C(=O)O-C 1-6 alkyl, -C(=O)NH(C 1-6 alkyl), -NHC(=O)-C 1-6 alkyl, -OC(=O)-C 1-6 alkyl and phenyl-C 1-6 alkoxy;

[0246] R E and R F are each independently selected from R a2 and R b2 ;

[0247] R a2 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, are each optionally substituted with one or more, identical or different, R b2 and / or R c2 are each independently selected from the group consisting of -OR

[0248] each R b2 is independently selected from the group consisting of -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 ;

[0249] each R c2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, are each optionally substituted with one or more, identical or different, substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, -OH, -C(=O)OH, -C(=O)O-C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, and a bivalent substituent =O.

[0250] In another aspect [H2], the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein E is

[0251]

[0252] Q 1 is selected from the group consisting of -CH2-, -C(=O)-, -C(=O)NH- and -C(=O)N(C 1-4 alkyl)-;

[0253] R D is selected from hydrogen, halogen and C 1-6 alkyl;

[0254] R E and R F are each independently selected from R a2 and R b2 ;

[0255] R a2 is selected from hydrogen and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more, identical or different R b2 and / or R c2 ;

[0256] each R b2 is independently selected from -OR c2 and -C(=O)NR c2 R c2 ;

[0257] each R c2 is independently selected from C 1-6 alkyl and 3-11 membered heterocyclyl.

[0258] In another aspect [H3] the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein E is selected from

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] In another aspect [H4] the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein E is selected from

[0266]

[0267] In another aspect [H5] the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein E is

[0268]

[0269] Q 1 selected from -CH2-, -C(=0)-, -C(=0)N(R G1 )-, -C(=0)0-, -S(=0)2-, -S(=0)2N(R G1 )- and -C(=NR H1 )-;

[0270] each R G1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and hydroxy-C 1-6 alkyl;

[0271] each R H1 is independently selected from hydrogen, -OH, C 1-6 alkoxy, -CN and C 1-6 alkyl;

[0272] R F is selected from hydrogen and C 1-6 alkyl optionally substituted by a substituent selected from -OH, C 1-6 alkoxy, -NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2.

[0273] In another aspect [H6], the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein E is

[0274]

[0275] Q 1 selected from -C(=0)-, -C(=0)N(R G1 )-, -S(=0)2- and -S(=0)2N(R G1 )-;

[0276] each R G1 is independently selected from hydrogen and C 1-6 alkyl;

[0277] R F is selected from hydrogen and C 1-6 alkyl optionally substituted by a substituent selected from -OH, C 1-6 alkoxy, -NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2.

[0278] In another aspect [H7], the present application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein E is selected from

[0279]

[0280] In another aspect [H8] the application relates to a compound of formula (I), (I*), (la) or (la*), or a salt thereof, wherein E is selected from

[0281]

[0282]

[0283] All of the above structural aspects [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] and [D2], [E1] to [E9], [F1] to [F8], [G1] to [G3], and [H1] to [H8] are preferred embodiments of the respective structural aspects [AO], [BO], [CO], [DO], [EO], [FO], [GO], and [HO], respectively. The structural aspects [AO] to [A3], [BO] to [B5], [CO] to [C5], [DO] to [D3], [EO] to [E9], [FO] to [F8], [GO] to [G3], and [HO] to [H8] referring to the different molecular moieties of the compounds of formula (I), (I*), (la) and (la*) according to the application can be combined with each other in combinations [A][B][C][D][E][F][G][H] (for compounds of formula (I) and (I*)) and combinations [A][B][C][E][F][G][H] (for compounds of formula (la) and (la*)) as desired to obtain preferred compounds (I), (I*), (la) and (la*). Each such combination [A][B][C][D][E][F][G][H] represents and defines an individual embodiment or a generic subset of compounds (I) and (I*) according to the application. Each such combination [A][B][C][E][F][G][H] represents and defines an individual embodiment or a generic subset of compounds (la) and (la*) according to the application.

[0284] Preferred embodiments of the application of formula (la) are the example compounds la-1 to la-170 and any subset thereof.

[0285] The application further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of the compounds of formula (I), (I*), (la) and (la*) including all embodiments thereof.

[0286] The application further relates to hydrates of the compounds of formula (I), (I*), (la) and (la*) including all embodiments thereof.

[0287] The present application further relates to solvates of the compounds of formula (I), (I*), (Ia) and (Ia*) (including all embodiments thereof).

[0288] For example, compounds of formula (I), (I*), (Ia) and (Ia*) (including all embodiments thereof) with ester groups are potential prodrugs (the ester is cleaved under physiological conditions) and are also part of the present application.

[0289] The present application further relates to pharmaceutically acceptable salts of the compounds of formula (I), (I*), (Ia) and (Ia*) (including all embodiments thereof).

[0290] The present application further relates to pharmaceutically acceptable salts of the compounds of formula (I), (I*), (Ia) and (Ia*) (including all embodiments thereof).

[0291] Intermediates

[0292] In a fifth aspect, the present application relates to a compound of formula (II) or a salt thereof

[0293] wherein

[0294] R 1a , R 1b , R 2a , R 2b , Z, R 3 , ring A, U, V, W, R 5 and L are as defined in formula (I) in the first aspect.

[0295] The compound of formula (II) is an intermediate in the synthesis of the compound of formula (I) (the hydrogen in the residue H-L- is replaced / substituted by the group E in the last synthesis step).

[0296] In a sixth aspect, the present application relates to a compound of formula (II*) or a salt thereof

[0297] wherein

[0298] R 1a , R 1b , R 2a , R 2b , Z, R 3 , ring A, U, V, W, R 5 and L are as defined in formula (I) in the first aspect.

[0299] In a seventh aspect, the present application relates to a compound of formula (B-5) or a salt thereof

[0300] In a seventh aspect, the present application relates to a compound of formula (B-5) or a salt thereof wherein

[0301] R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 and L are as defined in formula (I) in the first aspect.

[0302] In an eighth aspect, the present application relates to a compound of formula (B-5*) or a salt thereof

[0303] wherein

[0304] R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 and L are as defined in formula (I) in the first aspect.

[0305] It is understood that compounds (II*), (B-5) and (B-5*) are each a subset of compounds (II) and that whenever reference is made to compounds (II), this is also intended to refer to and include compounds (II*), (B-5) and (B-5*) unless specified otherwise.

[0306] It is understood that compounds (B-5*) are a subset of the corresponding compounds (B-5) and that whenever reference is made to compounds (B-5), this is also intended to refer to and include compounds (B-5*) unless specified otherwise.

[0307] All of the above structural aspects [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] and [D2], [E1] to [E9], [F1] to [F8] and [G1] to [G3] of the preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0] and [G0] of the compounds of formula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) and (Ie*) are also preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0] and [G0] of the compounds of formula (II), (II*), (B-5) and (B-5*) disclosed.

[0308] Thus, the structural aspects [A0] to [A3], [B0] to [B5], [C0] to [C5], [D0] to [D2], [E0] to [E9], [F0] to [F8] and [G0] to [G3] of the different molecular moieties of the compounds of formula (II), (II*), (B-5) and (B-5*) can be combined with each other in the combinations [A][B][C][D][E][F][G] for compounds of formula (II) and (II*) and [A][B][C][E][F][G] for compounds of formula (B-5) and (B-5*) as desired to obtain preferred compounds of formula (II), (II*), (B-5) and (B-5*). Each such combination [A][B][C][D][E][F][G] represents and defines a separate embodiment or generic subset of compounds of formula (II) and (II*). Each such combination [A][B][C][E][F][G] represents and defines a separate embodiment or generic subset of compounds of formula (B-5) and (B-5*).

[0309] Pharmaceutical compositions

[0310] Suitable pharmaceutical compositions for administering the compounds of formula (I), (I*), (Ia) or (Ia*) according to the application will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions - in particular injection (subcutaneous, intravenous, intramuscular) and infusion (injectables) solutions, elixirs, syrups, cachets, emulsions, inhalers or dispersible powders. The content of the compounds (I), (I*), (Ia) or (Ia*) should range from 0.1 to 90 wt.-%, preferably from 0.5 to 50 wt.-% of the composition as a whole, i.e. in an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosages can be given several times a day.

[0311] Suitable tablets can be obtained, for example, by mixing the compounds (I), (I*), (Ia) or (Ia*) with known pharmaceutically acceptable excipients, such as inert diluents, carriers, disintegrants, adjuvants, surface-active agents, binders and / or lubricants. The tablets can also comprise several layers.

[0312] Coated tablets can in turn be prepared by coating a tablet core produced analogously to tablets with excipients customary for tablet coating, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or to prevent incompatibilities, the tablet core can also consist of a number of layers. Similarly, the tablet coating can consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

[0313] Syrups or elixirs containing one or more compounds (I), (I*), (Ia) or (Ia*) or combinations with one or more other pharmaceutically active substances can additionally contain excipients such as sweeteners (e.g. saccharin), sweeteners (e.g. aspartame), glycerol or sugar and flavourings (e.g. flavourings such as vanillin or orange extract etc.). They can also contain excipients such as suspension adjuvants or thickening agents such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoic acid esters.

[0314] Solutions for injection and infusion are prepared in the customary manner, e.g. by adding excipients such as isotonic agents, preservatives such as p-hydroxybenzoic acid esters, or stabilisers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, and if water is used as, for example, diluent, organic solvents can optionally be used as solvating agents or dissolution aids, and transferring them into injection vials or ampoules or infusion bottles.

[0315] Capsules containing one or more compounds (I), (I*), (Ia) or (Ia*) or combinations with one or more other pharmaceutically active substances can be prepared, for example, by mixing the compounds / active substance(s) with inert excipients (e.g. lactose or sorbitol) and packing them into gelatine capsules.

[0316] Suitable suppositories can be manufactured, for example, by mixing the compounds with the excipients provided for this purpose (such as neutral fats or polyethylene glycols or derivatives thereof).

[0317] Excipients which can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), monofunctional or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as, for example, natural mineral powders (e.g. high- silica chalk, clay, talc, calcium carbonate), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), saccharides (e.g. sucrose, lactose and glucose), emulsifiers (e.g. lignin, waste sulfite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium

[0318] The pharmaceutical compositions are administered by the usual methods, preferably by the oral or transdermal route, most preferably by the oral route. For oral administration, the tablets can, of course, contain, in addition to the excipients mentioned above, additional excipients such as sodium citrate, calcium carbonate and dicalcium phosphate together with various excipients such as starch, preferably potato starch, gelatine and the like. Furthermore, lubricants such as magnesium stearate, sodium

[0319] For parenteral administration, solutions of the active agent using suitable liquid

[0320] The dosage range of the compound of formula (I), (I*), (Ia) or (Ia*) applicable per day is generally from 1 mg to 2000 mg, preferably from 250 to 1250 mg.

[0321] However, it can sometimes be necessary to depart from the amounts specified, depending on the body weight, age, the route of administration, the severity of the disease, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered (continuous or intermittent treatment with one or more administrations per day). Thus, in certain cases, it can be sufficient to use less than the minimum dose given above, while in other cases it can be necessary to exceed the upper limit. When a large amount is administered, it can be advisable to divide it into a number of smaller doses spread over the day.

[0322] Thus, in a further aspect, the present application relates to a pharmaceutical composition comprising at least one, preferably one, compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0323] The compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof and the pharmaceutical compositions comprising such compounds and salts can also be co-administered with other pharmacologically active substances, for example with other anti-tumour compounds (e.g. chemotherapy), i.e. used in combination (see further below for combination therapy).

[0324] The elements of such combinations can be administered (whether dependently or independently) by methods customary to the skilled person, and as they are used in monotherapy, e.g. by oral, enteral, parenteral (e.g. intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implantation), nasal, vaginal, rectal or topical routes of administration, and can be formulated separately or together in suitable dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable excipients appropriate for each route of administration.

[0325] The combination can be administered in therapeutically effective single or divided daily doses. The active ingredients of the combination can be administered in monotherapy in such doses which are therapeutically effective, or in such doses which are lower than those used in monotherapy but which when combined produce the desired (joint) therapeutically effective amount.

[0326] However, when the combination of two or more active substances or principal components results in a synergistic effect, it is also possible to reduce the amount of one, more or all substances or principal components to be administered while still achieving the desired therapeutic effect. This can be used, for example, to avoid, limit or reduce any unwanted side effects associated with the use of one or more substances or principal components when they are used in their usual amounts, while still obtaining the desired pharmacological or therapeutic effect.

[0327] Thus, in a further aspect, the present application also relates to a pharmaceutical composition comprising a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0328] In a further aspect, the present application also relates to a pharmaceutical preparation comprising a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0329] The pharmaceutical composition to be co-administered or used in combination can also be provided in the form of a kit.

[0330] Thus, in a further aspect, the present application also relates to a kit comprising

[0331] • a first pharmaceutical composition or dosage form comprising a compound of formula (I), (I*), (Ia) or (Ia*) and optionally one or more pharmaceutically acceptable excipients, and

[0332] • a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0333] In one aspect, the kit comprises a third pharmaceutical composition or dosage form still comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0334] Medical uses - methods of treatment

[0335] Indications - patient population

[0336] The present application is primarily directed to RAS G12C inhibitors, in particular compounds of formula (I), (I*), (Ia) and (Ia*) (including all embodiments thereof), which can be useful for the treatment and / or prevention of diseases and / or conditions mediated by RAS G12C mutations (e.g. and preferably KRAS G12C, NRAS G12C and HRAS G12C).

[0337] Thus, in a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0338] In a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0339] In a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease and / or a condition mediated by RAS G12C mutations.

[0340] In a further aspect, the present application relates to the use of a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and / or prevention of a disease and / or a condition mediated by RAS G12C mutations.

[0341] In a further aspect, the present application relates to a method of treatment and / or prevention of a disease and / or a condition mediated by RAS G12C mutations, which method comprises administering to a human a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof.

[0342] In a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer.

[0343] In a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, for use in a method of treatment and / or prevention of cancer of the human or animal body.

[0344] In a further aspect, the present application relates to the use of a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and / or prevention of cancer.

[0345] In a further aspect, the present application relates to a method of treatment and / or prevention of cancer, which method comprises administering to a human a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof.

[0346] In a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, for use in providing inhibition of G12C mutant RAS.

[0347] In a further aspect, the present application relates to the use of a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for providing inhibition of G12C mutant RAS.

[0348] In a further aspect, the present application relates to a method for providing inhibition of G12C mutant RAS, comprising administering to a human a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof.

[0349] Another aspect is based on the identification of a link between the G12C mutation status of a patient and potential sensitivity to treatment with a compound of formula (I), (I*), (Ia) or (Ia*). RAS G12C inhibitors, such as compounds of formula (I), (I*), (Ia) or (Ia*), can subsequently be advantageously used to treat patients having a KRAS G12C, HRAS G12C or NRAS G12C mutation and who can be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients, in particular cancer patients, for treatment with a compound of formula (I), (I*), (Ia) or (Ia*). The selection is based on whether the tumour cells to be treated have a wild-type or G12C mutant KRAS, HRAS or NRAS gene. The G12C KRAS, HRAS or NRAS gene status can thus be used as a biomarker to indicate that it can be advantageous to select treatment with a compound of formula (I), (I*), (Ia) or (Ia*).

[0350] According to one aspect, there is provided a method of selecting a patient for treatment with a compound of formula (I), (I*), (Ia) or (Ia*), the method comprising

[0351] • providing a sample containing tumour cells from the patient;

[0352] • determining whether the RAS gene in the tumour cell-containing sample of the patient encodes a wild-type (glycine at position 12) or a mutant (cysteine at position 12) KRAS, HRAS or NRAS protein; and

[0353] • selecting the patient for treatment with a compound of formula (I), (I*), (Ia) or (Ia*) based thereon.

[0354] The method can or can not include an actual patient sample isolation step.

[0355] In one aspect, the patient is selected for treatment with a compound of formula (I), (I*), (Ia) or (Ia*) if the tumour cell DNA has a G12C mutant KRAS gene.

[0356] In another aspect, if the tumor cell DNA has a G12C mutant HRAS gene, the patient is selected for treatment with a compound of Formula (I), (I*), (Ia), or (Ia*).

[0357] In another aspect, if the tumor cell DNA has a G12C mutant NRAS gene, the patient is selected for treatment with a compound of Formula (I), (I*), (Ia), or (Ia*).

[0358] According to another aspect, there is provided a compound of Formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer having tumor cells carrying a G12C mutant RAS gene.

[0359] According to another aspect, there is provided a compound of Formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer having tumor cells carrying a G12C mutant KRAS gene.

[0360] According to another aspect, there is provided a compound of Formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer having tumor cells carrying a G12C mutant HRAS gene.

[0361] According to another aspect, there is provided a compound of Formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer having tumor cells carrying a G12C mutant NRAS gene.

[0362] According to another aspect, there is provided a method of treating a cancer having tumor cells carrying a G12C mutant RAS gene, the method comprising administering to a human an effective amount of a compound of Formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof.

[0363] According to another aspect, there is provided a method of treating a cancer having tumor cells carrying a G12C mutant KRAS, HRAS, or NRAS gene, the method comprising administering an effective amount of a compound of Formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof.

[0364] Determining whether a tumor or cancer comprises a G12C KRAS, HRAS, or NRAS mutation can be performed by assessing the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein, by assessing the amino acid sequence of the KRAS, HRAS, or NRAS protein, or by assessing the characteristics of the putative KRAS, HRAS, or NRAS mutant protein. The sequence of wild-type human KRAS, HRAS, or NRAS is known in the art. Methods for detecting mutations in the KRAS, HRAS, or NRAS nucleotide sequence are known to one of skill in the art. The methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, the sample is evaluated for G12C KRAS, HRAS, or NRAS mutations by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRAS, HRAS, or NRAS G12C mutation is used. When the mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS, HRAS, or NRAS G12C mutation is identified using a direct sequencing method of a specific region of the KRAS, HRAS, or NRAS gene, such as exon 2 and / or exon 3. This technique will identify all possible mutations in the sequenced region. Methods for detecting mutations in the KRAS, HRAS, or NRAS protein are known to one of skill in the art. These methods include, but are not limited to, detecting KRAS, HRAS, or NRAS mutants using binding agents specific for the mutant protein, such as antibodies, protein electrophoresis, Western blots, and direct peptide sequencing.

[0365] Methods for determining whether a tumor or cancer comprises a G12C KRAS, HRAS, or NRAS mutation can use various samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In some embodiments, the sample is a liquid biopsy and the test is performed on a blood sample to look for tumor cancer cells circulating in the blood or DNA fragments from tumor cells in the blood.

[0366] According to the methods and uses as defined and disclosed herein (above and below), the disease / condition / cancer / tumor / cancer cell to be treated / prevented with a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, appendix cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0367] In another aspect, according to the methods and uses as defined and disclosed herein (above and below), the disease / condition / cancer / tumor / cancer cell to be treated / prevented with a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is selected from the group consisting of pancreatic cancer, lung cancer (preferably non-small cell lung cancer (NSCLC)), cholangiocarcinoma and colorectal cancer.

[0368] Particularly preferably, according to the methods and uses as defined and disclosed herein (above and below), the cancer to be treated / prevented with a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0369] • lung adenocarcinoma (preferably non-small cell lung cancer (NSCLC)) harboring a KRAS G12C mutation;

[0370] • colorectal adenocarcinoma harboring a KRAS G12C mutation;

[0371] • pancreatic cancer (preferably pancreatic ductal adenocarcinoma (PDAC)) harboring a KRAS G12C mutation.

[0372] Additionally, the following cancers, tumors and other proliferative diseases can be treated with a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof - without limitation. Preferably, the methods of treatment, methods, uses, compounds for use and pharmaceutical compositions for use as disclosed herein (above and below) are applied to treat a disease / condition / cancer / tumor as described and / or referred to herein (i.e. the corresponding cell) harboring a RAS G12C mutation (preferably a KRAS G12C mutation) or which has been identified to harbor a RAS G12C mutation (preferably a KRAS G12C mutation):

[0373] Cancers / tumors / carcinomas of the head and neck: e.g., tumors / cancers / carcinomas of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including the lips, gingiva, alveolar ridge, retromolar trigone, floor of the mouth, tongue, hard palate, buccal mucosa), oropharynx (including the base of tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including the supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands);

[0374] Cancers / tumors / carcinomas of the lung: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma);

[0375] Mediastinal neoplasms: e.g., neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, nodular ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangioendothelioma, lymphangioleiomyoma);

[0376] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; cystadenocarcinoma of the liver; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), 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 kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms tumor), adrenal rest tumor, Grawitz tumor; ureter; bladder, e.g., urachal cancer, urothelial carcinoma; urethra, e.g., distal, globular, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-resistant), penis) tumors / cancers / carcinomas;

[0377] Cancers / tumors / carcinomas of the testes: e.g., seminoma, non-seminoma,

[0378] Gynecologic cancer / tumor / carcinoma: e.g., tumors / carcinomas / cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus);

[0379] Cancer / tumor / carcinoma of the breast: e.g., breast cancer (infiltrating ductal, colloid, lobular invasive, tubular, cystic, papillary, medullary, mucinous), 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;

[0380] Cancer / tumor / carcinoma of the endocrine system: e.g., tumors / carcinomas / cancers of the endocrine glands, thyroid (thyroid cancer / tumor; papillary, follicular, anaplastic, medullary), parathyroid (parathyroid cancer / tumor), adrenal cortex (adrenal cortex cancer / tumor), pituitary (including prolactinomas, craniopharyngiomas), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, paraganglioma, pancreatic endocrine tumor (PET; nonfunctional PET, pancreatic polypeptide tumor, gastrinoma, insulinoma, secretinoma, glucagonoma, somatostatinoma, growth hormone releasing factor tumor, adrenocorticotropic hormone tumor), carcinoid tumor;

[0381] Soft tissue sarcoma: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extra-renal rhabdoid tumor, desmoplastic small cell tumor;

[0382] Osteosarcoma: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, juxtacortical, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0383] Mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma;

[0384] Cancers of the skin: e.g., basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer;

[0385] Neoplasms of the central nervous system and brain: e.g., astrocytoma (brain, cerebellum, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, pilocytic, plump cell type), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, neurilemmoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroblastoma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic), spinal cord tumor;

[0386] Lymphomas and leukemias: e.g., B-cell non-Hodgkin lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL)), T-cell non-Hodgkin lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), T-cell lymphoblastic lymphoma (T-LBL), adult T-cell lymphoma, B-cell lymphoblastic lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL) B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastic lymphoma, Hodgkin disease (HD) (including nodular lymphocyte predominant HD (NLPHD), nodular sclerosis HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous / myeloid leukemia (AML), acute lymphatic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphatic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0387] Carcinoma of unknown primary site (CUP);

[0388] All cancers / tumors / carcinomas referred to above, by their specific location / origin in the body, are intended to include primary tumors and metastatic tumors derived therefrom.

[0389] All cancers / tumors / carcinomas referred to above can be further distinguished by their histopathological classification:

[0390] Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, verrucous, pseudosarcoma, spindle squamous, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oxyphilic cell carcinoma;

[0391] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, hemangiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphomas, melanomas, germ cell tumors, hematological tumors, mixed and undifferentiated carcinomas;

[0392] The compounds of the present application can be used in treatment regimens in the context of first line, second line, or any other line of treatment.

[0393] The compounds of the present application can be used in the prevention, short-term or long-term treatment of the diseases / conditions / cancers / tumors referred to above, optionally also in combination with radiotherapy and / or surgery.

[0394] The methods of treatment, methods, uses, and compounds for use as disclosed herein (above and below) can be carried out with any compound of formula (I), (I*), (Ia), or (Ia*), or a pharmaceutically acceptable salt as disclosed or defined herein, and with any pharmaceutical composition or kit comprising a compound of formula (I), (I*), (Ia), or (Ia*), or a pharmaceutically acceptable salt thereof (each including all individual embodiments or generic subsets of compounds (I), (I*), (Ia), or (Ia*)).

[0395] Combination therapy

[0396] It is also possible to co-administer a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising such compounds and salts, with other pharmacologically active substances, for example with other anti-tumour compounds (e.g. chemotherapy), or in combination with other treatments such as radiotherapy or surgical intervention, either as an adjunct to or following surgery. Preferably, the pharmacologically active substance(s) co-administered is an anti-tumour compound(s).

[0397] Thus, in a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, for use as defined above, wherein the compound is administered before, after or with the other pharmacologically active substance(s).

[0398] In a further aspect, the present application relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, for use as defined above, wherein the compound is administered in combination with the other pharmacologically active substance(s).

[0399] In a further aspect, the present application relates to the use of a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, as defined above, wherein the compound is administered before, after or with the other pharmacologically active substance(s).

[0400] In a further aspect, the present application relates to a method (e.g. a method of treatment and / or prevention) as defined above, wherein the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is administered before, after or with a therapeutically effective amount of the other pharmacologically active substance(s).

[0401] In a further aspect, the present application relates to a method (e.g. a method of treatment and / or prevention) as defined above, wherein the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of the other pharmacologically active substance(s).

[0402] In a further aspect, the present application relates to a method for the treatment and / or prevention of cancer, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*) 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*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and the other pharmacologically active substance(s) are administered simultaneously, concurrently, sequentially, successively, alternately or separately.

[0403] In a further aspect, the present application relates to a method for the treatment and / or prevention of cancer, which method comprises administering to a patient in need thereof 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 further pharmacologically active substances, wherein the RAS G12C inhibitor, preferably the KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, is administered in combination with the one or more further pharmacologically active substances.

[0404] In a further aspect, the present application relates to a compound of formula (I), (I*), (la) or (la*), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the compound of formula (I), (I*), (la) or (la*), or a pharmaceutically acceptable salt thereof, is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the one or more further pharmacologically active substances.

[0405] In a further aspect, the present application relates to a RAS G12C inhibitor, preferably a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the RAS G12C inhibitor, preferably the KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof, is administered in combination with the one or more further pharmacologically active substances.

[0406] In a further aspect, the present application relates to a kit comprising

[0407] • a first pharmaceutical composition or dosage form comprising a compound of formula (I), (I*), (la) or (la*), or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, and

[0408] • a second pharmaceutical composition or dosage form comprising another pharmacologically active substance optionally one or more pharmaceutically acceptable excipients,

[0409] for the treatment and / or prevention of cancer, wherein the first pharmaceutical composition is to be administered simultaneously, concurrently, sequentially, successively, alternately or separately with the second and / or further pharmaceutical composition or dosage form.

[0410] In one aspect, such a kit for use comprises a third pharmaceutical composition or dosage form, which still comprises another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients

[0411] In another embodiment of the present application, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the present application (including all embodiments) are administered simultaneously.

[0412] In another embodiment of the application, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the application (including all embodiments) are administered concurrently.

[0413] In another embodiment of the application, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the application (including all embodiments) are administered sequentially.

[0414] In another embodiment of the application, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the application (including all embodiments) are administered consecutively.

[0415] In another embodiment of the application, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the application (including all embodiments) are administered alternately.

[0416] In another embodiment of the application, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the application (including all embodiments) are administered separately.

[0417] The one or more pharmacologically active substances used together with / in combination with a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) and / or with a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof (including all individual embodiments or generic subsets of compounds (I), (I*), (Ia) or (Ia*)) or in one or more of the medical uses, uses, methods of treatment and / or prevention as defined herein (above and below) can be selected from any one or more of the following (preferably, one or two additional pharmacologically active substances are used in all of these embodiments):

[0418] 1. an inhibitor of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutants thereof

[0419] a. irreversible inhibitors: e.g. afatinib, dacomitinib, canertinib, neratinib, icotinib, poziotinib, AV 412, PF-6274484, HKI 357, olmutinib, osimertinib, amuvatinib, nazartinib, lazertinib, pelitinib;

[0420] b. reversible inhibitors: e.g. erlotinib, gefitinib, icotinib, sapitinib, lapatinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340;

[0421] c. anti-EGFR antibodies: e.g. necitumumab, panitumumab, cetuximab, evatumumab;

[0422] d. anti-HER2 antibodies: e.g. pertuzumab, trastuzumab, emtansine;

[0423] e. inhibitors of mutant EGFR;

[0424] f. inhibitors of HER2 with exon 20 mutations;

[0425] g. preferred irreversible inhibitors are afatinib;

[0426] h. preferred anti-EGFR antibodies are cetuximab.

[0427] 2. inhibitors of MEK and / or any of its mutants

[0428] a. e.g. trametinib, cobimetinib, binimetinib, selumetinib, refametinib, BI 3011441 ;

[0429] b. preferred are trametinib and BI 3011441 ;

[0430] c. most preferred is BI 3011441 ;

[0431] d. MEK inhibitors disclosed in WO 2013 / 136249;

[0432] e. MEK inhibitors disclosed in WO 2013 / 136254

[0433] 3. inhibitors of SOS1 and / or any of its mutants (i.e. compounds modulating / inhibiting the GEF function of SOS1, e.g. by binding to SOS1 and preventing the protein-protein interaction between SOS1 and (mutant) Ras proteins, e.g. KRAS)

[0434] a. e.g. BAY-293, BI-3406, BI 1701963;

[0435] b. preferred are BI-3406 and BI 1701963;

[0436] c. most preferred is BI 1701963;

[0437] d. SOS1 inhibitors disclosed in WO 2018 / 115380;

[0438] e. SOS1 inhibitors disclosed in WO 2019 / 122129;

[0439] f. SOS1 inhibitors disclosed in WO 2020 / 180768, WO 2020 / 180770, WO 2018 / 172250 and WO 2019 / 201848.

[0440] 4. Oncolytic viruses

[0441] 5. RAS vaccines

[0442] a. e.g. TG02 (Targovax).

[0443] 6. Cell cycle inhibitors

[0444] a. e.g. inhibitors of CDK4 / 6 and / or any mutants thereof

[0445] i. e.g. palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600;

[0446] ii. Preferred are palbociclib and abemaciclib;

[0447] iii. Most preferred is abemaciclib.

[0448] b. e.g. vinca alkaloids

[0449] i. e.g. vinorelbine.

[0450] c. e.g. inhibitors of aurora kinases and / or any mutants thereof

[0451] i. e.g. alisertib, baricitinib.

[0452] 7. Inhibitors of PTK2 (= FAK) and / or any mutants thereof

[0453] a. e.g. TAE226, BI 853520.

[0454] 8. Inhibitors of SHP2 and / or any mutants thereof

[0455] a. e.g. SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0456] 9. Inhibitors of PI3 kinases (= PI3K) and / or any mutants thereof

[0457] a. for example, inhibitors of PI3Ka and / or any mutants thereof

[0458] i. for example, alpelisib, cerdulixib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactolisib, pictilisib, taselisib.

[0459] 10. inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutants thereof

[0460] a. for example, pralsetinib, infigratinib, nintedanib.

[0461] 11. inhibitors of AXL and / or any mutants thereof

[0462] 12. taxanes

[0463] a. for example, paclitaxel, nab-paclitaxel, docetaxel;

[0464] b. Preferred is paclitaxel.

[0465] 13. platinum-containing compounds

[0466] a. for example, cisplatin, carboplatin, oxaliplatin

[0467] b. Preferred is oxaliplatin.

[0468] 14. antimetabolites

[0469] a. for example, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, a combination of trifluridine and tipiracil (= TAS102);

[0470] b. Preferred is 5-fluorouracil.

[0471] 15. immunotherapeutics

[0472] a. for example immune checkpoint inhibitors

[0473] i. for example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb;

[0474] ii. Preferred is an anti-PD1 mAb;

[0475] iii. for example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, emibetuzumab;

[0476] iv. Preferred are Nivolumab, Pembrolizumab, Epacadride and PDR-001 (= Spartalizumab);

[0477] v. Most preferred are Epacadride, Pembrolizumab and Nivolumab.

[0478] 16. Inhibitors of topoisomerases

[0479] a. For example, Irinotecan, Liposomal Irinotecan (nal-IRI), Topotecan, Etoposide;

[0480] b. Most preferred are Irinotecan and Liposomal Irinotecan (nal-IRI).

[0481] 17. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutants thereof

[0482] a. For example, Encorafenib, Dabrafenib, Vermurafenib, PLX-8394, RAF-709 (= Example 131 in WO 2014 / 151616), LXH254, Sorafenib, LY-3009120 (= Example 1 in WO 2013 / 134243), Refametinib, TAK-632, Abagovomab, CCT196969, RO5126766, RAF265.

[0483] 18. Inhibitors of mTOR

[0484] a. For example, Rapamycin, Temsirolimus, Everolimus, Ridaforolimus, Zotarolimus, Sapacitabine, Torin 1, Dactolisib, GDC-0349, VS-5584, Vistusertib, AZD8055.

[0485] 19. Epigenetic modulators

[0486] a. For example, BET inhibitors

[0487] 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;

[0488] ii. Preferred is BI 894999.

[0489] 20. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutants thereof

[0490] a. e.g. Zanatumamab (antibody 60833 in WO 2010 / 066868), MEDI-573 (=dusigitumab), linifanib.

[0491] 21. an inhibitor of Src family kinases and / or any mutants thereof

[0492] a. e.g. an inhibitor of Src A subfamily kinases and / or any mutants thereof, i.e. an inhibitor of Src, Yes, Fyn, Fgr and / or any mutants thereof;

[0493] b. e.g. an inhibitor of Src B subfamily kinases and / or any mutants thereof, i.e. an inhibitor of Lck, Hck, Blk, Lyn and / or any mutants thereof;

[0494] c. e.g. an inhibitor of Frk subfamily kinases and / or any mutants thereof, i.e. an inhibitor of Frk and / or any mutants thereof;

[0495] d. e.g. dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU6656, WH-4-023.

[0496] 22. an apoptosis modulator

[0497] a. e.g. an MDM2 inhibitor, e.g. an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 and / or any mutants thereof;

[0498] i. e.g. HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115, BI 907828;

[0499] ii. Preferred are HDM-201, RG-7388, AMG-232 and BI 907828;

[0500] iii. Most preferred is BI 907828;

[0501] iv. MDM2 inhibitors disclosed in WO 2015 / 155332;

[0502] v. MDM2 inhibitors disclosed in WO 2016 / 001376;

[0503] vi. MDM2 inhibitors disclosed in WO 2016 / 026937;

[0504] vii. the MDM2 inhibitor disclosed in WO 2017 / 060431 ;

[0505] b. for example, a PARP inhibitor;

[0506] c. for example, a MCL-1 inhibitor;

[0507] i. for example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0508] 23. an inhibitor of c-MET and / or any mutant thereof

[0509] a. for example, semapimib, cabozantinib, foretinib;

[0510] b. MET antibodies, for example, inotuzumab, emibetuzumab;

[0511] 24. an inhibitor of ERK and / or any mutant thereof

[0512] a. for example, ulixertinib, LTT462;

[0513] 25. an inhibitor of farnesyl transferase and / or any mutant thereof

[0514] a. for example, tipifarnib;

[0515] In further embodiments of the (combination) use and methods (e.g. therapeutic and / or prophylactic methods) as described hereinabove, one other pharmacologically active substance will be administered before, after or with the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, wherein the one other pharmacologically active substance is

[0516] • a SOS1 inhibitor; or

[0517] • BI 1701963; or

[0518] • a MEK inhibitor; or

[0519] • trametinib, or

[0520] • BI 3011441; or

[0521] • an anti-PD-1 antibody; or

[0522] • epacadostat; or

[0523] • cetuximab; or

[0524] • afatinib; or

[0525] • standard of care (SoC) for the given indication; or

[0526] • a PI3 kinase inhibitor.

[0527] In further embodiments of the (combined) uses and methods (e.g. therapeutic and / or prophylactic methods) as described hereinabove, one further pharmacologically active substance will be administered in combination with a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, wherein the one further pharmacologically active substance is

[0528] • a SOS1 inhibitor; or

[0529] • BI 1701963; or

[0530] • a MEK inhibitor; or

[0531] • trametinib; or

[0532] • BI 3011441; or

[0533] • an anti-PD-1 antibody; or

[0534] • efinalizumab; or

[0535] • cetuximab; or

[0536] • afatinib; or

[0537] • standard of care (SoC) for the given indication; or

[0538] • a PI3 kinase inhibitor.

[0539] In further aspects of the (combined) uses and methods (e.g. therapeutic and / or prophylactic methods) as described hereinabove, two further pharmacologically active substances will be administered before, after or with a compound of formula (I), (I*), (Ia) or (Ia*), or a pharmaceutically acceptable salt thereof, wherein the two further pharmacologically active substances are

[0540] • a MEK inhibitor (preferably BI 3011441) and a SOS1 inhibitor (preferably BI 1701963); or

[0541] • trametinib and a SOS1 inhibitor (preferably BI 1701963); or

[0542] • an anti-PD-1 antibody (preferably efinalizumab) and an anti-LAG-3 antibody; or

[0543] • an anti-PD-1 antibody (preferably efinalizumab) and a SOS1 inhibitor (preferably BI 1701963); or

[0544] • a MEK inhibitor (preferably BI 3011441 ) and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0545] • a SOS1 inhibitor (preferably BI 1701963) and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0546] • a MEK inhibitor (preferably BI 3011441 ) and afatinib; or

[0547] • a MEK inhibitor (preferably BI 3011441 ) and cetuximab; or

[0548] • trametinib and afatinib; or

[0549] • trametinib and cetuximab; or

[0550] • a SOS1 inhibitor (preferably BI 1701963) and afatinib; or

[0551] • a SOS1 inhibitor (preferably BI 1701963) and cetuximab.

[0552] In further aspects of the (combination) uses and methods (e.g. therapeutic and / or prophylactic methods) as described hereinabove, two other pharmacologically active substances will be administered in combination with a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, wherein the two other pharmacologically active substances are

[0553] • a MEK inhibitor (preferably BI 3011441 ) and a SOS1 inhibitor (preferably BI 1701963); or

[0554] • trametinib and a SOS1 inhibitor (preferably BI 1701963); or

[0555] • an anti-PD-1 antibody (preferably pembrolizumab) and an anti-LAG-3 antibody; or

[0556] • an anti-PD-1 antibody (preferably pembrolizumab) and a SOS1 inhibitor (preferably BI 1701963); or

[0557] • a MEK inhibitor (preferably BI 3011441 ) and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0558] • a SOS1 inhibitor (preferably BI 1701963) and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0559] • a MEK inhibitor (preferably BI 3011441) and afatinib; or

[0560] • a MEK inhibitor (preferably BI 3011441) and cetuximab; or

[0561] • trametinib and afatinib; or

[0562] • trametinib and cetuximab; or

[0563] • a SOS1 inhibitor (preferably BI 1701963) and afatinib; or

[0564] • a SOS1 inhibitor (preferably BI 1701963) and cetuximab.

[0565] One or more additional pharmacologically active substances which can also be used together / in combination with the compounds of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof (including all individual embodiments or generic subsets of compounds (I), (I*), (Ia) or (Ia*)) or used in the medical uses, uses, treatment and / or prevention methods as defined herein (above and below) include without limitation: hormones, hormone analogs and anti-hormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, 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 respective receptors (growth factors such as e.g. 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, e.g. HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their respective receptors), inhibitors being e.g. (anti)growth factor antibodies, (anti)growth factor receptor antibodies and tyrosine kinase inhibitors such as e.g. cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed), pyrimidine analogs such as 5-fluorouracil (5-FU), ribo- and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytosine arabinoside (ara C), fludarabine); antitumor antibiotics (e.g. anthracyclines such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride), myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g. estramustine, nitrogen mustard, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as e.g. carmustine and lomustine, thiotepa); antimitotic agents (e.g. vinca alkaloids such as e.g. vinblastine, vindesine, vinorelbine and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g. talimogene laherparapvec), tubulin inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as, e.g., etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3K alpha inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimetics, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g., venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g., everolimus, temsirolimus, deforolimus, sirolimus), androgene synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g., carfilzomib), immunotherapeutics [such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins such as, e.g., ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), t cell engagers (e.g., bispecific T cell engagers such as, e.g., CD3 x BCMA, CD3 x CD33, CD3 x CD19, PSMA x CD3), tumor vaccines, and various chemotherapeutics (such as amifostin, anagrelide, clodronat, neulasta, interferon, interferon alpha, folinic acid, procarbazine, levamisole, myo-inositol, mitotane, pamidronate disodium, and porfimer sodium). such as, e.g., amifostin, anagrelide, clodronat, neulasta, interferon, interferon alpha, folinic acid, procarbazine, levamisole, myo-inositol, mitotane, pamidronate disodium, and porfimer sodium).

[0566] It is to be understood that the combination, composition, kit, method, use or compound for use according to the application can envisage the simultaneous, concurrent, sequential, successive, alternating or separate administration of the active ingredients or components. It is appreciated that the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be administered dependently or independently, e.g. the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be administered as part of the same pharmaceutical composition / dosage form, or preferably in separate pharmaceutical compositions / dosage forms.

[0567] In the present context, “combination” or “combined” within the meaning of the present application includes, without being limited to, products that result from the mixing or combining of more than one active ingredient, and includes fixed and non-fixed (e.g. free) combinations (including kits) and uses, e.g. like the simultaneous, concurrent, sequential, successive, alternating or separate use of components or ingredients. The term “fixed combination” means that the active ingredients are presented together in a single entity or dosage form for administration to a patient. The term “non-fixed combination” means that the active ingredients are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the compounds in the body of the patient.

[0568] The administration of the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be performed by co-administration of the active components or ingredients, e.g. like by administering them simultaneously or concurrently in one single or two or more separate formulations or dosage forms. Alternatively, the administration of the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be performed by sequential or alternating administration of the active components or ingredients, e.g. like in two or more separate formulations or dosage forms.

[0569] For example, concurrent administration includes substantially simultaneous administration. This form of administration can also be referred to as "concomitant" administration. Parallel administration includes administration of the active agents within the same general time period, e.g., on the same day or days, but not necessarily at the same time. Alternating administration includes administration of one agent for one period of time, e.g., over the course of days or a week, followed by administration of another agent or agents for a subsequent period of time, e.g., over the course of days or a week, and then repeating the pattern for one or more cycles. Sequential or successive administration includes administration of one agent using one or more doses over a first period of time, e.g., over the course of days or a week, followed by administration of the other agent or agents using one or more doses over a second and / or additional period of time, e.g., over the course of days or a week. Variations of these general guidelines can also be employed, e.g., depending on the agents used and the status of the subject.

[0570] Definitions

[0571] Terms not specifically defined herein should be given their ordinary and customary meaning to one of ordinary skill in the art in light of the disclosure and context. However, as used in the specification, unless expressly stated to the contrary, the following terms have the indicated meanings and adhere to the following conventions:

[0572] The prefix C where x and y each represent a positive integer (x < y) x-y The use of the designation indicates that the specified and recited chain or ring structure or combination of chain and ring structure as a whole can consist of a maximum of y and a minimum of x carbon atoms.

[0573] The designation of the number of members in a group containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) relates to the total number of atoms of all ring members or the sum of all ring and carbon chain members.

[0574] The designation of the number of carbon atoms in a group consisting of a combination of carbon chain and carbon ring structures (e.g., cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all carbon ring and carbon chain members. Obviously, a ring structure has at least three members.

[0575] Generally, for groups comprising two or more subgroups (e.g., heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, arylalkyl), the last named subgroup is the point of attachment of the group, e.g., aryl-C 1-6 An alkyl substituent means a group in which the alkyl group is bound to the C 1-6 The alkyl group is bound to the C

[0576] In groups like HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, the skilled person can see from the free valency of the group itself where the point of attachment to one or more groups of the molecule is.

[0577] alkyl represents a monovalent saturated hydrocarbon chain, which can occur in both straight-chain (unbranched) and branched forms. If the alkyl group is substituted, the substitution can occur independently of one another by mono- or polysubstitution at each occasion on all carbon atoms carrying hydrogen.

[0578] The term "C 1-5 Alkyl" includes, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0579] Further examples of alkyl groups are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1 -propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; isopropyl; -CH(CH3)2), 1 -butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu; isobutyl; -CH2CH(CH3)2), 2-butyl (sec-Bu; sec-butyl; -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu; tert-butyl; -C(CH3)3), 1-pentyl (n-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-l-butyl (i-pentyl; -CH2CH2CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-l -propyl (neopentyl; -CH2C(CH3)3), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl; -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)CH2CH2CH3), 2-methyl-2-hexyl (-C(CH3)2CH2CH2CH2CH3), 3-methyl-3-hexyl (-C(CH3)CH2CH2CH2CH3), 3-methyl-2-hexyl (-CH(CH3)CH2CH2CH2CH3), 4-methyl-2-hexyl (-CH(CH2CH3)CH2CH2CH3), 2-methyl-3-hexyl (-CH2CH(CH3)CH2CH2CH3), 2,3-dimethyl-2-hexyl (-C(CH3)2CH2CH2CH2CH3), 2,3-dimethyl-3-hexyl (-CH2CH(CH3)2CH2CH3), 3,3-dimethyl-2-hexyl (-CH(CH3)C(CH3)2CH2CH3), 3,4-dimethyl-3-hexyl (-CH2CH(CH2CH3)2), 2-ethyl-2-methyl-3-hexyl (-CH2CH(CH2CH3)CH2CH2CH3), 2-ethyl-2-methyl-2-hexyl (-C(CH2CH3)2CH2CH2CH3), 2-ethyl-3-methyl-3-hexyl (-CH2CH(CH3)CH2CH2CH3), 2-ethyl-3-methyl-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3-dimethyl-1-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1-pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (-CH2CH2CH(CH3)CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl), and the like.

[0580] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, without any further definition, mean a saturated hydrocarbon group with the corresponding number of carbon atoms, including all isomeric forms.

[0581] If the alkyl group is part of another (combined) group, such as for example C x-y alkylamino or C x-y alkyloxy, the above definitions for alkyl also apply.

[0582] The term alkylene Alkylene can also be derived from alkyl. Alkylene is divalent, unlike alkyl, and requires two binding partners. Formally, the second valence is created by removing a hydrogen atom from an alkyl group. Corresponding groups are for example -CH3and -CH2-, -CH2CH3and -CH2CH2- or >CHCH3, and the like.

[0583] The term "C 1-4"Alkylene" includes, for example, -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3))2)- and -C(CH3)(CH2CH3)-.

[0584] Further examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene and the like.

[0585] Without any further definition, the general terms propylene, butylene, pentylene, hexylene and the like are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

[0586] If alkylene is part of another (combined) group, for example like in HO-C x-y Alkyleneamino or H2N-C x-y Alkyleneoxy, the above definitions for alkylene apply.

[0587] Unlike alkyl groups, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are connected together by a C-C double bond and the carbon atoms can only be part of one C-C double bond. If in an alkyl group as defined above having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenyl group is formed.

[0588] Examples of alkenyl groups are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylene-propyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hex-1,3-dienyl, hex-1,4-dienyl, pent-1,4-dienyl, pent-1,3-dienyl, but-1,3-dienyl, 2,3-dimethylbut-1,3-diene, and the like.

[0589] Without any further definition, the general terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, and the like mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propenyl includes prop-1 -enyl and prop-2-enyl, butenyl includes but-1 -enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1 -enyl, 1-methyl-prop-2-enyl, and the like.

[0590] With regard to one or more double bonds, alkenyl groups can optionally be present in cis or trans or E or Z orientation.

[0591] When alkenyl is part of another (combined) group, for example like in C x-y Alkenylamino or C x-y Alkenyloxy, the above definitions for alkenyl apply.

[0592] Unlike alkylene groups, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are connected together by a C-C double bond, and the carbon atoms can only be part of one C-C double bond. If in an alkylene group as defined above having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valences are saturated by forming a second bond, the corresponding alkenylene group is formed.

[0593] Examples of alkenylene are ethenylene, propenylene, 1-methyl-ethenylene, butenylene, 1-methyl-propenylene, 1,1-dimethyl-ethenylene, 1,2-dimethyl-ethenylene, pentenylene, 1,1-dimethyl-propenylene, 2,2-dimethyl-propenylene, 1,2-dimethyl-propenylene, 1,3-dimethyl-propenylene, hexenylene and the like.

[0594] Without any further definition, the general terms propenylene, butenylene, pentenylene, hexenylene and the like are meant to include all conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methyl-ethenylene and butenylene includes 1-methyl-propenylene, 2-methyl-propenylene, 1,1-dimethyl-ethenylene and 1,2-dimethyl-ethenylene.

[0595] With regard to one or more double bonds, alkenylene can optionally be present in cis or trans or E or Z orientation.

[0596] When alkenylene is part of another (combined) group as for example in HO-C x-y alkenyleneamino or H2N-C x-y alkenyleneoxy, the above definitions for alkenylene apply.

[0597] Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C triple bond. If in an alkyl group as defined above having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and free valences are saturated by forming two additional bonds in each case, the corresponding alkinyl group is formed.

[0598] Examples of alkinyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl and the like.

[0599] Without any further definition, the general terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are meant to include all conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl and the like.

[0600] If the hydrocarbon chain carries at least one double bond and at least one triple bond, it belongs by definition to the sub-group of alkinyl groups.

[0601] If the alkynyl group is part of another (combined) group as for example in C x-y alkynylamino or C x-y alkynyloxy, the above definition for alkynyl also applies.

[0602] Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C triple bond. If in an alkynylene group as defined above having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms in each case are formally removed and free valences are saturated by forming two further bonds, the corresponding alkinylene group is formed.

[0603] Examples of alkinylene groups are ethynylene, propynylene, 1-methyl-ethynylene, butynylene, 1-methyl-propynylene, 1,1-dimethyl-ethynylene, 1,2-dimethyl-ethynylene, pentynylene, 1,1-dimethyl-propynylene, 2,2-dimethyl-propynylene, 1,2-dimethyl-propynylene, 1,3-dimethyl-propynylene, hexynylene, and the like.

[0604] Without any further definition, the general terms propynylene, butynylene, pentynylene, hexynylene, and the like mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propynylene includes 1-methyl-ethynylene, and butynylene includes 1-methyl-propynylene, 2-methyl-propynylene, 1,1-dimethyl-ethynylene, and 1,2-dimethyl-ethynylene.

[0605] If the alkinylene group is part of another (combined) group as for example in HO-C x-y alkynyleneamino or H2N-C x-y alkynyloxy, the above definition for alkynyl also applies.

[0606] heteroatom means oxygen, nitrogen and sulfur atoms.

[0607] haloalkyl (haloalkenyl, haloalkynyl) derived from the previously defined alkyl (alkenyl, alkynyl) groups by replacing one or more of the hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms which can be the same or different. If the halogenated alkyl (halogenated alkenyl, halogenated alkynyl) is to be further substituted, the substitution can take place independently of one another in each case in the form of a single substitution or multiple substitution on all carbon atoms carrying hydrogen.

[0608] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CC1=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, and the like.

[0609] From the previously defined haloalkyl (haloalkenyl, haloalkynyl), the term haloalkylidene (haloalkenylidene, haloalkynylidene) is also derived. haloalkylene (haloalkenylene, haloalkynylene) halogen Unlike haloalkyl (haloalkenyl, haloalkynyl), haloalkylidene (haloalkenylidene, haloalkynylidene) is divalent and requires two binding partners. Formally, the second valence is formed by removing a hydrogen atom from haloalkyl (haloalkenyl, haloalkynyl).

[0610] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F and the like.

[0611] The above definitions also apply if the corresponding halogen-containing group is part of another (combined) group.

[0612] cycloalkyl Refers to a fluorine, chlorine, bromine and / or iodine atom.

[0613] alicyclic Consists of the subgroups monocyclic cycloalkyl, bicyclic cycloalkyl and spiro-cycloalkyl. The ring system is saturated and formed by connected carbon atoms. In bicyclic cycloalkyl, two rings are connected together such that they have at least two carbon atoms in common. In spiro-cycloalkyl, one carbon atom (spiro atom) belongs to both rings.

[0614] If a cycloalkyl is to be substituted, the substitution can take place on all carbon atoms carrying hydrogen, in each case independently of one another, in the form of a single substitution or multiple substitution. The cycloalkyl group itself can be connected to the molecule via each suitable position of the ring system as a substituent.

[0615] Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl and the like.

[0616] If the cycloalkyl group is part of another (combined) group as for example in C x-y cycloalkylamino, C x-y cycloalkyloxy or C x-y cycloalkylalkyl, then the above definitions for cycloalkyl apply.

[0617] If the free valence of the cycloalkyl group is saturated, then cycloalkylene .

[0618] Thus, the term cycloalkenyl can be derived from the previously defined cycloalkyl group. Unlike cycloalkyl, cycloalkylene is divalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from the cycloalkyl group. Corresponding groups are for example:

[0619] cyclohexyl and cyclohexylene.

[0620] If the cycloalkylene group is part of another (combined) group as for example in HO- C x-y cycloalkyleneamino or H2N-C x-y cycloalkylenoxy, then the above definitions for cycloalkylene apply.

[0621] unsaturated alicyclic consists of the subgroups monocyclic cycloalkenyl, bicyclic cycloalkenyl and spiro-cycloalkenyl. However, the system is unsaturated, i.e. there is at least one C-C double bond but no aromatic system. If in the cycloalkyl group as defined above, two hydrogen atoms on adjacent ring carbon atoms are formally removed and the free valences are saturated to form a second bond, then the corresponding cycloalkenyl group is obtained.

[0622] If the cycloalkenyl group is to be substituted, the substitution can occur on all carbon atoms carrying hydrogen, in each case in the form of a single substitution or multiple substitution, independently of one another. The cycloalkenyl group itself can be connected to the molecule as a substituent via each suitable position of the ring system.

[0623] Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobut-1,3-dienyl, cyclopent-1,4-dienyl, cyclopent-1,3-dienyl, cyclopent-2,4-dienyl, cyclohex-1,3-dienyl, cyclohex-1,5-dienyl, cyclohex-2,4-dienyl, cyclohex-1,4-dienyl, cyclohex-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborn-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl and the like.

[0624] When cycloalkenyl is part of another (combined) group as for example in C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C x-y Cycloalkylalkyl, C

[0625] If the free valence of cycloalkenyl is saturated, then cycloalkenylene .

[0626] Thus, the term aryl may be derived from a cycloalkenyl group as defined previously. Unlike cycloalkenyl, cycloalkenylene is divalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a cycloalkenyl group. Corresponding groups are for example:

[0627] Cyclopentenyl and cyclopentenylene) and the like.

[0628] If cycloalkenylene is part of another (combined) group as for example in HO-C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C

[0629] aromatic group denotes a monocyclic, bicyclic or tricyclic carbocyclic ring having at least one aromatic carbon ring. Preferably, it denotes a monocyclic group having six carbon atoms (phenyl) 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 can also be aromatic but can also be partially saturated.

[0630] If an aryl group is to be replaced, the substitution can take place on all carbon atoms carrying hydrogen independently of one another in each case in the form of a single substitution or multiple substitution. The aryl group itself can be attached as a substituent to the molecule via every suitable position of the ring system.

[0631] Examples of aryl groups are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthryl, phenanthryl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, naphthindyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl and the like. Most preferred is phenyl.

[0632] If the aryl group is part of another (combined) group as for example in arylamino, aryloxy or arylalkyl, the above definition for aryl also applies.

[0633] If the free valence of the aryl group is saturated, one obtains arylene .

[0634] The term heterocyclic can also be derived from the previously defined aryl groups. Unlike aryl groups, arylene groups are divalent and require two binding partners. Formally, the second valence is formed by removing a hydrogen atom from an aryl group. Corresponding groups are for example:

[0635] phenyl and (ortho, meta, para-phenylene),

[0636] naphthyl and and the like.

[0637] If the arylene group is part of another (combined) group as for example in HO-aryleneamino or H2N-arylenoxy, the above definition for arylene also applies.

[0638] heterocycle denotes a ring system which is derived from the previously defined cycloalkyl, cycloalkenyl and aryl groups by replacing one or more groups -CH2- in the hydrocarbon ring independently of one another by a group -O-, -S- or -NH- or by replacing one or more groups =CH- by a group =N-, wherein a total of not more than five heteroatoms can be present, there must be at least one carbon atom between two oxygen atoms and between two sulfur atoms or between an oxygen and a sulfur atom, and the ring as a whole must have chemical stability. The heteroatoms can optionally be present in all possible stages of oxidation (sulfur -> sulfoxide -SO-, sulfone -SO2-; nitrogen -> N-oxide). In the heterocyclyl group heterocyclyl there is a heteroaromatic ring, i.e. no heteroatom is part of the aromatic system.

[0639] A direct consequence of the derivation from cycloalkyl, cycloalkenyl and aryl groups is that the heterocyclyl group consists of the subgroups monocyclic heterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl and spiroheterocyclyl, which can exist in saturated or unsaturated form.

[0640] Unsaturated means that there is at least one double bond present in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterocyclyl, two rings are connected together such that they have at least two common (hetero)atoms. In spiroheterocyclyl, one carbon atom (spiro atom) is common to both rings.

[0641] If substituted heterocyclyl, the substitution can occur independently of one another in each case in the form of a single substitution or multiple substitution on all carbon atoms and / or nitrogen atoms carrying hydrogen. The heterocyclyl group itself can be attached to the molecule via each suitable position of the ring system as a substituent. Substituents on the heterocyclyl group are not counted as members of the heterocyclyl group.

[0642] Examples of heterocyclyl are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazetidinyl, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[5.1.0]octanyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 1-aza-bicyclo[2.2.2]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,9-diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl, 1,4-dioxa-spiro[4.5]decanyl, 1-oxa-3,8-diaza-spiro[4.5]decanyl, 2,6-diaza-spiro[3.3]heptanyl, 2,7-diaza-spiro[4.4]nonanyl, 2,6-diaza-spiro[3.4]octanyl, 3,9-diaza-spiro[5.5]undecanyl, 2.8-diaza-spiro[4,5]decanyl and the like.

[0643] Other examples are the structures shown below, which can be attached via each hydrogen carrying atom (hydrogen exchange):

[0644]

[0645]

[0646]

[0647] Preferably, the monocyclic heterocyclyl group is 4- to 7-membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0648] Preferred monocyclic heterocyclyl groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl and azetidinyl.

[0649] Preferred bicyclic heterocyclyl groups are 6- to 10-membered and have one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0650] Preferred tricyclic heterocyclyl groups are 9-membered and have one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0651] Preferred spiro heterocyclyl groups are 7- to 11-membered and have one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0652] If the heterocyclyl group is part of another (combined) group as for example in heterocyclyl amino, heterocyclyl oxy or heterocyclyl alkyl, the above definition of the heterocyclyl group also applies.

[0653] If the free valence of the heterocyclyl group is saturated, one obtains heteroaryl .

[0654] The term heteroaromatic group is also derived from the previously defined heterocyclyl groups. Unlike the heterocyclyl group, the heterocyclyl ene group is divalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from the heterocyclyl group. Corresponding groups are for example:

[0655] piperidinyl and

[0656] 2,3-dihydro-lH-pyrrolyl and and the like.

[0657] If the heterocyclyl ene group is part of another (combined) group as for example in HO-heterocyclyl ene amino or H2N-heterocyclyl ene oxy, the above definition of the heterocyclyl ene group also applies.

[0658] heteroarylenemonocyclic heteroaromatic ring or a polycyclic ring having at least one heteroaromatic ring, which, compared to the corresponding aryl or cycloalkyl (cycloalkenyl), contains one or more identical or different heteroatoms instead of one or more carbon atoms, which heteroatoms are independently of one another selected from the group consisting of nitrogen, sulfur and oxygen, wherein the resulting group must be chemically stable. A prerequisite for the presence of a heteroaryl group is a heteroatom and a heteroaromatic system.

[0659] If a heteroaryl group is to be substituted, the substitution can occur in each case in the form of a single substitution or multiple substitution, independently of one another, on all carbon atoms and / or nitrogen atoms carrying hydrogen. The heteroaryl group itself can be attached as a substituent to the molecule via every suitable position (both carbon and nitrogen) of the ring system. Substituents on the heteroaryl group are not counted as members of the heteroaryl group.

[0660] Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolyl, indazolyl, isoquinolyl, quinolyl, quinoxalyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthylridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazothiazolyl, quinolyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzoimidazolyl-N-oxide and the like.

[0661] Further examples are the structures shown below, which can be attached via every atom carrying hydrogen (hydrogen exchange):

[0662]

[0663]

[0664] Preferably, the heteroaryl group is a 5-6 membered monocyclic or 9-10 membered bicyclic ring, each having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0665] If the heteroaryl group is part of another (combined) group as for example in heteroarylamino, heteroaryloxy or heteroarylalkyl, the above definition of heteroaryl also applies.

[0666] If the free valence of the heteroaryl group is saturated, one obtains substituted .

[0667] The term stereochemistry / solvate / hydrate: is also derived from the previously defined heteroaryl groups. In contrast to heteroaryl groups, heteroarylenes are divalent and require two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a heteroaryl group. Corresponding groups are for example:

[0668] pyrrolyl and and the like.

[0669] If the heteroarylene group is part of another (combined) group as for example in HO-heteroarylenamino or H2N-heteroarylenoxy, the above definition of heteroarylene also applies.

[0670] salts is meant that a hydrogen atom which is directly bound to the atom in question is replaced by another atom or another atom group (substituent). Depending on the starting conditions (number of hydrogen atoms), mono- or polysubstitution can occur on one atom. Only if the substituent and the allowed valence of the atom to be substituted correspond to each other and the substitution leads to a stable compound (i.e. a compound which does not spontaneously transform, for example, by rearrangement, cyclization or elimination), substitution with a particular substituent is possible.

[0671] A divalent substituent such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2or the like can only be a substituent on a carbon atom, while the divalent substituents =O and =NR can also be substituents on sulfur. In general, substitution can take place by a divalent substituent on the ring system and requires the replacement of two geminal hydrogen atoms, i.e. the hydrogen atoms which are bound to the same carbon atom before the substitution is saturated. Thus, substitution by a divalent substituent is only possible at a -CH2- or sulfur atom group of the ring system (only =O groups or =NR groups, possibly one or two =O groups or for example one =O group and one =NR group, each group replacing a pair of free electrons).

[0672] preparation of compounds according to the inventionUnless explicitly indicated otherwise, throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereoisomers and all tautomers (for example, enol and keto tautomers) of the structure unless otherwise indicated. It is intended that the description herein adequately disclose the scope of the invention and will enable others skilled in the art to use the invention in such, although the preferred embodiments of the invention contemplate the use of the compounds in the form of the racemate, single enantiomers, or a mixture of enantiomers, or as individual diastereomers, or mixtures of diastereomers, or as individual tautomers, or mixtures of tautomers, or as racemic mixtures, or as pure or partially purified compounds. The chemical formulas, names, and structures herein are intended to encompass all such isomeric forms of the illustrated compounds.

[0673] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to the person skilled in the art, for example by separation of the corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, for example starting from optically active starting materials and / or by using chiral reagents.

[0674] Enantiomerically pure compounds or intermediates of the present application can be prepared by asymmetric synthesis, for example by preparing and subsequently separating appropriate diastereomeric compounds or intermediates, which can be separated by known methods (for example, by chromatographic separation or crystallization) and / or by using chiral reagents (such as chiral starting materials, chiral catalysts or chiral auxiliaries).

[0675] Furthermore, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases or by resolution of the racemic mixtures using appropriate resolving agents, such as by means of diastereomeric salt formation of the racemic compounds with optically active acids or bases, subsequent separation of the salts and release of the desired compounds from the salts and by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomeric separation and removal of the chiral auxiliary group, or by kinetic resolution of the racemates (for example, by enzymatic resolution); by enantioselective crystallization from conglomerates of enantiopure crystals under suitable conditions or by (fractionated) crystallization from suitable solvents in the presence of optically active chiral auxiliary reagents.

[0676] experimental procedure for the synthesis of a-2a The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0677] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The ions of the pharmaceutically acceptable salts include, but are not limited to, inorganic acids salts or organic acids salts of basic residues such as amines; alkali salts or organic salts of acidic residues such as carboxylic acids; and the like.

[0678] For example, such salts include salts from benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gentisic, hydrobromic, hydrochloric, maleic, malic, malonic, mandelic, methanesulfonic, 4-methyl- benzenesulfonic, phosphoric, salicylic, succinic, sulfuric, and tartaric acids.

[0679] Other pharmaceutically acceptable salts can be formed from cations from ammonium, L-arginate, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0680] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0681] Salts of other acids (for example, trifluoroacetate) useful in the purification or isolation of the compounds of the present application, in addition to those described above, also form part of the present application.

[0682] In the illustrations, for example, like the following

[0683]

[0684] The letter A has the ring designation function in order to more easily indicate, for example, the attachment of the ring in question to other rings.

[0685] For divalent radicals, where it is essential to determine which adjacent radicals they are bound to and with which valency, the respective binding partners are indicated in parentheses for the purpose of clarification, as in the following illustration:

[0686] or (R 2 )-C(=O)NH- or (R 2 )-NHC(=O)-.

[0687] If such a specification is missing, the divalent radical can bind in both directions, i.e., for example, -C(=O)NH- also includes -NHC(=O)- (and vice versa).

[0688] Groups or substituents are generally selected from a number of alternative groups / substituents having the corresponding group designation (e.g., R a , R b , etc.). If such groups are repeatedly used to define compounds according to the application in different parts of the molecule, it should be noted that the various uses are considered to be completely independent of each other.

[0689] For the purposes of the present application, a therapeutically effective amount means the amount of substance which is capable of eliminating the symptoms of the illness or preventing or alleviating these symptoms, or prolonging the survival of the patient being treated.

[0690] Ras family proteins as used herein are meant to include KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey rat sarcoma viral oncogene) and any mutants thereof.

[0691] RAS G12C inhibitors as used herein refer to compounds which bind one or more of the following: G12C mutant RAS proteins KRAS G12C (= KRAS G12C inhibitor), NRAS G12C (= NRAS G12C inhibitor) and / or HRAS G12C (= HRAS G12C inhibitor), in particular KRAS G12C; and are capable of down-regulating or inhibiting the full or partial enzymatic activity of KRAS G12C and / or NRAS G12C and / or HRAS G12C, in particular KRAS G12C. While not wishing to be bound by theory, it is believed that the compounds of the present application can react selectively with KRAS G12C and / or HRAS G12C and / or NRAS G12C proteins, preferably with KRAS G12C, by forming a covalent bond with the cysteine at position 12 of KRAS G12C and / or HRAS G12C and / or NRAS G12C, preferably KRAS G12C, resulting in the modulation / inhibition of the enzymatic activity of said mutant Ras proteins.

[0692] List of abbreviations

[0693]

[0694]

[0695]

[0696] Examples

[0697] The features and advantages of the present application will become apparent from the detailed description of the application in which:

[0698] experimental procedure for the synthesis of a-3a

[0699] General

[0700] All reactions are carried out in a manner that is customary in the chemical laboratory, unless stated otherwise, using methods that are generally used in chemical laboratories. Starting materials that are sensitive to air and / or moisture are stored under protective gas and the corresponding reactions and manipulations using them are carried out under protective gas (nitrogen or argon).

[0701] If a compound can be represented by both a structural formula and a nomenclature thereof, the structural formula is determinative.

[0702] Microwave reactions are carried out in sealed vessels (preferably 2, 5 or 20 mL) in an Initiator / reactor made by Biotage or in a Discover made by CEM or in a Synthos 3000 or Monowave 3000 made by Anton Paar, preferably under stirring.

[0703] Chromatography

[0704] Thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescent indicator F-254) made by Merck.

[0705] Preparative high pressure chromatography (RP HPLC) of the compounds according to embodiments of the present application is carried out on Agilent or Gilson systems with columns made by Waters (name: SunFire Prep C18, OBD, 10 pm, 50 x 150 mm) and by YMC (name: Actus-Triart Prep C18, 5 pm, 30 x 50 mm). TM Preparative C18, OBD TM 10 pm, 50 x 150 mm or SunFire Prep C18, OBD, 10 pm, 50 x 150 mm TM Preparative C18 OBD TM 5 pm, 30 x 50 mm or XBridge Prep C18 OBD, 5 pm, 30 x 50 mm TM Preparative C18, OBD TM 10 pm, 50 x 150 mm or XBridge Prep C18, OBD, 10 pm, 50 x 150 mm TM Preparative C18, OBD TM 5 pm, 30 x 150 mm or XBridge Prep C18 OBD, 5 pm, 30 x 150 mm TM Preparative C18, OBD TM 5 pm, 30 x 50 mm) and by YMC (name: Actus-Triart Prep C18, 5 pm, 30 x 50 mm).

[0706] Compounds were eluted using different H2O / acetonitrile gradients, for the Agilent system, 5% acidic 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.

[0707] For chromatography under basic conditions, for the Agilent system, also H2O / acetonitrile gradients were used, while the water was made basic by adding 5% basic modifier (50 g NH4HCO3 + 50 mL NH3 (25% in H2O) to 1 L (with H2O)). For the Gilson system, the water was made basic as follows: 5 mL NH4HCO3 solution (158 g in 1 L H2O) and 2 mL NH3 (28% in H2O) were made up to 1 L with H2O.

[0708] Supercritical fluid chromatography (SFC) of intermediates and example compounds according to the application was performed on a JASCO SFC system with the following columns: Chiralcel OJ (250x20 mm, 5 pm), Chiralpak AD (250x20 mm, 5 pm), Chiralpak AS (250x20 mm, 5 pm), Chiralpak IC (250x20 mm, 5 pm), Chiralpak IA (250x20 mm, 5 pm), Chiralcel OJ (250x20 mm, 5 pm), Chiralcel OD (250x20 mm, 5 pm), Phenomenex Lux C2 (250x20 mm, 5 pm).

[0709] Analytical HPLC (reaction control) of intermediates and final compounds was performed using columns manufactured by Waters (name: XBridge C18, 2.5 pm, 2.1 x 20 mm or XBridge C18, 2.5 pm, 2.1 x 30 mm) and by YMC (name: Triart C18, 3.0 pm, 2.0 x 30 mm) and by Phenomenex (name: Luna C18, 5.0 pm, 2.0 x 30 mm). The analytical equipment was also equipped with a mass detector in each case. TM C18, 2.5 pm, 2.1 x 20 mm or XBridge C18, 2.5 pm, 2.1 x 30 mm) and by YMC (name: Triart C18, 3.0 pm, 2.0 x 30 mm) and by Phenomenex (name: Luna C18, 5.0 pm, 2.0 x 30 mm). The analytical equipment was also equipped with a mass detector in each case. TM C18, 2.5 pm, 2.1 x 20 mm or XBridge C18, 2.5 pm, 2.1 x 30 mm) and by YMC (name: Triart C18, 3.0 pm, 2.0 x 30 mm) and by Phenomenex (name: Luna C18, 5.0 pm, 2.0 x 30 mm). The analytical equipment was also equipped with a mass detector in each case.

[0710] HPLC-mass spectrometry / UV-spectrometry

[0711] Retention time / MS-ESI for characterizing example compounds according to the application +Produced using HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds eluting at the injection peak gave a retention time t Ret. = 0.00.

[0712] SFC - Method (Preparative)

[0713] Preparative SFC was performed in a Waters Thar SFC 80 system

[0714]

[0715] HPLC - Method (Analytical)

[0716] Method A

[0717] Samples were analysed on an Agilent 1200 series LC system coupled to an Agilent 6140 mass spectrometer. Purity was determined by UV detection over the range 230-400 nm with a 170 nm bandwidth. LC parameters were as follows:

[0718]

[0719] Method B

[0720]

[0721]

[0722] Method C

[0723]

[0724] Method D

[0725]

[0726] Method E

[0727]

[0728]

[0729] Method F

[0730]

[0731] Method G

[0732]

[0733] The compounds and intermediates according to the application are prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. These methods are intended to illustrate the application rather than limit the subject matter and scope of the compounds claimed for these examples. In cases where the preparation of starting compounds is not described, they are commercially available or their synthesis is described in the prior art or they can be prepared analogously to known prior art compounds or 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 synthesis methods. If the chemical structures depicted below do not have the exact configuration of a stereocenter, e.g. an asymmetrically substituted carbon atom, both configurations are to be considered as included and disclosed in such a depiction. Depictions of stereocenters in racemic form are always to be considered as including and disclosing both enantiomers (if no other defined stereocenters are present) or all other potential diastereomers and enantiomers (if further defined or undefined stereocenters are present).

[0734] General reaction scheme and synthesis routes to produce compounds (I) according to the application

[0735] Scheme 1:

[0736]

[0737] experimental procedure for the synthesis of a-4a

[0738]

[0739] To a suspension of sodium hydride (60% in mineral oil, 25.85 g, 646.3 mmol, 1.1 eq.) in THF (2.0 L) was added dropwise A-1a (93.46 mL, 587.5 mmol, 1.0 eq.) at 0-10 °C. The mixture was stirred at 10 °C for 30 min, then iodomethane (55.11 mL, 881.3 mmol, 1.5 eq.) was added dropwise to the mixture 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 saturated aqueous ammonium chloride solution. The product was extracted with EtOAc, and the organic layer was 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.

[0740] The following intermediates A-2 (Table 1) can be obtained in an analogous manner using different cyclic beta-keto esters A-1. If necessary, the crude product A-2 is purified by chromatography.

[0741] Table 1

[0742]

[0743] experimental procedure for the synthesis of a-4d

[0744]

[0745] To a solution of A-2a (108.00 g, 586.2 mmol) in toluene (1.03 L) was added malononitrile (58.04 g, 879.3 mmol, 1.5 eq.) followed by ammonium acetate (9.04 g, 117.2 mmol, 0.2 eq.) and acetic acid (13.41 mL, 234.5 mmol, 0.4 eq.) at room temperature. The mixture was stirred at 110 °C for 16 h. After complete conversion, the mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give crude product A-3a. This crude material was used for the next step without further purification (see also Naumann et al., Pharmazie 51 (1996), 4).

[0746] The following intermediates A-3 (Table 2) can be obtained in an analogous manner using different intermediates A-2. If necessary, the crude product A-3 is purified by chromatography.

[0747] Table 2

[0748]

[0749] experimental procedure for the synthesis of a-5a

[0750]

[0751] To a solution of A-3a (250.0 g, 1.1 mol) in DMF (3.0 L) was added sulfur (68.9 g, 2.2 mol, 2.0 eq.) and L-proline (24.8 g, 0.22 mol, 0.2 eq.) and the resulting mixture was stirred at 80 °C for 12 h. 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 crude product. The crude product was purified by column chromatography to give A-4a.

[0752] The following intermediates A-4 (Table 3) can be obtained in an analogous manner using different intermediates A-3. If necessary, the crude product A-4 is purified by chromatography.

[0753] Table 3:

[0754]

[0755]

[0756] experimental procedure for the synthesis of e-2a

[0757]

[0758] A stirred solution of A-la (12.00 g, 70.5 mmol) in EtOH (60.0 mL) was treated with sulfur (2.26 g, 70.5 mmol, 1.00 eq.), morpholine (6.14 g, 70.5 mmol, 1.0 eq.) and malononitrile (4.66 g, 70.5 mmol, 1.0 eq.). The reaction mixture was then stirred at 55 °C for 1 h. After complete conversion, the reaction mixture was concentrated, diluted with water, extracted with EtOAc and the extract was dried, filtered and concentrated under reduced pressure to give the crude product. This crude material was purified by column chromatography (20-30% EtOH in hexane) to give A-4d. (HPLC Method A; tR= 1.10 min; [M+H] ret = 251). +

[0759] experimental procedure for the synthesis of e-2b

[0760]

[0761] A-4a (78.0 mg, 0.3 mmol, 1.0 eq.) was dissolved in EtOH (1.5 mL) and potassium hydroxide (4 M in water, 0.37 mL, 1.5 mmol, 5.0 eq.) was added. The mixture was stirred at 78 °C for 16 h. After complete conversion, water and EtOAc were added to the mixture, the pH of the aqueous phase was set to pH 4 using a KHSO4solution (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 acidic reverse phase chromatography (gradient elution: 20% to 90% acetonitrile in water) to give A-5a.

[0762] The following intermediates A-5 (Table 4) can be obtained in a similar manner using different esters A-4. If necessary, the crude product A-5 is purified by chromatography, the enantiomers can be separated using preparative SFC chromatography as described herein, for example A-5a and A-5b and their enantiomers.

[0763] Table 4

[0764]

[0765]

[0766] Scheme 2a: ​

[0767]

[0768] Scheme 2b:

[0769]

[0770] experimental procedure for the synthesis of e-4a (method a)

[0771]

[0772] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)-ethan-1-ol (1.441 g, 11.15 mmol, 1.0 eq.) in DMSO was added DIPEA (2.882 g, 22.3 mmol, 2.0 eq.) and the mixture was cooled to 10 °C. E-1a (2.0 g, 11.15 mmol, 97% purity, 1.0 eq.) was added and the mixture was stirred at 10 °C for 45 min. The mixture was filtered and the filtrate was purified by basic reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give E-2a. (HPLC Method A; tR= 1.36 min; [M+H]+= 267). ret + = 267).

[0773] Additional intermediates E-2 can be obtained in a similar manner. If desired, the crude product E-2 can be purified by chromatography.

[0774] experimental procedure for the synthesis of e-4b (method b)

[0775]

[0776] 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 a glass frit, which was then washed with EtOAc. The solvent was removed by freeze-drying. The residue was purified by normal phase chromatography (gradient elution: 0% to 20% MeOH in DCM) to give E-2b.

[0777] The following intermediates E-2 (Table 5) can be obtained in a similar manner. If desired, the crude product E-2 is purified by chromatography.

[0778] Table 5

[0779]

[0780] experimental procedure for the synthesis of e-4c (method c) ​

[0781]

[0782] tert-Butyl 4-hydroxypiperidine-l-carboxylate (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 h. The reaction mixture was extracted from water into EtOAc and the organic phase was dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by basic reverse phase chromatography (gradient elution: 45% to 98% acetonitrile in water) to give E-4a.

[0783] experimental procedure for the synthesis of e-4d (method d)

[0784]

[0785] To a stirred solution of E-1b (5.00 g, 28.90 mmol) in DMSO (50.0 mL) was added tert-butyl piperazine-1 -carboxylate (5.92 g, 31.79 mmol, 1.1 eq.). DIPEA (11.21 g, 86.71 mmol, 3.0 eq.) was then added and the reaction mixture was stirred at 60 °C for 1 h. After complete conversion, the mixture was dissolved in EtOAc and washed with water (3x). 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.

[0786] experimental procedure for the synthesis of e-4e (method e)

[0787]

[0788] To a stirred solution of E-1c (10.20 g, 57.22 mmol) in DCM (60.0 mL) was added tert-butyl piperazine-1 -carboxylate (11.22 g, 57.22 mmol, 1.0 eq.). DIPEA (20.71 g, 160.21 mmol, 2.8 eq.) was then added and the reaction mixture was stirred at 60 °C for 1 h. After complete conversion, the mixture was dissolved in EtOAc and washed with water (3x). 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.

[0789] experimental procedure for the synthesis of e-6a

[0790]

[0791] N-(2-hydroxyethyl)-N-methylcarbamate tert-butyl ester (171 mg, 0.95 mmol, 1.1 eq.) was added to a stirred mixture of sodium hydride (22.8 mg, 0.95 mmol, 1.1 eq.) and THF (2 mL) under argon atmosphere, and the mixture was stirred for 5 min. E-1c (150 mg, 0.86 mmol, 1.0 eq.) was added, and the mixture was stirred for 1 h. The reaction was 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.

[0792] experimental procedure for the synthesis of e-6d

[0793]

[0794] E-1d (1.00 g, 6.62 mmol), tert-butyl piperazine-1-carboxylate (724.6 mg, 3.70 mmol, 0.8 eq.), sodium tert-butoxide (915.4 mg, 9.24 mmol, 2.0 eq.), 2-(di-tert-butylphosphino)biphenyl (275.7 mg, 0.92 mmol, 0.20 eq.), and tris(dibenzylacetone)palladium(0) (211.5 mg, 0.23 mmol, 0.05 eq.) were combined in anhydrous dioxane (9.00 mL) and the mixture was stirred at room temperature for 1 h. After complete conversion, the mixture was concentrated, diluted with water, and the product was extracted with DCM. The combined organic layers were dried, filtered, and concentrated. The crude product was purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to give E-4e.

[0795] According to methods A through E, the following (additional) intermediate E-4 can be obtained in a similar manner using different amines PG-LH and intermediate E-1 (Table 6). If necessary, the crude product E-4 can be purified by chromatography.

[0796] Table 6

[0797]

[0798]

[0799]

[0800]

[0801]

[0802] experimental procedure for the synthesis of e-6f

[0803]

[0804] E-1b (500 mg, 2.83 mmol, 1.0 eq.) and cesium fluoride (1.72 g, 11.33 mmol, 4.0 eq.) 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 solution of E-5a in DMA.

[0805] To a solution of (S)-tert-butyl 3-hydroxy-pyrrolidine-1-carboxylate (531 mg, 187.24 mmol, 1.0 eq.) in THF (5 mL) was added sodium hydride (158 mg, 3.97 mmol, 1.4 eq.) and the mixture was stirred for 30 min. This mixture was slowly added to a freshly prepared solution of E-5a (397 mg, 140.09 mmol, 1.0 eq.) in DMA and stirred for 5 min before water and EtOAc were added. The phases were separated and the aqueous phase was extracted twice with EtOAc (30 mL). The combined organic layers were dried over MgS04, filtered and the solvent was evaporated. The mixture was dissolved in acetonitrile and water and purified by acidic reverse phase chromatography to obtain the desired product E-6a.

[0806] The following intermediates E-6 (Table 7) can be obtained in a similar manner. If necessary, the crude product E-7 is purified by chromatography.

[0807] Table 7

[0808]

[0809] experimental procedure for the synthesis of g-2a

[0810]

[0811] E-1b (267 mg, 1.54 mmol, 1.0 eq.) and cesium fluoride (937 mg, 6.17 mmol, 4.0 eq.) 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 solution of E-5a in DMA. tert-Butyl 5,8-diazaspiro[3.5]nonane-4-carboxylate (349 mg, 1.54 mmol, 1.0 eq.) and DIPEA (0.667 mL, 3.86 mmol, 2.5 eq.) were added to the mixture and stirred at 60 °C for 30 min. The mixture was filtered and the filtrate was purified by basic reverse phase chromatography to obtain the desired product E-6d.

[0812] The following intermediates E-6 (Table 8) can be obtained in a similar manner. If necessary, the crude product E-6 is purified by chromatography.

[0813] Table 8

[0814]

[0815] experimental procedure for the synthesis of g-3a

[0816]

[0817] Intermediate E-4ap (60 mg, 0.19 mmol, 1.0 eq.) and cesium fluoride (56 mg, 0.37 mmol, 2.0 eq.) were dissolved in DMSO (2 mL) and stirred at 80 °C overnight and cooled to room temperature. Additional cesium fluoride (56 mg, 0.37 mmol, 2.0 eq.) 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 acidic reverse phase chromatography to yield the desired product E-6f.

[0818] The following intermediates E-6 (Table 9) can be obtained from other intermediates E-4 in a similar manner. If necessary, the crude product E-6 is purified by chromatography.

[0819] Table 9

[0820]

[0821] Various synthetic blocks H-R 5 of synthesis

[0822]

[0823] experimental procedure for the synthesis of g-4a (method f)

[0824] G-1a (500 mg, 2.33 mmol) was dissolved in dry THF (5.00 mL) with triethylamine (485 μL, 3.5 mmol, 1.5 eq.) and the mixture was cooled to 0 °C. Benzyl chloroformate (519 μL, 3.5 mmol, 1.5 eq.) was added portionwise and the mixture was stirred for 2 h and allowed to reach room temperature overnight. After complete conversion, water was added to the mixture and the product was extracted with DCM and the combined extracts were dried, 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).

[0825] experimental procedure for the synthesis of g-4b (method g)

[0826] G-2a (813 mg, 2.33 mmol) was dissolved in DCM (25.00 mL) and treated with HCI (4 M in dioxane, 11.67 mL, 46.66 mmol, 20.0 eq.). The mixture was stirred at room temperature for 2 h. After complete conversion, the mixture was concentrated and the product was isolated by basic reverse phase chromatography (gradient elution: 10% to 70% acetonitrile in water). (HPLC Method B, t 停留 = 0.478 min, [M+H] + = 249).

[0827] experimental procedure for the synthesis of g-5a

[0828]

[0829] G-3a (4.0 g, 16.12 mmol) was dissolved in dry DCM (50.00 mL) and treated with formaldehyde (37% in water, 1.21 mL, 16.12 mmol, 1.00 eq.) and acetic acid (92 μί, 1.61 mmol, 0.10 eq.). The mixture was stirred for 15 min, then sodium triacetoxyborohydride (6.335 g, 29.00 mmol, 1.80 eq.) 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 and the combined extracts were dried, filtered and concentrated. The crude product was purified by normal phase chromatography (DCM / MeOH).

[0830] experimental procedure for the synthesis of g-7a

[0831]

[0832] To a stirred solution of G-3a (250.0 mg, 1.00 mmol) in dry DMF (5.00 mL) was added K2CO3 (0.303 g, 2.51 mmol, 2.50 eq.) followed by 1-bromo-2-methoxy-ethane (0.122 g, 1.00 mmol, 1.00 eq.). The reaction mixture was stirred at 80 °C for 16 h. After complete conversion, water was added to the mixture and the product was extracted with EtOAc and the combined extracts were dried, filtered and concentrated. The crude product was purified by normal phase chromatography (DCM / MeOH).

[0833] The following (additional) intermediates G-4 (Table 10) can be obtained in an analogous manner according to Method F or Method G using G-3a and different aldehydes or ketones as alkylating agents. If necessary, the crude products G-4 can be purified by chromatography.

[0834] Table 10

[0835]

[0836] experimental procedure for the synthesis of e-10a

[0837]

[0838] G-5a (3.00 g, 11.44 mmol) was dissolved in MeOH (20.0 mL) and palladium (10% on carbon, 360 mg) was added. The mixture was stirred in a hydrogenation reactor at 5 bar of hydrogen pressure at room temperature for 16 h. After complete conversion, the catalyst was filtered off and the residue was concentrated. The crude product was used without purification in the following step.

[0839] The following intermediate G-5( Synthesis of building block H-R 5 Analogues G-4 with different substitutions can be obtained in a similar manner.

[0840] Table 11

[0841]

[0842]

[0843] experimental procedure for the synthesis of e-11a

[0844]

[0845] G-6a (590.0 mg, 2.49 mmol) was dissolved in dry THF (1.50 mL) and the mixture was cooled to 0°C. LiAlH4(2M in THF, 6.22 mL, 12.44 mmol, 5.00 eq.) was added dropwise and the mixture was stirred in a closed vessel at 70°C for 1.5 h. After complete conversion, the mixture was diluted with THF (15 mL), sodium potassium tartrate tetrahydrate was added slowly and the mixture was stirred at room temperature for 1.5 h. The mixture was filtered, the filtrate was concentrated and the crude product was used without purification in the following step.

[0846] The following intermediate G-7( Synthesis of building block H-R 5 Analogues G-6 with different substitutions can be obtained in a similar manner starting from the corresponding N-Boc-amino ketones G-5.

[0847] Table 12

[0848]

[0849] experimental procedure for the synthesis of e-8a

[0850]

[0851] A solution of piperazine-1-carboxylic acid tert-butyl ester (505 mg, 2.71 mmol; 1.0 eq.) in acetone (11 mL) was added to a solution of E-9a (500 mg, 2.71 mmol; 1.0 eq.) in acetone (6 mL). An aqueous solution of sodium bicarbonate (225.00 mg, 2.12 mmol; 0.78 eq.) in water (5 mL) was added, and the reaction was stirred at 0 °C for 3 h. The reaction mixture was filtered, 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).

[0852] experimental procedure for the synthesis of e-8b

[0853]

[0854] E-10a (1.04 g, 3.11 mmol, 1.0 eq.), (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (561.41 mg, 4.05 mmol, 1.3 eq.), and DIPEA (808.47 mg, 6.22 mmol, 2.0 eq.) were dissolved in anhydrous THF (12 mL) and stirred at room temperature for 3 h, followed by stirring at 40 °C for 1 h. The solvent was removed under vacuum, and the residue was purified by normal-phase chromatography (cyclohexane:EtOAc from 10:90 to 80:20) to obtain E-11a (HPLC method A, t ret = 1.54 min, [M+H] + =427).

[0855] experimental procedure for the synthesis of e-8d

[0856]

[0857] E-11a (898 mg, 1.68 mmol, 1.0 eq.) and sodium cyanide (329.85 mg, 6.73 mmol, 4.0 eq.) were dissolved in DMSO (5 mL) and stirred at 60 °C for 3 h. 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)

[0858] experimental procedure for the synthesis of e-8g (method a)

[0859]

[0860] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (792 mg, 6.13 mmol, 1.1 eq.) and DIPEA (1.94 mL, 11.15 mmol, 2 eq.) in DMSO (3 mL) was slowly added a solution of E-1a (1000 mg, 97% purity, 5.58 mmol, 1.0 eq.) in DMSO (3 mL). The mixture was stirred at room temperature for 30 min. After complete conversion was observed, (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.50 mg, 97% purity, 7.25 mmol, 1.3 eq.) and DIPEA (0.97 mL, 5.58 mmol, 1 eq.) were added to the mixture. The mixture was stirred at 60 °C for 60 min and DIPEA (0.97 mL, 5.58 mmol, 1 eq.) was added. The mixture was stirred at 70 °C for 50 min and at room temperature overnight. After complete conversion was observed, the reaction was diluted with water and DCM and the phases were separated. The aqueous phase was extracted with DCM (3x) and the organic phases were combined. The solvent was removed under vacuum to give the crude product E-8a. The crude product was dissolved in acetonitrile and water, filtered and purified by basic reverse phase chromatography (gradient elution: 35% to 95% acetonitrile in water) to give the desired purified product E-8b.

[0861] The following intermediates E-8 (Table 13) can be obtained in a similar manner without isolation of the corresponding intermediate E-2. If desired, the crude product E-8 is purified by chromatography.

[0862] Table 13

[0863]

[0864] experimental procedure for the synthesis of e-8h (method b)

[0865]

[0866] To a solution of E-1a (600 mg, 3.21 mmol, 93% purity, 1.0 eq.) in anhydrous DMSO (6 mL) was added cesium fluoride (1.218 g, 8.02 mmol, 2.5 eq.) and the resulting mixture was stirred at room temperature for 1 h 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-methylpyrrolidin-2-yl)ethan-1-ol (453 mg, 3.51 mmol, 1.1 eq.) and DIPEA (1.085 mL, 6.38 mmol, 2 eq.) was added. The mixture was stirred at room temperature for 1 h. After complete conversion of the starting material was observed, a solution of piperazine-1-carboxylic acid tert-butyl ester (674 mg, 3.51 mmol, 97% purity, 1.1. eq.) in anhydrous DMSO (3 mL) and DIPEA (1.085 mL, 6.38 mmol, 2 eq.) was added to the mixture. The mixture was stirred at room temperature for 30 min. After complete conversion was observed, the reaction was diluted with acetonitrile and water, filtered and purified by basic reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give the desired product E-8d.

[0867] The following intermediates E-8 (Table 14) can be obtained in a similar manner without isolating the corresponding intermediates E-5 and E-7, respectively. If desired, the crude product E-8 is purified by chromatography.

[0868] Table 14

[0869]

[0870]

[0871] experimental procedure for the synthesis of e-8i (method c)

[0872]

[0873] E-4f (50.0 mg, 0.148 mmol), G-5a (115 mg, 0.740 mmol, 5.0 eq.) and DIPEA (25.78 μL, 0.15 mmol, 1.0 eq.) were combined with anhydrous NMP (10 μL) and the mixture was stirred in a sealed vessel at 120 °C for 1 h. The product was isolated by basic reverse phase chromatography (gradient elution: 40% to 98% acetonitrile in water) to give E-8g.

[0874] The intermediates E-8 labeled as "A" (Table 15) can be obtained in a similar manner. If desired, the crude product E-8 is purified by chromatography.

[0875] experimental procedure for the synthesis of e-8j (method d)

[0876]

[0877] E-4e (400.0 mg, 1.24 mmol), N-methylpiperazine (352.1 mg, 3.48 mmol, 2.8 eq.), sodium tert-butoxide (246.3 mg, 2.49 mmol, 2.0 eq.), 2-(di-tert- butylphosphino)biphenyl (74.18 mg, 0.25 mmol, 0.20 eq.) and tris(dibenzylideneacetone)dipalladium(0) (56.9 mg, 0.062 mmol, 0.05 eq.) were combined in anhydrous dioxane (2.50 mL) and the mixture was stirred at 110 °C for 1 h. After complete conversion, the mixture was concentrated, diluted with water, the product was extracted with DCM and the combined organic layers were dried, filtered and concentrated. The crude product was purified by basic reverse-phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to afford E-8h.

[0878] The intermediate E-8 labeled “B” (Table 15) can be obtained in an analogous manner. If desired, the crude product E-8 is purified by chromatography.

[0879] experimental procedure for the synthesis of e-8k (method e)

[0880]

[0881] E-4b (1.00 g, 3.10 mmol), (S)-1,3-dimethylpiperazine (0.99 g, 8.67 mmol, 2.80 eq.), tris(dibenzylideneacetone)dipalladium(0) (141.85 mg, 0.154 mmol, 0.05 eq.), xantphos (184.80 mg, 0.31 mmol, 0.10 eq.), cesium carbonate (2.019 g, 6.196 mmol, 2.00 eq.) and anhydrous dioxane (8.00 mL) were combined and stirred at 110 °C in a closed vessel under an argon atmosphere for 16 h. 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 reverse-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to afford E-8i.

[0882] The intermediate E-8 labeled “C” (Table 15) can be obtained in an analogous manner. If desired, the crude product E-8 is purified by chromatography.

[0883] experimental procedure for the synthesis of e-8l (method f)

[0884]

[0885] E-4g (3.035 g, 8.51 mmol), (S)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester (3.645 g, 17.01 mmol, 2.00 eq.), tris(dibenzylideneacetone)dipalladium(0) (778.82 mg, 0.850 mmol, 0.10 eq.), 1,3-bis(2,6-di-isopropylphenyl)imidazolium chloride (723.0 mg, 1.701 mmol, 0.20 eq.), cesium carbonate (8.313 g, 25.514 mmol, 3.00 eq.) and dry dioxane (32.00 mL) were combined and stirred at 110 °C in a closed vessel under an argon atmosphere for 16 h. 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 reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give E-8j.

[0886] The intermediate E-8 labeled “D” (Table 15) can be obtained in a similar manner. If desired, the crude product E-8 is purified by chromatography.

[0887] experimental procedure for the synthesis of e-8m (method g)

[0888]

[0889] E-4b (400 mg, 1.239 mmol), 1-(1-methylpiperidin-4-yl)piperazine (273.0 mg, 1.49 mmol, 1.20 eq.), RuPhos Pd G3 (106.0 mg, 0.120 mmol, 0.10 eq.), potassium phosphate tribasic (553.0 mg, 2.605 mmol, 2.10 eq.) and dry dioxane (3.10 mL) were combined and stirred at 85 °C in a closed vessel under an argon atmosphere for 2 h. 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.

[0890] The intermediate E-8 labeled “E” (Table 15) can be obtained in a similar manner. If desired, the crude product E-8 is purified by chromatography.

[0891] experimental procedure for the synthesis of e-8n (method h)

[0892]

[0893] E-4b (100 mg, 0.31 mmol), pyridine-4-boronic acid (45.70 mg, 0.37 mmol, 1.20 eq.), RuPhos Pd G3 (27.3 mg, 0.031 mmol, 0.10 eq.), potassium phosphate tribasic (138.1 mg, 0.65 mmol, 2.10 eq.) and dry dioxane (0.9 mL) were combined and stirred at 80 °C in a closed vessel under an argon atmosphere for 1 h. After complete conversion, the mixture was concentrated. The crude product was purified by basic reverse-phase chromatography to yield E-8l.

[0894] The intermediate E-8 labelled “F” (Table 15) can be obtained in a similar manner. If necessary, the crude product E-8 is purified by chromatography.

[0895] experimental procedure for the synthesis of e-8o (method i)

[0896]

[0897] To a mixture of DIPEA (736.3 pL, 4.23 mmol, 3 eq.) and E-4i (560 mg, 1.41 mmol, 85% purity, 1 eq.) in DMSO (1 mL) was added (S)-1-((S)-1- methylpyrrolidin-2-yl)ethan-1-ol (922 mg, 5.64 mmol, 79% purity, 4.0 eq.) and the mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with acetonitrile and water, filtered and purified by acidic reverse-phase chromatography (gradient elution: 10 to 98% acetonitrile in water) to yield the desired product E-8m.

[0898] The intermediate E-8 labelled “F” (Table 15) can be obtained in a similar manner. If necessary, the crude product E-8 is purified by chromatography.

[0899] experimental procedure for the synthesis of e-8p (method j)

[0900]

[0901] A mixture of E-4k (1.50 g, 4.44 mmol, 1.0 eq.) and (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (688 mg, 5.33 mmol, 1.2 eq.) in THF (45 mL) was cooled to 0 °C. Sodium tert-butoxide (854 mg, 8.88 mmol, 2.0 eq.) was added to the mixture at 0 °C. The mixture was slowly warmed to room temperature and stirred at room temperature for 2 h. The reaction was 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 aqueous brine and concentrated under vacuum. The crude product was purified by normal-phase chromatography (2% MeOH in DCM) to give the desired product E-8n.

[0902] Intermediate E-8, labeled "H" (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0903] experimental procedure for the synthesis of intermediate e-8cc

[0904]

[0905] A solution of (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (312 mg, 2.42 mmol, 1.7 eq.) in THF (3 mL) was cooled to 0 °C, and sodium hydride (74 mg, 1.85 mmol, 1.3 eq.) was added in portions over 10 minutes. A solution of E-4l (500 mg, 1.42 mmol, 1.0 eq.) in THF (5 mL) was slowly added to the mixture, and the mixture was stirred for 18 h. The reaction was 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 in DCM) to give the desired product E-8o.

[0906] Intermediate E-8, labeled “I” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0907] experimental procedure for the synthesis of e-8cf (method k)

[0908]

[0909] To a mixture of E-4r (200 mg, 0.59 mmol, 1.0 eq.) and (S)-1-((S)-1- methylpyrrolidin-2-yl)ethan-1-ol (91.8 mg, 0.71 mmol, 1.2 eq.) in acetonitrile (1.5 mL) was added triethylamine (149.8 mg, 1.48 mmol, 2.5 eq.). The mixture was stirred at 40 °C for 2 h. The mixture was stirred at 80 °C for 16 h. 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.

[0910] The intermediate E-8 labelled “J” (Table 15) can be obtained in a similar manner. If necessary, the crude product E-8 is purified by chromatography.

[0911] Table 15

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919] experimental procedure for the synthesis of e-8cg (method l)

[0920]

[0921] E-2b (3.94 g, 20.93 mmol, 4.0 eq.), tert-butyl piperazine-1-carboxylate (1.76 g, 5.23 mmol, 1.0 eq.), sodium tert-butoxide (2.01 g, 20.93 mmol, 4.0 eq.), 2-(di-tert-butylphosphino)-biphenyl (624.45 mg, 0.21 mmol, 0.4 eq.), tris-(dibenzylideneacetone)-dipalladium (479.05 mg, 0.052 mmol, 0.1 eq.) in dioxane (10 mL) were added to a sealed tube and shaken at 45 °C under nitrogen overnight. The reaction mixture was mixed with EtOAc and water and extracted into EtOAc. The resulting organic phase was dried over magnesium sulfate and purified by silica gel normal phase chromatography (DCM:MeOH from 100:0 to 80:20).

[0922] The following intermediates E-8 (Table 16) can be obtained in a similar manner. If necessary, the crude product E-8 is purified by chromatography.

[0923] Table 16

[0924]

[0925]

[0926] experimental procedure for the synthesis of e-8ch (method m)

[0927]

[0928] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (1.335 g, 8.16 mmol, 2.5 eq.) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 652.8 mg, 16.32 mmol, 5.0 eq.) at room temperature. The mixture was stirred at room temperature for 10 min and E-6g (1.00 g, 3.26 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature for 3 h. The reaction was quenched by the addition of 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 reverse phase chromatography to give E-8cf.

[0929] The intermediates E-8 labelled“K” (Table 17) can be obtained in a similar manner. If necessary, the crude product E-8 is purified by chromatography.

[0930] experimental procedure for the synthesis of e-8cn

[0931]

[0932] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (52.6 mg, 0.41 mmol, 5.0 eq.) in THF (2 mL) was added potassium tert-butoxide (45.6 mg, 0.41 mmol, 5.0 eq.) at room temperature. The mixture was stirred at room temperature for 30 min and E-6b (25.0 mg, 0.081 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature for 15 min. The reaction was quenched by the addition of 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 acidic reverse phase chromatography to give E-8cg.

[0933] Intermediate E-8 labeled "L" (Table 17) can be obtained in a similar manner. If desired, the crude product E-8 is purified by chromatography.

[0934] experimental procedure for the synthesis of e-8cq

[0935]

[0936] E-6h (100.0 mg, 0.31 mmol, 1.0 eq.) and (S)-l,3-dimethylpiperazine (42.5 mg, 0.37 mmol, 1.2 eq.) were dissolved in DMSO (1 mL) at room temperature and DIPEA (115.0 μί, 0.62 mmol, 2.0 eq.) was added and the mixture was stirred for 1 h. The mixture was diluted with acetonitrile and water and purified by acidic reverse phase chromatography to give E-8ch.

[0937] Intermediate E-8 labeled "M" (Table 17) can be obtained in a similar manner. If desired, the crude product E-8 is purified by chromatography.

[0938] Table 17

[0939]

[0940] experimental procedure for the synthesis of e-14a

[0941]

[0942] E-8j (2.404 g, 4.50 mmol) in DCM (41 mL) was treated with HC1 (4 M in dioxane, 8.33 mL, 33.31 mmol, 7.4 eq.) and the mixture was stirred at room temperature for 5 h. After complete conversion, the mixture was concentrated and the crude product was purified by basic reverse phase chromatography (gradient elution: 25% to 100% acetonitrile in water) to give E-8cn.

[0943] The following intermediates E-8 (Table 18) can be obtained in a similar manner. If desired, the crude product E-8 is purified by chromatography.

[0944] Table 18

[0945]

[0946]

[0947] experimental procedure for the synthesis of e-15a

[0948]

[0949] E-8cn (231 mg, 0.532 mmol) in DCM (10.72 mL) was treated with formaldehyde (37% in water, 79.89 μL, 1.06 mmol, 2.0 eq.), acetic acid (304.0 μL, 5.32 mmol, 10.0 eq.) and a small amount of molecular sieves and the mixture was stirred for 15 min. Sodium triacetoxyborohydride (232.3 mg, 1.06 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature for 2 h. 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 reverse phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to give E-8cq.

[0950] The following intermediates E-8 (Table 19) can be obtained in an analogous manner. If necessary, the crude product E-8 is purified by chromatography.

[0951] Table 19

[0952]

[0953] Scheme 3:

[0954]

[0955] experimental procedure for the synthesis of e-16a

[0956]

[0957] E-8i (240.0 mg, 0.60 mmol), hydroxylamine hydrochloride (110.48 mg, 1.56 mmol, 2.60 eq.) and sodium carbonate (81.79 mg, 0.78 mmol, 1.30 eq.) were dissolved in dry EtOH (3.90 mL) and the mixture was stirred at 85 °C for 1 h. After complete conversion, the mixture was concentrated under reduced pressure to give E-14a which was used in the next step without further purification.

[0958] The following intermediates E-14 (Table 20) can be obtained in an analogous manner using different nitriles E-8. If necessary, the crude product E-14 is purified by chromatography.

[0959] Table 20

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971] experimental procedure for the synthesis of b-1a

[0972]

[0973] To a solution of E-1e (10.00 g, 45.99 mmol) in TEA (19.20 mL, 137.96 mmol, 3.0 eq.) and EtOH (100.0 mL) was added hydroxylamine hydrochloride (6.39 g, 91.98 mmol, 2.0 eq.) and the mixture was stirred at room temperature for 2 h. After complete conversion, the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and 10% Na2C03solution. The organic layer was collected and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give E-15a which was used in the next step without further purification.

[0974] experimental procedure for the synthesis of b-2a

[0975]

[0976] To a solution of E-4b (1.00 g, 3.10 mmol) in THF (0.50 mL) was added hydroxylamine (50% in water, 363 μL, 2.5 eq.) at room temperature. The mixture was stirred at room temperature for 3 h. After complete conversion, the mixture was concentrated under reduced pressure to give E-16a which was used in the next step without further purification.

[0977] The following intermediates E-16 (Table 21) can be obtained in an analogous manner using different nitriles E-4. If necessary, the crude product E-16 is purified by chromatography.

[0978] Table 21

[0979]

[0980] Option 4:

[0981]

[0982] experimental procedure for the synthesis of b-3a

[0983]

[0984] DIPEA (13.99 mL, 80.85 mmol, 3.0 eq.) was added to a stirred solution of E-15a (6.75 g, 26.95 mmol) and A-5a (7.00 g, 29.64 mmol, 1.1 eq.) in DMF (70 mL) at room temperature. The mixture was cooled to 0 °C, and benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (21.04 g, 40.42 mmol, 1.5 eq.) was added. The mixture was allowed to reach room temperature and stirred for 16 h. After complete conversion, the mixture was diluted with EtOAc, washed with water and brine, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc) and then ground with DCM to obtain B-1a.

[0985] The reaction here can also be carried out using enantiomeric starting material A-5 to obtain enantiomeric product B-1.

[0986] experimental procedure for the synthesis of b-4a

[0987]

[0988] A benzyltrimethylammonium hydroxide solution (40 wt.%, 1.962 g; 11.73 mmol, 2.2 eq. in MeOH) was added to a stirred solution of B-1a (2.50 g, 5.33 mmol) in 250 mL of THF at 0 °C, and the mixture was stirred at room temperature for 6 min. The reaction was quenched by adding 25 mL of water and 25 mL of EtOAc. The layers were separated, and the organic phase was washed with water, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc) to give B-2a.

[0989] experimental procedure for the synthesis of b-4c

[0990]

[0991] The reaction was carried out under an argon atmosphere. To a stirred mixture of zinc dust (497.22 mg, 7.60 mmol, 8.0 eq.) and dry DMA (1.24 mL) was added dropwise a 7:5 (v / v) mixture of chlorotrimethylsilane (0.730 mL) and 1,2-dibromoethane (0.520 mL) over a period of 10 min at room temperature and the resulting mixture was stirred at room temperature for a further 15 min. A solution of tert-butyl 4-iodopiperidine-l-carboxylate (1.941 g, 6.05 mmol, 13.2 eq.) in dry DMA (3.08 mL) was added portionwise while maintaining the temperature below 35 °C. The resulting mixture was stirred for a further 30 min while cooling to room temperature.

[0992] In a second flask, dry DMA (1.4 mL) was added to a mixture of B-2a (200.0 mg, 0.44 mmol), l,l’-bis(diphenylphosphino)ferrocenedichloropalladium(ll), DCM (16.82 mg, 0.02 mmol, 0.09 eq.) and copper(I) iodide (9.61 mg, 0.05 mmol, 0.23 eq.). The mixture was degassed and 1.14 mL of the previously prepared zincate solution of piperidinyl iodide (21% of a solution prepared according to the procedure described above) was added through a 0.45 pm syringe filter. The resulting solution was degassed again and then stirred at 80 °C for 1 h. After complete conversion, DCM, water and saturated ammonium chloride solution were added, the layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried, filtered and concentrated under reduced pressure and the crude product was purified by basic reverse phase chromatography (gradient elution: 50% to 98% acetonitrile in water) to give B-3a (HPLC Method B; tR= 0.88 min; [M+H] ret = 0.88 min; [M+H] + = 499).

[0993] experimental procedure for the synthesis of b-5a

[0994]

[0995] B-3a (200.0 mg, 0.360 mmol) was treated with 1-methylpiperazine (799.30 pL, 7.21 mmol, 20 eq.) and DIPEA (92.99 pL, 0.54 mmol, 1.5 eq.) and stirred in a sealed vessel at 80 °C for 16 h. After complete conversion, DCM, water and brine were added, the layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried, filtered and concentrated under reduced pressure to give B-4a which was used in the next step without further purification.

[0996] The following intermediates B-4 (Table 22) can be obtained in an analogous manner using different piperazine analogues B-3. If necessary, the crude products B-4 are purified by chromatography.

[0997] Table 22

[0998]

[0999] experimental procedure for the synthesis of b-6a

[1000]

[1001] B-3b (100.0 mg, 0.18 mmol) was treated with 1-pyrrolidin-3-yl-piperidine (277.39 mg, 1.80 mmol, 10 eq.) and DIPEA (154.7 μL, 0.90 mmol, 5.0 eq.) and stirred in a closed vessel at 100 °C for 16 h. After complete conversion, DCM, water and brine were added, the layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried, filtered and concentrated under reduced pressure to yield B-4c which was used in the next step without further purification.

[1002] The following intermediates B-4 (Table 23) can be obtained in an analogous manner using different intermediates B-3. If necessary, the crude products B-4 are purified by chromatography.

[1003] Table 23

[1004]

[1005]

[1006]

[1007]

[1008]

[1009] experimental procedure for the synthesis of b-7a

[1010]

[1011] B-4a (111.5 mg, 0.18 mmol) in DCM (2.00 mL) was treated with HC1 (4 M in dioxane, 900.8 μL, 3.60 mmol, 20.0 eq.) and the mixture was stirred at room temperature for 1 h. After complete conversion, the mixture was concentrated and the crude product was purified by basic reverse phase chromatography (gradient elution: 15% to 90% acetonitrile in water) to yield B-5a.

[1012] The following intermediates B-5 (Table 24) can be obtained in an analogous manner using different piperazine analogues B-4. If necessary, the crude product B-5 is purified by chromatography.

[1013] Table 24

[1014]

[1015] Scheme 5:

[1016]

[1017] experimental procedure for the synthesis of b-8a

[1018]

[1019] To a solution of B-2b (250.0 mg, 0.56 mmol) in DMF (3.5 mL) was added N,N- dimethylformamide dimethyl acetal (674.4 μL, 5.55 mmol, 10.0 eq.) and the reaction mixture was stirred at room temperature for 16 h. After complete conversion, the product was isolated by basic reversed-phase chromatography (gradient elution: 50% to 98% acetonitrile in water) to give B-6a (HPLC Method A; tR= 1.61 min; [M+H] = 505). ret = 1.61 min; [M+H] = 505). + = 1.61 min; [M+H] = 505).

[1020] experimental procedure for the synthesis of b-5c

[1021]

[1022] The procedure was performed in a nitrogen atmosphere glovebox. B-6a (1.00 g, 1.785 mmol), (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (369.0 mg, 2.86 mmol, 1.6 eq.), sodium tert-butoxide (257.3 mg, 2.68 mmol, 1.5 eq.) and [BrettPhos Pd (Brett)))] OTf (151.4 mg, 0.18 mmol, 0.1 eq.) were combined and anhydrous dioxane (15.0 mL) was added and the mixture was stirred at room temperature in a closed vessel for 16 h. After complete conversion, the mixture was poured into water, the pH was set to 10 by addition of 8 N NaOH, the product was extracted with DCM and the combined organic layers were dried, filtered and concentrated. The crude product was purified by basic reversed-phase chromatography (gradient elution: 60% to 98% acetonitrile in water) to give B-7a (HPLC Method A; tR= 1.74 min; [M+H] = 598). ret = 1.74 min; [M+H] = 598). + = 1.74 min; [M+H] = 598).

[1023] experimental procedure for the synthesis of b-9a

[1024]

[1025] The procedure was performed in a nitrogen atmosphere glovebox. B-7a (135.0 mg, 0.23 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (78.1 mg, 0.45 mmol, 2.0 equiv.), potassium phosphate (143.6 mg, 0.68 mmol, 3.0 eq.), palladium(II)acetate (5.1 mg, 0.023 mmol, 0.1 eq.) and 5-[di(1-adamantyl)phosphino]-1’,3’,5’- triphenyl-1’H-[1,4]bipyrazole (29.9 mg, 0.045 mmol, 0.2 eq.) were combined, anhydrous toluene (2.7 mL) was added, and the mixture was stirred in a closed vessel at 90 °C for 16 h. After complete conversion, the mixture was poured into water, the product was extracted with DCM, and the combined organic layers were dried, filtered, and concentrated. The crude product was purified by basic reverse-phase chromatography (gradient elution: 5% to 98% acetonitrile in water) to give B-8a.

[1026] The following intermediates B-8 (Table 25) can be obtained in a similar manner using different alcohols. If necessary, the crude product B-8 is purified by chromatography.

[1027] Table 25

[1028]

[1029] experimental procedure for the synthesis of b-3b

[1030]

[1031] B-8a (112.2 mg, 0.16 mmol) was dissolved in EtOH (2.75 mL) and treated with concentrated HCl (37% in water, 94.1 μL, 1.137 mmol, 7.0 eq.). The mixture was stirred at 100 °C for 1 h, and after complete conversion, the mixture was concentrated and the crude product was purified by basic reverse-phase chromatography (gradient elution: 15% to 98% acetonitrile in water) to give B-5c.

[1032] The following intermediates B-5 (Table 26) can be obtained in a similar manner using different analogues B-8. If necessary, the crude product B-5 is purified by chromatography.

[1033] Table 26

[1034]

[1035]

[1036] Scheme 6:

[1037]

[1038] experimental procedure for the synthesis of b-10a

[1039]

[1040] A-5a (67.09 mg, 0.28 mmol, 0.90 eq.) in DMSO (1.0 mL) was treated with HATU (125.9 mg, 0.32 mmol, 1.05 eq.) and TEA (89.2 μί, 0.62 mmol, 2.0 eq.) and the mixture was stirred at room temperature for 20 min. Then E-16a (110.0 mg, 0.31 mmol, 1.0 eq.) was added and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and the precipitate was collected, washed with water and dried to give B-9a which was used in the next step without further purification.

[1041] The reaction can also be performed with enantiopure starting material A-5 to give the single stereoisomer of product B-9.

[1042] The following intermediates B-9 (Table 27) can be obtained in a similar manner using different intermediates E-16 and acids A5. If necessary, the crude product B-9 is purified by chromatography.

[1043] Table 27

[1044]

[1045]

[1046]

[1047] experimental procedure for the synthesis of b-8c

[1048]

[1049] To a stirred solution of B-9a (180 mg, 0.31 mmol) in THF (1.0 mL) was added dropwise a solution of tetrabutylammonium hydroxide (40% in water, 0.152 mL, 0.23 mmol, 0.75 eq.) and the mixture was stirred at room temperature for 16 h. After complete conversion, the mixture was concentrated under reduced pressure and the crude product was purified by basic reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give B-3b.

[1050] The following intermediates B-3 (Table 28) can be obtained in an analogous manner using different intermediates B-9. If necessary, the crude product B-3 is purified by chromatography.

[1051] Table 28

[1052]

[1053]

[1054]

[1055] experimental procedure for the synthesis of b-5e

[1056]

[1057] In an analogous manner to the preparation of B-6 from B-2 (see e.g. Procedure B-6a→B-2a).

[1058] The following intermediates B-10 (Table 29) can be obtained in an analogous manner starting from different intermediates B-3. If necessary, the crude product B-10 is purified by chromatography.

[1059] Table 29

[1060]

[1061]

[1062] experimental procedure for the synthesis of b-11a

[1063]

[1064] The procedure was carried out in a glovebox under nitrogen atmosphere. B-10a (25.0 mg, 0.041 mmol), (1S)-1-[(2S)-1-methylpyrrolidin-2-yl]propan-1-ol (11.70 mg, 0.08 mmol, 2.0 eq.), sodium tert-butoxide (5.89 mg, 0.06 mmol, 2.0 eq.) and BrettPhos Pd(t-Bu)OTf (3.46 mg, 0.004 mmol, 0.1 eq.) were combined. Degassed dioxane (0.5 mL) was added and the mixture was stirred in a closed vessel at 60 °C under inert atmosphere for 16 h. The reaction mixture was filtered and the crude product was purified by acidic reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to yield B-8c.

[1065] The following intermediates B-8 (Table 30) can be obtained in an analogous manner starting from different intermediates B-10. If necessary, the crude product B-8 is purified by chromatography.

[1066] Table 30

[1067]

[1068]

[1069]

[1070]

[1071] experimental procedure for the synthesis of b-4y

[1072]

[1073] B-8c (140.0 mg, 0.195 mmol) was dissolved in EtOH (3 mL) and concentrated aqueous HC1 (134 mg, 1.36 mmol) was added. The mixture was stirred at 100 °C under inert atmosphere for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by basic reverse phase chromatography (gradient elution: 30% to 90% acetonitrile in water) to give B-5e.

[1074] The following intermediates B-5 (Table 31) can be obtained in an analogous manner using different intermediates B-8. If necessary, the crude product B-5 is purified by chromatography.

[1075] Table 31

[1076]

[1077]

[1078] Scheme 7:

[1079]

[1080] experimental procedure for the synthesis of b-5j

[1081]

[1082] A-5a (454.0 mg, 1.91 mmol, 1.0 eq.) in DMF (11.8 mL) was treated with HATU (724.5 mg, 1.91 mmol, 1.0 eq.) and DIPEA (0.923 mL, 5.72 mmol, 3.0 eq.) and the mixture was stirred at room temperature for 20 min. Then E-14a (874.8 mg, 1.48 mmol, 0.78 eq.) was added and the mixture was stirred at room temperature for 16 h. The crude mixture was purified by basic reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give B-11a.

[1083] The reaction can also be carried out using enantiomeric starting material A-5 to give a single stereoisomer of product B-11.

[1084] The following intermediate B-11 (Table 32) can be obtained in a similar manner using different intermediates E-14 and acid A-5. If necessary, the crude product B-11 can be purified by chromatography.

[1085] Table 32

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100] experimental procedure for the synthesis of boc and cbz deprotection of building block b-4 (b-4→b-5)

[1101]

[1102] Tetrabutylammonium fluoride solution (1 M, 2.168 mL, 2.17 mmol, 1.50 eq. in THF, 1.50 mL) was added dropwise to a stirred solution of B-11a (1.570 g, 1.45 mmol) in 16.0 mL of THF, and the mixture was stirred at room temperature for 16 h. After complete conversion, the mixture was filtered, concentrated under reduced pressure, and the crude product was purified by basic reversed-phase chromatography (gradient elution: 40% to 98% acetonitrile in water) to give B-4y.

[1103] The following intermediates B-4 (Table 33) can be obtained in an analogous manner using different intermediates B-11. If necessary, the crude product B-4 is purified by chromatography.

[1104] Table 33

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122] ​

[1123]

[1124] B-4cn (400 mg, 0.50 mmol, 1 eq.) is dissolved in MeOH and hydrogenated at 50 °C using a H-Cube apparatus with a hydrogenation cartridge employing palladium hydroxide. The solvent is removed in vacuo and the residue is purified using reverse phase chromatography to obtain B-5j (HPLC method A; tR= 9.6 min). ret= 1.34 min; [M+H] + = 606).

[1125] ​

[1126] The following intermediates B-5 (Table 34) can be obtained by Boc deprotection or Cbz deprotection analogous to the synthesis of building block B-4 described herein (see B-4a→B-5a and B-4cn→B-5e).

[1127] Table 34

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152] Synthesis of final compounds (I) according to the application:

[1153] Scheme 8:

[1154]

[1155] Experimental procedure for the synthesis of Ia-1

[1156]

[1157] B5-a (29.5 mg, 0.057 mmol), TEA (23.7 μL, 0.171 mmol, 3.0 eq.) and DMSO (900.0 μL) were dissolved in DCM (1.0 mL). Acryloyl chloride (5.5 μL, 0.068 mmol, 1.2 eq.) dissolved in DCM (1 mL) was added dropwise over a period of 10 min and the mixture was stirred at room temperature for 30 min. Acryloyl chloride (3.2 μL, 0.04 mmol, 0.7 eq.) dissolved in DCM (0.2 mL) was added dropwise again and the mixture was stirred for another 30 min. After complete conversion, the mixture was concentrated and the crude product was purified by acidic reverse phase chromatography (gradient elution: 5% to 60% acetonitrile in water) to yield la-1.

[1158] The following compounds (I) according to the application of the subcategory la (Table 35) can be obtained in an analogous manner using different analogues B-5. If necessary, the crude product la is purified by chromatography.

[1159] Table 35

[1160]

[1161] Experimental procedure for the synthesis of Ia-3

[1162]

[1163] An acryloyl chloride solution (1 M in acetone, 336.0 μί, 0.34 mmol, 3.0 eq.) was added to a mixture of potassium carbonate (46.4 mg, 0.34 mmol, 3.0 eq.), acetone (1.75 mL) and water (0.35 mL). The mixture was stirred at room temperature for 10 min, then B-5c (60.0 mg, 0.11 mmol) dissolved in acetone (1.75 mL) and water (0.35 mL) was added and the mixture was stirred at room temperature for 15 min. After complete conversion, the mixture was concentrated and the crude product was purified by basic reverse phase chromatography (gradient elution: 10% to 98% acetonitrile in water) to yield la-3.

[1164] The following compounds (I) of the subcategory la according to the application (Table 36) can be obtained in an analogous manner using different analogues B-5. If desired, the crude products la are purified by chromatography.

[1165] In some cases, the synthesis was performed using a mixture of diastereoisomers as starting material and, if desired, the enantiopure final compounds were separated by chiral SFC.

[1166] Table 36

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197] The compounds la depicted in Table 37 below can be obtained from the different intermediates B-5 and the corresponding carboxylic acids in a similar manner as further described below for the conversion of C-5a to Ic-8. If necessary, the crude product la is purified by chromatography.

[1198] Table 37

[1199]

[1200]

[1201]

[1202] The compounds la depicted in Table 38 below can be obtained from the different intermediates B-5 and 2-butynoic acid in a similar manner as further described below for the conversion of C-5a to Ic-8. If necessary, the crude product la is purified by chromatography.

[1203] Table 38

[1204]

[1205]

[1206] Experimental procedure for the synthesis of Ia-169

[1207]

[1208] B-5f (70.0 mg, 0.13 mmol) in dry DMF (0.75 mL) was treated with TEA (46.0 μL, 0.32 mmol, 2.5 eq.) followed by (2E)-4-bromo-N,N-dimethylbut-2-enamine (33.63 mg, 0.14 mmol, 1.1 eq.) dissolved in DMF (0.75 mL). The mixture was stirred at room temperature for 48 h. After complete conversion, the product was isolated by basic reverse phase chromatography (gradient elution: 15% to 52% acetonitrile in water) to yield la-169 (HPLC Method A; tR= 1.23 min; [M+H] = 661). Characterization and activity test data for compound la-169 are shown in Table 39. ret = 1.23 min; [M+H] = 661). Characterization and activity test data for compound la-169 are shown in Table 39. + = 1.23 min; [M+H] = 661). Characterization and activity test data for compound la-169 are shown in Table 39.

[1209] Table 39

[1210]

[1211]

[1212] Experimental procedure for the synthesis of Ia-170

[1213]

[1214] la-155 (84 mg, 0.13 mmol, 1 eq.) was dissolved in DCM (1 mL) and trifluoroacetic acid (145 mg, 1.27 mmol, 10 eq.) was added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and then purified using basic reverse phase chromatography (acetonitrile: water = 30:70→ 90:10). Purification was then performed using acidic reverse phase chromatography (acetonitrile: water = 5:95→ 60:40). The product containing fractions were lyophilized to yield la-170. Characterization and activity test data for compound la-170 are shown in Table 40.

[1215] Table 40

[1216]

[1217] The following examples describe the biological activity of compounds according to the application, but the application is not limited to these examples.

[1218] KRAS::SOS1 AlphaScreen binding assay

[1219] This assay can be used to check the potency of a compound according to the application binding to KRAS G12C to inhibit the protein-protein interaction between SOS1 and KRAS G12C. This inhibits the GEF function of SOS1 and locks KRAS G12C in its inactive GDP-bound state. Low IC 50 values in this assay setup indicate strong inhibition of the protein-protein interaction between SOS1 and KRAS:

[1220] Reagents:

[1221] • GST-tagged SOS1 (564_1049_GST_TEV_ECO), in-house production

[1222] • GST-TEV-SOS1 (564-1049), purchased from Viva Biotech Ltd.

[1223] • Expression construct for KRAS G12C containing a C-terminal avi-tag (amino acids 1-169 of reference sequence P01116-2 (uniprot) with additional mutations: C51S, C80L and C118S) was obtained by gene synthesis in a donor vector (pDONR-221) (GeneArt, Thermo Fisher) and transferred by recombination cloning into a pDEST17 vector with an N-terminal His6-tag. The protein was expressed in E. coli and the purified protein was biotinylated with E. coli biotin ligase (BirA) before use.

[1224] • GDP (Sigma cat. no. G7127)

[1225] • AlphaLISA glutathione acceptor beads (PerkinElmer, cat. no. AL109)

[1226] • AlphaScreen streptavidin donor beads (PerkinElmer cat. no. 6760002)

[1227] • Assay plates: Proxiplate-384 PLUS, white (PerkinElmer, cat. no. 6008289)

[1228] Assay buffer:

[1229] • 1 x PBS

[1230] • 0.1% BSA

[1231] • 0.05% Tween 20

[1232] KRAS::SOS1 GDP mix:

[1233] 7.5 nM (final assay concentration) KRAS G12C, 10 mM (final assay concentration) GDP and 5 nM (final assay concentration) GST-SOS1 were mixed in assay buffer and kept at room temperature before use.

[1234] bead mix:

[1235] AlphaLISA glutathione receptor beads and AlphaScreen streptavidin donor beads were mixed in assay buffer at a concentration of 10 pg / mL (final assay concentration) and kept at room temperature before use.

[1236] Assay protocol:

[1237] Compounds were diluted to a final starting concentration of 100 mM and tested in duplicate. An Access Labcyte workstation with Labcyte Echo 550 or 555 acoustic dispenser was used to generate an assay preparation plate (ARP). For compounds with a starting concentration of 100 mM, 150 nL of compound solution / well was transferred in duplicate at 11 concentrations with serial 1 :5 dilutions.

[1238] The assay was performed in a dark room below 100 lux using a fully automated robotic system. 10 pL KRAS::SOS1 GDP mix was added to column 1-24 to 150 nL of compound solution (final dilution 1 :100 in the assay, final DMSO concentration 1%).

[1239] After an incubation time of 30 min, 5 pL bead mix was added to columns 1-23. The plate was kept in a dark incubator at room temperature. After a further incubation of 60 min, the signal was measured using a PerkinElmer Envision HTS multi-label reader using AlphaScreen specifications from PerkinElmer. Each plate contained the following controls:

[1240] • Diluted DMSO + KRAS::SOS1 GDP mix + bead mix

[1241] • Diluted DMSO + KRAS::SOS1 GDP mix

[1242] Result calculation:

[1243] Calculating and analyzing ICs using a 4-parameter logic model 50 value.

[1244] The compounds disclosed in this article contain IC values ​​determined using the above assay method. 50 value.

[1245] Ba / F3 cell model generation and proliferation assay

[1246] Ba / F3 cells were ordered from DSMZ (ACC300, Lot 17) and grown at 37°C in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10 ng / mL IL-3 under a 5% CO2 atmosphere. 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 with the KRASG12 isotype. Platinum-E cells (Cell Biolabs) were used for retrovirus packaging. The retrovirus was added to the Ba / F3 cells. To ensure infection, 4 μg / mL polyglobulin was added and the infected cells were rotated. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10% to 20% were further incubated and selection was initiated with 1 μg / mL puromycin. Parental Ba / F3 cells were used as a control to demonstrate the selection status. Selection was considered successful when the parental Ba / F3 cell cultures died. To evaluate the transformation potential of the KRASG12 mutation, IL-3 was no longer supplemented in the growth medium. Ba / F3 cells with the empty vector were used as a control. Puromycin was discontinued approximately ten days prior to the experiment.

[1247] For proliferation assays, Ba / F3 cells were cultured in growth medium (RPMI-1640 + 10% FCS) at a concentration of 1 x 10⁻⁶ cells / mL. 3 60 μL of cells 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 performed technically in duplicate. Assays were performed using a fully automated robotic system. The treated cells were incubated at 37°C and 5% CO2 for 72 h. The reactive dye Alamar Blue was then added. TM (ThermoFisher) and fluorescence was measured in a PerkinElmer Envision HTS multi-label reader. The raw data were imported into Boehringer Ingelheim proprietary software MegaLab and analyzed (based on curve fitting of the PRISM program, GraphPad Inc.).

[1248] IC50values of representative compounds (I) according to the application measured with this assay 50 are presented in Table 41.

[1249] Table 41

[1250]

[1251] Additional proliferation assays on G12C mutant cancer cell lines

[1252] SW 837 CTG proliferation assay (CRC)

[1253] SW837 cells (ATCC# CCL-235) were grown in cell culture flasks (175 cm 2 ) using L-15 10% FCS, 1% L-Glu, lx NEAA and lx Na-Pyrovat. Cultures were incubated at 37°C and 0% CO2 in a humidified atmosphere with 2-3 medium changes or subcultures per week. The material used for the assay was CulturPlate-384- sterile and tissue culture treated white opaque 384-well microplate (Perkin Elmer #6007680), Leibovitz L15 medium and FBS #SH30071.03 (HyClone).

[1254] The proliferation assay was started by seeding cells in flat bottom 384-well microtiter plates at a density of 500 cells / well in 90 μΙ_ L-15 10% FCS, 1% L-Glu, lx NEAA and lx Na-Pyrovat (day 1). Any other format of luminescence compatible plate is possible. On day 2, 10 μΙ_ dilutions of test compounds covering a concentration range of between about 0.1 and 10.000 nM were added to the cells. Cells were incubated at 37°C in a humidified, CO2 controlled (no CO2) incubator for 5 days. On day 7, 100 μΙ_ Cell Titer Glow reagent (Cell titer Glo Luminescent Cat# G7571, Promega) was added to each well and incubated for another 10 min at room temperature (with agitation). Luminescence was measured on a Wallac Victor using standard luminescence readout. IC50values were calculated using the standard Levenburg Marquard algorithm (GraphPad Prism). 50

[1255] IC50values of representative compounds (I) according to the application measured with this assay 50 are presented in Table 42.

[1256] ​• MiaPaCa-2 CTG proliferation assay (pancreatic cancer)

[1257] MiaPaCa-2 cells ( CRM-CRL-1420 TM Cell culture flasks (175cm²) were used in DMEM medium supplemented with 10% fetal bovine serum. 2 Cultures were grown in a humid atmosphere at 37°C and 5% CO2, with medium changes or subculturing performed 2-3 times per week. Materials used for assays included CulturPlate-384 sterile, tissue culture-treated white opaque 384-well microplates (Perkin Elmer #6007680), DMEM medium, and FBS #SH30071.03 (HyClone).

[1258] Proliferation assays were initiated by seeding cells at a density of 500 cells / well in 90 μL of DMEM medium supplemented with 10% FBS in a flat-bottomed 384-well microtiter plate (Day 1). Any other luminescently compatible plate format was acceptable. On Day 2, 10 μL of a dilution of the test compound covering a concentration range between approximately 0.1 and 10,000 nM was added to the cells. Cells were incubated for 5 days at 37°C in a humidified incubator containing 5% CO2. 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 min at room temperature (with stirring). Luminescence was measured using a standard luminescence readout on a Wallac Victor. IC50 was calculated using the standard Levenberg Marquard algorithm (GraphPad Prism). 50 value.

[1259] The IC50 of the representative compound (I) according to the present invention was measured using this method. 50 The values ​​are presented in Table 42.

[1260] • NCI-H358 CTG proliferation assay (120h) (NSCLC)

[1261] NCI-H358 cells (ATCC number CRL-5807) were dispensed at a density of 2000 cells per well into 100 μΙ_ RPMI-1640 ATCC-formulation (Gibco #A10491) + 10% FCS in white opaque 96-well plates (Perkin Elmer catalog number 5680). Cells were incubated at 37°C in a humidified tissue culture incubator with 5% C02overnight. Compounds (10 mM stock in DMSO) were added in a logarithmic dose series (normalized for added DMSO) using a HP Digital dispenser D300 (Tecan). For the T0 time point measurement, untreated cells were analyzed at the time of compound addition. Plates were incubated for 120 hours and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability, expressed as percentage of control, was defined as the relative luminescent units RLU per well divided by the RLU of cells in the DMSO control. 50 Values were determined from viability measurements using a four parameter model by non-linear regression.

[1262] IC50values for representative compounds (I) according to the application measured with this assay are presented in Table 42. 50 Values were determined from viability measurements using a four parameter model by non-linear regression.

[1263] • NCI-H2122 CTG proliferation assay (120h) (NSCLC)

[1264] The CTG assay 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 calf serum (Life Technologies, Gibco BRL, cat. no. 10270-106). On "day 0", 1000 NCI-H2122 cells were seeded in 60 μΙ_ RPMI ATCC + 10% FCS + Penstrep in a 384-well flat bottom plate. Cells were then incubated in the plate at 37°C in a C02incubator overnight. On day 1, compounds were added using an ECHO acoustic liquid handling system (Beckman Coulter), including a DMSO control. Plates were incubated for 120 hours and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability, expressed as percentage of control, was defined as the relative luminescent units RLU per well divided by the RLU of cells in the DMSO control. 50 Values were determined from viability measurements using a four parameter model by non-linear regression.

[1265] Table 42

[1266]

[1267] ERK phosphorylation assay

[1268] The ERK phosphorylation assay was used to examine the potency of compounds to inhibit KRAS G12C-mediated signal transduction in KRAS G12C mutant human cancer cell lines in vitro. This demonstrates the molecular mode of action of the compounds according to the application by interfering with the RAS G12C protein signal transduction cascade. Low IC 50 values in this assay setting indicate a high potency of the compounds according to the application. It was observed that the compounds according to the application exhibit an inhibitory effect on ERK phosphorylation in KRAS G12C mutant human cancer cell lines, thus confirming the molecular mode of action of the compounds on the RAS G12C protein signal transduction.

[1269] The following human cell lines were used for the ERK phosphorylation assay:

[1270] NCI-H358 (ATCC (ATCC CRL-5807): human lung carcinoma with KRAS G12C mutation (→ Assay 1), and NCI-H358_Cas9_SOS2, i.e. the same cell line but wherein SOS2 was knocked out (→ Assay 2). The vector containing the designed DNA sequence for the generation of gRNA for SOS2 protein knock-out was obtained from Sigma-Aldrich. To generate the NCI-H358 SOS2 knock-out cell line, NCI-H358 cells expressing Cas9 endonuclease were transfected with XtremeGene9 reagent and the corresponding plasmid. Transfection efficiency was confirmed by measuring GFP positive cells using a cell analyser. GFP positive cells were collected and further expanded. These GFP positive cell banks were single cell diluted and SOS2 knock-out clones were identified by western blot and genomic DNA sequencing analysis.

[1271] Materials used for the assay:

[1272] RPMI-1640 medium (Gibco® 22400-165) 30-2001 TM )

[1273] Fetal Bovine Serum (FBS) from HyClone (SH30071.03)

[1274] Non-essential amino acids from Thermo Fischer Scientific (11140035)

[1275] Pyruvate from Thermo Fischer Scientific (11360039)

[1276] Glutamax from Thermo Fischer Scientific (35050061)

[1277] 384 plates from Greiner Bio-One (781182)

[1278] Proxiplate from PerkinElmer Inc. (6008280) TM 384 (6008280)

[1279] AlphaLISA SureFire Ultra p-ERK1 / 2 (Thr202 / Tyr204) assay kit (ALSU-PERK-A500)

[1280] EGF from Sigma (E4127)

[1281] Receptor mix: Protein A Receptor beads from PerkinElmer (6760137M)

[1282] Donor mix: AlphaScreen Streptavidin-coated donor beads from PerkinElmer (6760002)

[1283] Trametinib

[1284] Staurosporine from Sigma Aldrich (S6942)

[1285] Assay setup:

[1286] Cells were seeded at 40,000 cells / well in Greiner TC 384 plates in 60 pL RPMI containing 10% FBS, non-essential amino acids, pyruvate and glutamax. Cells were incubated for 1 h at room temperature and then incubated overnight in a humidified atmosphere at 37°C and 5% C02 in an incubator. 60 nL of compound solution (10 mM DMSO stock solution) was then added using a Labcyte Echo 550 instrument. After 1 h incubation in the above mentioned incubator, the medium was removed after centrifugation and cells were lysed by adding 20 pL of 1.6-fold lysis buffer from AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) assay kit with added protease inhibitors, 100 nM trametinib + 100 nM staurosporine. After 20 min incubation with shaking at room temperature, 6 pL of each lysate sample was transferred to a 384-well Proxiplate and analyzed for pERK (Thr202 / Tyr204) with AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) assay kit. 3 pL of acceptor mix and 3 pL of donor mix were added under reduced light and incubated for 2 h at room temperature in the dark before measuring the signal on a PerkinElmer Envision HTS multi-label reader. Raw data was imported into Boehringer Ingelheim proprietary software MegaLab and analyzed (curve fitting based on program PRISM, GraphPad Inc).

[1287] IC50values for representative compounds (I) according to the application measured with this assay 50 are presented in Table 43 (IC50values of Assay 2 marked with *, all others from Assay 1). 50

[1288] Table 43

[1289]

[1290]

[1291] The following formulation examples illustrate the application without limiting its scope:

[1292] Pharmaceutical formulation examples

[1293]

[1294] ​The finely ground active substance, lactose and some maize starch are mixed together. The mixture is sieved and then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remaining maize starch and the magnesium stearate are sieved and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

[1295]

[1296]

[1297] The finely ground active substance, some maize starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remaining maize starch and water to form granules, which are dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed in, and the mixture is compressed to form tablets of suitable size.

[1298]

[1299] The active substance, lactose and cellulose are mixed together. The mixture is sieved and then moistened with water, kneaded, wet granulated and dried or dry granulated, or directly end-blended with magnesium stearate and compressed into tablets of suitable shape and size. When wet granulation is used, additional lactose or cellulose and magnesium stearate are added and the mixture is compressed into tablets of suitable shape and size.

[1300] D) Ampoule solution

[1301] Active substance according to formula (I) 50 mg

[1302] Sodium chloride 50 mg

[1303] Water for injection 5 mL

[1304] The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered to remove pyrogens and the filtrate is transferred under sterile conditions into ampoules, which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims

1. A compound or a salt thereof, said compound being selected from:

2. A compound or a salt thereof, said compound being 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-mutated 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 a pharmaceutically acceptable salt thereof; and One or more pharmaceutically acceptable excipients.

7. A pharmaceutical composition comprising: The compound according to claim 1 or a pharmaceutically acceptable salt thereof; and One or more other pharmacologically active substances.

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