Cyclofused 2-amino-3-cyanothiophenes and derivatives for treating cancer

Abstract

The present invention provides compounds of formula (I), 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 in the specification), their use as inhibitors of mutant Ras family proteins, pharmaceutical compositions and formulations containing such compounds, and their use as medicines / medical uses, especially as agents for the treatment and / or prevention of neoplastic diseases. TIFF2023528623000316.tif5438

Description

[Technical Field]

[0001] The present invention relates to fused ring 2-amino-3-cyanothiophenes and derivatives of formula (I): [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , R 5 , A, U, V, W, L and E have the meanings indicated in the claims and in the specification), their use as inhibitors of mutant Ras family proteins, pharmaceutical compositions and formulations containing such compounds, and their use as medicines / medical uses, especially as agents for the treatment and / or prevention of neoplastic diseases, such as cancer. [Background technology]

[0002] Ras family proteins, including KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey murine sarcoma viral oncogene) and all their mutant forms, are small GTPases that exist in cells in either a GTP- 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 slow nucleotide exchange rates (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. Binding of guanine nucleotide exchange factors (GEFs), such as SOS1 (Son of Sevenless 1), promotes GDP release from Ras family proteins, allowing them to bind GTP (Chardin et al., Science, 1993, 260(5112):1338-43). 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 diverse 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).

[0003] Cancer-associated mutations in Ras family proteins suppress 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 sustained activation of downstream effector pathways of mutant Ras family proteins (e.g., RAF / MEK / ERK, PI3K / AKT / mTOR, RalGDS pathways). KRAS mutations (e.g., amino acids G12, G13, Q61, A146) have been found in various 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 various human cancer types, but are typically 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 a mechanism 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).

[0004] Glycine-to-cysteine ​​mutations at residue 12 of Ras family proteins (G12C mutations, e.g., KRAS G12C, NRAS G12C, and HRAS G12C) arise from a GC-to-TA base transversion at codon 12 and are commonly found in RAS genes, accounting for 14% of all KRAS mutations, 2% of all NRAS mutations, and 2% of all HRAS mutations across cancer types. G12C mutations are particularly prevalent in KRAS-mutant non-small cell lung cancers, approximately half of which harbor this mutation, which is associated with DNA adducts formed by cigarette smoke. G12C mutations are not unique to lung cancer; they are also found in other RAS-mutant cancer types, including, for example, 3-5% of all KRAS-mutant colorectal cancers.

[0005] Inhibitors of G12C mutant Ras family proteins that can covalently bind to such proteins, such as covalent binders for KRAS G12C, NRAS G12C, and HRAS G12C, are expected to inhibit downstream signal transduction (e.g., ERK phosphorylation) in cells of the Ras family proteins. In cancer cells associated with dependence on mutant Ras family proteins (e.g., KRAS mutant cancer cell lines), such binders / inhibitors are expected to have anti-cancer efficacy (e.g., inhibition of proliferation, survival, metastasis, etc.).

[0006] To date, no inhibitors of G12C mutant Ras family proteins have been approved for treatment. In recent years, first-line drugs for KRAS G12C have entered clinical development, and sotorasib and adagrasib are already in advanced stages of treatment for KRAS G12C-driven lung cancer (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 inhibitors of G12C mutant Ras family proteins suitable for clinical use. DETAILED DESCRIPTION OF THE INVENTION

[0007] compound Surprisingly, compounds of formula (I) (R 1a , R 1b , R 2a , R 2b , Z, R 3 , R 5 It has now been found that compounds of formula (I) (wherein A, p, U, V, W, L, and E have the meanings given hereinafter) act as inhibitors of G12C mutant Ras family proteins involved in the control of cell proliferation, have anti-tumor activity, and are useful for inhibiting uncontrolled cell proliferation resulting from malignant diseases. This anti-tumor activity is believed to derive from the inhibition of G12C mutant Ras family proteins, particularly KRAS G12C, which is a key mediator of proliferation and survival in certain tumor cells. The compounds according to the present invention are further believed to interact with G12C mutant Ras family proteins, particularly KRAS G12C, and then covalently bond thereto (as confirmed by crystallography for KRAS G12C) via an electrophilic moiety (e.g., a Michael acceptor) present in the compound of formula (I). Upon covalent binding to a G12C mutant Ras family protein, particularly KRAS G12C, which most likely occurs at position 12 of a Ras family protein, the compound impairs or substantially eliminates the ability of the G12C Ras family protein to access its active, pro-growth / pro-survival conformation.

[0008] Indeed, binding of compounds of formula (I) according to the present invention can result in selective and highly potent antiproliferative cellular activity and a wide range of selectivity in G12C mutant KRAS cell lines compared to wild-type KRAS cells. This superior potency can potentially lead to lower systemic exposure and / or doses required for full efficacy in humans, thus resulting in better / better tolerability (e.g., lower risk of idiosyncratic toxicity), and, if necessary, more potent targeting of the pathway, providing benefits and leading to improved therapeutic flexibility in combination therapy. The compounds exhibit potent biomarker modulation, e.g., pERK, in G12C mutant KRAS cell lines. Selected compounds have been tested in selectivity panels and show good selectivity against other human targets, e.g., kinases. Last but not least, selected compounds disclosed herein have been tested and show good permeability, excellent solubility, and finely tunable PK properties.

[0009] Thus, in a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, [A0] R 1a and R 1b Both are 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 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; R 2a and R 2b Both are 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)2, C 3-5 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; and / or R 1a or R 1b One of the R 2a or R 2b together with the carbon atoms to which they are attached may form a cyclopropane ring; [B0] Z is -(CR 6a R 6b ) n - and R 6a and R 6b are hydrogen and 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 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2;

[0010] [C0] R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -CN, C 3-5 selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; [D0] Ring A is oxadiazole or thiadiazole; [E0] U is nitrogen (=N-) and R A Carbon substituted by (=C(RA )-) selected from the group consisting of V is nitrogen (=N-) and R B Carbon substituted by (=C(R B )-) selected from the group consisting of W is nitrogen (=N-) and R C Carbon substituted by (=C(R C )-) selected from the group consisting of R A , R B and R C is hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), 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, -SC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-5 Cycloalkyl, 3- to 5-membered heterocyclyl and C 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) and -C(=O)N(C 1-4 each independently selected from the group consisting of (alkyl), (which may be substituted with a substituent selected from the group consisting of alkyl); [F0] R 5 is R a1 and R b1 is selected from the group consisting of R a1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be one or more of the same or different R b1 and / or R c1 and optionally substituted by R b1 are respectively -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 the divalent substituent =O;

[0011] R c1 are hydrogen and 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, C6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively -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 the divalent substituent =O; R e1 are hydrogen and 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 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5-10 membered heteroaryls are C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl (one or more of the same or different C 1-4 optionally substituted with 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 and optionally substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; [G0] L is -L 1 -L 2 -L 3 - and L 1 is connected to E, L 1 is 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 selected from the group consisting of cycloalkylene, phenylene, 4- to 12-membered heterocyclylene, and 5- to 10-membered heteroarylene; L 2 is C 1-6 Alkylene, C 3-7 selected from the group consisting of cycloalkylene, phenylene, 4- to 12-membered heterocyclylene, and 5- to 10-membered heteroarylene; L 3 is 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 selected from the group consisting of cycloalkylene, phenylene, 4- to 12-membered heterocyclylene, and 5- to 10-membered heteroarylene;

[0012] L 1 , L 2 and L 3 C in 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4- to 12-membered heterocyclylene, and 5- to 10-membered heteroarylene are each 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), -C(=O)OH, -C(=O)-OC 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl)2, divalent substituents =O and C 1-6 Alkyl (halogen, -OH, -CN, C 1-4 Alkoxy, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl), -C(=O)OH, -C(=O)-OC 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl) and -C(=O)N(C 1-4alkyl) which may be independently substituted with one or more identical or different substituents selected from the group consisting of [H0] E is

[0013] [ka] and [ka] represents a double or triple bond, Q 1 is 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 )-, R G1 are hydrogen and 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 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; R H1 are hydrogen, -OH, and C, respectively. 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl,

[0014] [ka] If represents a double bond, R D is hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, -CN, C 1-6 Alkoxy, -C(=O)OC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl and C 1-6 Alkyl (phenyl, 3-11 membered heterocyclyl, C 1-6 Alkoxy, halogen, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -C(=O)OH, -C(=O)OC 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), which may be substituted with one or more identical or different substituents selected from the group consisting of R E and R F is R a2 and R b2 are each independently selected from the group consisting of: R a2 is 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; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be one or more of the same or different R b2 and / or R c2 and optionally substituted by R b2 are respectively -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 the divalent substituent =O; R c2 are hydrogen and 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 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5-10 membered heteroaryls are C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -OH, -C(=O)OH, -C(=O)OC 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 and optionally substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; or R D and R Etogether with the carbon atoms to which they are attached, form a 4- to 7-membered unsaturated alicyclic ring or a 4- to 7-membered unsaturated heterocyclic ring, and this 4- to 7-membered unsaturated alicyclic ring or 4- to 7-membered unsaturated heterocyclic ring is F In addition, C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -NH2, -CN, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, halogen, -C(=O)OC 1-6 optionally substituted with one or more identical or different substituents selected from the group consisting of alkyl and the divalent substituent =O; or Q 1 But -C(=O)N(R G1 )-, -C(=O)N(R G1 )-R G1 and R F together form a linker selected from the group consisting of -C(=O)-, -CH2-, -CH2-C(=O)-, -C(=O)-CH2- and -C2H4-;

[0015] [ka] represents a triple bond, R D and R E is neither present, R F is R a2 and R a2 is 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; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10All aryls and 5- to 10-membered heteroaryls may be one or more of the same or different R b2 and / or R c2 and optionally substituted by R b2 are respectively -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 the divalent substituent =O; R c2 are hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; or E is

[0016] [ka] and Q 2 is 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 )-, R G2 are hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy-C1-6 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 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; R H2 are hydrogen, -OH, and C, respectively. 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R I is selected from the group consisting of hydrogen and halogen; R J is hydrogen, or R I and R J together with the carbon atoms to which they are attached form a cyclopropane or oxirane ring, R K is hydrogen, C 1-6 selected from the group consisting of alkyl, —CN, and halogen; R L is hydrogen, C 1-6 Alkyl, -CN, halogen and -C(=O)-C 1-6 is selected from the group consisting of alkyl, or E is

[0017] [ka] and Q 3 -C(=O)-, -C(=O)N(R G3 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G3 )- and -C(=NR H3 )-, R G3 are hydrogen and C 1-6Alkyl, 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 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; R H3 are hydrogen, -OH, and C, respectively. 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R M is halogen, -CN and -OC(=O)-C 1-6 is selected from the group consisting of alkyl, or E is

[0018] [ka] and Q 4 is a bond, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C 1-4 -S(=O)2-, -S(=O)2NH-, -S(=O)2 ... Ring B is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, and 5-membered heteroaryl; q is selected from the group consisting of 1, 2, 3 and 4; R N are respectively, C 1-4 Alkyl, C 1-4 Haloalkyl, vinyl, ethinyl, halogen, -CN, nitro and C 1-4 alkoxy) or a salt thereof.

[0019] In a second aspect, the present invention provides a compound of formula (I * ) or a salt thereof [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , Ring A, U, V, W, R 5 , L and E are defined as in formula (I) in the first aspect).

[0020] In a third aspect, the present invention provides a compound of formula (Ia) or a salt thereof [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 , L and E are defined as in formula (I) in the first aspect).

[0021] In a fourth aspect, the present invention provides a compound of formula (Ia * ) or a salt thereof [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 , L and E are defined as in formula (I) in the first aspect).

[0022] Compound (I * ), (Ia) and (Ia * ) are each a subset of compound (I), and whenever compound (I) is mentioned, unless otherwise specified, this also includes compound (I* ), (Ia) and (Ia * ) are also intended to refer to and include these. Compound (Ia * ) is a subset of the individual compounds (Ia), and whenever compound (Ia) is mentioned, unless otherwise specified, this also includes compound (Ia * ), which should be understood to be intended to refer to and include the same. The following structural aspects represent preferred embodiments [A1]-[A3], [B1]-[B5], [C1]-[C5], [D1]-[D2], [E1]-[E9], [F1]-[F8], [G1]-[G3] and [H1]-[H8] of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0] and [H0], respectively.

[0023] In one aspect [A1], the present invention provides a method for manufacturing a semiconductor device comprising: R 1a and R 1b Both hydrogen and C 1-4 independently selected from the group consisting of alkyl, R 2a and R 2b are both independently selected from the group consisting of hydrogen and halogen; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [A2], the present invention provides a method for manufacturing a pharmaceutical composition comprising: R 1a and R 1b are both independently selected from the group consisting of hydrogen and methyl; R 2a and R 2b are both independently selected from the group consisting of hydrogen and fluorine; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [A3], the present invention provides a method for manufacturing a semiconductor device comprising: R 1a , R 1b , R2a and R 2b is hydrogen, Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [B1], the present invention provides a method for manufacturing a pharmaceutical composition comprising: Z is -(CR 6a R 6b ) n - and n is 0 Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0024] In another aspect [B2], the present invention provides a method for manufacturing a semiconductor device comprising: Z is -(CR 6a R 6b ) n - and n is 1, R 6a and R 6b Both are 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 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [B3], the present invention provides a method for manufacturing a semiconductor device comprising: Z is -CH2-; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0025] In another aspect [B4], the present invention provides a method for manufacturing a semiconductor device comprising: Z is -(CR 6a R 6b )n - and n is 2, R 6a and R 6b are hydrogen and C, respectively. 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 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [B5], the present invention provides a method for manufacturing a semiconductor device comprising: Z is -CH2-CH2-, Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0026] In another aspect [C1], the present invention provides a method for producing a composition comprising: R 3 But 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 selected from the group consisting of -alkyl)2 and -CN; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0027] In another aspect [C2], the present invention provides a method for producing a composition comprising: R 3is selected from the group consisting of hydrogen, methyl, ethyl, —CF3, —CHF2, methoxy, trifluormethoxy, cyanomethyl, —OH, and —CN; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [C3], the present invention provides a method for producing a composition comprising: R 3 is hydrogen, Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [C4], the present invention provides a method for producing a composition comprising: R 3 But C 1-4 is alkyl, Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [C5], the present invention provides a method for producing a composition comprising: R 3 is methyl, Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0028] In another aspect [D1], the present invention provides a method for manufacturing a semiconductor device comprising: Ring A is [ka] selected from the group consisting of Formula (I) or (I * ) or a salt thereof.

[0029] In another aspect [D2], the present invention provides a method for manufacturing a semiconductor device comprising: Ring A is [ka] That is, Formula (I) or (I * ) or a salt thereof.

[0030] In another aspect [E1], the present invention provides a method for producing a composition comprising: U is R A Carbon substituted by (=C(R A )-) and V is R B Carbon substituted by (=C(R B )-) and W is nitrogen (=N-), R A and R B But hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), 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- to 5-membered heterocyclyl and C 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) and -C(=O)N(C 1-4 each independently selected from the group consisting of (alkyl) and (optionally substituted with a substituent selected from the group consisting of alkyl) Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [E2], the present invention provides a method for producing a composition comprising: U is =CH-, V is ═CH—; W is nitrogen (=N-), Formula (I), (I * ), (Ia) or (Ia* ) or a salt thereof.

[0031] In another aspect [E3], the present invention provides a method for producing a composition comprising: U is R A Carbon substituted by (=C(R A )-) and V is R B Carbon substituted by (=C(R B )-) and W is R C Carbon substituted by (=C(R C )-) and R A , R B and R C are hydrogen and C, respectively. 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), 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- to 5-membered heterocyclyl and C 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) and -C(=O)N(C 1-4 each independently selected from the group consisting of (alkyl) and (optionally substituted with a substituent selected from the group consisting of alkyl) Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0032] In another aspect [E4], the present invention provides a method for producing a composition comprising: U is =CH-, V is ═CH—; W is =CH-; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0033] In another aspect [E5], the present invention provides a method for producing a composition comprising: U is nitrogen (=N-), V is R B Carbon substituted by (=C(R B )-) and W is nitrogen (=N-), R B But hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), 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- to 5-membered heterocyclyl and C 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) and -C(=O)N(C 1-4 alkyl)2) optionally substituted with a substituent selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [E6], the present invention provides a method for producing a composition comprising: U is nitrogen (=N-), V is ═CH—; W is nitrogen (=N-), Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0034] In another aspect [E7], the present invention provides a method for producing a composition comprising: U is R A Carbon substituted by (=C(R A )-) and V is nitrogen (=N-), W is nitrogen (=N-), R A But hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), 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- to 5-membered heterocyclyl and C 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) and -C(=O)N(C 1-4 alkyl)2) optionally substituted with a substituent selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0035] In another aspect [E8], the present invention provides a method for producing a composition comprising: U is R A Carbon substituted by (=C(R A)-) and V is nitrogen (=N-), W is nitrogen (=N-), R A is selected from the group consisting of hydrogen and halogen; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0036] In another aspect [E9], the present invention provides a method for producing a composition comprising: U is nitrogen (=N-), V is nitrogen (=N-), W is nitrogen (=N-), Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0037] In another aspect [F1], the present invention provides a method for producing a composition comprising: R 5 But R a1 and R b1 is selected from the group consisting of R a1 But 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; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl may be one or more of the same or different R b1 and / or R c1 and optionally substituted by R b1 are respectively, -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 the divalent substituent =O; R c1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl may be one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively, -OR e1 , -NR e1 R e1 , halogen, -CN, -C(=O)R e1 , -C(=O)NR e1 R e1 and the divalent substituent =O; R e1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls are C 1-6Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl (one or more of the same or different C 1-4 optionally substituted with 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 optionally substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0038] In another aspect [F2], the present invention provides a method for producing a composition comprising: R 5 But R a1 and R a1 are selected from the group consisting of 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl, and all of the 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl are selected from the group consisting of one or more of the same or different R b1 and / or R c1 and optionally substituted by R b1 are respectively, -OR c1 , -NR c1 R c1 , halogen, -C(=O)OR c1 and the divalent substituent =O; R c1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; 1-6 Alkyl, C 1-6Haloalkyl, C 3-10 All of the cycloalkyl and 3- to 11-membered heterocyclyl groups may be one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively, -OR e1 , -NR e1 R e1 and halogen; R e1 are hydrogen and C, respectively. 1-6 Alkyl, C 3-10 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; 1-6 Alkyl, C 3-10 Cycloalkyl and 3- to 11-membered heterocyclyl are all C 1-6 Alkyl and 3-11 membered heterocyclyl (one or more of the same or different C 1-4 and optionally substituted by one or more identical or different substituents selected from the group consisting of: Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0039] In another aspect [F3], the present invention provides a method for producing a composition comprising: R 5 but, [ka] R selected from the group consisting of a1 and R a1 each of which is one or more identical or different R b1 and / or R c1 and optionally substituted by R b1 are respectively, -OR c1 , -NR c1 R c1 , halogen, -C(=O)OR c1 and the divalent substituent =O; R c1are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 All of the cycloalkyl and 3- to 11-membered heterocyclyl groups may be one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively, -OR e1 , -NR e1 R e1 and halogen; R e1 are hydrogen and C, respectively. 1-6 Alkyl, C 3-10 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; 1-6 Alkyl, C 3-10 Cycloalkyl and 3- to 11-membered heterocyclyl are all C 1-6 Alkyl and 3-11 membered heterocyclyl (one or more of the same or different C 1-4 and optionally substituted by one or more identical or different substituents selected from the group consisting of: Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0040] In another aspect [F4], the present invention provides a method for producing a composition comprising: R 5 but, [ka] R selected from the group consisting of a1 and R a1 each represents one or more of the same or different, C 3-6 Cycloalkyl, hydroxy, -NH2, -NH(C 1-4alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkoxy and 3- to 7-membered heterocyclyl (C 1-4 optionally substituted by one or more identical or different substituents selected from the group consisting of C 1-6 Alkyl C, optionally substituted with one or more of the same or different halogens 3-6 cycloalkyl C 1-4 Alkyl, C 3-6 3- to 11-membered heterocyclyl optionally substituted with one or more identical or different substituents selected from the group consisting of cycloalkyl and halogen, and Halogens, -C(=O)-OC 1-6 Alkyl, C 1-6 Haloalkyl, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 a substituent selected from the group consisting of alkyl)2 and the divalent substituent =O optionally substituted by Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [F5], the present invention provides a method for producing a composition comprising: R 5 but,

[0041] [ka] [ka] [ka]

[0042] selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [F6], the present invention provides a method for producing a composition comprising: R 5 But R b1 and R b1 But, -OR c1 and -NR c1 R c1 are independently selected from the group consisting of R c1 are hydrogen and C, respectively. 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively, -OR e1 , -NR e1 R e1 , halogen, -C(=O)R e1 and -C(=O)NR e1 R e1 are independently selected from the group consisting of R e1 are hydrogen and C, respectively. 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5-10 membered heteroaryls are C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl (one or more of the same or different C 1-4 optionally substituted with alkyl), C 1-6optionally substituted with one or more identical or different substituents selected from the group consisting of alkoxy, halogen and the divalent substituent =O, Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0043] In another aspect [F7], the present invention provides a method for producing a composition comprising: R 5 But R b1 and R b1 But, -OR c1 and R c1 are respectively, C 1-6 Alkyl, C 3-10 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; 1-6 Alkyl, C 3-10 All of the cycloalkyl and 3- to 11-membered heterocyclyl groups may be one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively, -NR e1 R e1 and halogen; R e1 are hydrogen and C, respectively. 1-6 independently selected from the group consisting of alkyl and 3- to 11-membered heterocyclyl; 1-6 All alkyl and 3- to 11-membered heterocyclyl are C 1-6 Alkyl and 3-11 membered heterocyclyl (one or more of the same or different C 1-4 and optionally substituted by one or more identical or different substituents selected from the group consisting of: Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0044] In another aspect [F8], the present invention provides a method for producing a composition comprising: R 5but, [ka] selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0045] In another aspect [G1], the present invention provides a method for producing a composition comprising: L is -L 1 -L 2 -L 3 - and L 1 is connected to E, L 1 But, bond, C 1-6 selected from the group consisting of alkylene and 4- to 12-membered heterocyclylene; L 2 But C 1-6 selected from the group consisting of alkylene, phenylene, and 4- to 12-membered heterocyclylene; L 3 is a bond, -NH-, -N(C 1-4 is selected from the group consisting of -alkyl)- and -O-; L 1 and L 2 C in 1-6 Alkylene, phenylene and 4- to 12-membered heterocyclylene are each 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), -C(=O)OH, -C(=O)-OC 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl)2, divalent substituents =O and C 1-6 Alkyl (halogen, -OH, -CN, -NH2, C 1-4 Alkoxy, -NH(C 1-4alkyl), -N(C 1-4 alkyl), -C(=O)OH, -C(=O)-OC 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl) and -C(=O)N(C 1-4 alkyl) which may be independently substituted with one or more identical or different substituents selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0046] In another aspect [G2], the present invention provides a method for producing a composition comprising: L is -L 1 -L 2 -L 3 - and L 1 is connected to E, L 1 But, bond, C 1-6 selected from the group consisting of alkylene and 4- to 12-membered heterocyclylene; L 2 But C 1-6 selected from the group consisting of alkylene, phenylene, and 4- to 12-membered heterocyclylene; L 3 is a bond, -NH-, -N(C 1-4 is selected from the group consisting of -alkyl)- and -O-; L 1 and L 2 C in 1-6 Alkylene, phenylene and 4- to 12-membered heterocyclylene are each independently one or more of the same or different C 1-6 optionally substituted independently by alkyl; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [G3], the present invention provides a method for manufacturing a semiconductor device comprising: L,

[0047] [ka] [ka]

[0048] selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [H1], the present invention provides a method for manufacturing a pharmaceutical composition comprising: E is, [ka] and Q 1 is -CH2-, -C(=O)-, -C(=O)N(R G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 )- and -C(=NR H1 )-, R G1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl and Hydroxy-C 1-6 independently selected from the group consisting of alkyl, R H1 are hydrogen, -OH, and C, respectively. 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R D But hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, -CN, C 1-6 Alkoxy, -C(=O)OC 1-6 Alkyl and C 1-6 Alkyl (phenyl, 3-11 membered heterocyclyl, C 1-6 Alkoxy, halogen, -OH, -N(C 1-6 alkyl), -C(=O)OH, -C(=O)OC 1-6 Alkyl, -C(=O)NH(C 1-6 alkyl), -NHC(=O)-C 1-6Alkyl, -OC(=O)-C 1-6 Alkyl and phenyl-C 1-6 alkoxy), which may be substituted with one or more identical or different substituents selected from the group consisting of R E and R F But R a2 and R b2 are each independently selected from the group consisting of: R a2 But 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; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be one or more of the same or different R b2 and / or R c2 and optionally substituted by R b2 are respectively, -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 are independently selected from the group consisting of R c2 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, 3-11 membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; 1-6 Alkyl, C 1-6Haloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryls and 5-10 membered heteroaryls are C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -OH, -C(=O)OH, -C(=O)OC 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 optionally substituted with one or more identical or different substituents selected from the group consisting of alkyl)2 and the divalent substituent =O; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0049] In another aspect [H2], the present invention provides a method for producing a composition comprising: E is, [ka] and Q 1 -CH2-, -C(=O)-, -C(=O)NH- and -C(=O)N(C 1-4 is selected from the group consisting of alkyl)-; R D However, hydrogen, halogens and C 1-6 is selected from the group consisting of alkyl, R E and R F But R a2 and R b2 are each independently selected from the group consisting of: R a2 But hydrogen and C 1-6 alkyl, C 1-6 Alkyl can be one or more of the same or different R b2 and / or R c2 and optionally substituted by R b2 are respectively, -OR c2 and -C(=O)NR c2 R c2are independently selected from the group consisting of R c2 are respectively, C 1-6 independently selected from the group consisting of alkyl and 3- to 11-membered heterocyclyl; Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [H3], the present invention provides a method for producing a composition comprising: E is,

[0050] [ka] [ka] [ka] [ka] [ka] selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0051] In another aspect [H4], the present invention provides a method for producing a composition comprising: E is, [ka] selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0052] In another aspect [H5], the present invention provides a method for manufacturing a pharmaceutical composition comprising: E is, [ka] and Q 1 is -CH2-, -C(=O)-, -C(=O)N(R G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 )- and -C(=NR H1 )-, R G1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl and Hydroxy-C 1-6 independently selected from the group consisting of alkyl, R H1 are hydrogen, -OH, and C, respectively. 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R F But hydrogen and C 1-6 Alkyl (-OH, C 1-6 Alkoxy, -NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2) optionally substituted with a substituent selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0053] In another aspect [H6], the present invention provides a method for manufacturing a semiconductor device comprising: E is, [ka] and Q 1 -C(=O)-, -C(=O)N(R G1 )-, -S(=O)2- and -S(=O)2N(R G1 )-, R G1 are hydrogen and C, respectively. 1-6 independently selected from the group consisting of alkyl, R F But hydrogen and C 1-6 Alkyl (-OH, C 1-6Alkoxy, -NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2) optionally substituted with a substituent selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof.

[0054] In another aspect [H7], the present invention provides a method for manufacturing a semiconductor device comprising: E is, [ka] selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. In another aspect [H8], the present invention provides a method for manufacturing a semiconductor device comprising: E is,

[0055] [ka]

[0056] selected from the group consisting of Formula (I), (I * ), (Ia) or (Ia * ) or a salt thereof. 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 all preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0], and [H0], respectively. * ), (Ia) and (Ia *The structural aspects [A0]-[A3], [B0]-[B5], [C0]-[C5], [D0]-[D3], [E0]-[E9], [F0]-[F8], [G0]-[G3] and [H0]-[H8] relating to the different molecular parts of the compounds of (I), (I * ), (Ia) and (Ia * ) to obtain the combinations [A][B][C][D][E][F][G][H] (formula (I) and (I * )) and combinations [A][B][C][E][F][G][H] (for compounds of formula (Ia) and (Ia * In the case of compounds of formula (I) and (I), they may be combined with each other if desired. Such combinations [A][B][C][D][E][F][G][H] are compounds of formula (I) and (I * Each of these combinations [A][B][C][E][F][G][H] represents and defines an individual embodiment or general subset of compounds (Ia) and (Ia) according to the present invention. * ) represents and defines an individual embodiment or a general subset of.

[0057] Preferred embodiments of the present invention according to formula (Ia) are Example compounds Ia-1 to Ia-170, and any subset thereof. The present invention relates to a compound of formula (I), (I * ), (Ia) and (Ia * The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of the compound of formula (I), including all embodiments thereof. The present invention relates to a compound of formula (I), (I * ), (Ia) and (Ia * ) (including all of its embodiments). The present invention relates to a compound of formula (I), (I * ), (Ia) and (Ia * ) (including all embodiments thereof). For example, the formula (I) having an ester group, * ), (Ia) and (Ia *) (including all of its embodiments) are potential prodrugs, the esters being cleaved under physiological conditions and also becoming part of the present invention. The present invention relates to a compound of formula (I), (I * ), (Ia) and (Ia * ) (including all of its embodiments). The present invention relates to a compound of formula (I), (I * ), (Ia) and (Ia * ) with an organic or inorganic acid or an organic base, including all of its embodiments.

[0058] Intermediates In a fifth aspect, the present invention provides a compound of formula (II) or a salt thereof [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , Ring A, U, V, W, R 5 and L is defined as in formula (I) in the first aspect).

[0059] The compounds of formula (II) are intermediates in the synthesis of compounds of formula (I) (the hydrogen in the residue HL- is replaced / substituted by the group E in the last synthetic step).

[0060] In a sixth aspect, the present invention provides a compound of formula (II * ) or a salt thereof [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , Ring A, U, V, W, R 5and L is defined as in formula (I) in the first aspect).

[0061] In a seventh aspect, the present invention provides a compound of formula (B-5) or a salt thereof: [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 and L is defined as in formula (I) in the first aspect).

[0062] In an eighth aspect, the present invention provides a compound of formula (B-5 * ) or a salt thereof [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , U, V, W, R 5 and L is defined as in formula (I) in the first aspect).

[0063] Compound (II * ), (B-5) and (B-5 * ) are each a subset of compound (II), and whenever compound (II) is mentioned, unless otherwise specified, this also includes compound (II) * ), (B-5) and (B-5 * ) are also intended to refer to and include these. Compound (B-5 * ) is a subset of the individual compounds (B-5), and whenever compound (B-5) is mentioned, unless otherwise specified, this also includes compound (B-5 * ), which should be understood to be intended to refer to and include the same. Formula (I), (I * ), (Ib), (Ib * ), (Ic), (Ic * ), (Id), (Id * ), (Ie) and (Ie * All 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], which are disclosed as 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 * ) are also preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0] and [G0] of the compounds of formula (I).

[0064] Therefore, the formula (II), (II * ), (B-5) and (B-5 * These structural aspects [A0]-[A3], [B0]-[B5], [C0]-[C5], [D0]-[D2], [E0]-[E9], [F0]-[F8] and [G0]-[G3], which relate to different molecular parts of the compound of formula (II), (II * ), (B-5) and (B-5 * ) to obtain the preferred compounds of the formula (II) and (II * )) and combinations [A][B][C][E][F][G] (in the case of compounds of formula (B-5) and (B-5 * In the case of compounds of formula (II) and (II), these combinations [A][B][C][D][E][F][G] may be combined with each other if desired. * Each of these combinations [A][B][C][E][F][G] represents and defines an individual embodiment or general subset of compounds of formula (B-5) and (B-5 * ) represents and defines an individual embodiment or general subset of compounds of

[0065] Pharmaceutical Composition The compounds of formula (I), (I * ), (Ia) or (Ia * Suitable pharmaceutical compositions for administering the compounds of formula (I), (I) will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, particularly injectable solutions (subcutaneous, intravenous, intramuscular), and infusions (injectables), elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. * ), (Ia) or (Ia * The content of the active ingredient (s) should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. The specified dose may be administered several times a day as needed. A suitable tablet contains Compound (I), (I * ), (Ia) or (Ia * ) with known pharmaceutically acceptable excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. The tablet may also comprise several layers.

[0066] Thus, coated tablets can be prepared by coating a core similar to that of a tablet with an excipient typically used in tablet coatings, such as collidone, shellac, gum arabic, talc, titanium dioxide, or sugar. The core may also consist of several layers to achieve delayed release or to prevent incompatibilities. Similarly, tablet coatings may consist of several layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

[0067] One or more compounds (I), (I * ), (Ia) or (Ia *Syrups or elixirs containing the compound (I), or a combination thereof with one or more other pharmaceutically active substances, may further contain excipients such as sweeteners, such as saccharin, cyclamate, glycerol or sugar, and flavor enhancers, e.g., flavorings, such as vanillin or orange extract. They may also contain excipients such as suspension adjuvants or thickeners, e.g., sodium carboxymethylcellulose, wetting agents, e.g., condensation products of fatty alcohols with ethylene oxide, or preservatives, e.g., p-hydroxybenzoates.

[0068] Solutions for injection and infusion are prepared in the usual manner by adding excipients such as an isotonic agent, a preservative such as p-hydroxybenzoate, and a stabilizer such as an alkali metal salt of ethylenediaminetetraacetic acid (emulsifying agents and / or dispersing agents may also be used); however, when water is used as a diluent, an organic solvent may be used as a solubilizing agent or dissolution aid, and the solution may be transferred into an injection vial, an ampoule, or an infusion bottle. One or more compounds (I), (I * ), (Ia) or (Ia * ), or a combination with one or more other pharmaceutically active substances, can be prepared, for example, by mixing the compound / active substance with an inert excipient such as lactose or sorbitol and filling it into a gelatin capsule. Suitable suppositories may be prepared, for example, by mixing with excipients which achieve this purpose, such as neutral fats or polyethylene glycol or derivatives thereof. Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents (such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol)), carriers (such as natural inorganic powders (e.g., kaolin, clay, talc, chalk), synthetic inorganic powders (e.g., highly dispersed silicic acid and silicates)), sugars (e.g., cane sugar, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite pulp liquor, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0069] This pharmaceutical composition is administered by conventional methods, preferably by oral or transdermal route, most preferably by oral route.For oral administration, in addition to the above-mentioned excipients, tablets may naturally contain additional excipients such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various excipients such as starch, preferably potato starch, gelatin, etc.In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used at the same time in the tableting process.For aqueous suspensions, active substances may be combined with various flavor enhancers or colorants in addition to the above-mentioned excipients. For parenteral use, solutions of the active substances with suitable liquid excipients may be used. Applicable daily formula (I), (I * ), (Ia) or (Ia * The dosage range of the compound of formula (1) is usually 1 mg to 2000 mg, preferably 250 to 1250 mg.

[0070] However, it may sometimes be necessary to deviate from the specified amount (single or multiple doses per day, continuous or intermittent treatment) depending on the body weight, age, route of administration, severity of the disease, individual response to the drug, the nature of its formulation, and the time or interval at which the drug is administered. Thus, in some cases, it may be sufficient to use less than the minimum dose indicated above, while in other cases the upper limit may have to be exceeded. When administering larger amounts, it may be advisable to divide them into several smaller doses over the course of a day. Thus, in a further aspect, the present invention provides a compound 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.

[0071] Formula (I), (I * ), (Ia) or (Ia * ), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts, may also be co-administered, i.e., used in combination, with other pharmacologically active substances, such as other anti-neoplastic compounds (e.g., chemotherapy) (see further below, Combination Therapy).

[0072] The elements of such combinations may be administered by methods conventional to those skilled in the art (depending or independently), and when used in monotherapy, for example, by oral, enteral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or implant), nasal, vaginal, rectal, or topical routes of administration, and may be formulated, either alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration. The combination may be administered in a single therapeutically effective dose or in divided doses per day. The active components of the combination may be administered in such doses that are therapeutically effective in monotherapy, or in such doses that are lower than those used in monotherapy but which, in combination, provide the desired (joint) therapeutically effective amount.

[0073] However, when the combined use of two or more active substances or ingredients produces a synergistic effect, it may be possible to reduce the amount of one, more, or all of the substances or ingredients administered while still achieving the desired therapeutic effect. For example, this may be useful to avoid, limit, or reduce any undesirable side effects associated with the use of one or more substances or ingredients when the substances or ingredients are used in their normal amounts, while still achieving the desired pharmacological or therapeutic effect. Thus, in a further aspect, the present invention also provides compounds 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. In a further aspect, the present invention also provides compounds 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. Pharmaceutical compositions to be co-administered or used in combination may also be supplied in the form of a kit.

[0074] Thus, in a further aspect, the present invention also provides a method for treating a pulmonary arthritis with a pulmonary arthritis virus, comprising: Formula (I), (I * ), (Ia) or (Ia * a first pharmaceutical composition or dosage form comprising a compound of formula (I) and optionally one or more pharmaceutically acceptable excipients; and A second pharmaceutical composition or dosage form containing another pharmacologically active agent and optionally containing one or more pharmaceutically acceptable excipients. The present invention relates to a kit comprising: In one embodiment, such a kit comprises a third pharmaceutical composition or dosage form that comprises yet another pharmacologically active agent and optionally one or more pharmaceutically acceptable excipients.

[0075] Medical Use - Treatment Methods Indications - Patient Populations The present invention relates to RAS G12C inhibitors, particularly those represented by formula (I), (I * ), (Ia) and (Ia * ) (including all of its embodiments), which are potentially useful in the treatment and / or prevention of diseases and / or conditions mediated by RAS G12C mutations, such as, preferably, KRAS G12C, NRAS G12C and HRAS G12C. Thus, in a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention relates to a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof.

[0076] In a further aspect, the present invention provides a method for treating and / or preventing a disease and / or condition mediated by a RAS G12C mutation, comprising administering a therapeutically effective amount of a compound represented by formula (I), (I * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof to a human. In a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention relates to a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention provides a method for treating and / or preventing cancer, comprising administering a therapeutically effective amount of a compound represented by formula (I), (I * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof to a human. In a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention relates to a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention provides a method for achieving an inhibitory effect on G12C mutant RAS, comprising administering a therapeutically effective amount of a compound represented by formula (I), (I * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof to a human.

[0077] Another aspect relates to the G12C mutation status of a patient and the presence of a compound of formula (I), (I * ), (Ia) or (Ia * The purpose of this study is to identify a relationship between the likelihood of susceptibility to treatment with a compound of formula (I), (I * ), (Ia) or (Ia * RAS G12C inhibitors such as the compounds of formula (I), (I) can be advantageously used to treat patients with KRAS G12C, HRAS G12C or NRAS G12C mutations, which may be resistant to other therapies. * ), (Ia) or (Ia * This provides an opportunity, a way and a means for selecting patients, particularly cancer patients, for treatment with a compound of formula (I), (I). This selection is based on whether the tumor cells to be treated have a wild-type or G12C mutant KRAS, HRAS or NRAS gene. Thus, the G12C KRAS, HRAS or NRAS gene status can be determined by the compound of formula (I), (I * ), (Ia) or (Ia * ) can be used as a biomarker to indicate that there may be an advantage in selecting treatment with a compound.

[0078] According to one embodiment, the compound of formula (I), (I * ), (Ia) or (Ia * 1. A method for selecting a patient for treatment with a compound of formula (I), comprising: providing a sample containing tumor cells from a patient; determining whether the RAS gene in the patient's tumor cell-containing sample encodes a wild-type (glycine at position 12) or mutant (cysteine ​​at position 12) KRAS, HRAS, or NRAS protein; and Based on the above determination, the formula (I), (I * ), (Ia) or (Ia * selecting a patient for treatment with the compound of A method is provided, comprising: The method may or may not include the step of isolating the actual patient sample. In one embodiment, the patient is treated with a medicament comprising ... * ), (Ia) or (Ia * ) is selected for treatment with a compound of formula (I). In another embodiment, the patient is treated with a medicament comprising ... * ), (Ia) or (Ia * ) is selected for treatment with a compound of formula (I). In another embodiment, the patient is treated with a compound of formula (I), (I) if the tumor cell DNA has a G12C mutation in the NRAS gene. * ), (Ia) or (Ia * ) is selected for treatment with a compound of formula (I). According to another aspect, there is provided a compound of formula (I), (I) for use in the treatment of cancer having tumor cells harboring a G12C mutant RAS gene. * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof. According to another aspect, there is provided a compound of formula (I), (I) for use in the treatment of cancer having tumor cells harboring a G12C mutant KRAS gene. * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof. According to another aspect, a compound of formula (I), (I) for use in the treatment of cancer having tumor cells harboring a G12C mutant HRAS gene is provided. * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof. According to another aspect, a compound of formula (I), (I) for use in treating cancer having tumor cells harboring a G12C mutant NRAS gene is provided.* ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof. According to another aspect, there is provided a method for treating cancer having tumor cells harboring a G12C mutant RAS gene, comprising administering an effective amount of a compound of formula (I), (I * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof to a human.

[0079] According to another aspect, there is provided a method for treating cancer having tumor cells harboring a G12C mutant KRAS, HRAS, or NRAS gene, comprising administering to said cancer a therapeutically effective amount of a compound of formula (I), (I * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof.

[0080] Determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein, by evaluating the amino acid sequence of the KRAS, HRAS, or NRAS protein, or by evaluating the characteristics of a 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 KRAS, HRAS, or NRAS nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) 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, a sample is assessed for a G12C KRAS, HRAS, or NRAS mutation by real-time PCR. Real-time PCR uses a fluorescent probe specific for the KRAS, HRAS, or NRAS G12C mutation. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS, HRAS, or NRAS G12C mutation is identified using direct sequencing of a specific region (e.g., exon 2 and / or exon 3) in the KRAS, HRAS, or NRAS gene. This technique identifies all possible mutations in the sequenced region. Methods for detecting mutations in KRAS, HRAS, or NRAS proteins are known to those skilled in the art. These methods include, but are not limited to, detecting KRAS, HRAS, or NRAS mutations using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis, Western blotting, and direct peptide sequencing.

[0081] The methods for determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In some embodiments, the sample is a liquid biopsy, and the test is performed on a sample of blood to look for cancer cells from the tumor circulating in the blood, or pieces of DNA from tumor cells present in the blood.

[0082] The compounds of formula (I), (I * ), (Ia) or (Ia * The disease / condition / cancer / tumor / cancer cell treated / prevented by a compound of formula (I) 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. In another aspect, the compounds of formula (I), (I * ), (Ia) or (Ia * The disease / condition / cancer / tumor / cancer cell to be treated / prevented by the compound of formula (I), 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.

[0083] Particularly preferred is the production of compounds of formula (I), (I *), (Ia) or (Ia * The cancers treated / prevented by a compound of formula (I) or a pharmaceutically acceptable salt thereof are Lung adenocarcinoma harboring the KRAS G12C mutation (preferably non-small cell lung cancer (NSCLC)) Colorectal adenocarcinoma harboring the KRAS G12C mutation Pancreatic adenocarcinoma harboring the KRAS G12C mutation (preferably pancreatic ductal adenocarcinoma (PDAC)) is selected from the group consisting of:

[0084] Furthermore, the following cancers, tumors and other proliferative diseases can be treated with a compound represented by formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof. Preferably, the methods of treatment, methods, uses, compounds to be used, and pharmaceutical compositions to be used disclosed herein (above and below) are applied to the treatment of diseases / conditions / cancers / tumors (i.e., individual cells) that carry a RAS G12C mutation (preferably a KRAS G12C mutation) or are identified as carrying a RAS G12C mutation (preferably a KRAS G12C mutation) as described and / or referred to herein: Cancers / tumors / carcinomas of the head and neck: for example, tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, and oral mucosa), oropharynx (including base of tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, and pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, and vocal cords), hypopharynx, and salivary glands (including minor salivary glands);

[0085] 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, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma); Mediastinal neoplasms: for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, posterior mediastinal gangliocytoma, neuroblastoma, pheochromocytoma, and paraganglioma), germ cell tumors (including seminoma, teratoma, and non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, and thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal cell tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangiomyopericytoma, and lymphangioleiomyoma); Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., esophagus, stomach (gastric cancer), pancreas, liver and biliary system (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, hybrid HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, and Clark's tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, and ileum) ), large intestine (including cecum, colon, rectum, and anus; colorectal cancer and gastrointestinal stromal tumors (GISTs)), genitourinary system (including kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal gland tumor, and Grawitz tumor; ureter; bladder, e.g., urachal carcinoma and urothelial carcinoma; urethra, e.g., distal, bulbomembranous, and prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, and hormone-refractory), and penis); Cancer / tumor / carcinoma of the testis: e.g., seminoma, non-seminoma, Gynecological cancers / tumors / carcinomas: for example, tumors / carcinomas / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, uterine corpus (including endometrium, fundus);

[0086] Cancers / tumors / carcinomas of the breast: for example, breast adenocarcinoma (invasive ductal, colloid, lobular invasive, tubular, adenoid 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; Cancers / tumors / carcinomas of the endocrine system: for example, endocrine glands, thyroid gland (thyroid carcinoma / tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumors), adrenal cortex (adrenocortical carcinoma / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, tumors / carcinomas / cancer of the carotid body, pancreatic islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; non-functioning PET, PP-producing tumors, gastrinoma, insulinoma, VIP-producing tumors, glucagonoma, somatostatin-producing tumors, GRF-producing tumors, ACTH-producing tumors), carcinoid tumors; Sarcomas of soft tissues: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexus sarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal cell tumor, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdomyosarcoma-like tumor, desmoplastic small cell tumor; Bone sarcomas: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade superficial, small cell, radiation-induced osteosarcoma, and 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, and chondroblastoma; Mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma; Cancers of the skin: for example, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentigo, nodular, and intraocular melanoma), actinic keratosis, and eyelid cancer;

[0087] Neoplasms of the central nervous system and brain: for example, astrocytoma (cerebral, cerebellar, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, round cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, posterior mediastinal ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic nerve), spinal axis tumor; Lymphomas and leukemias: for example, B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), and Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia (ATL)), disease / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastoma B-cell 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), skin T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, and lymphopenic HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / Myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / 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); carcinoma of unknown primary site (CUP); All of the above cancers / tumors / carcinomas, characterized by their particular location / origin in the body, are intended to include both the primary tumor and any metastatic tumors derived therefrom.

[0088] All of the above cancers / tumors / carcinomas can be further differentiated by their histopathological classification: Epithelial cancers, such as squamous cell carcinoma (SCC) (in situ, superficially invasive, verrucous, pseudosarcoma, undifferentiated, transitional, lymphoepithelial), adenocarcinoma (AC) (well differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, fusiform) spindle cell, clear cell, oat cell, colloid, gastric adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumor (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma; Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas. The compounds of the invention may be used in treatment regimens in the first line, second line, or any further line of treatment setting. The compounds of the present invention can be used for the prevention, short-term treatment or long-term treatment of the above diseases / conditions / cancers / tumors, and may also be used in combination with radiation therapy and / or surgery.

[0089] The methods of treatment, methods, uses, and compounds for use disclosed herein (above and below) include compounds of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof, and * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof (each of which is a compound (I), (I * ), (Ia) or (Ia * This can be done with any pharmaceutical composition or kit that includes all or a general subset of the individual embodiments of ).

[0090] Combination treatment Formula (I), (I * ), (Ia) or (Ia * ), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts, may also be co-administered with other pharmacologically active agents, such as other anti-neoplastic compounds (e.g., chemotherapy), or may be used in combination with other treatments, such as radiation or surgical intervention, either as a pre- or post-operative adjuvant. Preferably, the pharmacologically active agent for co-administration is an anti-neoplastic compound.

[0091] Thus, in a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, said compound is administered before, after, or together with one or more other pharmacologically active agents.

[0092] In a further aspect, the present invention relates to a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof, said compound is administered in combination with one or more other pharmacologically active substances. In a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, said compound is administered before, after, or together with one or more other pharmacologically active agents.

[0093] In a further aspect, the present invention relates to a method (e.g., a method for treatment and / or prevention) as defined hereinbefore, comprising administering to a subject a compound of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, is administered before, after, or together with a therapeutically effective amount of one or more other pharmacologically active agents. In a further aspect, the present invention relates to a method (e.g., a method for the treatment and / or prevention) as defined hereinbefore, comprising administering to a subject a compound of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of one or more other pharmacologically active agents.

[0094] In a further aspect, the present invention provides a method for administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I * ), (Ia) or (Ia * A method for treating and / or preventing cancer, comprising administering a compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances. * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof is administered simultaneously, concomitantly, sequentially, consecutively, alternatingly, or separately with one or more other pharmacologically active substances. In a further aspect, the present invention relates to a method for treating and / or preventing cancer, comprising the step of 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 other pharmacologically active substances, wherein the RAS G12C inhibitor (preferably, a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0095] In a further aspect, the present invention provides a compound of formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof, when administered simultaneously, in combination, sequentially, consecutively, alternatingly, or separately with one or more other pharmacologically active substances. In a further aspect, the present invention 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 a KRAS G12C inhibitor), or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other pharmacologically active substances. In a further aspect, the present invention provides a compound comprising: Formula (I), (I * ), (Ia) or (Ia * or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; and A second pharmaceutical composition or dosage form containing another pharmacologically active agent and optionally containing one or more pharmaceutically acceptable excipients. A kit comprising: Kits in which the first pharmaceutical composition is administered simultaneously, concomitantly, sequentially, consecutively, alternatingly, or separately from the second and / or additional pharmaceutical compositions or dosage forms.

[0096] In one aspect, such kit for said use comprises a third pharmaceutical composition or dosage form comprising a third pharmaceutical composition or dosage form that further comprises another pharmacologically active agent and optionally includes one or more pharmaceutically acceptable excipients. In a further embodiment of the present invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use (including all embodiments) according to the present invention are administered simultaneously. In a further embodiment of the present invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the present invention (including all embodiments) are administered concomitantly. In a further embodiment of the present invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use (including all embodiments) according to the present invention are administered sequentially. In a further embodiment of the present invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use (including all embodiments) according to the present invention are administered sequentially. In a further embodiment of the present invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use (including all embodiments) according to the present invention are administered one after the other. In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use (including all embodiments) according to the invention are administered separately.

[0097] together with / in combination with a RAS G12C inhibitor (preferably a KRAS G12C inhibitor), and / or * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof (compound (I), (I * ), (Ia) or (Ia * ), or in the medical uses, methods of treatment and / or prevention as defined herein (above and below), may be selected from any one or more of the following (preferably there are one or two additional pharmacologically active agents used in all of these embodiments):

[0098] 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4), or any mutants thereof Irreversible inhibitors: for example, afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV412, PF-6274484, HKI357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib; b. Reversible inhibitors: e.g., erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW583340; c. Anti-EGFR antibodies: e.g., necitumumab, panitumumab, cetuximab, amivantamab; d. Anti-HER2 antibodies: e.g., pertuzumab, trastuzumab, trastuzumab emtansine; e. Inhibitors of mutant EGFR; f. Inhibitors of HER2 with exon 20 mutations; g. A preferred irreversible inhibitor is afatinib; h. A preferred anti-EGFR antibody is cetuximab.

[0099] 2. Inhibitors of MEK and / or its mutants a. For example, trametinib, cobimetinib, binimetinib, selumetinib, refametinib, BI3011441; b. Preferred are trametinib and BI3011441; c. Most preferred is BI3011441; d. MEK inhibitors disclosed in WO2013 / 136249; e MEK inhibitors disclosed in WO2013 / 136254

[0100] 3. Inhibitors of SOS1 and / or any mutants thereof (i.e., compounds that modulate / inhibit the GEF function of SOS1, for example, by binding to SOS1 and blocking the protein-protein interaction between SOS1 and (mutated) Ras proteins, for example, KRAS). a. For example, BAY-293, BI-3406, BI1701963; b. Preferred are BI-3406 and BI1701963; c. Most preferred is BI1701963; d. SOS1 inhibitors disclosed in WO2018 / 115380; e. SOS1 inhibitors disclosed in WO2019 / 122129; f. SOS1 inhibitors disclosed in WO2020 / 180768, WO2020 / 180770, WO2018 / 172250 and WO2019 / 201848. 4. Oncolytic viruses 5. RAS Vaccine a. For example, TG02 (Targovax).

[0101] 6. Cell Cycle Inhibitors a. For example, inhibitors of CDK4 / 6 and / or any mutants thereof i. For example, palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600; ii. Preferred are palbociclib and abemaciclib; iii. Most preferred is abemaciclib. b. For example, vinca alkaloids i. For example, vinorelbine c. For example, inhibitors of Aurora kinase and / or any mutants thereof i. For example, alisertib, barasertib. 7. Inhibitors of PTK2 (=FAK) and / or any mutants thereof a. For example, TAE226, BI853520. 8. Inhibitors of SHP2 and / or any mutants thereof a. For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0102] 9. Inhibitors of PI3 kinase (=PI3K) and / or any mutants thereof a. For example, inhibitors of PI3K alpha and / or any mutants thereof i. For example, alpelisib, selavelisib, GDC-0077, HH-CYH33, AMG511, buparlisib, dactolisib, pictilisib, taselisib. 10. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutants thereof a. For example, ponatinib, infigratinib, nintedanib. 11. Inhibitors of AXL and / or any mutants thereof 12. Taxanes a. For example, paclitaxel, nab-paclitaxel, docetaxel; b. Preferred is paclitaxel. 13. Platinum-containing compounds a. For example, cisplatin, carboplatin, oxaliplatin b. Preferred is oxaliplatin. 14. Anti-metabolites a. For example, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, trifluridine in combination with tipiracil (=TAS102); b. Preferred is 5-fluorouracil.

[0103] 15. Immunotherapeutic Agents a. For example, immune checkpoint inhibitors i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb; ii. Preferred is an anti-PD1 mAb; iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab; iv. Preferred are nivolumab, pembrolizumab, ezabenlimab and PDR-001 (= spartalizumab); v. Most preferred are ezabenlimab, pembrolizumab and nivolumab.

[0104] 16. Topoisomerase inhibitors a. For example, irinotecan, irinotecan liposomal (nal-IRI), topotecan, etoposide; b. Most preferred are irinotecan and irinotecan liposomal (nal-IRI).

[0105] 17. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutants thereof a. For example, encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (= Example 131 of WO2014 / 151616), LXH254, sorafenib, LY-3009120 (= Example 1 of WO2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265. 18. mTOR inhibitors a. For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin1, dactolisib, GDC-0349, VS-5584, bistusertib, AZD8055.

[0106] 19. Epigenetic Regulators a. For example, BET inhibitors i. For example, JQ-1, GSK525762, OTX-015, CPI-0610, TEN-010, OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601, CC-90010, AZD5153, I-BET151, BI894999; ii. Preferred is BI894999. 20. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutants thereof a. For example, xentuzumab (antibody 60833 in WO2010 / 066868), MEDI-573 (=dusigitumab), linsitinib.

[0107] 21. Inhibitors of Src family kinases and / or any mutants thereof a. For example, inhibitors of kinases of the SrcA superfamily and / or any mutants thereof, i.e. inhibitors of Src, Yes, Fyn, Fgr and / or any mutants thereof; b. For example, inhibitors of kinases of the SrcB superfamily and / or any mutants thereof, i.e. inhibitors of Lck, Hck, Blk, Lyn and / or any mutants thereof; c. For example, inhibitors of kinases of the Frk superfamily and / or any mutants thereof, i.e. inhibitors of Frk and / or any mutants thereof; d. For example, dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU6656, WH-4-023.

[0108] 22. Apoptosis Regulators a. For example, an MDM2 inhibitor, such as an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2, and / or any mutants thereof; i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115, BI907828; ii. Preferred are HDM-201, RG-7388, AMG-232 and BI907828; iii. Preferred is BI907828; iv. MDM2 inhibitors disclosed in WO2015 / 155332; v. MDM2 inhibitors disclosed in WO2016 / 001376; vi. MDM2 inhibitors disclosed in WO2016 / 026937; vii. MDM2 inhibitors disclosed in WO2017 / 060431; b. For example, PARP inhibitors; c. For example, MCL-1 inhibitors; i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0109] 23. Inhibitors of c-MET and / or any of its mutants a. For example, savolitinib, cabozantinib, foretinib; b. MET antibodies, e.g., emibetuzumab, amivantamab; 24. Inhibitors of ERK and / or any mutants thereof a. For example, ulixertinib, LTT462; 25. Inhibitors of farnesyltransferase and / or any mutant thereof a. For example, tipifarnib;

[0110] In a further embodiment of the (combined) uses and methods (e.g., methods of treatment and / or prevention) described hereinbefore, one other pharmacologically active substance is a compound of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, wherein the one other pharmacologically active agent is administered before, after, or together with a compound of SOS1 inhibitors; or BI1701963; or MEK inhibitors; or Trametinib or BI3011441; or anti-PD-1 antibodies; or ezabenlimab; or cetuximab; or afatinib; or the standard of care (SoC) for a given indication; or PI3 kinase inhibitors is.

[0111] In a further embodiment of the (combined) uses and methods (e.g., methods of treatment and / or prevention) described hereinbefore, one other pharmacologically active substance is a compound of formula (I), (I* ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, wherein the one other pharmacologically active agent is SOS1 inhibitors; or BI1701963; or MEK inhibitors; or trametinib; or BI3011441; or anti-PD-1 antibodies; or ezabenlimab; or cetuximab; or afatinib; or the standard of care (SoC) for a given indication; or PI3 kinase inhibitors is.

[0112] In a further embodiment of the (combined) uses and methods (e.g., methods of treatment and / or prevention) described hereinbefore, the two other pharmacologically active substances are compounds of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, wherein the two other pharmacologically active agents are administered before, after, or together with a compound of an MEK inhibitor (preferably BI3011441) and an SOS1 inhibitor (preferably BI1701963); or Trametinib and an SOS1 inhibitor (preferably BI1701963); or an anti-PD-1 antibody (preferably, ezabenlimab) and an anti-LAG-3 antibody; or an anti-PD-1 antibody (preferably, ezabenlimab) and an SOS1 inhibitor (preferably, BI1701963); or an inhibitor selected from the group consisting of a MEK inhibitor (preferably BI3011441) and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or an inhibitor selected from the group consisting of an SOS1 inhibitor (preferably BI1701963) and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or MEK inhibitors (preferably BI3011441) and afatinib; or MEK inhibitor (preferably BI3011441) and cetuximab; or trametinib and afatinib; or trametinib and cetuximab; or an SOS1 inhibitor (preferably BI1701963) and afatinib; or SOS1 inhibitor (preferably BI1701963) and cetuximab is.

[0113] In a further embodiment of the (combined) uses and methods (e.g., methods of treatment and / or prevention) described hereinbefore, the two other pharmacologically active substances are compounds of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, wherein the two other pharmacologically active agents are an MEK inhibitor (preferably BI3011441) and an SOS1 inhibitor (preferably BI1701963); or Trametinib and an SOS1 inhibitor (preferably BI1701963); or an anti-PD-1 antibody (preferably, ezabenlimab) and an anti-LAG-3 antibody; or an anti-PD-1 antibody (preferably, ezabenlimab) and an SOS1 inhibitor (preferably, BI1701963); or an inhibitor selected from the group consisting of a MEK inhibitor (preferably BI3011441), and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or an inhibitor selected from the group consisting of an SOS1 inhibitor (preferably BI1701963) and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or MEK inhibitors (preferably BI3011441) and afatinib; or MEK inhibitor (preferably BI3011441) and cetuximab; or trametinib and afatinib; or trametinib and cetuximab; or an SOS1 inhibitor (preferably BI1701963) and afatinib; or SOS1 inhibitor (preferably BI1701963) and cetuximab is.

[0114] Formula (I), (I * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof (compound (I), (I * ), (Ia) or (Ia *), or in the medical uses, methods of treatment and / or prevention as defined herein (above and below), additional pharmacologically active substances include, but are not limited to, hormones, hormone analogs and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin acetate, leuprolide), inhibitors of growth factors and / or their corresponding receptors (e.g., platelet-derived growth factor receptor 2 (PR2) receptor 3 (PR3) receptor 4 (PR4) receptor 5 (PR5) receptor 6 (PR6) receptor 7 (PR7) receptor 8 (PR8) receptor 9 (PR9) receptor 10 (PR10) receptor 11 (PR11) receptor 12 (PR12) receptor 13 (PR13) receptor 14 (PR14) receptor 15 (PR15) receptor 16 (PR16) receptor 17 (PR17) receptor 18 (PR18) receptor 19 (PR19) receptor 20 (PR19) receptor 21 (PR19) receptor 22 (PR19) receptor 23 (PR19) receptor 24 (PR19) receptor 25 (PR19) receptor 26 (PR19) receptor 27 (PR19) receptor 28 (PR19) receptor 29 (PR19) receptor 30 (PR19) receptor 31 (PR19) receptor 32 (PR19) Growth factors such as PDGF, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors), inhibitors include, for example, (anti) growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors (e.g., cetuximab, gefitinib, afatinib , nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, and trastuzumab); antimetabolites (e.g., antifolates (e.g., methotrexate, raltitrexed), pyrimidine analogs (e.g., 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine), purine and adenosine analogs (e.g., mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine, etc.));Antitumor antibiotics (e.g., anthracyclines (doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride), Myoset (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin, and idarubicin), mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosamide, temozolomide, nitrosoureas (e.g., carmustine and lomustine, thiotepa, etc.); antimitotic agents (e.g., vinca alkaloids (e.g., vinblastine, vindesine, vinorelbine, and vincristine, etc.); and taxanes (paclitaxel, docetaxel, etc.)); angiogenesis inhibitors (e.g., tasquinimod), tubuline inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins (e.g., etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, etc.)), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors) inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimetics, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g., venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs ( For example, everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (for example, carfilzomib), immunotherapeutic agents (immune checkpoint inhibitors (for example, CTLA4, PD1, PD-L1, PD-L2, LAG3 and TIM3 binding molecules / immunoglobulins (for example, ipilimumab, nivolumab, pembrolizumab, etc.)), ADCC (antibody-dependent cell-mediated cytotoxicity), These include tumor enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers (BiTEs®, such as CD3xBCMA, CD3xCD33, CD3xCD19, PSMAxCD3)), tumor vaccines, and various chemotherapeutic agents (such as amifostine, anaglide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer);

[0115] It should be understood that the combinations, compositions, kits, methods, uses or compounds for use according to the present invention may envisage simultaneous, concurrent, sequential, consecutive, alternating or separate administration of the active ingredients or components. * ), (Ia) or (Ia * ) or a pharmaceutically acceptable salt thereof, and one or more other pharmacologically active substances, can be used, for example, compounds of formula (I), (I * ), (Ia) or (Ia * It will be understood that the compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more other pharmacologically active agents may be administered either concurrently or independently, such as either as part of the same pharmaceutical composition / dosage form or, preferably, in separate pharmaceutical compositions / dosage forms.

[0116] In the present context, "combination" or "combined" within the meaning of the present invention includes, but is not limited to, a product resulting from mixing or bringing together more than one active ingredient, and includes both fixed and loose (e.g., free) combinations (including kits), and uses such as simultaneous, concurrent, sequential, sequential, alternating or separate use of the components or ingredients. The term "fixed combination" means that the active ingredients are administered to a patient simultaneously in the form of a single entity or single dosage. The term "unfixed combination" means that the active ingredients are administered to a patient as separate entities, either simultaneously, concurrently or sequentially, without specific time restrictions, where such administration results in therapeutically effective levels of the compounds in the patient's body.

[0117] Formula (I), (I * ), (Ia) or (Ia *The administration of a compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, and one or more other pharmacologically active substances can be achieved by co-administering the active components or ingredients, such as by administering the active components or ingredients simultaneously or in combination in a single or two or more separate formulations or dosage forms. Alternatively, a compound of formula (I), (I * ), (Ia) or (Ia * ), or a pharmaceutically acceptable salt thereof, and one or more other pharmacologically active substances, may be administered, for example, by sequential or alternating administration of the active components or ingredients, such as in two or more separate formulations or dosage forms.

[0118] For example, simultaneous administration includes administration at substantially the same time. Such forms of administration may also be referred to as "concurrent" administration. Concomitant administration includes administration of active agents within the same general period, e.g., on the same day, but not necessarily at the same time. Alternating administration includes administering one agent over a period of time, e.g., the course of several days or a week, followed by administering the other agent over a subsequent period, e.g., the course of several days or a week, and then repeating this pattern for one or more cycles. Sequential or consecutive administration includes administering one agent using one or more doses for a first period (e.g., the course of several days or a week), followed by administering the other agent using one or more doses for a second and / or additional period (e.g., the course of several days or a week). Overlapping schedules may also be used, which do not necessarily follow a regular order, and include administering active agents on different days over the course of treatment. Variations on these general guidelines may also be used, depending, for example, on the agent used and the subject's condition.

[0119] definition Terms not specifically defined herein should be given the meaning that would be given them by one of ordinary skill in the art in view of this disclosure and the context. However, as used herein, unless expressly stated to the contrary, the following terms have the indicated meanings and are subject to the following conventions: Prefix C, where x and y each represent positive integers (x < y). x-y The use of x-y indicates that the chain or ring structure, which is explicitly stated and referred to directly, or the combination of chain and ring structures as a whole, can consist of carbon atoms with a maximum of y and a minimum of x.

[0120] For groups containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocycyl, heterocycylalkyl), the indication of the number of members relates to the total number of atoms of all ring members or the sum of all rings and carbon chain members. For groups consisting of a combination of carbon chains and carbon ring structures (e.g., cycloalkylalkyl, arylalkyl), the indication of the number of carbon atoms relates to the total number of carbon atoms of all carbon rings and carbon chain members. Clearly, the ring structure has at least three members.

[0121] Generally, for a group containing two or more sub - groups (e.g., heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl), the last - named sub - group is the radical bonding point. For example, the substituent aryl - C 1-6 Alkyl means an aryl group bonded to a C 1-6 alkyl group, and C 1-6 alkyl is bonded to the nucleus or group to which the substituent is attached. In groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., those skilled in the art can understand the radical bonding point to the molecule from the free valence of the group itself. Alkyl represents a monovalent saturated hydrocarbon chain, which can exist in both straight - chain (unbranched) and branched forms. When alkyl is substituted, the substitution can occur independently of each other on all hydrogen - bearing carbon atoms, either by mono - substitution or multi - substitution in each case.

[0122] 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)-.

[0123] Further examples of alkyl are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; iso-propyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (iso-butyl; i-Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH3)3), 1-pentenyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-3-propyl (tert-butyl; t-Bu; -C(CH3)3), 2-pentenyl (n-butyl; n-Bu; -CH2 ... ethyl (n-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-1-butyl (iso-pentyl; -CH2CH2CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neo-pentyl; -CH2C(CH3)3), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl;-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(C H3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3-dimethyl-1-butyl (-CH2CH (CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1-pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (-CH2CH2CH(CH3)CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl), etc.; The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., without further definition, refer to saturated hydrocarbon groups with the corresponding number of carbon atoms, including all isomeric forms. The alkyl may be replaced by another (composite) group, e.g., C x-y Alkylamino or C x-y When part of alkyloxy, the above definition of alkyl also applies.

[0124] The term alkylene can also be derived from alkyl. Unlike alkyl, alkylene is divalent and requires two binding partners. Formally, the second valency is created by removing a hydrogen atom in alkyl. Corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2-, or >CHCH3.

[0125] The term “C 1-4 Examples of "alkylene" include -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2 -CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-C Includes H(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3))2)- and -C(CH3)(CH2CH3)-.

[0126] Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene, and the like. The generic names propylene, butylene, pentylene, hexylene, etc., without further definition, refer to all possible isomeric forms with the corresponding number of carbon atoms, i.e., propylene includes 1-methylethylene, butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene. The alkylene is, for example, HO-C x-y Alkyleneamino or H2N-C x-yWhen it is part of another (composite) group, such as in alkyleneoxy, the above definition of alkylene also applies.

[0127] Unlike alkyl, alkenyl consists of at least two carbon atoms, at least two adjacent carbon atoms are connected to each other by a C—C double bond, and a carbon atom may be part of only one C—C double bond. In an alkyl as defined herein above having at least two carbon atoms, when two hydrogen atoms on adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenyl is formed. Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl , 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbuta-1,3-dienyl, and the like.

[0128] Generic names such as propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc., without further definition, refer to all possible isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, etc. The alkenyl may be in the cis or trans or E or Z configuration about the double bond(s). Alkenyl is, for example, C x-y Alkenylamino or C x-y When it is part of another (composite) group, such as in alkenyloxy, the above definition of alkenyl also applies.

[0129] Unlike alkylene, alkenylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are connected to each other by a CC double bond, and a carbon atom may be part of only one CC double bond. In an alkylene as defined herein above having at least two carbon atoms, when two hydrogen atoms of adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenylene is formed. Examples of alkenylene include ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene, and the like.

[0130] Generic names such as propenylene, butenylene, pentenylene, hexenylene, etc., without further definition, refer to all possible isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene, butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene. The alkenylene may be in the cis or trans or E or Z configuration about the double bond(s). Alkenylene is, for example, HO-C x-y Alkenyleneamino or H2N-C x-y When it is part of another (composite) group, such as in alkenyleneoxy, the above definition of alkenylene also applies.

[0131] Unlike alkyl, alkynyl consists of at least two carbon atoms, and at least two adjacent carbon atoms are bonded to each other by a C—C triple bond. In alkyl as defined herein above having at least two carbon atoms, when two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valences are saturated to form two additional bonds, the corresponding alkynyl is formed. Examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, and the like.

[0132] Generic names such as propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc. without further definition mean all possible isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc. If the hydrocarbon chain contains both at least one double bond and also at least one triple bond, it belongs by definition to the alkynyl subgroup. Alkynyl is, for example, C x-y Alkynylamino or C x-y When it is part of another (composite) group, as in alkynyloxy, the above definition for alkynyl also applies.

[0133] Unlike alkylene, alkynylene consists of at least two carbon atoms, and at least two adjacent carbon atoms are bonded to each other by a CC triple bond. In alkylene as defined herein above having at least two carbon atoms, when two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valences are saturated to form two additional bonds, the corresponding alkynylene is formed. Examples of alkynylene include ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, and the like.

[0134] Generic names such as propynylene, butynylene, pentynylene, hexynylene, etc., without further definition, refer to all possible isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene, butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene. The alkynylene may be, for example, HO-C x-y Alkynyleneamino or H2N-C x-y When it is part of another (composite) group, as in alkynyleneoxy, the above definition of alkynylene also applies. Heteroatoms means oxygen, nitrogen and sulfur atoms. Haloalkyl (haloalkenyl, haloalkynyl) is derived from the alkyl (alkenyl, alkynyl) defined above by independently replacing one or more hydrogen atoms of the hydrocarbon chain with halogen atoms, which may be the same or different. If haloalkyl (haloalkenyl, haloalkynyl) is further substituted, the substitutions may take place independently of one another on all hydrogen-carrying carbon atoms, in the form of mono- or polysubstitutions in each case.

[0135] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, and the like. The terms haloalkylene (haloalkenylene, haloalkynylene) are also derived from the haloalkyl (haloalkenyl, haloalkynyl) defined above. Haloalkylene (haloalkenylene, haloalkynylene) differs from haloalkyl (haloalkenyl, haloalkynyl) in that it is divalent and requires two bonding partners. Formally, the second valency is formed by removing a hydrogen atom from the haloalkyl (haloalkenyl, haloalkynyl). Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F. If the corresponding halogen-containing group is part of another (composite) group, the above definition also applies. Halogen relates to fluorine, chlorine, bromine and / or iodine atoms.

[0136] Cycloalkyl is made up of the subgroups monocyclic cycloalkyl, bicyclic cycloalkyl and spirocycloalkyl. The ring system is saturated and is formed by linked carbon atoms. In bicyclic cycloalkyl, the two rings are bonded to each other so that they have at least two carbon atoms in common. In spirocycloalkyl, one carbon atom (spiroatom) belongs to both rings. If a cycloalkyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all hydrogen-carrying carbon atoms. The cycloalkyl itself may be linked to the molecule as a substituent via any suitable position of the ring system.

[0137] Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (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.

[0138] Cycloalkyl may be, for example, C x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y When it is part of another (composite) group, as in cycloalkylalkyl, the above definition of cycloalkyl also applies. If the free valence of a cycloalkyl is saturated, an alicyclic ring results.

[0139] Thus, the term cycloalkylene can be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups include, for example: Cyclohexyl and [ka] or [ka] or [ka] (cyclohexylene). The cycloalkylene may be, for example, HO-C x-y Cycloalkyleneamino or H2N-C x-y When it is part of another (composite) group, as in cycloalkyleneoxy, the above definition of cycloalkylene also applies.

[0140] Cycloalkenyl is composed of the subgroups monocyclic cycloalkenyl, bicyclic cycloalkenyl, and spirocycloalkenyl. However, the system is unsaturated, i.e., there is at least one C-C double bond, but there is no aromatic system. In the cycloalkyl defined herein above, when two hydrogen atoms of adjacent ring carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding cycloalkenyl is obtained. If a cycloalkenyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all hydrogen-carrying carbon atoms. The cycloalkenyl itself may be linked to the molecule as a substituent via any suitable position of the ring system.

[0141] Examples of cycloalkenyl include cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobut-1,3-dienyl, cyclopenta- -1,4-dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl, and the like.

[0142] Cycloalkenyl is, for example, C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C x-y When it is part of another (composite) group, as in cycloalkenylalkyl, the above definition of cycloalkenyl also applies. If the free valence of a cycloalkenyl is saturated, an unsaturated alicyclic ring results.

[0143] Thus, the term cycloalkenylene can be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from cycloalkenyl. Corresponding groups include, for example: Cyclopentenyl and [ka] or [ka] or [ka] or [ka] (cyclopentenylene), etc. The cycloalkenylene may be, for example, HO-C x-y Cycloalkenyleneamino or H2N-C x-y When it is part of another (composite) group, as in cycloalkenyleneoxy, the above definition of cycloalkenylene also applies.

[0144] Aryl represents a mono-, bi- or tricyclic carbocycle having at least one aromatic carbocycle. Preferably, aryl represents a monocyclic group having 6 carbon atoms (phenyl) or a bicyclic group having 9 or 10 carbon atoms (two 6-membered rings or one 6-membered and one 5-membered ring), the second ring of which may also be aromatic or partially saturated. If an aryl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all hydrogen-carrying carbon atoms. The aryl itself may be linked to the molecule as a substituent via any suitable position of the ring system.

[0145] Examples of aryl include phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl, etc. Most preferred is phenyl. If aryl is part of another (composite) group, as for example in arylamino, aryloxy or arylalkyl, the above definition of aryl also applies. When the free valence of an aryl is saturated, an aromatic group is obtained.

[0146] The term arylene can also be derived from aryl as defined above. Unlike aryl, arylene is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups include, for example: Phenyl and [ka] or [ka] or [ka] (o, m, p-phenylene), naphthyl and [ka] or [ka] or [ka] And so on. If arylene is part of another (composite) group, as in, for example, HO-aryleneamino or H2N-aryleneoxy, the above definition of arylene also applies.

[0147] Heterocyclyl represents a ring system derived from the previously defined cycloalkyl, cycloalkenyl, and aryl by independently replacing one or more -CH2- groups in the hydrocarbon ring with -O-, -S-, or -NH- groups, or by replacing one or more =CH- groups with =N- groups, and a total of up to five heteroatoms may be present, with at least one carbon atom between two oxygen atoms and two sulfur atoms or between an oxygen atom and a sulfur atom, and the ring as a whole must be chemically stable. Heteroatoms may be present in all possible oxidation states (sulfur → sulfoxide -SO2-, sulfone -SO2-; nitrogen → N-oxide). In heterocyclyl, there are no aromatic heterocycles, i.e., the heteroatoms are not part of the aromatic system.

[0148] A direct consequence of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl consists of the sub-classes monocyclic heterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl and spiroheterocyclyl, which may exist in saturated or unsaturated form.

[0149] Unsaturated means that there is at least one double bond in the ring system, but no heteroaromatic system is formed. In a bicyclic heterocyclyl, the two rings are linked together with at least two (hetero)atoms in common. In a spiroheterocyclyl, one carbon atom (spiroatom) belongs to both rings. When a heterocyclyl is substituted, the substitutions may occur independently on all hydrogen-carrying carbon and / or nitrogen atoms, in the form of mono- or polysubstitutions in each case. The heterocyclyl itself may be linked to the molecule as a substituent via any suitable position of the ring system. Substituents on a heterocyclyl are not included in the number of members of the heterocyclyl.

[0150] Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide. Oxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide cido, 2,3-dihydroazeto, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza- Bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4,5]decyl, and the like. Further examples are the structures shown below, which can be bonded through each hydrogen-bearing atom (exchanged for hydrogen):

[0151] [ka] [ka] [ka] Preferred monocyclic heterocyclyls are 4 to 7 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur. Preferred monocyclic heterocyclyls are piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azetidinyl. Preferred bicyclic heterocyclyls are 6-10 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Preferred tricyclic heterocyclyls are nine-membered and have one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. Preferred spiroheterocyclyls are 7-11 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. If heterocyclyl is part of another (composite) group, as in, for example, heterocyclylamino, heterocyclyloxy or heterocyclylalkyl, the above definition of heterocyclyl also applies. If the free valence of a heterocyclyl is saturated, a heterocyclic ring is obtained.

[0152] The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups include, for example: Piperidinyl and [ka] or [ka] or [ka] , 2,3-dihydro-1H-pyrrolyl, and [ka] or [ka] or [ka] or [ka] And so on. If heterocyclylene is part of another (composite) group, as in, for example, HO-heterocyclyleneamino or H2N-heterocyclyleneoxy, the above definition of heterocyclylene also applies.

[0153] Heteroaryl refers to a monocyclic aromatic heterocycle or a polycyclic ring with at least one aromatic heterocycle, which, compared to the corresponding aryl or cycloalkyl(alkenyl), contains one or more identical or different heteroatoms, independently selected from nitrogen, sulfur and oxygen, instead of one or more carbon atoms, and the resulting group must be chemically stable. The presence of heteroaryl requires the presence of a heteroatom and a heteroaromatic system.

[0154] When heteroaryl is substituted, the substitutions can be carried out independently on all hydrogen-carrying carbon and / or nitrogen atoms, in the form of mono- or polysubstitution in each case.Heteroaryl itself can be linked to the molecule as a substituent via any suitable position of the ring system, both carbon and nitrogen.Substituents on heteroaryl are not included in the number of members of heteroaryl.

[0155] Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzophenone ... zothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benz Examples of the benzothiazolyl-N-oxide include benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, and benzimidazolyl-N-oxide. Further examples are the structures shown below, which can be bonded through each hydrogen-bearing atom (exchanged for hydrogen):

[0156] [ka] Preferably, the heteroaryl is a 5- to 6-membered monocyclic or a 9- to 10-membered bicyclic ring, each having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. If heteroaryl is part of another (composite) group, as in, for example, heteroarylamino, heteroaryloxy or heteroarylalkyl, the above definition of heteroaryl also applies. When the free valence of a heteroaryl is saturated, a heteroaromatic group is obtained.

[0157] The term heteroarylene is also derived from the previously defined heteroaryl. Unlike heteroaryl, heteroarylene is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups include, for example: Pyrrolyl and [ka] or [ka] or [ka] or [ka] And so on. If heteroarylene is part of another (composite) group, as in, for example, HO-heteroaryleneamino or H2N-heteroaryleneoxy, the above definition of heteroarylene also applies.

[0158] Substitution means that a hydrogen atom directly bonded to the atom under consideration is replaced with another atom or another group (substituent) of the atom. Depending on the starting conditions (number of hydrogen atoms), mono- or polysubstitutions can be carried out on an atom. Substitution with a specific substituent is only possible if the allowed valences of the substituent and the allowed valences of the atom to be substituted correspond to each other and the substitution results in a stable compound (i.e., a compound that does not spontaneously transform, for example, by rearrangement, cyclization, or elimination).

[0159] Divalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, and =N2 can only be carbon atom substituents, whereas the divalent substituents =O and =NR can also be sulfur substituents. Generally, substitution may be carried out by divalent substituents only on the ring system and requires the replacement of two geminal hydrogen atoms, i.e., hydrogen atoms attached to the same carbon atom that is saturated before substitution. Thus, substitution by divalent substituents is only possible on -CH2- groups or sulfur atoms of the ring system (=O or =NR groups only, one or two =O groups possible, or, for example, one =O and one =NR group, each group replacing a free electron pair).

[0160] Stereochemistry / Solvates / Hydrates: Unless specifically indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.), as well as racemates thereof and mixtures of different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the aforementioned forms in which such isomers and enantiomers exist, as well as salts thereof, including pharmaceutically acceptable salts, and solvates thereof, for example, solvates and hydrates, including solvates and hydrates of the free compound or salts of the compound.

[0161] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. It is well known in the art how to prepare optically active forms, such as by resolution or synthesis of racemic forms, for example, starting from optically active starting materials and / or using chiral reagents. Enantiomerically pure compounds of the invention or intermediates may be prepared by asymmetric synthesis, for example by the preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g., by chromatographic separation or crystallization), and / or by the use of chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliaries.

[0162] Furthermore, methods for preparing enantiomerically pure compounds from the corresponding racemic mixtures are known to those skilled in the art, for example, by chromatographic separation of the corresponding racemic mixtures using chiral stationary phases, or by resolution of the racemic mixtures using suitable resolving agents, for example, by formation of diastereomeric salts of the racemates with optically active acids or bases followed by resolution of the salts and liberation of the desired compound from the salts, or by derivatization of the corresponding racemates with optically active chiral auxiliary reagents followed by diastereomeric separation and removal of the chiral auxiliary, or by kinetic resolution of the racemates (for example by enzymatic resolution); by enantioselective crystallization from a mass of bipolar crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary. Salts: The phrase "pharmaceutically acceptable" is used herein to refer to 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.

[0163] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Further pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of the compound with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0164] For example, salts of acids other than those mentioned above that are useful in purifying or isolating the compounds of this invention (eg, trifluoroacetate salts) also form part of this invention. for example, [ka] or [ka] or [ka] In expressions such as the letter A has the function of a ring name, for example to make it easy to indicate the attachment of the ring to another ring.

[0165] For divalent groups where it is important to determine which adjacent group is attached and at which valency, the corresponding binding partner is shown in parentheses when necessary for clarity, as in the following notation: [ka] or (R 2 )—C(O)NH— or (R 2 )-NHC(O)-. In the absence of such clarification, divalent groups can be attached in both directions, ie, for example, -C(=O)NH- also includes -NHC(=O)- (and vice versa).

[0166] A group or substituent may be replaced by a corresponding group designation (e.g., R a , R b It is often the case that the group is selected from among several alternative groups / substituents having the formula (e.g., aryl, aryl, aryl, aryl) and the formula (e.g., aryl ... A therapeutically effective amount for purposes of this invention means that amount of substance that is capable of obviating symptoms of the disease or preventing or alleviating these symptoms or prolonging the survival of the patient being treated.

[0167] As used herein, Ras family proteins are intended to include KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey murine sarcoma viral oncogene), and any mutants thereof.

[0168] A RAS G12C inhibitor, as used herein, refers to a compound that is capable of binding to one or more of the G12C mutant RAS proteins KRAS G12C (= KRAS G12C inhibitor), NRAS G12C (= NRAS G12C inhibitor) and / or HRAS G12C (= HRAS G12C inhibitor), in particular KRAS G12C, and negatively modulating or inhibiting all or part of the enzymatic activity of KRAS G12C and / or NRAS G12C and / or HRAS G12C, in particular KRAS G12C. Without wishing to be bound by theory, it is believed that the compounds of the present invention can selectively react with KRAS G12C and / or HRAS G12C and / or NRAS G12C proteins (preferably 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 modulation / inhibition of the enzymatic activity of these mutant Ras proteins.

[0169] List of abbreviations [Table 1] TIFF0007808058000072.tif249135 TIFF0007808058000073.tif53143 [Example]

[0170] The features and advantages of the present invention will become apparent from the following detailed examples which illustrate, by way of example, the principles of the invention, without limiting its scope: Preparation of compounds according to the invention overview Unless otherwise stated, all reactions are carried out in commercially available equipment using methods commonly used in chemical laboratories. Air- and / or moisture-sensitive starting materials are stored under protective gas, and the corresponding reactions and manipulations with them are carried out under protective gas (nitrogen or argon). When a compound is represented by both a structural formula and its nomenclature, the structural formula shall prevail in the event of a conflict.

[0171] Microwave reactions are carried out in a Biotage Initiator / Reactor or a CEM Explorer or an Anton Paar Synthos 3000 or Monowave 3000 in a closed vessel (preferably 2, 5 or 20 mL), preferably with stirring. Chromatography Thin layer chromatography is performed on pre-made silica gel 60 TLC plates on glass from Merck (using fluorescent indicator F-254).

[0172] Preparative high pressure chromatography (RP HPLC) of exemplary compounds according to the invention is carried out on Agilent or Gilson systems using columns manufactured by Waters (designation: SunFire™ Prep C18, OBD™ 10 μm, 50×150 mm or SunFire™ Prep C18 OBD™ 5 μm, 30×50 mm or XBridge™ Prep C18, OBD™ 10 μm, 50×150 mm or XBridge™ Prep C18, OBD™ 5 μm, 30×150 mm or XBridge™ Prep C18, OBD™ 5 μm, 30×50 mm) and YMC (designation: Actus-Triart Prep C18, 5 μm, 30×50 mm). Different gradients of HO / acetonitrile are used to elute the compounds: for the Agilent system, 5% acidic modifier (20 mL HCOOH to 1 L HO / acetonitrile (1 / 1)) is added to water (acidic conditions), and for the Gilson system, water is added to 0.1% HCOOH.

[0173] For chromatography under basic conditions on the Agilent system, a HO / acetonitrile gradient is also used, but the water is made alkaline by the addition of 5% basic modifier (50 g NH4HCO3 + 50 mL NH3 (25% in HO), plus HO to 1 L). For the Gilson system, the water is made alkaline as follows: 5 mL of NH4HCO3 solution (158 g in 1 L HO) and 2 mL of NH3 (28% in HO), made up to 1 L with HO.

[0174] Supercritical fluid chromatography (SFC) of intermediates and exemplary compounds according to the invention is carried out on a JASCO SFC system using the following columns: Chiralcel OJ (250 x 20 mm, 5 μm), Chiralpak AD (250 x 20 mm, 5 μm), Chiralpak AS (250 x 20 mm, 5 μm), Chiralpak IC (250 x 20 mm, 5 μm), Chiralpak IA (250 x 20 mm, 5 μm), Chiralcel OJ (250 x 20 mm, 5 μm), Chiralcel OD (250 x 20 mm, 5 μm), Phenomenex Lux C2 (250 x 20 mm, 5 μm).

[0175] Analytical HPLC of intermediates and final compounds (reaction controls) is carried out using columns manufactured by Waters (designation: XBridge™ C18, 2.5 μm, 2.1 × 20 mm or XBridge™ C18, 2.5 μm, 2.1 × 30 mm or Aquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm), YMC (designation: Triart C18, 3.0 μm, 2.0 × 30 mm) and Phenomenex (designation: Luna C18, 5.0 μm, 2.0 × 30 mm). The analytical equipment is also equipped with a mass detector in all cases.

[0176] HPLC mass spectrometry / UV spectroscopy Retention time / MS-ESI to characterize exemplary compounds according to the present invention using an HPLC-MS device (High Performance Liquid Chromatography with Mass Detector) +The compounds eluting in the injection peak have retention time t Ret. =0.00 is assigned. SFC method (for preparative separation) Preparative SFC is performed on a Waters Thar SFC80 system. Column: Chiralpak AD-H (21×250mm), 5μm Flow rate: 25g / min Mobile phase: 75% CO2 + 25% MeOH (0.5% isopropylamine) ABPR: 120 bar Temperature: 35℃ UV: 220 nm Stack time: 8 minutes HPLC method (for analysis) Method A Samples were analyzed on an Agilent 1200 Series LC system coupled to an Agilent 6140 mass spectrometer. Purity was determined via UV detection in the range of 230-400 nm, using a bandwidth of 170 nm. LC parameters were as follows: Column: Waters Xbridge C18 column, 3.5 μm particle size, 2.1 × 30 mm; Flow rate 1mL / min; column temperature 60°C; Injection 5μL injection; Solvent A: 20mM NH4HCO3 / NH3 pH 9 B: MS grade acetonitrile; Gradient: 0.0-1.5 min, 10%-95% B 1.5~2.0 minutes 95%B 2.0~2.1 minutes 95%~10%B

[0177] Method B HPLC Agilent 1100 / 1200 Series MS Agilent LC / MSD SL Column: Waters X-Bridge BEH C18, 2.5 μm, 2.1 x 30 mm XP Solvent A: 28 mM NH3 in 20 mM NH4HCO3 / H2O; B: acetonitrile (HPLC grade) Detection MS: positive and negative modes Mass range 100~750m / z Flow rate 1.40mL / min Column temperature: 45°C Gradient 0.00-1.00 min: 15%B → 95%B 1.00~1.30 minutes: 95%B

[0178] Method C HPLC Agilent 1100 / 1200 Series MS Agilent LC / MSD SL Column: Waters Sunfire C18, 2.5 μm, 2.1 × 30 mm XP Solvent A: 0.1% HCOOH in HO; B: 0.1% HCOOH in acetonitrile (HPLC grade) Detection MS: positive and negative modes Mass range 150~750m / z Flow rate 1.40mL / min Column temperature: 45°C Gradient 0.00-1.00 min: 15%B → 100%B 1.00~1.13 minutes: 100%B

[0179] Method D HPLC Agilent 1100 / 1200 System MS 1200 Series LC / MSD (MM-ES+APCI±3000V, Quadrupol, G6130B) MSD signal setting Scan pos 150~750 Column: Waters, Part No. 186003389, XBridge BEH C18, 2.5 μm, 2.1 × 30 mm column Eluent A: 5mM NH4HCO3 / 18mM NH3(pH=9.2) B: Acetonitrile (HPLC grade) Detection signal: UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (0.063 sec response time, 80 Hz) Injection 0.5μL standard injection Flow rate 1.4mL / min Column temperature: 45°C Gradient 0.0-1.0 min 15% → 95%B 1.0~1.1 minutes 95%B Downtime: 1.3 minutes

[0180] Method E HPLC Agilent 1100 / 1200 System MS 1200Series LC / MSD (API-ES±3000 / 3500V, Quadrupol, G6140A) MSD signal setting Scan pos 150~750 Column: YMC; Part No. TA12S03-0302WT; Triart C18, 3 μm, 12 nm; 30 × 2.0 mm column Eluent A: H2O + 0.11% formic acid B:MeCN+0.1% formic acid (HPLC grade) Detection signal: UV 254 nm, 230 nm, 214 nm (bandwidth 10, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (0.063 sec response time, 80 Hz) Injection 0.5μL standard injection Flow rate 1.4mL / min Column temperature: 45°C Gradient 0.0-1.0 min 15% → 95%B 1.0~1.1 minutes 95%B Downtime: 1.23 minutes

[0181] Method F HPLC Agilent 1100 / 1200 System MS 1200 Series LC / MSD (API-ES±3000 / 3500V, Quadrupol, G6140A) MSD signal setting Scan pos / neg 150~750 Column: YMC; Part No. TA12S03-0302WT; Triart C18, 3 μm, 12 nm; 30 × 2.0 mm column Eluent A: H2O + 0.11% formic acid B:MeCN+0.1% formic acid (HPLC grade) Detection signal: UV 254 nm, 230 nm, 214 nm (bandwidth 10, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (0.063 sec response time, 80 Hz) Injection 0.5μL standard injection Flow rate 1.4mL / min Column temperature: 45°C Gradient 0.0-1.0 min 15% → 95%B 1.0~1.1 minutes 95%B Downtime: 1.23 minutes

[0182] Method G HPLC Agilent 1100 / 1200 System MS 1200 Series LC / MSD (MM-ES+APCI±3000V, Quadrupol, G6130B) MSD signal setting Scan pos / neg 150~750 Column: Waters, Part No. 186003389, XBridge BEH C18, 2.5 μm, 2.1 × 30 mm column Eluent A: 5mM NH4HCO3 / 18mM NH3(pH=9.2) B: Acetonitrile (HPLC grade) Detection signal: UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (0.063 sec response time, 80 Hz) Injection 0.5μL standard injection Flow rate 1.4mL / min Column temperature: 45°C Gradient 0.0-1.0 min 15% → 95%B 1.0~1.1 minutes 95%B Downtime: 1.3 minutes

[0183] The compounds and intermediates according to the present invention are prepared by the synthetic methods described herein below, in which the substituents of the general formulae have the meanings previously assigned herein. These methods are intended to be illustrative of the present invention without limiting the subject matter and scope of the compounds claimed for these examples. Where the preparation of starting compounds is not described, the starting compounds are commercially available, or their synthesis is described in the prior art, or the starting compounds can be prepared analogously to known prior art compounds or methods described herein, i.e., it is within the skill of an organic chemist to synthesize these compounds. Materials described in the literature can be prepared according to published synthetic methods. When the chemical structures below are shown without the exact configuration of a stereocenter, e.g., an asymmetrically substituted carbon atom, such representation includes both configurations and is considered to be disclosed. The representation of a racemic stereocenter should always be considered to include and disclose both enantiomers (if any other defined stereocenter is not present) or all other possible diastereomers and enantiomers (if additional stereocenters, defined or undefined, are present).

[0184] General reaction scheme and overview of synthetic routes to compounds (I) according to the present invention Scheme 1: [ka]

[0185] Experimental procedure for the synthesis of A-2a [ka] To a suspension of sodium hydride (60% in mineral oil, 25.85 g, 646.3 mmol, 1.1 equiv.) in THF (2.0 L) was added A-1a (93.46 mL, 587.5 mmol, 1.0 equiv.) dropwise at 0-10°C. The mixture was stirred at 10°C for 30 min, and then methyl iodide (55.11 mL, 881.3 mmol, 1.5 equiv.) was added dropwise to the mixture at 10°C. The mixture was allowed to warm to 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 combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to yield A-2a, which was used in the next step without further purification.

[0186] The following intermediates A-2 (Table 1) are accessible in an analogous manner using different cyclic β-ketoesters A-1: ​​If necessary, the crude product A-2 is purified by chromatography. [Table 2]

[0187] Experimental procedure for the synthesis of A-3a [ka] 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 equiv.), followed by the addition of ammonium acetate (9.04 g, 117.2 mmol, 0.2 equiv.) and acetic acid (13.41 mL, 234.5 mmol, 0.4 equiv.) at room temperature. The mixture was stirred at 110° C. for 16 hours. After complete conversion, the mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude product A-3a. This crude material was used in the next step without further purification (see also Naumann et al., Pharmazie, vol. 51 (1996), p. 4).

[0188] The following intermediates A-3 (Table 2) can be obtained in an analogous manner using different intermediates A-2: The crude products A-3 are purified by chromatography if necessary. [Table 3]

[0189] Experimental procedure for the synthesis of A-4a [ka] 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 yield the crude product. The crude product was purified via column chromatography to yield A-4a.

[0190] The following intermediates A-4 (Table 3) can be obtained in an analogous manner using different intermediates A-3: The crude products A-4 are purified by chromatography if necessary. [Table 4]

[0191] Experimental procedure for the synthesis of A-4d [ka] A stirred solution of A-1a (12.00 g, 70.5 mmol) in EtOH (60.0 mL) is treated with sulfur (2.26 g, 70.5 mmol, 1.00 equiv.), morpholine (6.14 g, 70.5 mmol, 1.0 equiv.), and malononitrile (4.66 g, 70.5 mmol, 1.0 equiv.). The reaction mixture is then stirred at 55 °C for 1 h. After complete conversion, the reaction mixture is concentrated, diluted with water, extracted with EtOAc, and the extract is dried, filtered, and concentrated under reduced pressure to give the crude product. This crude material is purified by column chromatography (20-30% EtOH in hexanes) to afford A-4d. (HPLC Method A; t ret =1.10 minutes;[M+H] + =251).

[0192] Experimental procedure for the synthesis of A-5a [ka] A-4a (78.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in EtOH (1.5 mL) and potassium hydroxide (4 M in water, 0.37 mL, 1.5 mmol, 5.0 equiv) 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 KHSO solution (10% in water), and the product was extracted using EtOAc. The combined organic layers were dried, filtered, and concentrated. The crude product was purified via acidic reverse-phase chromatography (gradient elution: 20% to 90% acetonitrile in water) to afford A-5a.

[0193] The following intermediates A-5 (Table 4) can be obtained in an analogous manner using different esters A-4. The crude product A-5 can be purified by chromatography if necessary, and the enantiomers can be separated by preparative SFC chromatography as described herein, for example, to separate A-5a into A-5b and its enantiomer.

[0194] [Table 5]

[0195] Scheme 2a: [ka]

[0196] Scheme 2b: [ka]

[0197] Experimental procedure for the synthesis of E-2a [ka] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)-ethan-1-ol (1.441 g, 11.15 mmol, 1.0 equiv.) in DMSO, DIPEA (2.882 g, 22.3 mmol, 2.0 equiv.) is added and the mixture is cooled to 10 °C. E-1a (2.0 g, 11.15 mmol, 97% purity, 1.0 equiv.) is added and the mixture is stirred at 10 °C for 45 min. The mixture is filtered and the filtrate is purified via basic reverse-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to afford E-2a. (HPLC Method A; t ret =1.36 minutes;[M+H] + =267). Additional intermediate E-2 is accessible in a similar manner. The crude product E-2 can be purified by chromatography if necessary.

[0198] Experimental procedure for the synthesis of E-2b [ka] E-3a (3.50 g, 15.9 mmol) is dissolved in DMF (10 mL). 2-Dimethylaminoethyl chloride HCl salt (6.87 g, 47.72 mmol) is added, and the mixture is stirred at 150 °C for 25 min. The mixture is cooled to room temperature, filtered through a glass frit, and then washed with EtOAc. The solvent is removed by lyophilization. The residue is purified by normal phase chromatography (gradient elution: 0% to 20% MeOH in DCM) to afford E-2b.

[0199] The following intermediate E-2 (Table 5) is available in an analogous manner: The crude product E-2 is purified by chromatography, if necessary. [Table 6]

[0200] Experimental Procedure for the Synthesis of E-4a (Method A) [ka] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.76 g, 13.73 mmol) and cesium carbonate (2.76 g, 13.73 mmol) are dissolved in DMA (10 mL). E-1b (2.50 g, 13.73 mmol) is added, and the mixture is stirred at 90 °C for 1 h. The reaction mixture is extracted with water into EtOAc, and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure, and the residue is purified via basic reverse-phase chromatography (gradient elution: 45% to 98% acetonitrile in water) to afford E-4a.

[0201] Experimental Procedure for the Synthesis of E-4b (Method B) [ka] To a stirred solution of E-1b (5.00 g, 28.90 mmol) in DMSO (50.0 mL) is added piperazine-1-carboxylic acid tert-butyl ester (5.92 g, 31.79 mmol, 1.1 equiv). DIPEA (11.21 g, 86.71 mmol, 3.0 equiv) is then added, and the reaction mixture is stirred at 60 °C for 1 h. After complete conversion, the mixture is dissolved in EtOAc and washed with water (3x). The organic phase is dried, filtered, and concentrated under reduced pressure. The crude product is purified via column chromatography (EtOAc / hexanes) to afford E-4b.

[0202] Experimental Procedure for the Synthesis of E-4c (Method C) [ka] To a stirred solution of E-1c (10.20 g, 57.22 mmol) in DCM (60.0 mL) is added piperazine-1-carboxylic acid tert-butyl ester (11.22 g, 57.22 mmol, 1.0 equiv). DIPEA (20.71 g, 160.21 mmol, 2.8 equiv) is then added and the reaction mixture is stirred at 60 °C for 1 h. After complete conversion, the mixture is dissolved in EtOAc and washed with water (3x). The organic phase is dried, filtered, and concentrated under reduced pressure. The crude product is purified via column chromatography (DCM / MeOH) to afford E-4c.

[0203] Experimental procedure for the synthesis of E-4d (Method D) [ka] To a stirred mixture of sodium hydride (22.8 mg, 0.95 mmol, 1.1 equiv.) and THF (2 mL) under argon, tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (171 mg, 0.95 mmol, 1.1 equiv.) was added at room temperature and the mixture was stirred for 5 min. E-1c (150 mg, 0.86 mmol, 1.0 equiv.) was added and the mixture was stirred for 1 h. The reaction was quenched by the addition of a few drops of water, and the solvent was removed under vacuum. The crude product was dissolved in DCM and purified via column chromatography (DCM / MeOH) to afford E-4d.

[0204] Experimental procedure for the synthesis of E-4e (Method E) [ka] E-1d (1.00 g, 6.62 mmol), piperazine-1-carboxylic acid tert-butyl ester (724.6 mg, 3.70 mmol, 0.8 equiv), sodium tert-butoxide (915.4 mg, 9.24 mmol, 2.0 equiv), 2-(di-tert-butylphosphino)biphenyl (275.7 mg, 0.92 mmol, 0.20 equiv), and tris(dibenzylideneacetone)dipalladium(0) (211.5 mg, 0.23 mmol, 0.05 equiv) were combined in dry dioxane (9.00 mL) and the mixture was stirred at room temperature for 1 h. After complete conversion, the mixture was concentrated and diluted with water. The product was extracted with DCM. The combined organic layers were dried, filtered, and concentrated. The crude product is purified via basic reverse-phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to afford E-4e.

[0205] The following (additional) intermediates E-4 (Table 6) can be obtained in an analogous manner using different amines PG-LH and intermediate E-1 according to methods A to E. The crude product E-4 can be purified by chromatography, if necessary.

[0206] [Table 7] TIFF0007808058000095.tif245147 TIFF0007808058000096.tif244149 TIFF0007808058000097.tif185160

[0207] Experimental procedure for the synthesis of E-6a [ka] E-1b (500 mg, 2.83 mmol, 1.0 equiv) and cesium fluoride (1.72 g, 11.33 mmol, 4.0 equiv) are dissolved in DMA (5 mL) and heated by microwave irradiation to 110° C. The mixture is filtered and the solid is washed with a small amount of DMA to give a crude solution of E-5a in DMA.

[0208] To a solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (531 mg, 187.24 mmol, 1.0 equiv.) in THF (5 mL) was added sodium hydride (158 mg, 3.97 mmol, 1.4 equiv.) 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 equiv.) in DMA and stirred for 5 min, followed by the addition of water and EtOAc. The phases were separated and the aqueous phase was extracted twice with EtOAc (30 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated. The mixture was dissolved in acetonitrile and water and purified by acidic reverse-phase chromatography to give the desired product E-6a.

[0209] The following intermediate E-6 (Table 7) is available in an analogous manner: The crude product E-7 is purified by chromatography if necessary. [Table 8]

[0210] Experimental procedure for the synthesis of E-6d [ka] E-1b (267 mg, 1.54 mmol, 1.0 equiv) and cesium fluoride (937 mg, 6.17 mmol, 4.0 equiv) are dissolved in DMA (3 mL) and heated to 110 °C by microwave irradiation. The mixture is filtered, and the solid is washed with a small amount of DMA to give 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 equiv) and DIPEA (0.667 mL, 3.86 mmol, 2.5 equiv) are added to the mixture, which is stirred at 60 °C for 30 min. The mixture is filtered, and the filtrate is purified by basic reverse-phase chromatography to give the desired product E-6d.

[0211] The following intermediate E-6 (Table 8) is available in a similar manner: The crude product E-6 is purified by chromatography if necessary. [Table 9]

[0212] Experimental procedure for the synthesis of E-6f [ka] Intermediate E-4ap (60 mg, 0.19 mmol, 1.0 equiv) and cesium fluoride (56 mg, 0.37 mmol, 2.0 equiv) are dissolved in DMSO (2 mL), stirred at 80 °C overnight, and cooled to room temperature. Additional cesium fluoride (56 mg, 0.37 mmol, 2.0 equiv) is added, and the mixture is stirred at 110 °C to drive the reaction to completion. Water and acetonitrile are added, and the mixture is purified by acidic reverse-phase chromatography to give the desired product E-6f.

[0213] The following intermediates E-6 (Table 9) are accessible in an analogous manner from other intermediates E-4: The crude product E-6 is purified by chromatography if necessary. [Table 10]

[0214] Various structural units of HR 5 Synthesis of [ka]

[0215] Experimental procedure for the synthesis of G-2a G-1a (500 mg, 2.33 mmol) is dissolved in dry THF (5.00 mL) together with triethylamine (485 μL, 3.5 mmol, 1.5 equiv.) and the mixture is cooled to 0 °C. Benzyl chloroformate (519 μL, 3.5 mmol, 1.5 equiv.) is added portionwise and the mixture is stirred for 2 h and allowed to warm to room temperature overnight. After complete conversion, water is added to the mixture, the product is extracted with DCM, and the combined extracts are dried, filtered, and concentrated. The crude product is used in the next step without further purification (HPLC method B, t ret =0.766 minutes, [M+H] + =249 / 293).

[0216] Experimental procedure for the synthesis of G-3a G-2a (813 mg, 2.33 mmol) is dissolved in DCM (25.00 mL) and treated with HCl (4 M in dioxane, 11.67 mL, 46.66 mmol, 20.0 equiv.). The mixture is stirred at room temperature for 2 h. After complete conversion, the mixture is concentrated and the product is isolated via basic reverse-phase chromatography (gradient elution: 10% to 70% acetonitrile in water). (HPLC Method B, t ret =0.478 minutes, [M+H] + =249).

[0217] Experimental procedure for the synthesis of G-4a (Method F) [ka] 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 equiv.) and acetic acid (92 μL, 1.61 mmol, 0.10 equiv.). The mixture was stirred for 15 min, then sodium triacetoxyborohydride (6.335 g, 29.00 mmol, 1.80 equiv.) was added, and the mixture was stirred at room temperature for 1 h. After complete conversion, water was added to the mixture, and the product was extracted with DCM. The combined extracts were dried, filtered, and concentrated. The crude product was purified via normal phase chromatography (DCM / MeOH).

[0218] Experimental Procedure for the Synthesis of G-4b (Method G) [ka] To a stirred solution of G-3a (250.0 mg, 1.00 mmol) in dry DMF (5.00 mL) was added KCO (0.303 g, 2.51 mmol, 2.50 equiv), followed by 1-bromo-2-methoxyethane (0.122 g, 1.00 mmol, 1.00 equiv). The reaction mixture was stirred at 80 °C for 16 h. After complete conversion, water was added to the mixture, the product was extracted with EtOAc, and the combined extracts were dried, filtered, and concentrated. The crude product was purified via normal phase chromatography (DCM / MeOH).

[0219] The following (additional) intermediates G-4 (Table 10) are accessible in an analogous manner using G-3a and different aldehydes or ketones as alkylating agents according to Methods F or G. The crude product G-4 can be purified by chromatography if necessary. [Table 11]

[0220] Experimental procedure for the synthesis of G-5a [ka] G-5a (3.00 g, 11.44 mmol) is dissolved in MeOH (20.0 mL) and palladium (10% on carbon, 360 mg) is added. The mixture is stirred in a hydrogenation reactor under 5 bar hydrogen pressure at room temperature for 16 h. After complete conversion, the catalyst is filtered off and the residue is concentrated. The crude product is used in the following step without further purification.

[0221] The following intermediate G-5 (≒ building block HR 5 ;Table 11) can be obtained in an analogous manner using the differently substituted analog G-4. [Table 12]

[0222] Experimental procedure for the synthesis of G-7a [ka] G-6a (590.0 mg, 2.49 mmol) is dissolved in dry THF (1.50 mL) and the mixture is cooled to 0 °C. LiAlH (2 M in THF, 6.22 mL, 12.44 mmol, 5.00 equiv.) is added dropwise, and the mixture is stirred in a sealed vessel at 70 °C for 1.5 h. After complete conversion, the mixture is diluted with THF (15 mL), sodium potassium tartrate tetrahydrate is added slowly, and the mixture is stirred at room temperature for 1.5 h. The mixture is filtered, the filtrate is concentrated, and the crude product is used in the following step without purification.

[0223] The following intermediate G-7 (≒ building block HR 5 ; Table 12) are accessible in an analogous manner starting from the corresponding N-Boc-aminoketone G-6. [Table 13]

[0224] Experimental procedure for the synthesis of E-10a [ka] To E-9a (500 mg, 2.71 mmol, 1.0 equiv.) in acetone (11 mL) at 0° C. is added a solution of piperazine-1-carboxylic acid tert-butyl ester (505 mg, 2.71 mmol; 1.0 equiv.) in acetone (6 mL). A solution of sodium bicarbonate (225.00 mg, 2.12 mmol; 0.78 equiv.) in water (5 mL) is added and the reaction is stirred at 0° C. for 3 h. The reaction mixture is filtered, and the solid is washed with water and dried to give the desired compound E-10a (HPLC Method A, t ret =1.47 minutes, [M+H] + =334).

[0225] Experimental procedure for the synthesis of E-11a [ka] E-10a (1.04 g, 3.11 mmol, 1.0 equiv.), (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (561.41 mg, 4.05 mmol, 1.3 equiv.), and DIPEA (808.47 mg, 6.22 mmol, 2.0 equiv.) were dissolved in anhydrous THF (12 mL) and stirred at room temperature for 3 h, then at 40 °C for 1 h. The solvent was removed under reduced pressure, and the residue was purified by normal phase chromatography (cyclohexane: EtOAc 10:90 to 80:20) to give E-11a (HPLC method A, t ret =1.54 minutes, [M+H] + =427).

[0226] Experimental procedure for the synthesis of E-8a [ka] E-11a (898 mg, 1.68 mmol, 1.0 equiv.) and sodium cyanide (329.85 mg, 6.73 mmol, 4.0 equiv.) are dissolved in DMSO (5 mL) and stirred at 60 °C for 3 h. The solvent is removed and the residue is purified by reverse phase chromatography to give the desired compound E-8a (HPLC method A, t ret =1.53 minutes, [M+H] + =418).

[0227] Experimental procedure for the synthesis of E-8b [ka] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (792 mg, 6.13 mmol, 1.1 equiv.) and DIPEA (1.94 mL, 11.15 mmol, 2 equiv.) in DMSO (3 mL), a solution of E-1a (1000 mg, 97% purity, 5.58 mmol, 1.0 equiv.) in DMSO (3 mL) is slowly added. The mixture is stirred at room temperature for 30 min. After complete conversion of the starting material is observed, tert-butyl (R)-3-methylpiperazine-1-carboxylate (1.50 mg, 97% purity, 7.25 mmol, 1.3 equiv.) and DIPEA (0.97 mL, 5.58 mmol, 1 equiv.) are added to the mixture. The mixture is stirred at 60°C for 60 minutes, and DIPEA (0.97 mL, 5.58 mmol, 1 equiv.) is added. The mixture is stirred at 70°C for 50 minutes, then at room temperature overnight. After complete conversion is observed, the reaction is diluted with water and DCM, and the phases are separated. The aqueous phase is extracted with DCM (3 times), and the organic phases are combined. The solvent is removed in vacuo to give crude product E-8a. The crude product is 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 product E-8b.

[0228] The following intermediates E-8 (Table 13) can be obtained in an analogous manner without isolating the corresponding intermediates E-2: Crude product E-8 is purified by chromatography if necessary. [Table 14]

[0229] Experimental procedure for the synthesis of E-8d [ka] To a solution of E-1a (600 mg, 3.21 mmol, 93% purity, 1.0 equiv.) in anhydrous DMSO (6 mL) was added cesium fluoride (1.218 g, 8.02 mmol, 2.5 equiv.), 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 equiv.) and DIPEA (1.085 mL, 6.38 mmol, 2 equiv.). The mixture was stirred at room temperature for 1 h. After complete conversion of the starting material was observed, a solution of tert-butyl piperazine-1-carboxylate (674 mg, 3.51 mmol, 97% purity, 1.1 equiv.) in anhydrous DMSO (3 mL) and DIPEA (1.085 mL, 6.38 mmol, 2 equiv.) were 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.

[0230] The following intermediate E-8 (Table 14) can be obtained in a similar manner without isolating the corresponding intermediates E-5 and E-7, respectively. The crude product E-8 is purified by chromatography if necessary. [Table 15]

[0231] Experimental Procedure for the Synthesis of E-8g (Method A) [ka] E-4f (50.0 mg, 0.148 mmol), G-5a (115 mg, 0.740 mmol, 5.0 equiv.), and DIPEA (25.78 μL, 0.15 mmol, 1.0 equiv.) were mixed 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. Intermediate E-8 (Table 15), designated "A," is available in a similar manner. The crude product E-8 is purified by chromatography if necessary.

[0232] Experimental Procedure for the Synthesis of E-8h (Method B) [ka] E-4e (400.0 mg, 1.24 mmol), N-methylpiperazine (352.1 mg, 3.48 mmol, 2.8 equiv), sodium tert-butoxide (246.3 mg, 2.49 mmol, 2.0 equiv), 2-(di-tert-butylphosphino)biphenyl (74.18 mg, 0.25 mmol, 0.20 equiv), and tris(dibenzylideneacetone)dipalladium(0) (56.9 mg, 0.062 mmol, 0.05 equiv) are mixed in anhydrous dioxane (2.50 mL), and the mixture is stirred at 110 °C for 1 h. After complete conversion, the mixture is concentrated and diluted with water. The product is extracted with DCM, and the combined organic layers are dried, filtered, and concentrated. The crude product is purified by basic reverse phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to afford E-8h. Intermediate E-8 (Table 15), designated "B," is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0233] Experimental procedure for the synthesis of E-8i (Method C) [ka] E-4b (1.00 g, 3.10 mmol), (S)-1,3-dimethylpiperazine (0.99 g, 8.67 mmol, 2.80 equiv), tris(dibenzylideneacetone)dipalladium(0) (141.85 mg, 0.154 mmol, 0.05 equiv), Xantphos (184.80 mg, 0.31 mmol, 0.10 equiv), cesium carbonate (2.019 g, 6.196 mmol, 2.00 equiv), and anhydrous dioxane (8.00 mL) were mixed and stirred in a sealed vessel under argon at 110 °C for 16 h. After complete conversion, brine was added to the mixture, and the product was extracted with DCM. The combined organic phase was dried, filtered, and concentrated under reduced pressure. The crude product is purified by basic reverse-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to afford E-8i. Intermediate E-8 (Table 15), designated "C," is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0234] Experimental procedure for the synthesis of E-8j (Method D) [ka] E-4g (3.035 g, 8.51 mmol), tert-butyl (S)-3-ethylpiperazine-1-carboxylate (3.645 g, 17.01 mmol, 2.00 equiv), tris(dibenzylideneacetone)dipalladium(0) (778.82 mg, 0.850 mmol, 0.10 equiv), 1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (723.0 mg, 1.701 mmol, 0.20 equiv), cesium carbonate (8.313 g, 25.514 mmol, 3.00 equiv), and anhydrous dioxane (32.00 mL) were mixed and stirred in a sealed vessel under argon at 110 °C for 16 h. After complete conversion, brine was added to the mixture, and the product was extracted with DCM. The combined organic phases are dried, filtered, and concentrated under reduced pressure. The crude product is purified by basic reverse-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to afford E-8j. Intermediate E-8 (Table 15), designated "D," is accessible in a similar manner. The crude product E-8 is purified by chromatography if necessary.

[0235] Experimental procedure for the synthesis of E-8k (Method E) [ka] E-4b (400 mg, 1.239 mmol), 1-(1-methylpiperidin-4-yl)piperazine (273.0 mg, 1.49 mmol, 1.20 equiv), RuPhosPdG3 (106.0 mg, 0.120 mmol, 0.10 equiv), potassium phosphate tribasic (553.0 mg, 2.605 mmol, 2.10 equiv), and anhydrous dioxane (3.10 mL) were combined and stirred in a sealed vessel under argon at 85 °C 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. Intermediate E-8 (Table 15), designated with an "E", is available in a similar manner. The crude product E-8 is purified by chromatography if necessary.

[0236] Experimental Procedure for the Synthesis of E-8l (Method F) [ka] E-4b (100 mg, 0.31 mmol), pyridine-4-boronic acid (45.70 mg, 0.37 mmol, 1.20 equiv), RuPhosPdG3 (27.3 mg, 0.031 mmol, 0.10 equiv), potassium phosphate tribasic (138.1 mg, 0.65 mmol, 2.10 equiv), and anhydrous dioxane (0.9 mL) were mixed and stirred in a sealed vessel under argon at 80 °C for 1 h. After complete conversion, the mixture was concentrated. The crude product was purified by basic reverse-phase chromatography to give E-8l. Intermediate E-8 (Table 15), designated "F," is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0237] Experimental procedure for the synthesis of E-8m (Method G) [ka] To a mixture of DIPEA (736.3 μL, 4.23 mmol, 3 equiv.) and E-4i (560 mg, 1.41 mmol, 85% purity, 1 equiv.) in DMSO (1 mL), (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (922 mg, 5.64 mmol, 79% purity, 4.0 equiv.) is added and the mixture is stirred at 100 °C for 16 h. The mixture is 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 give the desired product E-8m. Intermediate E-8 (Table 15), designated "G," is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0238] Experimental Procedure for the Synthesis of E-8n (Method H) [ka] A mixture of E-4k (1.50 g, 4.44 mmol, 1.0 equiv) and (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (688 mg, 5.33 mmol, 1.2 equiv) in THF (45 mL) is cooled to 0 °C. At 0 °C, sodium tert-butoxide (854 mg, 8.88 mmol, 2.0 equiv) is added to the mixture. The mixture is slowly warmed to room temperature and stirred at room temperature for 2 h. The reaction is quenched by the addition of cold water and EtOAc. The phases are separated, and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine and concentrated in vacuo. The crude product is purified by normal phase chromatography (2% MeOH in DCM) to give the desired product E-8n. Intermediate E-8 (Table 15), designated "H," is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0239] Experimental Procedure for the Synthesis of E-8o (Method I) [ka] A solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (312 mg, 2.42 mmol, 1.7 equiv) in THF (3 mL) was cooled to 0 °C, and sodium hydride (74 mg, 1.85 mmol, 1.3 equiv) was added portionwise over 10 min. To the mixture was slowly added a solution of E-4l (500 mg, 1.42 mmol, 1.0 equiv) in THF (5 mL), and the mixture was stirred for 18 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution. 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. Intermediate E-8 (Table 15), designated "I," is accessible in a similar manner. The crude product E-8 is purified by chromatography if necessary.

[0240] Experimental procedure for the synthesis of E-8p (Method J) [ka] To a mixture of E-4r (200 mg, 0.59 mmol, 1.0 equiv) and (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (91.8 mg, 0.71 mmol, 1.2 equiv) in acetonitrile (1.5 mL) is added trimethylamine (149.8 mg, 1.48 mmol, 2.5 equiv). The mixture is stirred at 40 °C for 2 h. The mixture is stirred at 80 °C for 16 h. The solvent is removed under reduced pressure, and the crude product is purified by normal phase chromatography (gradient elution: 0% to 90% MeOH in DCM + ammonia) to give the desired product E-8p.

[0241] Intermediate E-8 (Table 15), designated "J," is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary. [Table 16] TIFF0007808058000130.tif245160 TIFF0007808058000131.tif243157 TIFF0007808058000132.tif243150 TIFF0007808058000133.tif244152 TIFF0007808058000134.tif243151 TIFF0007808058000135.tif43163

[0242] Experimental Procedure for the Synthesis of Intermediate E-8cc [ka] E-2b (3.94 g, 20.93 mmol, 4.0 equiv.), tert-butyl piperazine-1-carboxylate (1.76 g, 5.23 mmol, 1.0 equiv.), sodium tert-butoxide (2.01 g, 20.93 mmol, 4.0 equiv.), 2-(di-tert-butylphosphino)-biphenyl (624.45 mg, 0.21 mmol, 0.4 equiv.), and tris-(dibenzylideneactone)-dipalladium (479.05 mg, 0.052 mmol, 0.1 equiv.) in dioxane (10 mL) were added to a sealed tube and shaken overnight at 45° C. under a nitrogen atmosphere. The reaction mixture was mixed with EtOAc and water and extracted with EtOAc. The organic phase is dried over magnesium sulfate and purified by normal phase chromatography on silica gel (DCM:MeOH 100:0 to 80:20).

[0243] The following intermediate E-8 (Table 16) is available in a similar manner: The crude product E-8 is purified by chromatography if necessary. [Table 17]

[0244] Experimental procedure for the synthesis of E-8cf (Method K) [ka] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (1.335 g, 8.16 mmol, 2.5 equiv.) in DMF (50 mL) is added sodium hydride (60% dispersion in mineral oil, 652.8 mg, 16.32 mmol, 5.0 equiv.) at room temperature. The mixture is stirred at room temperature for 10 minutes, and E-6g (1.00 g, 3.26 mmol, 1.0 equiv.) is added. The mixture is stirred at room temperature for 3 hours. The reaction is quenched by the addition of water and EtOAc. The phases are separated, and the aqueous phase is extracted with EtOAc. The organic layers are combined, dried, filtered, and the solvent is removed in vacuo. The crude product is purified by basic reverse-phase chromatography to give E-8cf. Intermediate E-8 (Table 17), designated "K," is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0245] Experimental procedure for the synthesis of E-8cg (Method L) [ka] To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (52.6 mg, 0.41 mmol, 5.0 equiv) in THF (2 mL) is added potassium tert-butoxide (45.6 mg, 0.41 mmol, 5.0 equiv) at room temperature. The mixture is stirred at room temperature for 30 minutes, and E-6b (25.0 mg, 0.081 mmol, 1.0 equiv) is added. The mixture is stirred at room temperature for 15 minutes. The reaction is quenched by the addition of water and EtOAc. The phases are separated, and the aqueous phase is extracted with EtOAc. The organic layers are combined, and the solvent is removed under vacuum. The crude product is purified by acidic reverse-phase chromatography to give E-8cg. Intermediate E-8 (Table 17), designated "L," is available in a similar manner. The crude product E-8 is purified by chromatography if necessary.

[0246] Experimental procedure for the synthesis of E-8ch (Method M) [ka] E-6h (100.0 mg, 0.31 mmol, 1.0 equiv) and (S)-1,3-dimethylpiperazine (42.5 mg, 0.37 mmol, 1.2 equiv) were dissolved in DMSO (1 mL) at room temperature, DIPEA (115.0 μL, 0.62 mmol, 2.0 equiv) 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.

[0247] Intermediate E-8 (Table 17), designated "M," is accessible in a similar manner. The crude product E-8 is purified by chromatography if necessary. [Table 18]

[0248] Experimental procedure for the synthesis of E-8cn [ka] Treat E-8j (2.404 g, 4.50 mmol) in DCM (41 mL) with HCl (4 M in dioxane, 8.33 mL, 33.31 mmol, 7.4 equiv.) and stir the mixture at room temperature for 5 h. After complete conversion, concentrate the mixture and purify the crude product by basic reverse-phase chromatography (gradient elution: 25% to 100% acetonitrile in water) to give E-8cn.

[0249] The following intermediate E-8 (Table 18) is available in a similar manner: The crude product E-8 is purified by chromatography if necessary. [Table 19]

[0250] Experimental procedure for the synthesis of E-8cq [ka] 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 equiv.), acetic acid (304.0 μL, 5.32 mmol, 10.0 equiv.), 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 equiv.) 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.

[0251] The following intermediate E-8 (Table 19) is available in a similar manner: The crude product E-8 is purified by chromatography if necessary. [Table 20]

[0252] Scheme 3: [ka]

[0253] Experimental procedure for the synthesis of E-14a [ka] E-8i (240.0 mg, 0.60 mmol), hydroxylamine hydrochloride (110.48 mg, 1.56 mmol, 2.60 equiv.), and sodium carbonate (81.79 mg, 0.78 mmol, 1.30 equiv.) are dissolved in absolute EtOH (3.90 mL), and the mixture is stirred for 1 h at 85° C. After complete conversion, the mixture is concentrated under reduced pressure to give E-14a, which is used in the next step without further purification.

[0254] The following intermediates E-14 (Table 20) are accessible in an analogous manner using various nitriles E-8: The crude product E-14 is purified by chromatography if necessary. [Table 21] TIFF0007808058000149.tif244145 TIFF0007808058000150.tif244155 TIFF0007808058000151.tif244151 TIFF0007808058000152.tif243152 TIFF0007808058000153.tif243148 TIFF0007808058000154.tif245140 TIFF0007808058000155.tif245147 TIFF0007808058000156.tif245144 TIFF0007808058000157.tif124157

[0255] Experimental procedure for the synthesis of E-15a [ka] To a solution of E-1e (10.00 g, 45.99 mmol) in TEA (19.20 mL, 137.96 mmol, 3.0 equiv.) and EtOH (100.0 mL) was added hydroxylamine hydrochloride (6.39 g, 91.98 mmol, 2.0 equiv.), 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% Na2CO3 solution. 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.

[0256] Experimental procedure for the synthesis of E-16a [ka] 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 equiv.) 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.

[0257] The following intermediates E-16 (Table 21) are accessible in an analogous manner using various nitriles E-4: The crude product E-16 is purified by chromatography if necessary. [Table 22]

[0258] Scheme 4: [ka]

[0259] Experimental procedure for the synthesis of B-1a [ka] To a stirred solution of E-15a (6.75 g, 26.95 mmol) and A-5a (7.00 g, 29.64 mmol, 1.1 equiv.) in DMF (70 mL) was added DIPEA (13.99 mL, 80.85 mmol, 3.0 equiv.) at room temperature. The mixture was cooled to 0 °C, and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (21.04 g, 40.42 mmol, 1.5 equiv.) 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 titrated with DCM to give B-1a. The reaction here can also be carried out using enantiopure starting material A-5 to give enantiopure product B-1.

[0260] Experimental procedure for the synthesis of B-2a [ka] To a stirred solution of B-1a (2.50 g, 5.33 mmol) in THF (250 mL) at 0 °C, benzyltrimethylammonium hydroxide solution (40 wt% in MeOH, 1.962 g; 11.73 mmol, 2.2 equiv.) is added, and the mixture is stirred at room temperature for 6 min. The reaction is quenched by adding 25 mL of water and 25 mL of EtOAc. The layers are separated, and the organic phase is washed with water, dried, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (hexane / EtOAc) to give B-2a.

[0261] Experimental procedure for the synthesis of B-3a [ka] The reaction is carried out under an argon atmosphere. To a stirred mixture of zinc powder (497.22 mg, 7.60 mmol, 8.0 equiv.) and anhydrous DMA (1.24 mL), 160 μL of a 7:5 (v / v) mixture of chlorotrimethylsilane (0.730 mL) and 1,2-dibromoethane (0.520 mL) is added dropwise over 10 min at room temperature, and the resulting mixture is stirred for an additional 15 min at room temperature. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (1.941 g, 6.05 mmol, 13.2 equiv.) in anhydrous DMA (3.08 mL) is added in portions, maintaining the temperature below 35 °C. The resulting mixture is stirred for an additional 30 min while cooling to room temperature.

[0262] In a second flask, anhydrous DMA (1.4 mL) is added to a mixture of B-2a (200.0 mg, 0.44 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, DCM (16.82 mg, 0.02 mmol, 0.09 equiv.), and copper(I) iodide (9.61 mg, 0.05 mmol, 0.23 equiv.). This mixture is degassed, and 1.14 mL of the previously prepared piperidyl zinc iodide solution (21% of the solution prepared in the above procedure) is added through a 0.45 μm syringe filter. The resulting solution is degassed again and then stirred at 80 °C for 1 h. After complete conversion, DCM, water, and saturated ammonium chloride solution are added, the layers are separated, and the aqueous layer is 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; ret =0.88 minutes;[M+H] + =499).

[0263] Experimental procedure for the synthesis of B-4a [ka] B-3a (200.0 mg, 0.360 mmol) was treated with 1-methylpiperazine (799.30 μL, 7.21 mmol, 20 equiv.) and DIPEA (92.99 μL, 0.54 mmol, 1.5 equiv.) 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.

[0264] The following intermediates B-4 (Table 22) are accessible in an analogous manner using various piperazine analogs B-3: The crude product B-4 is purified by chromatography if necessary. [Table 23]

[0265] Experimental procedure for the synthesis of B-4c [ka] B-3b (100.0 mg, 0.18 mmol) is treated with 1-pyrrolidin-3-yl-piperidine (277.39 mg, 1.80 mmol, 10 equiv) and DIPEA (154.7 μL, 0.90 mmol, 5 equiv) and stirred in a sealed vessel at 100° C. for 16 h. After complete conversion, DCM, water, and brine are added, the layers are separated, and the aqueous layer is extracted with DCM. The organic layers are combined, dried, filtered, and concentrated under reduced pressure to give B-4c, which is used in the next step without further purification.

[0266] The following intermediates B-4 (Table 23) can be obtained in an analogous manner using various intermediates B-3: The crude product B-4 is purified by chromatography if necessary. [Table 24] TIFF0007808058000169.tif250142 TIFF0007808058000170.tif250150 TIFF0007808058000171.tif203151

[0267] Experimental procedure for the synthesis of B-5a [ka] Treat B-4a (111.5 mg, 0.18 mmol) in DCM (2.00 mL) with HCl (4 M in dioxane, 900.8 μL, 3.60 mmol, 20.0 equiv.) and stir the mixture at room temperature for 1 h. After complete conversion, concentrate the mixture and purify the crude product by basic reverse-phase chromatography (gradient elution: 15% to 90% acetonitrile in water) to obtain B-5a.

[0268] The following intermediates B-5 (Table 24) are accessible in an analogous manner using various piperazine analogs B-4: The crude product B-5 is purified by chromatography if necessary. [Table 25]

[0269] Scheme 5: [ka]

[0270] Experimental procedure for the synthesis of B-6a [ka] To a solution of B-2b (250.0 mg, 0.56 mmol) in DMF (3.5 mL) add N,N-dimethylformamide dimethyl acetal (674.4 µL, 5.55 mmol, 10.0 equiv.) and stir the reaction mixture at room temperature for 16 h. After complete conversion, the product is isolated by basic reverse-phase chromatography (gradient elution: 50% to 98% acetonitrile in water) to give B-6a (HPLC method A; t ret =1.61 minutes;[M+H] + =505).

[0271] Experimental procedure for the synthesis of B-7a [ka] The procedure is carried out in a glovebox under a nitrogen atmosphere. 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 equiv.), sodium tert-butoxide (257.3 mg, 2.68 mmol, 1.5 equiv.), and [BrettPhosPd(crotyl)]OTf (151.4 mg, 0.18 mmol, 0.1 equiv.) are mixed, anhydrous dioxane (15.0 mL) is added, and the mixture is stirred in a sealed vessel at room temperature for 16 h. After complete conversion, the mixture is poured into water, the pH is set to 10 by adding 8 N NaOH, and the product is extracted with DCM. The combined organic layers are dried, filtered, and concentrated. The crude product was purified by basic reverse-phase chromatography (gradient elution: 60% to 98% acetonitrile in water) to give B-7a (HPLC method A; ret =1.74 minutes;[M+H] + =598).

[0272] Experimental procedure for the synthesis of B-8a [ka] The procedure was carried out in a glovebox under a nitrogen atmosphere. 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 equiv.), palladium(II) acetate (5.1 mg, 0.023 mmol, 0.1 equiv.), and 5-[di(1-adamantyl)phosphino]-1',3',5'-triphenyl-1'H-[1,4]bipyrazole (29.9 mg, 0.045 mmol, 0.2 equiv.) were mixed, anhydrous toluene (2.7 mL) was added, and the mixture was stirred in a sealed 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 is purified by basic reverse-phase chromatography (gradient elution: 5% to 98% acetonitrile in water) to afford B-8a.

[0273] The following intermediate B-8 (Table 25) can be obtained in a similar manner using various alcohols: The crude product B-8 is purified by chromatography if necessary. [Table 26]

[0274] Experimental procedure for the synthesis of B-5c [ka] 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 equiv.). The mixture was stirred at 100 °C 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 98% acetonitrile in water) to give B-5c.

[0275] The following intermediates B-5 (Table 26) are accessible in an analogous manner using various analogs B-8: The crude product B-5 is purified by chromatography if necessary. [Table 27]

[0276] Scheme 6: [ka]

[0277] Experimental procedure for the synthesis of B-9a [ka] A-5a (67.09 mg, 0.28 mmol, 0.90 equiv.) in DMSO (1.0 mL) was treated with HATU (125.9 mg, 0.32 mmol, 1.05 equiv.) and TEA (89.2 μL, 0.62 mmol, 2.0 equiv.), and the mixture was stirred at room temperature for 20 min. E-16a (110.0 mg, 0.31 mmol, 1.0 equiv.) was then 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. This reaction can also be carried out using enantiopure starting material A-5 to give a single stereoisomer of product B-9.

[0278] The following intermediates B-9 (Table 27) are accessible in an analogous manner using various intermediates E-16 and acids A5: The crude products B-9 are purified by chromatography if necessary. [Table 28] TIFF0007808058000184.tif241146 TIFF0007808058000185.tif51140

[0279] Experimental procedure for the synthesis of B-3b [ka] To a stirred solution of B-9a (180 mg, 0.31 mmol) in THF (1.0 mL), add tetrabutylammonium hydroxide solution (40% in water, 0.152 mL, 0.23 mmol, 0.75 equiv.) dropwise and stir the mixture at room temperature for 16 h. After complete conversion, concentrate the mixture under reduced pressure and purify the crude product by basic reverse-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to obtain B-3b.

[0280] The following intermediates B-3 (Table 28) can be obtained in an analogous manner using various intermediates B-9: The crude product B-3 is purified by chromatography if necessary. [Table 29] TIFF0007808058000188.tif79125

[0281] Experimental procedure for the synthesis of B-10a [ka] This is carried out in a manner similar to the preparation of B-2 to B-6 (see, for example, procedure B-6a → B-2a).

[0282] The following intermediates B-10 (Table 29) are available in a similar manner starting from various intermediates B-3: Crude product B-10 is purified by chromatography if necessary. [Table 30]

[0283] Experimental procedure for the synthesis of B-8c [ka] The procedure was carried out in a glovebox under a 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 equiv.), sodium tert-butoxide (5.89 mg, 0.06 mmol, 2.0 equiv.), and BrettPhosPd(crotyl)OTf (3.46 mg, 0.004 mmol, 0.1 equiv.) were mixed. Degassed dioxane (0.5 mL) was added, and the mixture was stirred in a sealed vessel under an inert atmosphere at 60 °C 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 give B-8c.

[0284] The following intermediates B-8 (Table 30) are available in a similar manner starting from various intermediates B-10: Crude product B-8 is purified by chromatography if necessary. [Table 31] TIFF0007808058000193.tif249147 TIFF0007808058000194.tif243152

[0285] Experimental procedure for the synthesis of B-5e [ka] Dissolve B-8c (140.0 mg, 0.195 mmol) in EtOH (3 mL) and add concentrated aqueous hydrochloric acid (134 mg, 1.36 mmol). Stir the mixture at 100 °C under an inert atmosphere for 2 h. Concentrate the reaction mixture in vacuo, and purify the crude product by basic reverse-phase chromatography (gradient elution: 30% to 90% acetonitrile in water) to give B-5e.

[0286] The following intermediates B-5 (Table 31) can be obtained in an analogous manner using various intermediates B-8: Crude product B-5 is purified by chromatography if necessary. [Table 32]

[0287] Scheme 7: [ka]

[0288] Experimental procedure for the synthesis of B-11a [ka] A-5a (454.0 mg, 1.91 mmol, 1.0 equiv.) in DMF (11.8 mL) was treated with HATU (724.5 mg, 1.91 mmol, 1.0 equiv.) and DIPEA (0.923 mL, 5.72 mmol, 3.0 equiv.), and the mixture was stirred at room temperature for 20 min. E-14a (874.8 mg, 1.48 mmol, 0.78 equiv.) was then 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. This reaction can be carried out using enantiopure starting material A-5 to afford a single stereoisomer of product B-11.

[0289] The following intermediate B-11 (Table 32) can be obtained in an analogous manner using various intermediates E-14 and acids A-5: The crude product B-11 is purified by chromatography if necessary. [Table 33] TIFF0007808058000200.tif242129 TIFF0007808058000201.tif241147 TIFF0007808058000202.tif243130 TIFF0007808058000203.tif243148 TIFF0007808058000204.tif243131 TIFF0007808058000205.tif244144 TIFF0007808058000206.tif244137 TIFF0007808058000207.tif244136 TIFF0007808058000208.tif243136 TIFF0007808058000209.tif245136 TIFF0007808058000210.tif245134 TIFF0007808058000211.tif161147

[0290] Experimental procedure for the synthesis of B-4y [ka] To a stirred solution of B-11a (1.570 g, 1.45 mmol) in THF (16.0 mL), add tetrabutylammonium fluoride solution (1 M in THF, 2.168 mL, 2.17 mmol, 1.50 equiv.) dropwise and stir the mixture at room temperature for 16 h. After complete conversion, filter the mixture, concentrate under reduced pressure, and purify the crude product by basic reverse-phase chromatography (gradient elution: 40% to 98% acetonitrile in water) to obtain B-4y.

[0291] The following intermediates B-4 (Table 33) can be obtained in an analogous manner using various intermediates B-11: The crude product B-4 is purified by chromatography if necessary. [Table 34] TIFF0007808058000214.tif244138 TIFF0007808058000215.tif243148 TIFF0007808058000216.tif238148 TIFF0007808058000217.tif243136 TIFF0007808058000218.tif243137 TIFF0007808058000219.tif245147 TIFF0007808058000220.tif245138 TIFF0007808058000221.tif245141 TIFF0007808058000222.tif243146 TIFF0007808058000223.tif245144 TIFF0007808058000224.tif243145 TIFF0007808058000225.tif240148 TIFF0007808058000226.tif243148 TIFF0007808058000227.tif243148 TIFF0007808058000228.tif44148

[0292] Experimental procedure for the synthesis of B-5j [ka] B-4cn (400 mg, 0.50 mmol, 1 equiv.) is dissolved in MeOH and hydrogenated at 50 °C using an H-Cube apparatus with a palladium hydroxide cartridge. The solvent is removed in vacuo and the residue is purified using reverse phase chromatography to give B-5j (HPLC Method A; t ret =1.34 minutes;[M+H] + =606).

[0293] Experimental Procedure for Boc and Cbz Deprotection of Building Block B-4 (B-4 → B-5) The following intermediates B-5 (Table 34) can be obtained by Boc or Cbz deprotection of building block B-4 by analogy as described herein (see B-4a → B-5a and B-4cn → B-5e).

[0294] [Table 35] TIFF0007808058000231.tif244150 TIFF0007808058000232.tif244151 TIFF0007808058000233.tif243138 TIFF0007808058000234.tif238154 TIFF0007808058000235.tif243142 TIFF0007808058000236.tif240156 TIFF0007808058000237.tif243153 TIFF0007808058000238.tif243146 TIFF0007808058000239.tif243140 TIFF0007808058000240.tif243153 TIFF0007808058000241.tif244146 TIFF0007808058000242.tif243151 TIFF0007808058000243.tif238151 TIFF0007808058000244.tif244149 TIFF0007808058000245.tif243138 TIFF0007808058000246.tif243143 TIFF0007808058000247.tif244152 TIFF0007808058000248.tif245150 TIFF0007808058000249.tif245140 TIFF0007808058000250.tif243139 TIFF0007808058000251.tif243151 TIFF0007808058000252.tif56152

[0295] Synthesis of the final compound (I) according to the invention Scheme 8: [ka]

[0296] Experimental procedure for the synthesis of Ia-1 [ka] Dissolve B5-a (29.5 mg, 0.057 mmol), TEA (23.7 μL, 0.171 mmol, 3.0 equiv.), and DMSO (900 μL) in DCM (1.0 mL). Add acryloyl chloride (5.5 μL, 0.068 mmol, 1.2 equiv.) dissolved in DCM (1 mL) dropwise over 10 min, and stir the mixture at room temperature for 30 min. Add additional acryloyl chloride (3.2 μL, 0.04 mmol, 0.7 equiv.) dissolved in DCM (0.2 mL) dropwise, and stir the mixture for an additional 30 min. After complete conversion, concentrate the mixture, and purify the crude product by acidic reverse-phase chromatography (gradient elution: 5% to 60% acetonitrile in water) to obtain Ia-1.

[0297] The following compounds (I) according to the invention of subgenus Ia (Table 35) can be obtained in an analogous manner using various analogs B-5: The crude product Ia is purified by chromatography if necessary.

[0298] [Table 36]

[0299] Experimental procedure for the synthesis of Ia-3 [ka] A solution of acryloyl chloride (1 M in acetone, 336.0 μL, 0.34 mmol, 3.0 equiv.) was added to a mixture of potassium carbonate (46.4 mg, 0.34 mmol, 3.0 equiv.), acetone (1.75 mL), and water (0.35 mL). The mixture was stirred at room temperature for 10 min, and 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 give Ia-3. The following compounds (I) according to the invention of subgenus Ia (Table 36) can be obtained in an analogous manner using various analogs B-5: The crude product Ia is purified by chromatography if necessary.

[0300] In some cases, the synthesis is carried out using mixtures of diastereomers as starting materials and, if necessary, the enantiopure final compounds are separated by chiral SFC.

[0301] [Table 37] TIFF0007808058000258.tif244170 TIFF0007808058000259.tif242159 TIFF0007808058000260.tif233170 TIFF0007808058000261.tif225170 TIFF0007808058000262.tif236170 TIFF0007808058000263.tif244162 TIFF0007808058000264.tif245164 TIFF0007808058000265.tif244163 TIFF0007808058000266.tif245156 TIFF0007808058000267.tif245165 TIFF0007808058000268.tif241170 TIFF0007808058000269.tif233170 TIFF0007808058000270.tif242160 TIFF0007808058000271.tif243157 TIFF0007808058000272.tif237170 TIFF0007808058000273.tif244166 TIFF0007808058000274.tif244170 TIFF0007808058000275.tif246163 TIFF0007808058000276.tif244164 TIFF0007808058000277.tif242167 TIFF0007808058000278.tif244170 TIFF0007808058000279.tif240170 TIFF0007808058000280.tif242170 TIFF0007808058000281.tif244155 TIFF0007808058000282.tif241170 TIFF0007808058000283.tif47170

[0302] Compounds Ia, shown in Table 37 below, are available starting from various intermediates B-5 and the corresponding carboxylic acids in a manner similar to the conversion of C-5a to Ic-8, described further below. The crude products Ia are purified by chromatography if necessary.

[0303] [Table 38] TIFF0007808058000285.tif218164

[0304] Compound Ia, shown in Table 38 below, can be obtained starting from various intermediates B-5 and 2-butanoic acid in a manner similar to the conversion of C-5a to Ic-8, described further below. The crude product Ia can be purified by chromatography if necessary.

[0305] [Table 39]

[0306] Experimental procedure for the synthesis of Ia-169 [ka] B-5f (70.0 mg, 0.13 mmol) in anhydrous DMF (0.75 mL) was treated with TEA (46.0 μL, 0.32 mmol, 2.5 equiv.) followed by (2E)-4-bromo-N,N-dimethylbut-2-enamide (33.63 mg, 0.14 mmol, 1.1 equiv.) 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 give Ia-169 (HPLC method A; t ret =1.23 minutes;[M+H] + =661).

[0307] [Table 40]

[0308] Experimental procedure for the synthesis of Ia-170 [ka] Ia-155 (84 mg, 0.13 mmol, 1 equiv.) was dissolved in DCM (1 mL) and trifluoroacetic acid (145 mg, 1.27 mmol, 10 equiv.) 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). Subsequently, it was purified using acidic reverse-phase chromatography (acetonitrile:water = 5:95 → 60:40). The product-containing fractions were lyophilized to give Ia-170.

[0309] [Table 41] The following examples illustrate the biological activities of the compounds according to the present invention, but the present invention is not limited to these examples.

[0310] KRAS::SOS1 AlphaScreen binding assay This assay can be used to test the efficacy of compounds according to the present invention that bind to KRAS G12C to inhibit the protein-protein interaction between SOS1 and KRAS G12C, which inhibits the GEF function of SOS1 and locks KRAS G12C in its inactive GDP-bound state. Low IC in this assay setting 50 The values ​​indicate a strong inhibition of the protein-protein interaction between SOS1 and KRAS.

[0311] reagent: Homemade GST-tagged SOS1 (564_1049_GST_TEV_ECO) GST-TEV-SOS1(564-1049) is purchased from Viva Biotech Ltd. An expression construct for KRAS G12C containing a C-terminal avi-tag (amino acids 1–169 of the reference sequence P01116-2 (uniprot) with additional mutations: C51S, C80L, and C118S) was obtained by gene synthesis (GeneArt, Thermo Fisher Scientific) in a donor vector (pDONR-221) and introduced into the pDEST17 vector with an N-terminal His6-tag by recombination cloning. The protein was expressed in E. coli, and the purified protein was biotinylated with E. coli biotin ligase (BirA) before use. GDP (Sigma Catalog No. G7127) AlphaLISA glutathione acceptor beads (PerkinElmer, Catalog No. AL109) AlphaScreen Streptavidin Donor Beads (PerkinElmer, Catalog No. 6760002) Assay Plate: Proxiplate-384PLUS, white (PerkinElmer, Catalog No. 6008289) Assay buffer: 1x PBS 0.1% BSA 0.05% Tween 20 KRAS::SOS1 GDP mix: 7.5 nM (final assay concentration) KRAS G12C, 10 μM (final assay concentration) GDP and 5 nM (final assay concentration) GST-SOS1 are mixed in assay buffer and kept at room temperature before use. Bead Mix: AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads are mixed in assay buffer at a concentration of 10 μg / mL each (final assay concentration) and kept at room temperature before use.

[0312] Assay Protocol: Compounds are diluted to a final starting concentration of 100 μM and tested in duplicate. Assay-ready plates (ARP) are prepared using an Access Labcyte Workstation equipped with a Labcyte Echo 550 or 555 acoustic dispenser. For compounds starting at 100 μM, 150 nL of compound solution is transferred in duplicate per well at 11 concentrations in a 1:5 serial dilution. The assay is performed in a dark room under 100 lux using a fully automated robotic system. Add 10 µL of KRAS::SOS1 GDP mix to columns 1-24 to 150 nL of compound solution (1:100 final dilution in the assay, 1% final DMSO concentration).

[0313] After a 30 minute incubation period, 5 μL of bead mix is ​​added to columns 1-23. The plates are kept at room temperature in a darkened incubator. After a further 60 minutes of incubation, the signal is measured using a PerkinElmer Envision HTS Multilabel Reader using the PerkinElmer AlphaScreen specification. Each plate contains the following controls: Diluted DMSO + KRAS::SOS1 GDP mix + bead mix Diluted DMSO + KRAS::SOS1 GDP mix Calculating the result: I C 50 Values ​​are calculated and analyzed using a four-parameter logistic model. The table of exemplary compounds disclosed herein shows the IC determined using the above assay. 50 Contains a value.

[0314] Generation of Ba / F3 cell model and proliferation assay Ba / F3 cells were ordered from DSMZ (ACC300, Lot 17) and grown in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10 ng / ml IL-3 at 37°C in a 5% CO2 atmosphere. Plasmids containing KRASG12 mutants were obtained from GeneScript. To generate KRASG12-dependent Ba / F3 models, Ba / F3 cells were transduced with retroviruses containing vectors carrying KRASG12 isoforms. Platinum-E cells (Cell Biolabs) were used for retroviral packaging. Retroviruses were added to Ba / F3 cells. To ensure infection, 4 μg / mL polybrene was added, and the cells were spinfected. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10%–20% were further cultured and puromycin selection was initiated at 1 μg / mL. As a control, parental Ba / F3 cells were used to demonstrate selection. Selection was considered successful when the culture of parental Ba / F3 cells died. To evaluate the transforming potential of KRASG12 mutations, the growth medium was not further supplemented with IL-3. Ba / F3 cells carrying an empty vector were used as a control. Puromycin was removed approximately 10 days before the experiment was performed.

[0315] For proliferation assays, Ba / F3 cells were cultured at 1 × 10 in growth medium (RPMI-1640 + 10% FCS). 3Cells were seeded at 60 μL per well into 384-well plates. Compounds were added using an Access Labcyte Workstation equipped with a Labcyte Echo 550 or 555 acoustic dispenser. All treatments were performed in duplicate. The assay was performed using a fully automated robotic system. Treated cells were incubated at 37°C and 5% CO2 for 72 hours. The viability stain AlamarBlue™ (ThermoFisher) was added, and fluorescence was measured using a PerkinElmer Envision HTS Multilabel Reader. Raw data were imported into and analyzed using Boehringer Ingelheim's proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0316] The IC of the representative compound (I) according to the present invention measured by this assay 50 The values ​​are presented in Table 41. [Table 42]

[0317] Further proliferation assays using G12C mutant cancer cell lines SW 837 CTG Proliferation Assay (CRC) SW837 cells (ATCC#CCL-235) were cultured in a cell culture flask (175 cm) using L-15 10% FCS, 1% L-Glu, 1x NEAA, and 1x Na-Pyrovane. 2 ) cultures were incubated at 37°C and 0% CO2 in a humidified atmosphere with medium changes or subcultures 2-3 times per week. Materials used in the assay were CulturPlate-384, White Opaque 384-well Microplate, Sterile and Tissue Culture Treated (Perkin Elmer #6007680), Leibovitz L15 Medium, and FBS #SH30071.03 (HyClone).

[0318] The proliferation assay began with seeding cells at a density of 500 cells / well in flat-bottom 384-well microtiter plates in 90 μL L-15 10% FCS, 1% L-Glu, 1x NEAA, and 1x Na-Pyrovat (Day 1). Any other luminescence-compatible plate format is also possible. On Day 2, 10 μL dilutions of test compound covering a concentration range of approximately 0.1 to 10,000 nM were added to the cells. The cells were incubated at 37°C in a humidified CO2-controlled (CO2-free) incubator for 5 days. On Day 7, 100 μL of Cell Titer Glow reagent (Cell Titer Glo Luminescent Catalog No. G7571, Promega) was added to each well and incubated for an additional 10 minutes at room temperature (with agitation). Luminescence was measured using a standard luminescence readout on a Wallac Victor. IC 50 Values ​​were calculated using the standard Levenburg Marquard algorithm (GraphPad Prism). The IC of the representative compound (I) according to the present invention measured by this assay 50 The values ​​are presented in Table 42.

[0319] MiaPaCa-2 CTG proliferation assay (pancreatic cancer) MiaPaCa-2 cells (ATCC® CRM-CRL-1420™) were cultured in cell culture flasks (175 cm) using DMEM medium supplemented with 10% fetal bovine serum. 2 ) cultures were incubated at 37°C and 5% CO in a humidified atmosphere with medium changes or subcultures two to three times per week. Materials used in the assay were CulturPlate-384, White Opaque 384-well microplates, Sterile and Tissue Culture Treated (Perkin Elmer #6007680), DMEM medium, and FBS #SH30071.03 (HyClone).

[0320] The proliferation assay began with seeding cells at a density of 500 cells / well in 90 μL of DMEM medium supplemented with 10% FBS into flat-bottom 384-well microtiter plates (day 1). Any other luminescence-compatible plate format is also possible. On day 2, 10 μL dilutions of test compound covering a concentration range of approximately 0.1 to 10,000 nM were added to the cells. The cells were incubated at 37°C with 5% CO2 in a humidified incubator for 5 days. On day 7, 100 μL of Cell Titer Glow reagent (Cell Titer Glo Luminescent Catalog No. G7571, Promega) was added to each well and incubated for an additional 10 minutes at room temperature (with agitation). Luminescence was measured using a standard luminescence readout on a Wallac Victor. IC 50 Values ​​were calculated using the standard Levenburg Marquard algorithm (GraphPad Prism). The IC of the representative compound (I) according to the present invention measured by this assay 50 The values ​​are presented in Table 42.

[0321] NCI-H358 CTG proliferation assay (120 hours) (NSCLC) NCI-H358 cells (ATCC No. CRL-5807) were dispensed into white-bottom opaque 96-well plates (Perkin Elmer catalog no. 5680) at a density of 2000 cells per well in 100 μL RPMI-1640 ATCC-Formulation (Gibco #A10491) + 10% FCS. Cells were incubated overnight at 37°C in a humidified tissue culture incubator with 5% CO2. Compounds (10 mM stock in DMSO) were added in logarithmic dose series using an HP Digital Dispenser D300 (Tecan) and normalized to the added DMSO. For TO time point measurements, 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 a percent of control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. 50 Values ​​were determined from viability measurements by nonlinear regression using a four-parameter model. The IC of the representative compound (I) according to the present invention measured by this assay 50 The values ​​are presented in Table 42.

[0322] NCI-H2122 CTG proliferation assay (120 hours) (NSCLC) A 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, GibcoBRL, Catalog No. 10270-106). On day 0, 1,000 NCI-H2122 cells were seeded into a flat-bottom 384-well plate in 60 μL RPMI ATCC + 10% FCS + Penstrep. The cells were then incubated overnight in a CO2 incubator at 37°C. On day 1, a DMSO control was included and compounds were added using an ECHO acoustic liquid handler system (Beckman Coulter). Plates were incubated for 120 hours and cell viability was measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (expressed as a percent of control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50 Values ​​were determined from viability measurements by nonlinear regression using a four-parameter model.

[0323] [Table 43]

[0324] ERK phosphorylation assay The ERK phosphorylation assay is used to examine the efficacy of compounds in inhibiting KRAS G12C-mediated signal transduction in vitro in KRAS G12C mutant human cancer cell lines. This demonstrates the molecular mode of action of the compounds according to the present invention by interfering with the RAS G12C protein signal transduction cascade. Low IC in this assay setting 50The values ​​indicate the high potency of the compounds according to the present invention. It was observed that the compounds according to the present invention demonstrate an inhibitory effect on ERK phosphorylation in KRAS G12C mutant human cancer cell lines, thus supporting the molecular mode of action of the compounds on RAS G12C protein signaling.

[0325] ERK phosphorylation assays are performed using the following human cell lines: NCI-H358 (ATCC (ATCC CRL-5807): a human lung cancer harboring a KRAS G12C mutation (→ Assay 1)) and NCI-H358_Cas9_SOS2, the same cell line in which SOS2 has been knocked out (→ Assay 2). A vector containing a DNA sequence designed for the production of gRNA for SOS2 protein knockout was obtained from Sigma-Aldrich. To generate the NCI-H358 SOS2 knockout 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 analyzer. GFP-positive cells were collected and further expanded. These GFP-positive cell pools were subjected to single-cell dilution, and SOS2 knockout clones were identified by Western blot and genomic DNA sequence analysis.

[0326] Materials used in the assay: RPMI-1640 medium (ATCC® 30-2001™) HyClone fetal bovine serum (FBS) (SH30071.03) Thermo Fisher Scientific Non-Essential Amino Acids (11140035) Thermo Fischer Scientific pyruvic acid (11360039) Glutamax (35050061) manufactured by Thermo Fischer Scientific Greiner Bio-One 384 Plate (781182) PerkinElmer Inc. Proxiplate™ 384 (6008280) AlphaLISA SureFire Ultra p-ERK1 / 2 (Thr202 / Tyr204) Assay Kit (ALSU-PERK-A500) Sigma EGF (E4127) Acceptor mix: PerkinElmer Protein A acceptor beads (6760137M) Donor mix: PerkinElmer AlphaScreen streptavidin-coated donor beads (6760002) Trametinib Staurosporine (S6942) from Sigma Aldrich

[0327] Assay configuration: Cells were seeded at 40,000 cells per well in 60 μL of RPMI containing 10% FBS, non-essential amino acids, pyruvate, and glutamax in a Greiner TC 384 plate. The cells were incubated at room temperature for 1 hour, then incubated overnight in a humidified atmosphere at 37°C and 5% CO2 in an incubator. Then, 60 nL of compound solution (10 mM DMSO stock solution) was added using a Labcyte Echo 550 device. After 1 hour of incubation in the incubator, the medium was removed after centrifugation, and the cells were lysed by adding 20 μL of 1.6x lysis buffer from the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) Assay Kit supplemented with the protease inhibitors 100 nM trametinib and 100 nM staurosporine. After 20 minutes of incubation with shaking at room temperature, 6 μL of each lysate sample was transferred to a 384-well Proxiplate and analyzed for pERK (Thr202 / Tyr204) using the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) Assay Kit. 3 μL of acceptor mix and 3 μL of donor mix were added under dim light, and after 2 hours of incubation at room temperature in the dark, the signal was measured using a PerkinElmer Envision HTS Multilabel Reader. Raw data were imported into and analyzed using Boehringer Ingelheim's proprietary software, MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0328] The IC of the representative compound (I) according to the present invention measured by this assay 50 Values ​​are presented in Table 57. (IC from Assay 2 50 are marked with an *, all others are from Assay 1).

[0329] [Table 44]

[0330] The following formulation examples are illustrative without limiting the scope of the invention. Examples of pharmaceutical preparations A) Per tablet 100 mg of active substance according to formula (I) Lactose 140mg Corn starch 240mg Polyvinylpyrrolidone 15mg Magnesium stearate 5mg 500mg

[0331] The finely ground active substance, lactose and a portion of corn starch are mixed together. This mixture is sieved, moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated and dried. The granules, the remaining corn starch and magnesium stearate are sieved and mixed together. The mixture is compressed to produce tablets of suitable shape and size. B) Per tablet 80 mg of active substance according to formula (I) Lactose 55mg Corn starch 190mg Microcrystalline cellulose 35mg Polyvinylpyrrolidone 15mg Sodium starch glycolate 23mg Magnesium stearate 2mg 400mg

[0332] The finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together, the mixture is sieved, the remaining corn starch and water are added and worked to form granules, which are dried and sieved, sodium starch glycolate and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of suitable size. C) Per tablet 25 mg of active substance according to formula (I) Lactose 50mg Microcrystalline cellulose 24mg Magnesium stearate 1mg 100mg

[0333] The active substance, lactose and cellulose are mixed together. The mixture is screened, moistened with water, kneaded, wet-granulated and dried, or dry-granulated or directly final blended with magnesium stearate, and compressed into tablets of suitable shape and size. In the case of wet-granulation, lactose or cellulose and magnesium stearate are further added, and the mixture is compressed to produce tablets of suitable shape and size. D) Ampoule liquid 50 mg of active substance according to formula (I) Sodium chloride 50mg Water for injection 5mL

[0334] The active substance is dissolved in water at its own pH or, optionally, at pH 5.5-6.5, and isotonicized with sodium chloride. The resulting solution is filtered to make it pyrogen-free, and the filtrate is transferred under aseptic conditions into ampoules, which are sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg, and 50 mg of the active substance.

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, R 1a and R 1b Both are hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 3-5 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; R 2a and R 2b Both are hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 3-5 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; and / or R 1a or R 1b One of the and R 2a or R 2b together with the carbon atoms to which they are attached may form a cyclopropane ring; Z is -(CR 6a R 6b ) n - and R 6a and R 6b are hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 3-5 independently selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2; R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-6 Alkyl, halogen, —OH, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -CN,C 3-5 selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; Ring A is oxadiazole or thiadiazole; U is nitrogen (=N-) and R A A carbon substituted with (=C(R A )-) V is nitrogen (=N-) and R B A carbon substituted with (=C(R B )-) W is nitrogen (=N-) and R C A carbon substituted with (=C(R C )-) R A , R B and R C is hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , -SC 1-6 Alkyl, —S(═O) 2 -C 1-6 Alkyl, C 3-5 Cycloalkyl, 3- to 5-membered heterocyclyl and C 1-6 Alkyl (C 1-6 Alkoxy, -CN, -OH, -NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 and each independently selected from the group consisting of: R 5 is R a1 and R b1 is selected from the group consisting of R a1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be substituted with one or more of the same or different R b1 and / or R c1 and optionally substituted by R b1 are respectively -OR c1 , -NR c1 R c1 , halogen, —CN, —C(═O)R c1 , -C(=O)OR c1 , —C(═O)NR c1 R c1 , -S(=O) 2 R c1 , -S(=O) 2 NR c1 R c1 , -NHC(=O)R c1 , -N(C 1-4 alkyl)C(=O)R c1 , -NHS(=O) 2 R c1 , -N(C 1-4 alkyl)S(=O) 2 R c1 , -NHC(=O)OR c1 , -N(C 1-4 alkyl)C(=O)OR c1 and the divalent substituent =O; R c1 are hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be substituted with one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively -OR e1 , -NR e1 R e1 , halogen, —CN, —C(═O)R e1 , -C(=O)OR e1 , —C(═O)NR e1 R e1 , -S(=O) 2 R e1 , -S(=O) 2 NR e1 R e1 , -NHC(=O)R e1 , -N(C 1-4 alkyl)C(=O)R e1 , -NHC(=O)OR e1 , -N(C 1-4 alkyl)C(=O)OR e1 and the divalent substituent =O; R e1 are hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls are C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl (one or more of the same or different C 1-4 optionally substituted by alkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, —OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, halogen, -CN, -NH 2 , -C(=O)C 1-4 Alkyl, —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 and the divalent substituent ═O, L is -L 1 -L 2 -L 3 - and L 1 is connected to E, L 1 is 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 selected from the group consisting of cycloalkylene, phenylene, 4- to 12-membered heterocyclylene, and 5- to 10-membered heteroarylene; L 2 is C 1-6 Alkylene, C 3-7 selected from the group consisting of cycloalkylene, phenylene, 4- to 12-membered heterocyclylene, and 5- to 10-membered heteroarylene; L 3 is 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 selected from the group consisting of cycloalkylene, phenylene, 4- to 12-membered heterocyclylene, and 5- to 10-membered heteroarylene; L 1 , L 2 and L 3 C in 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4- to 12-membered heterocyclylene and 5- to 10-membered heteroarylene are each C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, —OH, —CN, C 1-6 Alkoxy, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -C(=O)OH, -C(=O)-OC 1-6 Alkyl, —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , divalent substituents = O and C 1-6 Alkyl (halogen, -OH, -CN, C 1-4 Alkoxy, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -C(=O)OH, -C(=O)-OC 1-6 Alkyl, —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 and E is 【Chemistry 2】 and 【Transformation 3】 represents a double or triple bond, Q 1 is a bond, -CH 2 -, -CH(OH)-, -C(=O)-, -C(=O)N(R G1 )-, -C(=O)O-, -S(=O) 2 -, -S(=O) 2 N (R G1 )- and -C(=NR H1 )- is selected from the group consisting of R G1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy-C 1-6 Alkyl, H 2 N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 alkyl)HN-C 1-6 Alkyl, (C 1-4 alkyl) 2 N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; R H1 are hydrogen, -OH, and C 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, 【Chemistry 4】 If represents a double bond, R D is 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, —NH 2 , —NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(=O)OH, -C(=O)OC 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), which may be substituted with one or more identical or different substituents selected from the group consisting of: R E and R F is R a2 and R b2 are each independently selected from the group consisting of: R a2 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be substituted with one or more of the same or different R b2 and / or R c2 and optionally substituted by R b2 are respectively -OR c2 , -NR c2 R c2 , halogen, —CN, —C(═O)R c2 , -C(=O)OR c2 , —C(═O)NR c2 R c2 , -S(=O) 2 R c2 , -S(=O) 2 NR 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 the divalent substituent =O; R c2 are hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 cycloalkenyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls are 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)NH 2 , -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl) 2 and the divalent substituent ═O, or R D and R E together with the carbon atoms to which they are attached form a 4- to 7-membered unsaturated alicyclic ring or a 4- to 7-membered unsaturated heterocyclic ring, and this 4- to 7-membered unsaturated alicyclic ring or 4- to 7-membered unsaturated heterocyclic ring is F In addition, C 1-6 Alkyl, C 1-6 Haloalkyl, —OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, —NH 2 , -CN, -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , halogen, —C(═O)O—C 1-6 optionally substituted with one or more identical or different substituents selected from the group consisting of alkyl and the divalent substituent =O; or Q 1 is -C(=O)N(R G1 )-, -C(=O)N(R G1 )-R G1 and R F are taken together to form -C(=O)-, -CH 2 -, -CH 2 -C(=O)-, -C(=O)-CH 2 - and - C 2 H 4 - forming a linker selected from the group consisting of 【Transformation 5】 represents a triple bond, R D and R E is neither present, R F is R a2 and R a2 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be substituted with one or more of the same or different R b2 and / or R c2 and optionally substituted by R b2 are respectively -OR c2 , -NR c2 R c2 , halogen, —CN, —C(═O)R c2 , -C(=O)OR c2 , —C(═O)NR c2 R c2 , -S(=O) 2 R c2 , -S(=O) 2 NR 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 the divalent substituent =O; R c2 are hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5-10 membered heteroaryl; or E is 【Transformation 6】 and Q 2 is a bond, -CH 2 -, -CH(OH)-, -C(=O)-, -C(=O)N(R G2 )-, -C(=O)O-, -S(=O) 2 -, -S(=O) 2 N (R G2 )- and -C(=NR H2 )- is selected from the group consisting of R G2 are hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy-C 1-6 Alkyl, H 2 N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 alkyl)HN-C 1-6 Alkyl, (C 1-4 alkyl) 2 N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; R H2 are hydrogen, -OH, and C 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R I is selected from the group consisting of hydrogen and halogen; R J is hydrogen, or R I and R J together with the carbon atoms to which they are attached form a cyclopropane or oxirane ring, R K is hydrogen, C 1-6 selected from the group consisting of alkyl, —CN and halogen; R L is hydrogen, C 1-6 Alkyl, —CN, halogen and —C(═O)—C 1-6 is selected from the group consisting of alkyl, or E is 【Transformation 7】 and Q 3 is -C(=O)-, -C(=O)N(R G3 )-, -C(=O)O-, -S(=O) 2 -, -S(=O) 2 N (R G3 )- and -C(=NR H3 )- is selected from the group consisting of R G3 are hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy-C 1-6 Alkyl, H 2 N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 alkyl)HN-C 1-6 Alkyl, (C 1-4 alkyl) 2 N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 independently selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; R H3 are hydrogen, -OH, and C 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R M represents halogen, —CN and —O—C(═O)—C 1-6 is selected from the group consisting of alkyl, or E is 【Transformation 8】 and Q 4 is a bond, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C 1-4 alkyl)-, -S(=O) 2 - and -S(=O) 2 NH—; Ring B is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, and 5-membered heteroaryl; q is selected from the group consisting of 1, 2, 3 and 4; R N are respectively, C 1-4 Alkyl, C 1-4 Haloalkyl, vinyl, ethynyl, halogen, -CN, nitro and C 1-4 alkoxy) Or its salt.

2. 2. The compound or salt of claim 1, which is of formula (Ia): 【Chemistry 9】 (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 ,U,V,W,R 5 , L and E are defined as in claim 1)

3. Compound of formula (II) 【Chemistry 10】 (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 , ring A, U, V, W, R 5 and L are defined as in formula (I) in claim 1, and -L 1 -L 2 -L 3 -L 1 is connected to a hydrogen of the group HL-) or a salt thereof.

4. R 1a and R 1b Both are hydrogen and C 1-4 independently selected from the group consisting of alkyl, R 2a and R 2b are both independently selected from the group consisting of hydrogen and halogen; The compound or salt according to any one of claims 1 to 3.

5. R 3 But hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano-C 1-4 Alkyl, halogen, —OH, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 and —CN, The compound or salt according to any one of claims 1 to 4.

6. Ring A is 【Chemistry 11】 selected from the group consisting of The compound or salt according to any one of claims 1 to 5.

7. U is R A A carbon substituted with (=C(R A )-) and V is R B A carbon substituted with (=C(R B )-) and W is nitrogen (=N-), R A and R B But hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , C 3-5 Cycloalkyl, 3- to 5-membered heterocyclyl and C 1-6 Alkyl (C 1-6 Alkoxy, -CN, -OH, -NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 each independently selected from the group consisting of: The compound or salt according to any one of claims 1 to 6.

8. U is R A A carbon substituted with (=C(R A )-) and V is R B A carbon substituted with (=C(R B )-) and W is R C A carbon substituted with (=C(R C )-) and R A , R B and R C But hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , C 3-5 Cycloalkyl, 3- to 5-membered heterocyclyl and C 1-6 Alkyl (C 1-6 Alkoxy, -CN, -OH, -NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 each independently selected from the group consisting of: The compound or salt according to any one of claims 1 to 6.

9. U is nitrogen (=N-), V is R B A carbon substituted with (=C(R B )-) and W is nitrogen (=N-), R B But hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , C 3-5 Cycloalkyl, 3- to 5-membered heterocyclyl and C 1-6 Alkyl (C 1-6 Alkoxy, -CN, -OH, -NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 and optionally substituted with a substituent selected from the group consisting of: The compound or salt according to any one of claims 1 to 6.

10. U is R A A carbon substituted with (=C(R A )-) and V is nitrogen (=N-), W is nitrogen (=N-), R A But hydrogen, C 1-6 Haloalkyl, C 2-6 Alkynyl (C 3-5 optionally substituted by cycloalkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , C 3-5 Cycloalkyl, 3- to 5-membered heterocyclyl and C 1-6 Alkyl (C 1-6 Alkoxy, -CN, -OH, -NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 and optionally substituted with a substituent selected from the group consisting of: The compound or salt according to any one of claims 1 to 6.

11. U is nitrogen (=N-), V is nitrogen (=N-), W is nitrogen (=N-); The compound or salt according to any one of claims 1 to 6.

12. R 5 But, R a1 and R b1 is selected from the group consisting of R a1 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl may be one or more of the same or different R b1 and / or R c1 and optionally substituted by R b1 are respectively -OR c1 , -NR c1 R c1 , halogen, —CN, —C(═O)R c1 , -C(=O)OR c1 , —C(═O)NR c1 R c1 , -S(=O) 2 R c1 , -S(=O) 2 NR c1 R c1 , -NHC(=O)R c1 , -N(C 1-4 alkyl)C(=O)R c1 and the divalent substituent =O; R c1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl may be one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively -OR e1 , -NR e1 R e1 , halogen, —CN, —C(═O)R e1 , —C(═O)NR e1 R e1 and the divalent substituent =O; R e1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls are C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl (one or more of the same or different C 1-4 optionally substituted by alkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, —OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, halogen, -CN, -NH 2 , -C(=O)C 1-4 Alkyl, —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 and the divalent substituent =O, The compound or salt according to any one of claims 1 to 11.

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

14. R 5 But, R b1 and R b1 But, -OR c1 and -NR c1 R c1 are independently selected from the group consisting of R c1 are hydrogen and C, respectively. 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be substituted with one or more of the same or different R d1 and / or R e1 and optionally substituted by R d1 are respectively -OR e1 , -NR e1 R e1 , halogen, —C(═O)R e1 and —C(═O)NR e1 R e1 are independently selected from the group consisting of R e1 are hydrogen and C, respectively. 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls are C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl (one or more of the same or different C 1-4 optionally substituted by alkyl), C 1-6 optionally substituted with one or more identical or different substituents selected from the group consisting of alkoxy, halogen and the divalent substituent =O, The compound or salt according to any one of claims 1 to 11.

15. L is -L 1 -L 2 -L 3 - and L 1 is connected to E, L 1 is bond, C 1-6 selected from the group consisting of alkylene and 4- to 12-membered heterocyclylene; L 2 But C 1-6 selected from the group consisting of alkylene, phenylene, and 4- to 12-membered heterocyclylene; L 3 is a bond, -NH-, -N(C 1-4 is selected from the group consisting of —alkyl)- and —O—; L 1 and L 2 C in 1-6 Alkylene, phenylene and 4- to 12-membered heterocyclylene are each C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, —OH, —CN, C 1-6 Alkoxy, —NH 2 , —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -C(=O)OH, -C(=O)-OC 1-6 Alkyl, —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl) 2 , divalent substituents = O and C 1-6 Alkyl (halogen, -OH, -CN, -NH 2 , C 1-4 Alkoxy, —NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -C(=O)OH, -C(=O)-OC 1-6 Alkyl, —C(═O)NH 2 , -C(=O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 and optionally substituted independently with one or more identical or different substituents selected from the group consisting of: The compound or salt according to any one of claims 1, 2, and 4 to 14.

16. L, 【Chemistry 12-1】 【Chemistry 12-2】 selected from the group consisting of 16. A compound or salt according to claim 15.

17. E, 【Chemistry 13】 and Q 1 But -CH 2 -, -C(=O)-, -C(=O)N(R G1 )-, -C(=O)O-, -S(=O) 2 -, -S(=O) 2 N (R G1 )- and -C(=NR H1 )- is selected from the group consisting of R G1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl and hydroxy-C 1-6 independently selected from the group consisting of alkyl, R H1 are hydrogen, -OH, and C 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R D But hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, —CN, C 1-6 Alkoxy, —C(═O)O—C 1-6 Alkyl and C 1-6 alkyl (phenyl, 3- to 11-membered heterocyclyl, C 1-6 Alkoxy, halogen, —OH, —N(C 1-6 alkyl) 2 , -C(=O)OH, -C(=O)OC 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), which may be substituted with one or more identical or different substituents selected from the group consisting of: R E and R F But, R a2 and R b2 are each independently selected from the group consisting of: R a2 But hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls may be substituted with one or more of the same or different R b2 and / or R c2 and optionally substituted by R b2 are respectively -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 are independently selected from the group consisting of R c2 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, C 6-10 independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 haloalkyl, 3- to 11-membered heterocyclyl, C 6-10 All aryls and 5- to 10-membered heteroaryls are 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)NH 2 , -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl) 2 and the divalent substituent =O, The compound or salt according to any one of claims 1, 2, and 4 to 16.

18. E, 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 selected from the group consisting of 18. A compound or salt according to claim 17.

19. E, 【Chemistry 15】 and Q 1 But -CH 2 -, -C(=O)-, -C(=O)N(R G1 )-, -C(=O)O-, -S(=O) 2 -, -S(=O) 2 N (R G1 )- and -C(=NR H1 )- is selected from the group consisting of R G1 are hydrogen and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl and hydroxy-C 1-6 independently selected from the group consisting of alkyl, R H1 are hydrogen, -OH, and C 1-6 Alkoxy, -CN and C 1-6 independently selected from the group consisting of alkyl, R F is hydrogen and C 1-6 Alkyl (-OH, C 1-6 Alkoxy, —NH 2 , —NH(C 1-4 alkyl) and -N(C 1-4 alkyl) 2 and optionally substituted with a substituent selected from the group consisting of: The compound or salt according to any one of claims 1, 2, and 4 to 16.

20. E, 【Chemistry 16】 selected from the group consisting of 20. A compound or salt according to claim 19.

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

22. The compound or salt thereof according to claim 3, which is selected from the group consisting of: 【Chemistry 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 【Chemistry 18-4】 【Chemistry 18-5】 【Chemistry 18-6】 【Chemistry 18-7】 【Chemistry 18-8】 【Chemistry 18-9】 【Chemistry 18-10】 【Chemistry 18-11】 【Chemistry 18-12】

23. 3. A pharmaceutical composition comprising a compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof.

24. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of cancer.

25. 25. The pharmaceutical composition of any one of claims 23 and 24, wherein the compound or salt is administered before, after or together with one or more other pharmacologically active substances.

26. 25. The pharmaceutical composition of any one of claims 23 and 24, wherein the compound or salt is administered in combination with one or more other pharmacologically active substances.

27. The pharmaceutical composition according to any one of claims 23 to 26, wherein the cancer 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.

28. The pharmaceutical composition according to any one of claims 23 to 27, further comprising one or more pharmaceutically acceptable excipients.

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