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

Abstract

The present invention relates to a compound of formula (I) [R 1a , R 1b , R 2a , R 2b , Z, R 3 ~R 5 The present invention encompasses compounds of formula (I)], in which A, p, U, V, W and L have the meanings given in the claims and the specification, their use as inhibitors of mutant Ras family proteins, pharmaceutical compositions and preparations containing such compounds, and their use as medicinal / medical uses, in particular as agents for the treatment and / or prevention of neoplastic diseases.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a compound of formula (I): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 ~R 5 , A, p, U, V, W and L have the meanings given in the claims and the specification. The present invention relates to ring-fused 2-amino-3-cyanothiophenes and derivatives of the formula: [Background technology]

[0002] 2. Background of the Invention 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 any of their mutants, are small GTPases that exist in cells in either GTP-bound or GDP-bound states (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Nimnual et al., Sci. STKE., 2002, 2002(145):pe36). Ras family proteins have weak intrinsic GTPase activity and 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 the release of GDP from Ras family proteins, allowing GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). When in the GTP-bound state, Ras family proteins are active and engage effector proteins, including C-RAF and phosphoinositide 3-kinase (PI3K), to promote the RAF / mitogen or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian target of rapamycin (mTOR) pathway, and the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).These pathways affect 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 their intrinsic and GAP-induced GTPase activity, leading to an increase in the population of GTP-bound / active mutant Ras family proteins (McCormick et al., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). This, in turn, leads to sustained activation of effector pathways downstream 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) are found in a wide variety of human cancers, including lung, colon, and pancreatic cancers (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Mutations in HRAS (e.g., amino acids G12, G13, Q61) and NRAS (e.g., amino acids G12, G13, Q61, A146) are also found in a wide variety of human cancer types, but usually at a lower frequency than KRAS mutations (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Additionally, alterations (e.g., mutations, overexpression, gene amplification) in Ras family proteins / Ras genes have been described as a resistance mechanism to cancer therapeutics 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, 7 5(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 transversion at codon 12 and are common mutations 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 enriched in KRAS mutant non-small cell lung cancers, which harbor this mutation in about half of their cancers, which is associated with DNA adducts produced by cigarette smoke. G12C mutations are not exclusively associated with lung cancer but are also found in other RAS mutant cancer types, including, for example, 3-5% of all KRAS mutant colorectal cancers. Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there is a need for new inhibitors of G12C mutant Ras family proteins that have the required pharmacological properties suitable for clinical use. [Means for solving the problem]

[0006] Surprisingly, it has been found that the compounds described herein have antitumor activity and are useful in controlling uncontrolled cell proliferation resulting from malignant diseases. This antitumor activity is believed to result from the inhibition of G12C mutant Ras family proteins, particularly KRAS G12C, which are important mediators of proliferation and survival in certain tumor cells. Furthermore, the compounds of the present invention are believed to interact with and then covalently bind to G12C mutant Ras family proteins, particularly KRAS G12C, via an electrophilic moiety (e.g., Michael acceptor) present in the compound of formula (I) (as confirmed by crystallography of KRAS G12C). By covalently binding to G12C mutant Ras family proteins, particularly KRAS G12C, which most likely occurs at position 12 of the Ras family protein, the compounds impair or substantially eliminate the ability of G12C Ras family proteins to reach their active, pro-pro-proliferative / pro-survival conformation.

[0007] Such covalent binders to mutant Ras family proteins, e.g., KRAS G12C, NRAS G12C, and HRAS G12C, are expected to inhibit downstream cell signaling of the Ras family proteins (e.g., ERK phosphorylation). In cancer cells that are dependent on mutant Ras family proteins (e.g., KRAS mutant cancer cell lines), such binders / inhibitors are expected to exert anti-cancer effects (e.g., inhibition of proliferation, survival, metastasis, etc.).

[0008] Indeed, the binding of the compounds of formula (I) according to the present invention results in selective and highly potent anti-proliferative cellular effects in G12C mutant KRAS cell lines and a large selectivity window compared to KRAS wild-type cells. This superior potency can lead to lower systemic exposure required for full efficacy in humans, and therefore better tolerability. The compounds show strong biomarker modulation, e.g., pERK, in G12C mutant KRAS cell lines. Selected compounds show good selectivity against other human targets, e.g., kinases, when tested in selectivity panels. Last but not least, the series of compounds disclosed herein show good permeability, excellent solubility, and have fine-tuned PK properties. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description of the Invention compound It has now been surprisingly discovered that a compound of formula (I): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 3 ~R 5 , A, p, U, V, W and L have the meanings given herein below. It has been found that the compound represented by the formula (I) acts as an inhibitor of G12C mutant Ras family protein, which is involved in the control of cell proliferation. Therefore, the compound according to the present invention can be used, for example, in the treatment of diseases characterized by excessive or abnormal cell proliferation.

[0010] Thus, in a first aspect, the present invention provides a compound of formula (I): [ka] [In the formula, R1a and R 1b are each independently 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 selected from the group consisting of cycloalkyl and 3-5 membered heterocyclyl; R 2a and R 2b are each independently 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 selected from the group consisting of cycloalkyl and 3-5 membered heterocyclyl; and / or, optionally, R 1a or R 1b One of the two and R 2a or R 2b together with the carbon atom to which they are attached form a cyclopropane ring; Z is -(CR 6a R 6b ) n - and; Each R 6a and R 6b are independently 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 selected from the group consisting of cycloalkyl and 3-5 membered heterocyclyl; Or R 6a and R 6b together with the carbon atoms to which they are attached form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; -L- is a bond or is selected from -O-, -S- and -N(R 13 )-(wherein, R 13 is hydrogen or C 1-6 alkyl; R 3 is substituted with E, and -L- is -O-, -S- and -N(R 13 )-, R 3 is C 1-6 Alkyl, C 1-6 alkoxy, 5- to 10-membered heteroaryl, and 3- to 11-membered heterocyclyl, wherein C 1-6 Alkyl, 5-10 membered heteroaryl, C 1-6 All alkoxy and 3- to 11-membered heterocyclyl are optionally and independently selected from halogen, C 1-6 Alkyl, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, C 3-5 substituted with one or more identical or different substituents selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; When -L- is a bond, R 3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5-10 membered heteroaryl may optionally and independently be one or more of the same or different R 7 and / or R 8 is replaced by Each R 7 are independently halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8, -C(=O)R 8 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , -NHC(=O)OR 8 and a divalent substituent selected from the group consisting of ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl, 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl may each be one or more of the same or different R 9 and / or R 10 optionally substituted with; Each R 9 are independently -OR 10 and; Each R 10 are independently hydrogen, C 1-6 selected from the group consisting of alkyl, 3- to 11-membered heterocyclyl, and 5- to 10-membered heteroaryl; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R 11 )=; R 11 is hydrogen, halogen and C 1-4 alkoxy; Ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole, and triazole; Each R 4 If present, independently, 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(C1-4 Alkyl)2, -CN, C 3-5 selected from the group consisting of cycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1, 2 and 3; R 5 is one or more identical or different, C 1-6 Alkyl, C 1-6 3- to 11-membered heterocyclyl optionally substituted with alkoxy or 5- to 6-membered heterocyclyl, where C 1-6 alkyl is optionally substituted with cyclopropyl; or R 5 is substituted with 3-11 membered heterocyclyl -OC 1-6 alkyl, where the 3- to 11-membered heterocyclyl is one or more of the same or different R 12 optionally substituted with; Each R 12 is C 1-6 Alkyl, C 1-6 selected from the group consisting of alkoxy, halogen, and 3- to 11-membered heterocyclyl; E is [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 )- selected from the group consisting of; Each R G1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, Cyano-C1-6 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 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; Each R H1 are independently hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 selected from the group consisting of alkyl; [ka] When 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, phenyl, 3-11 membered heterocyclyl, C 1-6 Alkoxy, halogen, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, -C(=O)OH, -C(=O)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 C optionally substituted with one or more identical or different substituents selected from the group consisting of alkoxy 1-6 selected from the group consisting of alkyl; R E and R F are each independently R a2 and R b2 selected from the group consisting of; R a2 is hydrogen, C 1-6 Alkyl, C 1-6Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5-10 membered heteroaryl may have one or more identical or different R b2 and / or R c2 optionally substituted with; Each R b2 are independently -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 a divalent substituent selected from the group consisting of ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 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, aryl, aryloxy ... R D and R E together with the carbon atom to which they are attached form a 4- to 7-membered unsaturated alicycle or a 4- to 7-membered unsaturated heterocycle, wherein the 4- to 7-membered unsaturated alicycle or the 4- to 7-membered unsaturated heterocycle is optionally 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 substituted with one or more identical or different substituents selected from the group consisting of alkyl and the divalent substituent =O; or Q 1 -C(=O)N(R G1 )-, then -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-; [ka] When represents a triple bond, RD and R E are not present together; 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, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All aryl and 5-10 membered heteroaryl may have one or more identical or different R b2 and / or R c2 optionally substituted with; Each R b2 are independently -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 a divalent substituent selected from the group consisting of ═O; Each R c2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 selected from the group consisting of aryl and 5-10 membered heteroaryl; or E is [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 )- selected from the group consisting of; Each R G2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, Cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; Each R H2 are independently hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 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 atom 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 [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 )- selected from the group consisting of; Each R G3 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, Cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; Each R H3 are independently hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 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 [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; Each R N is independently 1-4 Alkyl, C 1-4 Haloalkyl, vinyl, ethynyl, halogen, -CN, nitro and C 1-4 alkoxy] or a salt thereof.

[0011] In another aspect, the present invention provides a compound comprising R 1a and R 1b are each independently hydrogen and C 1-4 The present invention relates to a compound of formula (I), or a salt thereof, wherein the compound is selected from the group consisting of alkyl.

[0012] In another aspect, the present invention provides a compound comprising R 2a and R 2b and are both independently selected from the group consisting of hydrogen and halogen, or a salt thereof.

[0013] In another aspect, the present invention provides a compound comprising R 1a and R 1b and R are each independently selected from the group consisting of hydrogen and methyl, or a salt thereof.

[0014] In another aspect, the present invention provides a compound comprising R 2a and R 2b and are both independently selected from the group consisting of hydrogen and fluorine, or a salt thereof.

[0015] In another aspect, the present invention provides a compound comprising R 1a , R 1b , R 2a and R 2b is hydrogen, or a salt thereof.

[0016] In another embodiment, the present invention relates to a compound of formula (I) or a salt thereof, wherein n is 0.

[0017] In another aspect, the present invention provides a method for producing a composition comprising: n is 1; Each R 6a and R 6b are independently 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 The present invention relates to a compound represented by formula (I), or a salt thereof, wherein R is selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl.

[0018] In another embodiment, the present invention relates to a compound of formula (I) or a salt thereof, wherein Z is -CH2-.

[0019] In another embodiment, the present invention provides a compound according to the present invention, wherein n is 2; 6a and R 6b are independently 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 The present invention relates to a compound represented by formula (I), or a salt thereof, wherein R is selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl.

[0020] In another aspect, the present invention relates to a compound of formula (Ia), or a salt thereof: [ka] [In the formula, A, V, U, W, L, R 3 and R 5 are as defined herein.

[0021] In another aspect, the present invention relates to a compound of formula (Ib), or a salt thereof: [ka] [In the formula, A, V, U, W, L, R 3 and R 5 are as defined herein.

[0022] In another aspect, the present invention relates to a compound wherein ring A is [ka] The present invention relates to a compound represented by formula (I), (Ia) or (Ib), or a salt thereof, selected from the group consisting of:

[0023] In another aspect, the present invention relates to a compound wherein ring A is [ka] The present invention relates to a compound represented by formula (I), (Ia) or (Ib), or a salt thereof, selected from the following:

[0024] In another aspect, the present invention relates to a compound wherein ring A is [ka] The present invention relates to a compound represented by formula (I), (Ia) or (Ib), or a salt thereof,

[0025] In another aspect, the present invention relates to a compound wherein ring A is [ka] The present invention relates to a compound represented by formula (I), (Ia) or (Ib), or a salt thereof,

[0026] In another aspect, the present invention relates to a compound of formula (Ic), or a salt thereof: [ka] [In the formula, V, U, W, L, R 3 and R 5 are as defined herein.

[0027] In another aspect, the present invention relates to a compound of formula (Id), or a salt thereof: [ka] [In the formula, V, U, W, L, R 3 and R 5 are as defined herein.

[0028] In another aspect, the present invention relates to a compound of formula (Ie), or a salt thereof: [ka] [In the formula, V, U, W, L, R 3 and R 5 are as defined herein.

[0029] In another aspect, the present invention relates to a compound represented by formula (If), or a salt thereof: [ka] [In the formula, V, U, W, L, R 3 and R 5 are as defined herein.

[0030] In another aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein at least one of W, V and U is nitrogen.

[0031] In another aspect, the present invention provides a method for producing a composition comprising: W is nitrogen (-N=); V is nitrogen (-N=); U is =C(R 11 )- and; R 11 However, hydrogen, halogens and C 1-4 alkoxy is selected from the group consisting of aryl, aryloxy ...

[0032] In another aspect, the present invention provides a method for producing a composition comprising: W is -CH=; V is nitrogen (-N=); U is =C(R 11 )- and; R 11 However, hydrogen, halogens and C 1-4 alkoxy is selected from the group consisting of aryl, aryloxy ...

[0033] In another aspect, the present invention provides a method for producing a composition comprising: V is -CH=; W is nitrogen (-N=); U is =C(R 11 )- and; R 11 However, hydrogen, halogens and C 1-4 alkoxy is selected from the group consisting of aryl, aryloxy ...

[0034] In another aspect, the present invention provides a method for producing a composition comprising: R 11 is selected from hydrogen, fluorine, chlorine and -O-CH3, or a salt thereof.

[0035] In another aspect, the present invention provides a method for producing a composition comprising: V is nitrogen (-N=); W is -CH=; The compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein U is nitrogen (-N=).

[0036] In another aspect, the present invention provides a method for producing a composition comprising: W is nitrogen (-N=); V is -CH=; The compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein U is nitrogen (-N=).

[0037] In another aspect, the present invention provides a method for producing a composition comprising: W is -CH=; V is -CH=; The compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein U is nitrogen (-N=).

[0038] In another aspect, the present invention provides a method for producing a composition comprising: W is nitrogen (-N=); V is nitrogen (-N=); The compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein U is nitrogen (-N=).

[0039] In another aspect, the present invention provides a method for producing a composition comprising: R 5 may contain one or more identical or different C 1-6 Alkyl, C 1-6 6- to 11-membered heterocyclyl optionally substituted with alkoxy or 5- to 6-membered heterocyclyl, wherein C 1-6 The present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein alkyl is optionally substituted with cyclopropyl.

[0040] In another aspect, the present invention provides a method for producing a composition comprising: R 5However, one or more identical or different C 1-4 The present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, which is 7-membered heterocyclyl optionally substituted with alkyl.

[0041] In another aspect, the present invention provides a method for producing a composition comprising: R 5 is substituted with 5-8 membered heterocyclyl -OC 1-6 alkyl, wherein the 5- to 8-membered heterocyclyl is one or more of the same or different R 12 and optionally substituted with Each R 12 But, C 1-6 Alkyl, C 1-6 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein:

[0042] In another aspect, the present invention provides a method for producing a composition comprising: R 5 but, [ka] The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0043] In another aspect, the present invention provides a method for producing a composition comprising: R 5 but, [ka] The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0044] In another aspect, the present invention provides a method for producing a composition comprising: R 5 but, [ka] The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0045] In another aspect, the present invention provides a method for producing a composition comprising: R 5 but, [ka] The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof,

[0046] In another aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein L is a bond.

[0047] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is a bond; R 3 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein 3-11 membered heterocyclyl, C 6-10 The aryl and 5- to 10-membered heteroaryl may all optionally and independently be one or more of the same or different R 7 and / or R 8 is replaced by; Each R 7 are independently halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8 , -C(=O)R 8 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , -NHC(=O)OR8 and a divalent substituent selected from the group consisting of ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl groups are each independently selected from one or more of the same or different R 9 and / or R 10 is optionally replaced by Each R 9 But independently, -OR 10 selected from the group consisting of; Each R 10 are independently hydrogen, C 1-6 Alkyl, C 3-10 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, which is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl.

[0048] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is a bond; R 3 is selected from the group consisting of 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein all of the 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl are optionally and independently selected from one or more of the same or different R 7 and / or R 8 is replaced by; Each R 7 are independently halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8 , -C(=O)R 8 , -C(=O)OR 8 , -C(=O)NR8 R 8 , -NHC(=O)OR 8 and a divalent substituent selected from the group consisting of ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl groups are each independently selected from one or more of the same or different R 9 and / or R 10 optionally substituted with; Each R 9 is -OH or C 1-6 is alkoxy; Each R 10 But independently, C 1-6 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein the compound is selected from the group consisting of alkyl, 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl.

[0049] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is a bond; R 3 but, [ka] TIFF2024543983000027.tif70161 is selected from the group consisting of Each of these groups is attached to formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) at any ring position by removal of a hydrogen atom, and optionally and independently, one or more of the same or different R 7 and / or R 8 where: Each R 7 are independently halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8 , -C(=O)R 8 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , -NHC(=O)OR 8 and a divalent substituent selected from the group consisting of ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl groups are each independently selected from one or more of the same or different R 9 and / or R 10 optionally substituted with; Each R 9 is -OH or C 1-6 is alkoxy; Each R 10 But independently, C 1-6 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein the compound is selected from the group consisting of alkyl, 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl.

[0050] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is a bond; R 3 but, [ka] TIFF2024543983000029.tif213161 TIFF2024543983000030.tif221161 TIFF2024543983000031.tif210161 TIFF2024543983000032.tif196161 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0051] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is a bond; R 3 but, [ka] is a 3- to 11-membered heterocyclyl selected from the group consisting of Each of the 3- to 11-membered heterocyclyls is optionally and independently selected from the group consisting of one or more identical or different R 7 and / or R 8 is replaced by; Each R 7 are independently -OH, C 1-6 Alkoxy, -C(=O)R 8 and a divalent substituent selected from the group consisting of ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 3-10 The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein the compound is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl.

[0052] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is a bond; R 3 but, [ka] is a 3- to 11-membered heterocyclyl or an 8- to 9-membered heteroaryl selected from the group consisting of Each of the 3- to 11-membered heterocyclyl or 8- to 9-membered heteroaryl may optionally and independently be one or more of the same or different R 7 and / or R 8 is replaced by; Each R 7 But independently, -OR 8 , -NR 8 R 8 , halogen, -CN, -C(=O)R 8 , -C(=O)OR 8 , -C(=O)NR 8 R 8 , -NHC(=O)OR 8 and a divalent substituent selected from the group consisting of ═O; Each R 8 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl groups are each independently selected from one or more of the same or different R 9 and / or R 10 optionally substituted with; Each R 9 is -OH or C 1-6 is alkoxy; Each R 10 But independently, C 1-6 The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein the compound is selected from the group consisting of alkyl, 3- to 11-membered heterocyclyl and 5- to 10-membered heteroaryl.

[0053] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is -O-, -S- and -N(R 13 )-(wherein, R 13 is hydrogen or C 1-6 alkyl; R 3 But, C 1-6 Alkyl, C 1-6 alkoxy, 5- to 6-membered heteroaryl, and 4- to 5-membered heterocyclyl, wherein C 1-6 Alkyl, 5-6 membered heteroaryl, C 1-6 Alkoxy and 4- to 5-membered heterocyclyl are all optionally and independently selected from the same or different halogens, C 1-6 Alkyl, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, C 3-5 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, which is substituted by cycloalkyl or 3- to 11-membered heterocyclyl.

[0054] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is -O-, -S- and -N(R 13 )-(wherein, R 13 is hydrogen or C 1-6 alkyl; R 3 But, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkoxy, 5- to 6-membered heteroaryl, and 4- to 5-membered heterocyclyl; Here, C 1-6 Alkyl, 5-6 membered heteroaryl, C 1-6 Alkoxy and 4- to 5-membered heterocyclyl are all optionally and independently selected from one or more of the same or different halogen, C 1-6 Alkyl, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, C 3-5The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, which is substituted by cycloalkyl or 3- to 11-membered heterocyclyl.

[0055] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is -O-, -S- and -N(R 13 )-(wherein, R 13 is hydrogen or C 1-6 alkyl; R 3 is 4-7 membered heterocyclyl or C 3-5 Cycloalkyl-substituted -C 1-4 alkyl, where 4-7 membered heterocyclyl and C 3-5 Cycloalkyl may be one or more C 1-4 Alkyl or -N(C 1-4 The present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, optionally further substituted with alkyl).

[0056] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is -O-, -S- and -N(R 13 )-(wherein, R 13 is hydrogen or C 1-6 alkyl; R 3 But, C 1-6 selected from the group consisting of alkyl, -C(CH3)CH2-O-CH3, -(CH2)2-O-CH3, -(CH2)2-OH and -(CH2)2-N-(CH3)2; or R 3 but, [ka] is a ring selected from the group consisting of wherein each of these rings optionally and independently comprises one or more of the same or different halogens, C 1-6 Alkyl, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, C 3-5 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, which is substituted by cycloalkyl or 3- to 11-membered heterocyclyl.

[0057] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is -O-, -S- and -N(R 13 )-(wherein, R 13 is hydrogen or C 1-6 alkyl; R 3 But, C 1-6 Alkyl, -C(CH3)CH2-O-CH3, -(CH2)2-O-CH3, -(CH2)2-OH, -(CH2)2-N-(CH3)2, [ka] or a salt thereof; or a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), selected from the group consisting of:

[0058] In another aspect, the present invention provides a method for producing a composition comprising: R 3 is replaced by E; -L- is -O-; R 3 is a 4- to 5-membered heterocyclyl containing one or two nitrogen heteroatoms, wherein the 4- to 5-membered heterocyclyl is selected from the group consisting of one or more of the same or different halogens, C 1-6 Alkyl, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, C 3-5The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof, which is optionally substituted with cycloalkyl or 3- to 11-membered heterocyclyl.

[0059] In another aspect, the present invention provides a method for producing a composition comprising: -L- is a bond; R 3 but, [ka] The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof,

[0060] In another aspect, the present invention provides a method for producing a composition comprising: R 3 but, [ka] and E, [ka] TIFF2024543983000040.tif82161 The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0061] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] and [ka] represents a double bond; Q 1 is -C(=O)-; R D However, hydrogen, halogens, C 1-6alkoxy; R E and R F Each independently, R a2 and R b2 selected from the group consisting of; R a2 But hydrogen, C 1-6 Alkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 6-10 All of the aryl and 5- to 10-membered heteroaryl groups are each independently selected from one or more of the same or different R b2 and / or R c2 optionally substituted with; Each R b2 But independently, -OR c2 or a halogen; Each R c2 are independently hydrogen, C 1-6 alkyl, and 5-10 membered heteroaryl, wherein C 1-6 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein all of the alkyl and 5-10 membered heteroaryl are optionally substituted with one or more identical or different substituents selected from the group consisting of halogen or -OH.

[0062] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of

[0063] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0064] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] TIFF2024543983000046.tif225165 TIFF2024543983000047.tif230165 TIFF2024543983000048.tif230165 TIFF2024543983000049.tif216165 TIFF2024543983000050.tif230165 TIFF2024543983000051.tif101165 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0065] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0066] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0067] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] The present invention relates to a compound represented by formula (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0068] In another aspect, the present invention provides a method for producing a composition comprising: E, [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 )- selected from the group consisting of; Each R G1 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and Hydroxy-C 1-6 selected from the group consisting of alkyl; Each R H1 are independently hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 selected from the group consisting of alkyl; R F However, hydrogen, -OH, C 1-6 Alkoxy, -NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 C optionally substituted with a substituent selected from the group consisting of alkyl 1-6 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein:

[0069] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] and Q 1 However, -C(=O)-, -C(=O)N(R G1 )-, -S(=O)2- and -S(=O)2N(R G1 )- selected from the group consisting of; Each R G1 are independently hydrogen and C 1-6 selected from the group consisting of alkyl; R F However, hydrogen, -OH, C 1-6 Alkoxy, -NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 C optionally substituted with a substituent selected from the group consisting of alkyl 1-6 The present invention relates to a compound of the present invention, wherein the compound is selected from the group consisting of alkyl, or a salt thereof.

[0070] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0071] In another aspect, the present invention provides a method for producing a composition comprising: E, [ka] TIFF2024543983000059.tif115161 The present invention relates to a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, selected from the group consisting of:

[0072] Preferred embodiments of the compound represented by formula (I) according to the present invention are exemplified compounds Ia-1 to Ia-4, Ib-1 to Ib-9 and any subset thereof.

[0073] It is to be understood that any two or more aspects and / or preferred embodiments of formula (I) or subformulas thereof can be combined in any manner that results in a chemically stable structure to obtain further aspects and / or preferred embodiments of formula (I) or subformulas thereof.

[0074] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), including all embodiments thereof.

[0075] The present invention further relates to hydrates of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) (including all embodiments thereof).

[0076] The present invention further relates to solvates of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) (including all embodiments thereof).

[0077] For example, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) (including all embodiments thereof) bearing an ester group are potential prodrugs, where the ester is cleaved under physiological conditions, and are also part of the present invention.

[0078] The present invention further relates to pharma- ceutically acceptable salts of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), including all embodiments thereof.

[0079] The present invention further relates to pharma- ceutically acceptable salts of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) (including all embodiments thereof) with inorganic or organic acids or bases.

[0080] Pharmaceutical Compositions A further object of the present invention is a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0081] In one embodiment, the pharmaceutical composition optionally comprises one or more other pharmacologically active substances, which may be pharmacologically active substances or combination partners as defined herein.

[0082] Suitable pharmaceutical compositions for administering the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) according to the present invention are clear to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, suspensions, in particular solutions, suspensions or other mixtures for injection (sc, iv, im) and infusion (injections), elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. The content of the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) should be in the range of 0.1-90% by weight, preferably 0.5-50% by weight, of the total composition, i.e., an amount sufficient to achieve the dosage ranges specified below. The specified doses may be given several times a day, if necessary.

[0083] Suitable tablets can be obtained, for example, by mixing a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) with known pharma- ceutically acceptable excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. Tablets may also comprise several layers.

[0084] Coated tablets can be prepared by coating a core, which is prepared in the same manner as for tablets, with excipients usually used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar, if appropriate. The core may consist of multiple layers to achieve delayed release or to prevent incompatibilities. Similarly, the tablet coating may consist of multiple layers to achieve delayed release, optionally using the excipients mentioned above for tablets.

[0085] Syrups or elixirs containing one or more compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a combination with one or more other pharma- ceutically active substances may additionally contain excipients such as sweeteners, such as saccharin, cyclamate, glycerol or sugar, and flavour enhancers, for example flavours such as vanillin or orange extract. They may also contain excipients such as suspension adjuvants or thickeners, for example sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or preservatives, such as p-hydroxybenzoates.

[0086] Solutions for injection and infusion are prepared in the usual way, for example with the addition of excipients such as isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, and optionally with the use of emulsifiers and / or dispersants, but where water is used as diluent, for example with organic solvents, optionally as solvating or dissolving agents, and transferred into injection vials or ampoules or infusion bottles.

[0087] Capsules containing one or more compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a combination with one or more other pharma- ceutically active substances can be prepared, for example, by mixing the compounds / active substances with inert excipients such as lactose or sorbitol and filling them into gelatin capsules.

[0088] Suitable suppositories can be prepared by mixing with excipients provided for this purpose, such as, for example, neutral fats or polyethylene glycol or its derivatives.

[0089] Excipients that may be used include, for example, water, pharma- ceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly disperse silicic acid and silicates), sugars (e.g., sucrose, lactose and glucose), emulsifiers (e.g., lignin, spent sulfite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0090] The pharmaceutical composition is administered by conventional methods, preferably by oral or transdermal route, most preferably by oral route.For oral administration, tablets can of course contain additional excipients such as sodium citrate, calcium carbonate and dicalcium phosphate, apart from the above-mentioned excipients, together with various excipients such as starch, preferably potato starch, gelatin.Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used at the same time in the tableting process.In the case of aqueous suspensions, active substances can be combined with various flavor enhancers or colorants in addition to the above-mentioned excipients.

[0091] For parenteral use, solutions of the active substance and a suitable liquid excipient may be used.

[0092] The applicable daily dosage range of the compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) is usually 1 mg to 2000 mg, preferably 250 to 1250 mg.

[0093] However, the dosage may sometimes need to deviate from the specified amount depending on the body weight, age, route of administration, severity of the disease, individual response to the drug, the nature of its formulation and the time or interval at which the drug is administered (continuous or intermittent treatment with one or several doses per day). Thus, in some cases, it may be sufficient to use a dosage lower than the minimum dose given above, while in other cases, the upper limit may have to be exceeded. When administering larger amounts, it may be advisable to divide these into several smaller doses per day.

[0094] Therefore, in a further aspect, the present invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0095] The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or pharma- ceutically acceptable salts thereof, and pharmaceutical compositions containing 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 under Combination treatments).

[0096] The elements of such combinations can be administered (subordinately or independently) in a manner that is conventional to those of skill in the art and that is 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 can be formulated, either alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.

[0097] The combination may be administered in a single or divided daily dose that is therapeutically effective. The active components of the combination may be administered in such doses that are therapeutically effective in monotherapy, or in such doses that are less than the doses used in monotherapy but which, in combination, result in the desired (combined) therapeutically effective amount.

[0098] However, when the combination of two or more active substances or ingredients produces a synergistic effect, it is also possible to reduce the amount of one, more or all of the substances or ingredients administered while still achieving the desired therapeutic effect. This can be useful, for example, to avoid, limit or reduce any undesirable side effects associated with the use of one or more of the substances or ingredients when used in their usual amounts, while still ensuring the desired pharmacological or therapeutic effect.

[0099] Therefore, in a further aspect, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof and one or more (preferably, one or two, most preferably one) other pharmacologically active substances.

[0100] In a further aspect, the present invention also relates to a pharmaceutical preparation comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof and one or more (preferably, one or two, most preferably one) other pharmacologically active substances.

[0101] The pharmaceutical compositions to be administered simultaneously or in combination can also be provided in the form of a kit.

[0102] Thus, in a further aspect, the present invention also provides a method for producing a method for treating a pulmonary arthritis, comprising: a first pharmaceutical composition or dosage form comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) and optionally one or more pharma- ceutically acceptable excipients; and A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharma- ceutically acceptable excipients. The present invention relates to a kit comprising:

[0103] In one embodiment, such a kit comprises a third pharmaceutical composition or dosage form comprising an additional pharmacologically active agent and optionally one or more pharma- ceutically acceptable excipients.

[0104] Medical Use - Method of Treatment Indications – Patient population The present invention is primarily directed to RAS G12C inhibitors, in particular compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) (including all embodiments thereof), 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.

[0105] Thus, in a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use as a medicament.

[0106] In a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in a method of treatment of the human or animal body.

[0107] In a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of diseases and / or conditions mediated by RAS G12C mutation.

[0108] In a further aspect, the present invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of a disease and / or condition mediated by RAS G12C mutation.

[0109] In a further aspect, the present invention relates to a method for the treatment and / or prevention of diseases and / or conditions mediated by RAS G12C mutation comprising administering to a human a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof.

[0110] In a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer.

[0111] In a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in a method for the treatment and / or prophylaxis of cancer in the human or animal body.

[0112] In a further aspect, the present invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of cancer.

[0113] In a further aspect, the present invention relates to a method for the treatment and / or prevention of cancer comprising administering to a human a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof.

[0114] In a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in producing an inhibitory effect on G12C mutant RAS.

[0115] In a further aspect, the present invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for use in producing an inhibitory effect on G12C mutant RAS.

[0116] In a further aspect, the present invention relates to a method for producing an inhibitory effect on G12C mutant RAS comprising administering to a human a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof.

[0117] Another embodiment is based on identifying a relationship between the G12C mutation status of a patient and its potential sensitivity to treatment with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If). A RAS G12C inhibitor, such as a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), can then be advantageously used to treat patients with KRAS G12C, HRAS G12C or NRAS G12C mutations that may be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients, particularly cancer patients, for treatment with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If). The selection is based on whether the tumor cells being treated have a wild type KRAS, HRAS or NRAS gene or a G12C mutant KRAS, HRAS or NRAS gene. The status of the G12C KRAS, HRAS or NRAS gene can therefore be used as a biomarker to indicate that selecting treatment with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) may be advantageous.

[0118] According to one embodiment, there is provided a method for selecting a patient for treatment with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), comprising: Preparing a tumor cell-containing sample from a patient; determining whether the RAS gene in a sample containing the patient's tumor cells encodes a wild-type (glycine at position 12) KRAS, HRAS or NRAS protein or a mutant (cysteine ​​at position 12) KRAS, HRAS or NRAS protein; and and based thereon, selecting patients for treatment with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If). A method is provided that includes:

[0119] The method may or may not include the step of isolating the actual patient sample.

[0120] In one aspect, if the tumor cell DNA has a G12C mutant KRAS gene, the patient is selected for treatment with a compound represented by Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If).

[0121] In another embodiment, if the tumor cell DNA has a G12C mutant HRAS gene, the patient is selected for treatment with a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If).

[0122] In another embodiment, if the tumor cell DNA has a G12C mutant NRAS gene, the patient is selected for treatment with a compound represented by Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If).

[0123] According to another aspect, there is provided a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in treating a cancer having tumor cells harboring a G12C mutant RAS gene.

[0124] According to another aspect, there is provided a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in treating a cancer having tumor cells harboring a G12C mutant KRAS gene.

[0125] According to another aspect, there is provided a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in treating a cancer having tumor cells harboring a G12C mutant HRAS gene.

[0126] According to another aspect, there is provided a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use in treating a cancer having tumor cells carrying a G12C mutant NRAS gene.

[0127] According to another aspect, there is provided a method of treating a cancer having tumor cells carrying a G12C mutant RAS gene, comprising administering to a human an effective amount of a compound represented by Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof.

[0128] According to another aspect, there is provided a method of treating a cancer having tumor cells harboring a G12C mutant KRAS, HRAS or NRAS gene, comprising administering an effective amount of a compound represented by Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof.

[0129] 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) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high resolution melting assay, and microarray analysis. In some embodiments, samples are evaluated for G12C KRAS, HRAS or NRAS mutations by real-time PCR. In real-time PCR, a fluorescent probe specific for KRAS, HRAS or NRAS G12C mutations is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS, HRAS or NRAS G12C mutations are identified using direct sequencing of specific regions (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, detection of KRAS, HRAS or NRAS mutants using binding substances (e.g., antibodies) specific for mutant proteins, protein electrophoresis, Western blotting and direct peptide sequencing.

[0130] The method for determining whether a tumor or cancer contains a G12C KRAS, HRAS or NRAS mutation can use a wide 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 tests are performed on a blood sample to look for cancer cells from the tumor circulating in the blood or fragments of DNA from tumor cells in the blood.

[0131] Similarly, it can be determined whether the tumor or cancer contains KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D and KRAS G12R mutations, or is KRAS wild type, preferably amplified.

[0132] Preferably, the disease / condition / cancer / tumor / cancer cell to be treated / prevented according to the methods and uses as defined and disclosed herein (above and below) with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof is selected from the group consisting of pancreatic cancer, lung cancer, colon cancer, cholangiocarcinoma, appendix cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, gastroesophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0133] In another aspect, the disease / condition / cancer / tumor / cancer cell to be treated / prevented according to the methods and uses as defined and disclosed herein (above and below) with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically 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.

[0134] Particularly preferably, the cancer to be treated / prevented according to the methods and uses as defined and disclosed herein (above and below) with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof is selected from the group consisting of: Lung adenocarcinoma (preferably non-small cell lung cancer (NSCLC)) harboring the KRAS G12C mutation; · Colorectal adenocarcinoma harboring the KRAS G12C mutation; Pancreatic adenocarcinoma (preferably pancreatic ductal adenocarcinoma (PDAC)) harboring the KRAS G12C mutation.

[0135] Additionally, the following cancers, tumors and other proliferative diseases may be treated with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, but are not limited thereto. Preferably, the methods of treatment, methods, uses, compounds to be used and pharmaceutical compositions to be used as disclosed herein (above and below) are applied in the treatment of diseases / conditions / cancers / tumors (i.e., respective cells) that carry a RAS G12C mutation (preferably a KRAS G12C mutation) or that have been identified as carrying a RAS G12C mutation (preferably a KRAS G12C mutation) as described and / or referenced herein: Cancers / tumours / carcinomas of the head and neck: for example, tumours / carcinomas of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar triangle, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); Lung cancer / tumour / carcinoma: 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, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, nonseminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangiomoma, lymphangioleiomyoma); Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: for example, tumors / carcinomas / cancer of the following: esophagus, stomach (gastric cancer), pancreas, liver and biliary system (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gallbladder, extrahepatic bile duct, small intestine (duodenum, bladder, small intestine ... intestine, including ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal gland, Grabitz tumor; ureter; bladder, e.g., urachal carcinoma, urothelial carcinoma; urethra, e.g., distal, bulbomembranous, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis); Testicular cancer / tumor / carcinoma: e.g. seminoma, non-seminoma, Gynecologic cancer / tumor / carcinoma: for example, tumor / carcinoma / cancer of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus); Cancers / tumors / carcinomas of the breast: e.g., breast cancer (infiltrating ductal, colloid, lobular infiltrating, 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, tumors / tumors of the following: endocrine glands, thyroid (thyroid carcinoma / tumors; papillary, follicular, anaplastic, medullary), parathyroid (parathyroid carcinoma / tumors), adrenal cortex (adrenal cortical carcinoma / tumors), pituitary (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; non-functioning PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), 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 tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; Sarcomas of bone: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, superficial high-grade, 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: e.g. 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; Neoplasms of the central nervous system and brain: e.g., astrocytomas (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastomas, gliomas, oligodendrogliomas, oligoastrocytomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, schwannomas (e.g., auditory), spinal axis tumors; 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), Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (including ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T Cellular 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, lymphopenic HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid leukemia (ACML), / myelocytic 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);

[0136] All cancers / tumors / carcinomas mentioned above, characterized by their specific location / origin within the body, are meant to include both the primary tumor and the metastatic tumors derived therefrom.

[0137] All the above mentioned cancers / tumors / carcinomas can be further differentiated by their histopathological classification: Epithelial carcinomas, e.g., squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, warty carcinoma, pseudosarcoma, undifferentiated, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, tubular, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinic cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma; Non-epithelial carcinomas, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematopoietic tumors, mixed and undifferentiated carcinomas;

[0138] The compounds of the invention may be used in treatment regimens in the first line, second line, or any further line of treatment setting.

[0139] The compounds of the invention may be used for the prevention, short-term or long-term treatment of the above mentioned diseases / conditions / cancers / tumors, optionally also in combination with radiation therapy and / or surgery.

[0140] The methods of treatment, methods, uses and compounds of use as disclosed herein (above and below) may be practiced with any compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, as well as any pharmaceutical composition or kit comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof (including any individual embodiment or comprehensive subset of compound (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), respectively), as disclosed or defined herein.

[0141] Combination treatment The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or pharma- ceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds or salts, may also be co-administered with other pharmacologically active substances, such as other anti-neoplastic compounds (e.g. chemotherapy), or may be used as an adjuvant before or after surgery in conjunction with other treatments, such as radiation or surgical intervention. Preferably, the co-administered pharmacologically active substance is an anti-neoplastic compound.

[0142] Therefore, in a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use as hereinbefore defined, said compound or a pharma- ceutically acceptable salt thereof being administered before, after or together with one or more other pharmacologically active substances.

[0143] In a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof for use as hereinbefore defined, when administered in combination with one or more other pharmacologically active substances.

[0144] In a further aspect, the present invention relates to the use of compound (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof as defined hereinbefore, wherein said compound is administered before, after or together with one or more other pharmacologically active substances.

[0145] In a further aspect, the present invention relates to a method as defined herein above (e.g. a method for treatment and / or prevention), wherein a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof is administered before, after or together with a therapeutically effective amount of one or more other pharmacologically active substances.

[0146] In a further aspect, the present invention relates to a method as defined herein above (e.g. a method for treatment and / or prevention), wherein a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substances.

[0147] In a further aspect, the present invention relates to a method for the treatment and / or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof is administered simultaneously, in parallel, sequentially, consecutively, alternatingly or separately from the one or more other pharmacologically active substances.

[0148] In a further aspect, the present invention relates to a method for the treatment and / or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0149] In a further aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, administered simultaneously, in parallel, sequentially, consecutively, alternatingly or separately with one or more other pharmacologically active substances, for use in the treatment and / or prevention of cancer.

[0150] In a further aspect, the present invention relates to a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0151] In a further aspect, the present invention provides a method for producing a composition comprising the steps of: a first pharmaceutical composition or dosage form comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, and optionally one or more pharma- ceutically acceptable excipients; and A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharma- ceutically acceptable excipients. A kit for use in the treatment and / or prevention of cancer, comprising The present invention relates to a kit, wherein the first pharmaceutical composition is intended to be administered simultaneously, concurrently, sequentially, consecutively, alternatingly or separately from the second and / or additional pharmaceutical compositions or dosage forms.

[0152] In one embodiment, such a kit for said use comprises a third pharmaceutical composition or dosage form, which further comprises another pharmacologically active substance and optionally one or more pharma- ceutically acceptable excipients.

[0153] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds of use according to the invention (including all embodiments) are administered simultaneously.

[0154] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds of use according to the invention (including all embodiments) are administered concurrently.

[0155] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds of use according to the invention (including all embodiments) are administered sequentially.

[0156] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds of use according to the invention (including all embodiments) are administered sequentially.

[0157] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds of use according to the invention (including all embodiments) are administered alternately.

[0158] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds of use according to the invention (including all embodiments) are administered separately.

[0159] The pharmacologically active substance used together / in combination with a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) and / or with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof (including any individual embodiment or inclusive subset of compound (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If)) or used in the medical use, use as defined herein (above and below), method of treatment and / or prophylaxis, pharmaceutical composition may be selected from any one or more of the following (preferably there are one or two additional pharmacologically active substances used in all these embodiments):

[0160] 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutants thereof a. Irreversible inhibitors: e.g., afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib; b. Reversible inhibitors: e.g., erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340; c. Anti-EGFR antibodies: e.g., necitumumab, panitumumab, cetuximab, amivantamab; d. Anti-HER2 antibodies: for example, pertuzumab, trastuzumab, trastuzumab-emtansine; e. Inhibitors of mutant EGFR; f. Inhibitors of HER2 with exon 20 mutations; g. The preferred irreversible inhibitor is afatinib; h. A preferred anti-EGFR antibody is cetuximab.

[0161] 2. Inhibitors of MEK and / or its mutants For example, trametinib, cobimetinib, binimetinib, selumetinib, refametinib; b. Preferred is trametinib.

[0162] 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 (mutant) Ras proteins, such as KRAS). For example, BAY-293, BI-3406; b. Preferred is BI-3406.

[0163] 4. Oncolytic viruses

[0164] 5. RAS Vaccine For example, TG02 (Targovax)

[0165] 6. Cell Cycle Inhibitors For example, an inhibitor of CDK4 / 6 and / or any mutant 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, an inhibitor of Aurora kinase and / or any mutant thereof i. For example, alisertib, barasertib.

[0166] 7. Inhibitors of PTK2 (=FAK) and / or any mutants thereof For example, TAE226, BI 853520.

[0167] 8. Inhibitors of SHP2 and / or any mutant thereof a.For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0168] 9. Inhibitors of PI3 kinase (=PI3K) and / or any mutant thereof For example, an inhibitor of PI3K alpha and / or any mutant thereof i. For example, alpelisib, ceravelisib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactolisib, pictilisib, taselisib.

[0169] 10. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutants thereof For example, ponatinib, infigratinib, nintedanib.

[0170] 11. Inhibitors of AXL and / or any of its mutants

[0171] 12. Taxanes For example, paclitaxel, nab-paclitaxel, docetaxel; b. Preferred is paclitaxel.

[0172] 13.Platinum-containing compounds For example, cisplatin, carboplatin, oxaliplatin b. Preferred is oxaliplatin.

[0173] 14. Antimetabolites For example, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, trifluridine and tipiracil (=TAS102); b. Preferred is 5-fluorouracil.

[0174] 15. Immunotherapy 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.

[0175] 16. Topoisomerase inhibitors a. For example, irinotecan, liposomal irinotecan (nal-IRI), topotecan, etoposide; b. Most preferred are irinotecan and liposomal irinotecan (nal-IRI).

[0176] 17. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutants thereof For example, encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (= Example 131 in WO 2014 / 151616), LXH254, sorafenib, LY-3009120 (= Example 1 in WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265.

[0177] 18. mTOR inhibitors For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin 1, dactolisib, GDC-0349, VS-5584, vistusertib, AZD8055.

[0178] 19. Epigenetic Modulators For example, BET inhibitors i. For example, JQ-1, GSK 525762, OTX-015, CPI-0610, TEN-010, OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601, CC-90010, AZD5153, I-BET151, BI 894999; ii. Preferred is BI 894999.

[0179] 20. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutants thereof a. For example, xentuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (=ducigitumab), linsitinib.

[0180] 21. Inhibitors of Src family kinases and / or any mutants thereof For example, inhibitors of kinases of the SrcA subfamily and / or any mutants thereof, i.e. inhibitors of Src, Yes, Fyn, Fgr and / or any mutants thereof; b. For example, inhibitors of kinases of the SrcB subfamily and / or any mutants thereof, i.e. inhibitors of Lck, Hck, Blk, Lyn and / or any mutants thereof; c. For example, inhibitors of kinases of the Frk subfamily and / or any mutants thereof, i.e., inhibitors of Frk and / or any mutants thereof; d. For example, dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU 6656, WH-4-023.

[0181] 22. Apoptosis Regulator 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 mutant thereof; i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115; ii. Preferred are HDM-201, RG-7388 and AMG-232; b. For example, PARP inhibitors; c. For example, MCL-1 inhibitors; i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0182] 23. Inhibitors of c-MET and / or any of its mutants For example, savolitinib, cabozantinib, foretinib; b.MET antibodies, e.g., emibetuzumab, amivantamab;

[0183] 24. Inhibitors of ERK and / or any mutant thereof For example, ulixertinib, LTT462;

[0184] 25. Inhibitors of farnesyltransferase and / or any mutant thereof For example, tipifarnib;

[0185] 4. Inhibitors of YAP1, WWTR1, TEAD1, TEAD2, TEAD3 and / or TEAD4 a. Reversible inhibitors of TEAD transcription factors (e.g., as disclosed in WO 2018 / 204532); b. Irreversible inhibitors of TEAD transcription factors (e.g., as disclosed in WO 2020 / 243423); c. Protein-protein interaction inhibitors of the YAP / TAZ::TEAD interaction (e.g., as disclosed in WO 2021 / 186324); d. Inhibitors of TEAD palmitoylation.

[0186] In a further embodiment of the (combination) uses and methods (e.g. methods for treatment and / or prevention) as described herein above, another pharmacologically active substance is administered before, after or together with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, wherein said another pharmacologically active substance is: SOS1 inhibitors; or MEK inhibitors; or trametinib, or anti-PD-1 antibodies; or Ezabenlimab; or Cetuximab; or afatinib; or Standard of care (SoC) for a given indication; or PI3 kinase inhibitors.

[0187] In a further embodiment of the (combination) uses and methods (e.g. methods for treatment and / or prevention) as described herein above, one other pharmacologically active substance is administered in combination with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, wherein said one other pharmacologically active substance is: SOS1 inhibitors; or MEK inhibitors; or trametinib; or anti-PD-1 antibodies; or Ezabenlimab; or Cetuximab; or afatinib; or Standard of care (SoC) for a given indication; or PI3 kinase inhibitors.

[0188] In a further embodiment of the (combination) uses and methods (e.g. methods for treatment and / or prevention) as described herein above, two other pharmacologically active substances are administered before, after or together with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, wherein said two other pharmacologically active substances are: MEK inhibitors and SOS1 inhibitors; or trametinib and an SOS1 inhibitor; 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; or an inhibitor selected from the group consisting of a MEK inhibitor 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 and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or MEK inhibitors and afatinib; or MEK inhibitors and cetuximab; or trametinib and afatinib; or trametinib and cetuximab; or SOS1 inhibitors and afatinib; or · SOS1 inhibitors and cetuximab.

[0189] In a further embodiment of the (combination) uses and methods (e.g. methods for treatment and / or prevention) as described herein above, two other pharmacologically active substances are administered in combination with a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof, wherein said two other pharmacologically active substances are: MEK inhibitors and SOS1 inhibitors; or trametinib and an SOS1 inhibitor; 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; or an inhibitor selected from the group consisting of a MEK inhibitor 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 and an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or MEK inhibitors and afatinib; or MEK inhibitors and cetuximab; or trametinib and afatinib; or trametinib and cetuximab; or SOS1 inhibitors and afatinib; or · SOS1 inhibitors and cetuximab.

[0190] Additional pharmacologically active substances which may also be used together / in combination with the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or pharma- ceutically acceptable salts thereof (including any individual embodiment or inclusive subset of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If)) or in the medical uses, uses as defined herein (above and below), methods of treatment and / or prevention, pharmaceutical compositions, kits, include hormones, hormone analogues 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, leu luprolide), inhibitors of growth factors and / or their corresponding receptors (such as growth factors, e.g., platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4), and hepatocyte growth factor (HGF) and / or their corresponding receptors), such as, for example, (anti)growth factor antibodies, (anti)growth factor receptor antibodies, and Tyrosine kinase inhibitors, such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab; antimetabolites (e.g. folate antagonists, such as methotrexate, raltitrexed, pyrimidine analogues, such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues, such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose),C), fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, such as carmustine and lomustine, thiotepa; antimitotic agents (e.g., vinca alkaloids, such as vinblastine, vindesine, vinorelbine and vincristine; and taxanes, such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g., tasquinimod), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimetics, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g., venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogues (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g., carfilzomib) , immunotherapeutics, such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, such as ipilimumab, nivolumab, pembrolizumab, etc.), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), t-cell engagers (e.g., bispecific T-cell engagers (BiTEs®), such as CD3×BCMA, CD3×CD33, CD3×CD19, PSMA×CD3), tumor vaccines, and various chemotherapeutic agents, such as amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer.

[0191] It should be understood that the combinations, compositions, kits, methods, uses, pharmaceutical compositions 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. It will be appreciated that the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances may be formulated and administered dependently or independently, e.g., the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances may be administered as part of the same pharmaceutical composition / dosage form or, preferably, in separate pharmaceutical compositions / dosage forms.

[0192] In this context, "combination" or "combined" includes, but is not limited to, within the meaning of the present invention, products resulting from mixing or combining two or more active ingredients, including both fixed and non-fixed (e.g., free) combinations (including kits) and uses, such as simultaneous, parallel, sequential, consecutive, alternating or separate use of 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 dosage. The term "non-fixed combination" means that the active ingredients are administered to a patient as separate entities simultaneously, in parallel or sequentially without specific time limitations, such administration providing a therapeutically effective level of the compound in the patient's body.

[0193] The administration of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof and one or more other pharmacologically active substances may be carried out by co-administration of the active components or ingredients, such as by administering them simultaneously or in parallel in one single or two or more separate formulations or dosage forms. Alternatively, the administration of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharma- ceutically acceptable salt thereof and one or more other pharmacologically active substances may be carried out by administering the active components or ingredients sequentially or alternatingly, such as by administering them in two or more separate formulations or dosage forms.

[0194] For example, simultaneous administration includes administration at substantially the same time. This form of administration may also be referred to as "conjugated" administration. Concurrent administration includes administration of the active agents within the same general time period, e.g., on the same day, but not necessarily at the same time. Alternating administration includes administration of one agent during one period, e.g., over several days or a week, followed by administration of the other agent during a subsequent period, e.g., over several days or a week, and then repeating this pattern for one or more cycles. Sequential or consecutive administration includes administration of one agent with one or more doses during a first period (e.g., over several days or a week), followed by administration of the other agent with one or more doses during a second and / or further period (e.g., over several days or a week). Overlapping schedules may also be used, including administration of the active agents on different days over the treatment period, but not necessarily following a regular order. Variations of these general guidelines may also be used, for example, depending on the agents used and the condition of the subject.

[0195] definition Terms not specifically defined herein should be given the meaning that would be given to them by one of ordinary skill in the art in light of this disclosure and context. However, as used herein, unless expressly stated to the contrary, the following terms have the meanings indicated and the following conventions are observed:

[0196] Prefix C x-y [wherein, x and y each represent a positive integer (x < y)] is used to indicate that the entire chain or ring structure or combination of chain and ring structures directly associated and specified can consist of carbon atoms with a maximum value of y and a minimum value of x.

[0197] The indication of the number of members in a group containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) relates to the total number of atoms of all ring members or the total number of all ring members and the carbon chain portion.

[0198] The indication of the number of carbon atoms in a group consisting of a combination of a carbon chain and a carbon ring structure (e.g., cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all carbon ring members and the carbon chain portion. Of course, the ring structure has at least 3 members.

[0199] Generally, for a group containing two or more partial groups (e.g., heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, arylalkyl), the last named partial group is the point of attachment of the group. For example, the substituent aryl-C 1-6 Alkyl is C 1-6 means an aryl group bonded to an alkyl group, C 1-6 The alkyl group is bonded to a group to which a nucleus or a substituent is bonded.

[0200] For groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., those skilled in the art can understand the point of attachment of the group to the molecule from the free valence of the group itself.

[0201] The expression "compounds of the invention" and grammatical variations thereof include compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If), including all salts, aspects and preferred embodiments thereof as defined herein. Any reference to a compound of the invention or to a compound of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If) is intended to include a reference to each (part) aspect and embodiment.

[0202] Alkyl denotes a monovalent saturated hydrocarbon chain which may exist both in linear (unbranched) and branched form. If an alkyl is substituted, the substitutions may take place independently of one another, by mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.

[0203] "C 1-5 The term "alkyl" includes, for example, HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH-, HC-CH-CH-CH-, and HC-CH-CH(CHCH)-.

[0204] 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-pentene (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH3)3), 2-pentene (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(CH3)2CH2CH2CH3), 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.;

[0205] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., unless otherwise further defined, refer to saturated hydrocarbon groups having the corresponding number of carbon atoms and include all isomeric forms.

[0206] The above definition of alkyl also applies when alkyl is, for example, C x-y Alkylamino or C x-y This also applies when it is part of another (combined) group, such as alkyloxy.

[0207] AlkyleneThe term can also be derived from alkyl. Alkylene, unlike alkyl, is divalent and requires two binding partners. Formally, the second valency is generated by removing a hydrogen atom in an alkyl. Corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2- or >CHCH3.

[0208] "C 1-4 The term "alkylene" includes, for example, -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-C H2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2- CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3))2)- and -C(CH3)(CH2CH3)-.

[0209] 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.

[0210] The generic terms propylene, butylene, pentylene, hexylene, etc., unless any further definition is intended to mean all the 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.

[0211] The above definition of alkylene also means that alkylene is, for example, HO-C x-y Alkyleneamino or H2N-C x-y This also applies when it is part of another (combined) group, such as alkyleneoxy.

[0212] Unlike alkyl, Alkenyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are connected together by a CC double bond, and a carbon atom can only be part of one CC 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.

[0213] 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.

[0214] The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc., unless any further definition is intended to mean 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.

[0215] The alkenyl may optionally be in the cis or trans or E or Z configuration about the double bond.

[0216] The above definition of alkenyl also means that alkenyl is, for example, C x-y Alkenylamino or C x-y This also applies when it is part of another (combined) group, such as alkenyloxy.

[0217] Unlike alkylene, Alkenylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are connected together by a CC double bond, and a carbon atom can only be part of one CC double bond. In an alkylene 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 alkenylene is formed.

[0218] Examples of alkenylene are 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.

[0219] The generic terms propenylene, butenylene, pentenylene, hexenylene etc., unless any further definition is intended to mean all the possible isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.

[0220] Alkenylene may optionally be in the cis or trans or E or Z configuration about the double bond.

[0221] The above definition of alkenylene also applies when alkenylene is, for example, HO-C x-y Alkenyleneamino or H2N-C x-y This also applies when it is part of another (combined) group, such as alkenyleneoxy.

[0222] Unlike alkyl, Alkynyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are connected together by a C-C triple bond. In an alkyl as defined hereinabove having at least two carbon atoms, two hydrogen atoms from any adjacent carbon atom are formally removed to saturate the free valences and form two additional bonds to form the corresponding alkynyl.

[0223] Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, and the like.

[0224] The generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc., unless any further definition is intended to 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.

[0225] If the hydrocarbon chain also carries at least one double bond and at least one triple bond, then by definition this hydrocarbon chain belongs to an alkynyl moiety.

[0226] The above definition of alkynyl also means that alkynyl is, for example, C x-y Alkynylamino or C x-y This also applies when it is part of another (combined) group, such as alkynyloxy.

[0227] Unlike alkylene, Alkynylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are connected together by a C-C triple bond. In an alkylene as defined hereinabove having at least two carbon atoms, when two hydrogen atoms of any adjacent carbon atom are formally removed and the free valences are saturated to form two additional bonds, the corresponding alkynylene is formed.

[0228] Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, and the like.

[0229] The generic terms propynylene, butynylene, pentynylene, hexynylene, etc., unless any further definition is intended to mean all the possible isomeric forms with the corresponding number of carbon atoms, i.e., propynylene includes 1-methylethynylene, butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

[0230] The above definition of alkynylene also applies when alkynylene is, for example, HO-C x-y Alkynyleneamino or H2N-C x-y This also applies when it is part of another (combined) group, such as alkynyleneoxy.

[0231] Heteroatoms means oxygen, nitrogen and sulfur atoms.

[0232] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the alkyl (alkenyl, alkynyl) as defined above by the replacement of one or more hydrogen atoms of the hydrocarbon chain, independently of one another, by halogen atoms which may be identical or different. If a haloalkyl (alkenyl, haloalkynyl) is further 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.

[0233] Examples of haloalkyl (haloalkenyl, haloalkynyl) include -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, and the like.

[0234] From the haloalkyl (haloalkenyl, haloalkynyl) defined above: Haloalkylene (haloalkenylene, haloalkynylene)The term haloalkylene (haloalkenylene, haloalkynylene) is also derived. Haloalkyl (haloalkenyl, haloalkynyl) is different from haloalkyl (haloalkenyl, haloalkynyl) in that it is divalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from the haloalkyl (haloalkenyl, haloalkynyl).

[0235] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F.

[0236] The above definitions also apply if the corresponding halogen-containing groups are part of another (combined) group.

[0237] halogen relates to a fluorine, chlorine, bromine and / or iodine atom.

[0238] Cycloalkyl is composed of the subgroups monocyclic cycloalkyl, bicyclic cycloalkyl and spiro-cycloalkyl. The ring systems are saturated and are formed by linked carbon atoms. In bicyclic cycloalkyl, two rings are connected together in such a way that they share at least two carbon atoms. In spiro-cycloalkyl, one carbon atom (spiro atom) belongs to both rings together.

[0239] 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. Cycloalkyl itself, as a substituent, may be linked to the molecule via any suitable position of the ring system.

[0240] Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl, and the like.

[0241] The above definition of cycloalkyl also applies when cycloalkyl is, for example, C x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y This also applies when it is part of another (combined) group, such as cycloalkylalkyl. If the free valence of the cycloalkyl is saturated, alicyclic ring is obtained.

[0242] Cycloalkylene The term can therefore be derived from cycloalkyl as defined above. 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 are, for example: Cyclohexyl and [ka]

[0243] The above definition of cycloalkylene also applies when cycloalkylene is, for example, HO-C x-y Cycloalkyleneamino or H2N-C x-y This also applies when it is part of another (combined) group, such as cycloalkyleneoxy.

[0244] Cycloalkenylis composed of the subgroups monocyclic cycloalkenyl, bicyclic cycloalkenyl and spiro-cycloalkenyl. However, this system is unsaturated, i.e., there is at least one C-C double bond, but no aromatic system. In a cycloalkyl as defined hereinbefore, two hydrogen atoms of adjacent cyclic carbon atoms are formally removed and the free valences are saturated to form a second bond, resulting in the corresponding cycloalkenyl.

[0245] 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, as a substituent, may be linked to the molecule via any suitable position of the ring system.

[0246] Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-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.

[0247] The above definition of cycloalkenyl also applies when cycloalkenyl is, for example, C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C x-yThis also applies when they are part of another (combined) group, such as cycloalkenylalkyl.

[0248] When the free valence of the cycloalkenyl is saturated, unsaturated alicyclic ring is obtained.

[0249] Cycloalkenylene The term can therefore be derived from cycloalkenyl as defined above. 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 are, for example: Cyclopentenyl and [ka]

[0250] The above definition of cycloalkenylene also applies when cycloalkenylene is, for example, HO-C x-y Cycloalkenyleneamino or H2N-C x-y This also applies when they are part of another (combined) group, such as cycloalkenyleneoxy.

[0251] Aryl represents a monocyclic, bicyclic 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), where the second ring may be aromatic but may also be partially saturated.

[0252] 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, as a substituent, may be linked to the molecule via any suitable position of the ring system.

[0253] Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl, etc. Most preferred is phenyl.

[0254] The above definition of aryl also applies if aryl is part of another (combined) group, such as, for example, arylamino, aryloxy or arylalkyl.

[0255] If the free valence of the aryl is saturated, aromatic group is obtained.

[0256] Arylene The term may also be derived from aryl as defined above. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are, for example: Phenyl and [ka] Naphthyl and [ka]

[0257] The above definition for arylene also applies if arylene is part of another (combined) group, such as, for example, HO-aryleneamino or H2N-aryleneoxy.

[0258] Heterocyclylrepresents a ring system derived from the above-defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the -CH2- groups, independently of one another, in the hydrocarbon ring by the group -O-, -S- or -NH-, or by replacing one or more of the =CH- groups by the group =N-, where up to 5 heteroatoms may be present in total, at least one carbon atom must be present between two oxygen atoms and two sulfur atoms or between an oxygen atom and a sulfur atom, and the ring as a whole must have chemical stability. The heteroatoms may optionally be present in all possible oxidation stages (sulfur → sulfoxide-SO-, sulfone-SO2-; nitrogen → N-oxide). In heterocyclyl, there is no heteroaromatic ring, i.e. the heteroatoms are not part of the aromatic system.

[0259] A direct consequence of the derivation from cycloalkyl, cycloalkenyl, and aryl is that heterocyclyl is comprised of the subgroups monocyclic heterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl, and spiro-heterocyclyl, which may exist in saturated or unsaturated form.

[0260] Unsaturated means that there is at least one double bond in the ring system, but no heteroaromatic system is formed. In a bicyclic heterocyclyl, two rings are linked together to share at least two (hetero)atoms. In a spiro-heterocyclyl, one carbon atom (spiro atom) belongs to both rings together.

[0261] When a heterocyclyl 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 and / or nitrogen atoms. The heterocyclyl itself may be linked to the molecule as a substituent via any suitable position of the ring system. For the substituents on the heterocyclyl, the number of members of the heterocyclyl is not critical.

[0262] Examples of heterocyclyls 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-di. 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, etc.

[0263] Further examples are the structures illustrated below, which may be bonded (exchanged with hydrogen) through their respective hydrogen-carrying atoms: [ka] TIFF2024543983000065.tif222161 TIFF2024543983000066.tif226161 TIFF2024543983000067.tif221161

[0264] Preferred monocyclic heterocyclyls are 4-7 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0265] Preferred monocyclic heterocyclyls are piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azetidinyl.

[0266] Preferred bicyclic heterocyclyls are 6-10 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0267] Preferred tricyclic heterocyclyls are 9-membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0268] Preferred spiro-heterocyclyls are 7-11 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0269] The above definition of heterocyclyl also applies if heterocyclyl is part of another (combined) group, such as, for example, heterocyclylamino, heterocyclyloxy or heterocyclylalkyl.

[0270] If the free valence of the heterocyclyl is saturated, Heterocycle is obtained.

[0271] HeterocyclyleneThe term is also derived from heterocyclyl as defined above. 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 are, for example: Piperidinyl and [ka] 2,3-Dihydro-1H-pyrrolyl and [ka]

[0272] The above definition of heterocyclylene also applies if heterocyclylene is part of another (combined) group, such as, for example, HO-heterocyclyleneamino or H2N-heterocyclyleneoxy.

[0273] Heteroaryl represents a monocyclic heteroaromatic ring or a polycyclic ring having at least one heteroaromatic ring, which contains, in place of one or more carbon atoms, one or more identical or different heteroatoms selected from among nitrogen, sulfur and oxygen, in comparison with the corresponding aryl or cycloalkyl(alkenyl), where the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is the heteroatom and the heteroaromatic system.

[0274] When heteroaryl is substituted, the substitutions can be carried out independently of one another, in the form of monosubstitution or polysubstitution in each case, on all hydrogen-carrying carbon and / or nitrogen atoms.Heteroaryl itself can be linked to the molecule as a substituent at any suitable position of the ring system, i.e., via both carbon and nitrogen.For the substituent on heteroaryl, the number of members of heteroaryl is not important.

[0275] 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, benzo zothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, ben These include zothiazolyl, 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.

[0276] Further examples are the structures illustrated below, which may be bonded (exchanged with hydrogen) through their respective hydrogen-carrying atoms: [ka] TIFF2024543983000071.tif188161

[0277] Preferably, the heteroaryl is a 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, each having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0278] The above definition of heteroaryl also applies if heteroaryl is part of another (combined) group, such as, for example, heteroarylamino, heteroaryloxy or heteroarylalkyl.

[0279] If the free valence of the heteroaryl is saturated, Heteroaromatic groups is obtained.

[0280] Heteroarylene The term is also derived from heteroaryl as defined above. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are, for example: Pyrrolyl and [ka]

[0281] The above definition of heteroarylene also applies if heteroarylene is part of another (combined) group, such as, for example, HO-heteroaryleneamino or H2N-heteroaryleneoxy.

[0282] Has been replaced means that a hydrogen atom directly bonded to the atom under consideration is replaced by another atom or a group of another atom (substituent). Depending on the starting conditions (number of hydrogen atoms), mono- or polysubstitutions can be made 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 replaced correspond to each other and the substitution leads to a stable compound (i.e., a compound that is not spontaneously transformed, for example, by rearrangement, cyclization or elimination).

[0283] Divalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, etc. are only possible as substituents on carbon atoms, but the divalent substituents =O and =NR can also be substituents on sulfur. In general, substitutions can only be made on ring systems by divalent substituents and require the replacement of two geminal hydrogen atoms, i.e. hydrogen atoms attached to the same carbon atom that is saturated before the substitution. Thus, substitutions by divalent substituents are only possible on the group -CH2- or sulfur atoms of the ring system (only =O or =NR groups, one or two =O groups are possible, or, for example, one =O and one =NR group, each group replacing a free electron pair).

[0284] Isotopes: Any disclosure of atoms or compounds of the present invention should be understood to include all suitable isotopic variations, specifically reference to hydrogen also includes deuterium.

[0285] 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.) thereof, as well as racemates, as well as mixtures of the separate enantiomers in differing proportions, mixtures of diastereomers, or mixtures of any of the foregoing forms, where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts, and solvates thereof, such as solvates and hydrates of the free compounds or of a salt of the compounds, including solvates and hydrates.

[0286] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of the corresponding mixtures, by the use of stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, for example, by resolution of racemates or by synthesis, for example, starting from optically active starting materials and / or using chiral reagents.

[0287] Enantiomerically pure compounds or intermediates of the present invention may be prepared via asymmetric synthesis, for example by the preparation and subsequent separation of suitable diastereomeric compounds or intermediates which can be separated by known methods (e.g. chromatographic separation or crystallization), and / or by the use of chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.

[0288] Furthermore, methods for preparing enantiomerically pure compounds from the corresponding racemic mixtures are also known to the skilled artisan, for example by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases, or by resolution of the racemic mixtures using suitable resolving agents, for example by formation of diastereomeric salts of the 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 enzymatic resolution); by enantioselective crystallization from a consortium of enantiomeric crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0289] salt: The phrase "pharmacologically 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 undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0290] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0291] 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-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0292] Further pharma- ceutically 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.

[0293] The pharma- ceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0294] For example, salts of acids other than those mentioned above that are useful in the purification or isolation of the compounds of this invention (eg, trifluoroacetates) also form part of this invention.

[0295] for example, [ka] In depictions such as these, the letter A serves the function of designating a ring for easier reference, for example to indicate the attachment of that ring to another ring.

[0296] For divalent groups, it is very important to determine which adjacent group it is bonded to and with what valency, and the corresponding bond partner is shown in parentheses for clarity, where necessary, as in the following depiction: [ka] (R 2 )-C(=O)NH- or (R 2 )-NHC(=O)-.

[0297] Unless such clarification is given, divalent groups can be attached in both orientations, i.e., for example, -C(=O)NH- also includes -NHC(=O)- and vice versa.

[0298] A group or substituent often refers to a number of alternative groups / substituents for which the corresponding group is designated (e.g., R a , R b etc.) When such groups are used repeatedly in different parts of the molecule to define the compounds according to the invention, it is implied that the various uses should be considered completely independent of each other.

[0299] A therapeutically effective amount for purposes of this invention means an amount of a substance that is capable of eliminating symptoms of a disease, preventing or alleviating these symptoms, or prolonging the survival of the treated patient.

[0300] Ras family proteins as used herein are meant to include KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey murine sarcoma viral oncogene) and any mutants thereof.

[0301] A RAS G12C inhibitor as used herein refers to a compound 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 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.

[0302] [Table 1] TIFF2024543983000076.tif230161 TIFF2024543983000077.tif232161 TIFF2024543983000078.tif125161 EXAMPLES

[0303] 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:

[0304] Preparation of the Compounds of the Invention overview Unless otherwise specified, 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 are carried out under protective gas (nitrogen or argon).

[0305] When a compound is represented by both a structural formula and its nomenclature, in case of conflict, the structural formula shall be determining.

[0306] Microwave reactions are carried out in a Biotage synthesizer / 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.

[0307] Chromatography Thin layer chromatography is performed on Merck pre-made silica gel 60 TLC glass plates (with fluorescent indicator F-254).

[0308] Preparative high pressure chromatography (RP HPLC) of the exemplary compounds according to the present invention is carried out on an Agilent or Gilson system 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 columns manufactured by YMC (designation: Actus-Triart Prep C18, 5 μm, 30×50 mm).

[0309] Elute the compounds using different gradients of HO / acetonitrile, but for the Agilent system, add 5% acidity modifier (20 mL HCOOH to 1 L HO / acetonitrile (1 / 1)) to water (acidic conditions); for the Gilson system, add water to 0.1% HCOOH.

[0310] For chromatography under basic conditions on the Agilent system, the same H2O / acetonitrile gradient is used, but the water is made alkaline by adding 5% basic modifier (50 g NH4HCO3 + 50 mL NH3 (25% in H2O) to 1 L with H2O). For the Gilson system, the water is made alkaline as follows: 5 mL NH4HCO3 solution (158 g in 1 L H2O) and 2 mL NH3 (28% in H2O) made up to 1 L with H2O.

[0311] Supercritical fluid chromatography (SFC) of the intermediates and exemplary compounds of the present invention is performed on a JASCO SFC system using the following columns: Chiralcel OJ (250×20 mm, 5 μm), Chiralpak AD (250×20 mm, 5 μm), Chiralpak AS (250×20 mm, 5 μm), Chiralpak IC (250×20 mm, 5 μm), Chiralpak IA (250×20 mm, 5 μm), Chiralcel OJ (250×20 mm, 5 μm), Chiralcel OD (250×20 mm, 5 μm), Phenomenex Lux C2 (250×20 mm, 5 μm).

[0312] Analytical HPLC (reaction control) of intermediates and final compounds is carried out using columns from 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) and columns from YMC (designation: Triart C18, 3.0 μm, 2.0×30 mm) and columns from Phenomenex (designation: Luna C18, 5.0 μm, 2.0×30 mm). The analytical instruments are also equipped in each case with a mass detector.

[0313] HPLC mass spectrometry / UV spectroscopy Retention Time / MS-ESI for Characterizing Exemplary Compounds of the Present Invention + is generated using an HPLC-MS instrument (high performance liquid chromatography equipped with a mass detector). Compounds eluting in the injection peak have retention times t Ret. =0.00.

[0314] SFC method (preparative) Preparative SFC is performed on a Waters Thar SFC 80 system. Column: Chiralpak AD-H (21×250mm), 5μm Flow rate: 25g / min Mobile phase: 75% CO2 + 25% MeOH (0.5% isopropylamine) ABPR: 120 bar Temp:35℃ UV: 220nm Stack Time: 8 minutes

[0315] HPLC method (analysis) Method A Samples were analyzed on an Agilent 1200 series LC system coupled with an Agilent 6140 mass spectrometer. Purity was determined via UV detection in the range of 230-400 nm with 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 5 μL injection; Solvent A: 20mM NH4HCO3 / NH3 pH 9 B: MS grade acetonitrile; Gradient 0.0~1.5min 10%~95% B 1.5~2.0 minutes 95% B 2.0~2.1 minutes 95%~10% B

[0316] Method B HPLC Agilent 1100 / 1200 Series MS Agilent LC / MSD SL Column: Waters X-Bridge BEH C18, 2.5μm, 2.1×30mm XP Solvent A: 20mM NH4HCO3 / 28mM NH3 in H2O; B: Acetonitrile (HPLC grade) Detection MS: positive and negative modes Mass range 100~750m / z Flow rate 1.40mL / min Column temperature: 45℃ Gradient: 0.00-1.00 min: 15% B → 95% B 1.00~1.30 minutes: 95% B

[0317] Method C HPLC Agilent 1100 / 1200 Series MS Agilent LC / MSD SL Column: Waters SunFire C18, 2.5μm, 2.1×30mm 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℃ Gradient 0.00~1.00 min: 15% B → 100% B 1.00~1.13 minutes: 100% B

[0318] Method D HPLC Agilent 1100 / 1200 Systems MS 1200 Series LC / MSD(MM-ES+APCI+ / -3000V, Quadrupol, G6130B) MSD Signal Settings Scan Positive 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 254nm, 230nm, 214nm (bandwidth 8, reference off) Spectral range: 190~400nm; Slit: 4nm Peak width >0.0031 min (0.063 s response time, 80 Hz) Injection Standard injection of 0.5 μL Flow rate 1.4mL / min Column temperature: 45℃ Gradient 0.0~1.0 min 15%→95% B 1.0~1.1 minutes 95% B Downtime: 1.3 minutes

[0319] Method E HPLC Agilent 1100 / 1200 Systems MS 1200 Series LC / MSD(API-ES+ / -3000 / 3500V, Quadrupol, G6140A) MSD Signal Settings Scan Positive 150~750 Column YMC; Part. No. TA12S03-0302WT; Triart C18, 3μm, 12nm; 30×2.0mm column Eluent A: H2O + 0.11% formic acid B:MeCN+0.1% formic acid (HPLC grade) Detection signal UV 254nm, 230nm, 214nm (bandwidth 10, reference off) Spectral range: 190~400nm; Slit: 4nm Peak width >0.0031 min (0.063 s response time, 80 Hz) Injection Standard injection of 0.5 μL Flow rate 1.4mL / min Column temperature: 45℃ Gradient 0.0~1.0 min 15%→95% B 1.0~1.1 minutes 95% B Downtime: 1.23 minutes

[0320] Method F HPLC Agilent 1100 / 1200 Systems MS 1200 Series LC / MSD(API-ES+ / -3000 / 3500V, Quadrupol, G6140A) MSD Signal Settings Scan Positive / Negative 150~750 Column YMC; Part. No. TA12S03-0302WT; Triart C18, 3μm, 12nm; 30×2.0mm column Eluent A: H2O + 0.11% formic acid B:MeCN+0.1% formic acid (HPLC grade) Detection signal UV 254nm, 230nm, 214nm (bandwidth 10, reference off) Spectral range: 190~400nm; Slit: 4nm Peak width >0.0031 min (0.063 s response time, 80 Hz) Injection Standard injection of 0.5 μL Flow rate 1.4mL / min Column temperature: 45℃ Gradient 0.0~1.0 min 15%→95% B 1.0~1.1 minutes 95% B Stop Time: 1.23 minutes

[0321] Method G HPLC Agilent 1100 / 1200 Systems MS 1200 Series LC / MSD(MM-ES+APCI+ / -3000V, Quadrupol, G6130B) MSD Signal Settings Scan Positive / Negative 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 254nm, 230nm, 214nm (bandwidth 8, reference off) Spectral range: 190~400nm; Slit: 4nm Peak width >0.0031 min (0.063 s response time, 80 Hz) Injection Standard injection of 0.5 μL Flow rate 1.4mL / min Column temperature: 45℃ Gradient 0.0~1.0 min 15%→95% B 1.0~1.1 minutes 95% B Downtime: 1.3 minutes

[0322] The compounds and intermediates according to the invention are prepared by the synthetic methods described below in this specification, in which the substituents of the general formula have the meanings given herein above. These methods are intended as illustrations of the invention, and the subject matter and scope of the claimed compounds are not limited to these examples. Where the preparation of starting compounds is not described, they may be commercially available or their synthetic methods are described in the prior art, or may 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. Substances described in the literature can be prepared according to published synthetic methods. Hereinafter, when chemical structures are depicted without the exact configuration of stereocenters, e.g., asymmetrically substituted carbon atoms, both configurations shall be considered to be included and disclosed in such depiction. The depiction of stereocenters in racemates shall always be considered to include and disclose both enantiomers (if no other defined stereocenters exist) or all other potential diastereomers and enantiomers (if further defined or undefined stereocenters exist).

[0323] Experimental procedure for the synthesis of A-2a [ka] To a suspension of 5-chloropentanenitrile (22.9 g, 194.8 mmol, 1.0 equiv) in dry EtOH (136 mL) was added acetyl chloride (111.3 mL, 1.558 mol, 8.0 equiv) dropwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 12 h. The mixture was concentrated under reduced pressure, washed with EtO, and the crude product A-2a was used directly as the HCl salt in the next step without further purification.

[0324] Experimental procedure for the synthesis of A-3a [ka] Crude A-2a (HCl salt) (28 g, 139.9 mmol, 1.0 equiv) and ethylene glycol (7.382 g, 118.94 mmol, 0.9 equiv) were dissolved in DCM (300 mL) and stirred at room temperature for 6 h. The resulting suspension was concentrated under reduced pressure, diluted with Et2O (200 mL), and filtered. The filtrate was concentrated under reduced pressure, dissolved in DCM (200 mL), and treated with 2N KOH solution (150 mL). The mixture was stirred overnight at room temperature, keeping the phase intact. The phases were separated, the aqueous phase was extracted twice with DCM, and the combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude orthoester A-3a was used in the next step without further purification.

[0325] Experimental procedure for the synthesis of A-4a [ka] Crude A-3a (22.3 g, 106.9 mmol, 1.0 equiv), 1-cyclohexenyloxytrimethylsilane (16.42 mL, 82.3 mmol, 0.8 equiv) and zinc chloride (10.195 g, 74.8 mmol, 0.7 equiv) were dissolved in DCM (120 mL) and stirred at room temperature for 5 h. The reaction mixture was treated by addition of saturated sodium bicarbonate solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by NP-chromatography (gradient elution: 0% to 50% EtOAc in hexane) to give the desired compound A-4a.

[0326] Experimental procedure for the synthesis of A-5a [ka] A-4a (14.9 g, 57.14 mmol, 1.0 equiv.) and sodium iodide (25.954 g, 171.4 mmol, 3.0 equiv.) were dissolved in acetone (120 mL) and stirred under reflux for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM, and washed with saturated sodium thiosulfate solution. The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product A-5a was used in the next step without further purification.

[0327] Experimental procedure for the synthesis of A-6b [ka] A-5a (30 g, 85.0 mmol, 1.0 equiv.) was dissolved in THF. The mixture was treated with potassium tert.-butoxide (28.67 g, 256.0 mmol, 3.0 equiv.) at 0° C. and stirred at room temperature overnight. The reaction mixture was quenched by the addition of water (2 mL) and diluted with Et2O and saturated sodium bicarbonate solution. The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by NP-chromatography (gradient elution: 0% to 50% EtOAc in hexanes) to give (racemic) compound A-6a (reaction sequence A-1a → A-6a is based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., Eur. J. Org. Chem. 2004, 19:3962-3967).

[0328] The desired enantiomer A-6b could then be obtained after chiral separation by SFC (eg, using a CHIRACEL OX-3 column and acetonitrile as a co-solvent). Scheme 2a: [ka] Scheme 2b: [ka]

[0329] 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) was added and the mixture was cooled to 10° C. E-1a (2.0 g, 11.15 mmol, 97% purity, 1.0 equiv) was added and the mixture was stirred at 10° C. for 45 min. The mixture was filtered and the filtrate was purified by basic reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to yield E-2a (HPLC method A; t ret =1.36 minutes;[M+H] + =267).

[0330] Further intermediates E-2 are available in an analogous manner. The crude product E-2 can be purified by chromatography if necessary.

[0331] 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) was added piperazine-1-carboxylic acid tert-butyl ester (11.22 g, 57.22 mmol, 1.0 equiv). Then, DIPEA (20.71 g, 160.21 mmol, 2.8 equiv) was added and the reaction mixture was stirred at 60° C. for 1 h. After complete conversion, the mixture was dissolved in EtOAc and washed with water (3×). The organic phase was dried, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH) to yield E-4c.

[0332] 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 reduced pressure. The crude product was dissolved in DCM and purified by column chromatography (DCM / MeOH) to yield E-4d.

[0333] The following (further) intermediates E-4 (Table 2) are accessible in an analogous manner using different amines PG-LH and intermediate E-1 according to methods A to E. The crude products E-4 can be purified by chromatography if necessary. [Table 2]

[0334] Various building blocks HR 5 Synthesis of [ka]

[0335] Experimental procedure for the synthesis of G-2a G-1a (500 mg, 2.33 mmol) was dissolved in dry THF (5.00 mL) together with triethylamine (485 μL, 3.5 mmol, 1.5 equiv.) and the mixture was cooled to 0° C. Benzyl chloroformate (519 μL, 3.5 mmol, 1.5 equiv.) was added in small portions and the mixture was stirred for 2 h and allowed to reach room temperature overnight. After complete conversion, water was added to the mixture and the product was extracted with DCM, the combined extracts were dried, filtered and concentrated. The crude product was used in the next step without further purification (HPLC method B, t ret=0.766 minutes, [M+H] += 249 / 293).

[0336] Experimental procedure for the synthesis of G-3a G-2a (813 mg, 2.33 mmol) was dissolved in DCM (25.00 mL) and treated with HCl (4 M in dioxane, 11.67 mL, 46.66 mmol, 20.0 equiv). The mixture was stirred at room temperature for 2 h. After complete conversion, the mixture was concentrated and the product was isolated by basic reverse phase chromatography (gradient elution: 10% to 70% acetonitrile in water). (HPLC method B, t ret =0.478 minutes, [M+H] + =249)

[0337] 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, the product was extracted with DCM, and the combined extracts were dried, filtered and concentrated. The crude product was purified by normal phase chromatography (DCM / MeOH).

[0338] 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 K2CO3 (0.303 g, 2.51 mmol, 2.50 equiv.), followed by 1-bromo-2-methoxy-ethane (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 by normal phase chromatography (DCM / MeOH).

[0339] The following (further) intermediates G-4 (Table 6) are accessible in an analogous manner using G-3a as alkylating agent and different aldehydes or ketones according to methods F or G. The crude product G-4 can be purified by chromatography if necessary. [Table 3]

[0340] Experimental procedure for the synthesis of G-5a [ka] G-5a (3.00 g, 11.44 mmol) was dissolved in MeOH (20.0 mL) and palladium (10% on charcoal, 360 mg) was added. The mixture was stirred at room temperature for 16 h under 5 bar hydrogen pressure in a hydrogenation reactor. After complete conversion, the catalyst was filtered off and the residue was concentrated. The crude product was used in the subsequent step without further purification.

[0341] [Table 4]

[0342] 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 eq.) and DIPEA (1.94 mL, 11.15 mmol, 2 eq.) in DMSO (3 mL) was slowly added a solution of E-1a (1000 mg, 97% purity, 5.58 mmol, 1.0 eq.) in DMSO (3 mL). The mixture was stirred at room temperature for 30 min. After complete conversion of the starting material was observed, tert-butyl (R)-3-methylpiperazine-1-carboxylate (1.50 mg, 97% purity, 7.25 mmol, 1.3 eq.) and DIPEA (0.97 mL, 5.58 mmol, 1 eq.) were added to the mixture. The mixture was stirred at 60° C. for 60 min and DIPEA (0.97 mL, 5.58 mmol, 1 eq.) was added. The mixture was stirred at 70° C. for 50 min and at room temperature overnight. After complete conversion was observed, the reaction was diluted with water and DCM and the phases were separated. The aqueous phase was extracted with DCM (3×) and the organic phases were combined. The solvent was removed under reduced pressure to give the crude product E-8a. The crude product was dissolved in acetonitrile and water, filtered and purified by basic reverse phase chromatography (gradient elution: 35% to 95% acetonitrile in water) to give the desired purified product E-8b.

[0343] The following intermediates E-8 (Table 9) can be accessed in an analogous manner without isolating the corresponding intermediates E-2. The crude products E-8 are purified by chromatography if necessary. [Table 5]

[0344] 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), cesium fluoride (1.218 g, 8.02 mmol, 2.5 equiv.) was added 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.) was added. 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.) and DIPEA (1.085 mL, 6.38 mmol, 2 equiv.) in anhydrous DMSO (3 mL) was added to the mixture. The mixture was stirred at room temperature for 30 min. After complete conversion was observed, the reaction was diluted with acetonitrile and water, filtered, and purified by basic reverse phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give the desired product E-8d.

[0345] The following intermediate E-8 (Table 10) can be accessed 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 6]

[0346] 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.) was added and the mixture was stirred at 100° C. for 16 h. The mixture was cooled to room temperature, diluted with acetonitrile and water, filtered, and purified by acidic reverse phase chromatography (gradient elution: 10% to 98% acetonitrile in water) to give the desired product E-8m.

[0347] Intermediate E-8 (Table 11), marked "G", is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0348] 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) was cooled to 0° C. Sodium tert-butoxide (854 mg, 8.88 mmol, 2.0 equiv) was added to the mixture at 0° C. The mixture was allowed to warm slowly to room temperature and stirred at room temperature for 2 h. The reaction was quenched by the addition of ice water and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine solution and concentrated under reduced pressure. The crude product was purified by normal phase chromatography (2% MeOH in DCM) to give the desired product E-8n.

[0349] Intermediate E-8 (Table 11), marked with "H", is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary.

[0350] 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 in portions over 19 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 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 reduced pressure. The crude product was purified by normal phase chromatography (2% MeOH in DCM) to give the desired product E-8o.

[0351] Intermediate E-8 (Table 11), marked with "I", is accessible in a similar manner. The crude product E-8 is purified by chromatography if necessary.

[0352] 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) was added trimethylamine (149.8 mg, 1.48 mmol, 2.5 equiv). The mixture was stirred at 40° C. for 2 h. The mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the crude product was purified by normal phase chromatography (gradient elution: 0% to 90% MeOH in DCM+ammonia) to give the desired product E-8p.

[0353] Intermediate E-8 (Table 11), marked with "J", is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary. [Table 7] TIFF2024543983000105.tif245165

[0354] 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.

[0355] Intermediate E-8 (Table 13), marked with "M", is accessible in an analogous manner. The crude product E-8 is purified by chromatography if necessary. [Table 8]

[0356] Additional nitrile building blocks E-8 not expressly disclosed herein are disclosed (including synthesis) in WO 2021 / 245051 and WO 2021 / 245055, both of which are incorporated herein by reference for their disclosure of building blocks E-8, their synthesis and their synthetic uses. These building blocks can also be used in the synthesis of further compounds of formula (I) according to the invention not specifically disclosed herein. Scheme 3a: [ka]

[0357] Experimental procedure for the synthesis of E-12a [ka] To a solution of E-8aq (1.776 g, 4.26 mmol, 1 equiv) in MeOH (35 mL) was added a solution of sodium hydroxide in water (16 mL, 4 M, 63.96 mmol, 15.0 equiv) and the resulting mixture was stirred at 65 °C for 1.5 h. The reaction volume was reduced under reduced pressure to remove most of the MeOH and the remaining aqueous solution was carefully neutralized with aqueous HCl (8 M). The mixture was diluted with acetonitrile and purified by acidic reverse phase chromatography (gradient elution: 10% to 85% acetonitrile in water) to give the desired product E-12a.

[0358] Experimental procedure for the synthesis of E-12e [ka] To a solution of E-8c (2.2 g, 4.97 mmol, 1 equiv) in MeOH was added a solution of sodium hydroxide in water (6.2 mL, 4 M, 40 mmol, 5.0 equiv) and the resulting mixture was stirred at 65° C. for 4 h. The reaction mixture was concentrated under reduced pressure, suspended in MeOH, filtered and purified by acidic reverse phase chromatography (gradient elution: 10% to 85% acetonitrile in water). Product containing fractions were combined, concentrated under reduced pressure and lyophilized to give the desired product E-12e.

[0359] The following intermediates E-12 / E-12 * and E-13 / E-13 * Table 16 shows the different intermediates E-8 / E-8 * In a similar manner, starting from E-8 / E-8 can be used. * If necessary, the product is purified by chromatography. [Table 9]

[0360] Scheme 4a: [ka]

[0361] Experimental procedure for the synthesis of B-1a [ka] CDI (18.781 g, 112.352 mmol, 2.0 equiv) was dissolved in dry THF and heated to 50° C. In a second flask, E-12d (13.021 g, 28.088 mmol, 0.5 equiv) and the activated mole sieve in dry THF were stirred at room temperature for 10 min and then added to the CDI solution. The reaction mixture was stirred at 50° C. for 15 min. In a third flask, A-6b (15 g, 56.176 mmol, 1.0 equiv) was dissolved in a 1M LiHMDS solution in THF (117.969 mL, 117.969 mmol, 2.1 equiv) and stirred at room temperature for 10 min and then added to the activated ester. The reaction mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, diluted with DCM, and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by NP-chromatography (under basic conditions using a gradient MeOH / DCM 0-10%). The product containing fractions were combined and lyophilized to yield B-1a.

[0362] The following intermediates B-1 / B-1 * Table 17 shows the different intermediates E-12 / E-12 * and E-13 / E-13 * The crude products B-1 / B-1 can be obtained in a similar manner starting from * If necessary, it was purified by chromatography. [Table 10] Scheme 5a: [ka]

[0363] Experimental Procedure for the Synthesis of B-6a and B-7a [ka] To a solution of B-1a (12.7 g, 19 mmol, 1.0 equiv.) in EtOH / water was added hydroxylamine hydrochloride (containing 50% water, 3.131 g, 47 mmol, 2.5 equiv.) and the reaction mixture was heated to 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in MeOH (40 mL), and treated with concentrated HCl (40 mL). The reaction mixture was stirred at 60° C. for 1 h, concentrated under reduced pressure, dissolved in EtOAc, and neutralized by careful addition of saturated sodium carbonate solution. The aqueous phase was extracted with EtOAc (3 times), and the combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by RP-chromatography (using a gradient ACN / water 30-80% under basic conditions). Product containing fractions were combined and lyophilized to yield B-6a as well as the other isoxazole isomer B-7a.

[0364] The following intermediates B-4 / B-4 * , B-5 / B-5 * , B-6 / B-6 * , B-7 / B-7 * Table 18 shows the different intermediates B-1 / B-1 * An analogous method can be used starting from The crude product was purified by chromatography if necessary. [Table 11]

[0365] Scheme 6a: [ka]

[0366] Experimental procedure for the synthesis of C-3a [ka] To a solution of B-6a (1.2 g, 2.3 mmol, 1.0 equiv) in EtOH (10 mL) under nitrogen gas, malononitrile (95% purity, 798.2 mg, 11 mmol, 5.0 equiv), beta-alanine (95% purity, 646 mg, 6.9 mmol, 3.0 equiv) and activated molecular sieves (from Roth, 200 mg) were added at room temperature. The reaction mixture was heated to 80 °C for 3 h. Upon complete condensation reaction monitored by HPLC-MS, sulfur (220.9 mg, 6.9 mmol, 3.0 equiv) was added and the reaction mixture was stirred at 80 °C for 15 min. The reaction mixture was cooled to room temperature, dissolved with water and EtOAc, and filtered. The layers were separated. To the aqueous phase was added 4N NaOH solution (10 mL) and extracted three times with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using a gradient under basic conditions. The product containing fractions were combined and lyophilized to yield C-3a.

[0367] The following intermediates C-1 / C-1 * , C-2 / C-2 * , C-3 / C-3 * and C-4 / C-4 * Table 19 shows the different intermediates B-4 / B-4 * , B-5 / B-5 * , B-6 / B-6 * and B-7 / B-7 * The crude product can be purified by chromatography if necessary. [Table 12] TIFF2024543983000121.tif181165

[0368] Synthesis of compound (I) according to the invention: Scheme 7: [ka]

[0369] Experimental Procedure for the Synthesis of Compound Ia-1 [ka] To a solution of 2-fluoroacrylic acid (136 mg, 1.51 mmol, 2.6 equiv.) and HATU (552 mg, 1.452 mmol, 2.5 equiv.) in DMF (0.6 mL), TEA (353 mg, 3.484 mmol, 6.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 min. To the reaction mixture, a solution of C-3a (350 mg, 581 μmol, 1.0 equiv.) dissolved in DMF (3 mL) was added and the mixture was stirred at room temperature for 15 min. After completion of the reaction, the mixture 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 compound Ia-1.

[0370] Experimental procedure for the synthesis of compound Ib-1 [ka] To a solution of (2E)-4-fluorobut-2-enoic acid (10.4 mg, 100 μmol, 1.2 equiv.) and HATU (47.3 mg, 124 μmol, 1.5 equiv.) in DMF, TEA (21 mg, 207.4 μmol, 2.5 equiv.) was added and the reaction mixture was stirred at room temperature for 15 min. To the reaction mixture, C-4a (50 mg, 83 μmol, 1.0 equiv.) was added and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the mixture 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 compound Ib-1.

[0371] Experimental Procedure for the Synthesis of Compound Ia-2 [ka] To a solution of sodium carbonate (154 mg, 1.45 mmol, 2.5 equiv) in acetone / water (8:1) and C-3a (350 mg, 581 μmol, 1.0 equiv) was added a freshly prepared solution of acryloyl chloride (81.3 mg, 871 μmol, 1.5 equiv) in acetone. After completion of the reaction, the mixture 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 compound Ia-2. [Table 13] TIFF2024543983000127.tif245165 TIFF2024543983000128.tif157165

[0372] The following examples are intended to illustrate the biological activities of the compounds according to the invention, but are not intended to limit the invention.

[0373] KRAS::SOS1 AlphaScreen binding assay This assay can be used to test the potency of compounds of the 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. 50 The values ​​are indicative of strong inhibition of the protein-protein interaction between SOS1 and KRAS:

[0374] reagent · In-house GST tagged SOS1 (564_1049_GST_TEV_ECO) GST-TEV-SOS1 (564-1049) was purchased from Viva Biotech Ltd. An expression construct for KRAS G12C containing a C-terminal avi tag (amino acids 1-169 of reference sequence P01116-2 (uniprot) with additional mutations: C51S, C80L, and C118S) was obtained by gene synthesis (GeneArt, Thermo Fisher) in a donor vector (pDONR-221) and transferred by recombinational cloning into the pDEST17 vector with an N-terminal His6 tag. The protein was expressed in E. coli, and the purified protein was biotinylated with E. coli biotin ligase (BirA) before use. ·GDP (Sigma Cat No G7127) ·AlphaLISA Glutathione Acceptor Beads(PerkinElmer, Cat No AL109) ·AlphaScreen Streptavidin Donor Beads(PerkinElmer Cat No 6760002) Assay Plates: Proxiplate-384 PLUS, white (PerkinElmer, Cat No 6008289).

[0375] Assay Buffer: 1×PBS 0.1% BSA 0.05% Tween 20

[0376] 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 prior to use and kept at room temperature.

[0377] Bead Mix: AlphaLISA Glutathione Acceptor Beads and AlphaScreen Streptavidin Donor Beads are mixed in assay buffer at a concentration of 10 μg / mL (final assay concentration) and kept at room temperature before use.

[0378] Assay Protocol: Compounds are diluted to a final starting concentration of 100 μM and tested in duplicate. Assay plates (ARP) are prepared using an Access Labcyte Workstation equipped with a Labcyte Echo 550 or 555 acoustic dispenser. For a starting compound concentration of 100 μM, 150 nL of compound solution is transferred to each well in duplicate at 11 concentrations using a serial 1:5 dilution.

[0379] The assay is performed using a fully automated robotic system in a dark room at less than 100 Lux. Add 10 μL of KRAS::SOS1 GDP mix to 150 nL of compound solution in columns 1-24 (final dilution in assay 1:100, final DMSO concentration 1%).

[0380] After an incubation period of 30 minutes, 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 in a PerkinElmer Envision HTS Multilabel Reader using the PerkinElmer AlphaScreen specifications. Each plate contains the following controls: Diluted DMSO + KRAS::SOS1 GDP mix + bead mix Diluted DMSO + KRAS::SOS1 GDP mix

[0381] Calculating the result: I C 50 Values ​​are calculated and analyzed using a four-parameter logistic model.

[0382] The table of exemplary compounds disclosed herein shows the IC 50 Contains a value.

[0383] Generation of Ba / F3 cell model and proliferation assay Ba / F3 cells were obtained from DSMZ (ACC300, Lot17) and grown in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10ng / mL IL-3 in a 5% CO2 atmosphere at 37°C. Plasmids containing KRASG12 mutants were obtained from GeneScript. To generate a KRASG12-dependent Ba / F3 model, Ba / F3 cells were transduced with retroviruses containing vectors carrying KRASG12 isoforms. Platinum-E cells (Cell Biolabs) were used for retrovirus packaging. Retroviruses were added to Ba / F3 cells. To ensure infection, 4μg / mL polybrene was added and cells were spinfected. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with infection efficiency of 10%-20% were further cultured and puromycin selection was initiated at 1μg / mL. As a control, parental Ba / F3 cells were used to indicate the selection status. Selection was considered successful when the parental Ba / F3 cell culture died. To evaluate the transforming potential of KRASG12 mutations, the growth medium was no longer 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.

[0384] For proliferation assays, Ba / F3 cells were plated in 384-well plates at 1 × 10 in growth medium. 3Cells were seeded at 1000 cells / 60 μL. Compounds were added using an Access Labcyte Workstation equipped with a Labcyte Echo 550 or 555 acoustic dispenser. All treatments were performed in technical duplicates. The assay is run using a fully automated robotic system. Treated cells were incubated for 72 hours at 37°C and 5% CO2. AlamarBlue™ (ThermoFisher), a viability stain, was added and fluorescence was measured on a PerkinElmer Envision HTS Multilabel Reader. Raw data was imported and analyzed into Boehringer Ingelheim proprietary software MegaLab (GraphPad Inc., which performs curve fitting based on the program PRISM).

[0385] The IC of the representative compound (I) according to the present invention measured in this assay 50 The values ​​are presented in Table 21.

[0386] [Table 14]

[0387] ERK phosphorylation assay The ERK phosphorylation assay is used to examine the efficacy of the compounds to inhibit KRAS G12C-mediated signaling in KRAS G12C mutant human cancer cell lines in vitro. This demonstrates the molecular mechanism of action of the compounds of the present invention by interfering with the RAS G12C protein signaling cascade. The low IC 50 The values ​​are indicative of the high potency of the compounds of the present invention. It was observed that the compounds of the present invention demonstrate an inhibitory effect on ERK phosphorylation in KRAS G12C mutant human cancer cell lines, thus proving the molecular mechanism of action of the compounds on RAS G12C protein signaling.

[0388] The ERK phosphorylation assay is performed using the following human cell lines: NCI-H358 (ATCC (ATCC CRL-5807): human lung cancer harboring a KRAS G12C mutation (→ Assay 1) and NCI-H358_Cas9_SOS2, the same cell line in which SOS2 was knocked out (→ Assay 2). Vectors containing DNA sequences designed for gRNA production for SOS2 protein knockout were obtained from Sigma-Aldrich. To generate NCI-H358 SOS2 knockout cell lines, 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 via Western blot and genomic DNA sequence analysis.

[0389] Materials used in the assay: RPMI-1640 medium (ATCC® 30-2001™) Fetal bovine serum (FBS), HyClone (SH30071.03) Non-essential amino acids, Thermo Fischer Scientific (11140035) Pyruvate, Thermo Fischer Scientific (11360039) Glutamax, Thermo Fischer Scientific (35050061) 384 plate, Greiner Bio-One (781182) Proxiplate™ 384, PerkinElmer Inc. (6008280) AlphaLISA SureFire Ultra p-ERK1 / 2(Thr202 / Tyr204) Assay Kit(ALSU-PERK-A500) EGF, manufactured by Sigma (E4127) Acceptor Mix: Protein A Acceptor Beads, PerkinElmer (6760137M) Donor Mix: AlphaScreen Streptavidin-coated Donor Beads, manufactured by PerkinElmer (6760002) Trametinib Staurosporine, Sigma Aldrich (S6942)

[0390] Assay Setup: Cells are seeded at 40,000 cells / well in 60 μL of RPMI containing 10% FBS, non-essential amino acids, pyruvate and glutamax in a Greiner TC 384 plate. Cells are incubated at room temperature for 1 hour, then incubated overnight in an incubator at 37° C. and 5% CO2 in a humidified atmosphere. Then, 60 nL of compound solution (10 mM DMSO stock solution) is added using a Labcyte Echo 550 device. After 1 hour of incubation in the aforementioned incubator, the medium is removed after centrifugation, and the cells are lysed by adding 20 μL of 1.6x lysis buffer from the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) Assay Kit, and protease inhibitors, 100 nM trametinib + 100 nM staurosporine, are added. After 20 min incubation with shaking at room temperature, 6 μL of each lysate sample is transferred to a 384-well Proxiplate and pERK(Thr202 / Tyr204) is analyzed with AlphaLISA SureFire Ultra pERK1 / 2(Thr202 / Tyr204) Assay Kit. 3 μL of Acceptor Mix and 3 μL of Donor Mix are added in dim light and incubated at room temperature in the dark for 2 h before measuring the signal with a PerkinElmer Envision HTS Multilabel Reader. Raw data were imported and analyzed into Boehringer Ingelheim proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0391] The IC of the representative compound (I) according to the present invention measured in this assay 50 Values ​​are presented in Table 22 (IC from Assay 2 50 To * (marked with , all others are from Assay 1).

[0392] [Table 15]

[0393] Additional proliferation assays using mutant cancer cell lines NCI-H358 CTG proliferation assay (120 hours) (NSCLC, G12C) NCI-H358 cells (ATCC No. CRL-5807) are dispensed into white bottom opaque 96-well plates (Perkin Elmer cat no. 5680) at a density of 2000 cells / well in 100 μL of RPMI-1640 ATCC-Formulation (Gibco # A10491) + 10% FCS (fetal calf serum). Cells are incubated overnight at 37°C in a humidified tissue culture incubator with 5% CO2. Compounds (10 mM stock in DMSO) are added in a log dose series using a HP Digital Dispenser D300 (Tecan) and normalized to added DMSO and a DMSO control is included. For TO time point measurements, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (defined as a percentage of control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC 50 Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0394] NCI-H2122 CTG proliferation assay (120 hours) (NSCLC, G12C) The CTG assay is designed to quantitatively measure the proliferation of NCI-H2122 cells (ATCC CRL-5985) using the CellTiter Glow Assay Kit (Promega G7571). Cells are grown in RPMI medium (ATCC) supplemented with fetal bovine serum (Life Technologies, Gibco BRL, Cat. No. 10270-106). On "day 0", 200 NCI-H2122 cells are seeded in 60 μL of RPMI ATCC+10% FCS+Penstrep in a black 384-well plate, flat clear bottom (Greiner, PNr. 781091). Cells are then incubated overnight in the plate at 37° C. in a CO2 incubator. On day 1, compounds (10 mM stock in DMSO) are added with an ECHO acoustic liquid handler system (Beckman Coulter) and a DMSO control is included. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (defined as percent of control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC 50 Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0395] IC of representative compounds of the present invention measured in these assays in the indicated cell lines. 50 value:

[0396] [Table 16]

[0397] Metabolic (microsomal) stability assay The metabolic degradation of test compounds is assayed at 37°C using pooled liver microsomes (mouse (MLM), rat (RLM) or human (HLM)). A final incubation volume of 48 μL per time point contains TRIS buffer (pH 7.5; 0.1 M), magnesium chloride (6.5 mM), microsomal protein (0.5 mg / mL for mouse / rat and 1 mg / mL for human samples) and a final concentration of 1 μM of test compound. Following a short preincubation period at 37°C, the reaction is initiated by adding 12 μL of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 10 mM) and terminated by transferring aliquots to solvent after various time points (0, 5, 15, 30, 60 min). Additionally, NADPH-independent degradation is monitored by incubation without NADPH and terminated by adding acetonitrile at the final time point. The quenched incubations are pelleted by centrifugation (4,000 rpm, 15 min.) and an aliquot of the supernatant is assayed by LC-MS / MS to quantitate the concentration of parent compound in each sample.

[0398] In vitro intrinsic clearance (CL int、インビトロ ) is calculated from the time course of disappearance of the test drug during microsomal incubation. Each plot is divided into two parts, C(t) = C0 * exp(-ke * t), where C(t) and C0 are the unchanged test drug concentrations at incubation time t and preincubation, and ke is the elimination rate constant for the unchanged drug. Then, CL int、インビトロ (μL min -1 The protein amount) value was calculated from the incubation parameters using the equation CL int、インビボ =CL int、インビトロ Predicted CL according to: × (incubation volume (ml) / protein amount (mg)) × (protein amount (mg) / liver tissue g) × (liver weight / body weight) int、インビボ (mL min -1 ·kg -1 )

[0399] For better interspecies comparison, predicted clearance was expressed as percent hepatic blood flow [% QH] (mL min -1 ·kg -1 ) Generally, high compound stability across species (corresponding to low % QH) is desirable.

[0400] Metabolic stability of selected compounds (I) according to the invention as assayed in the disclosed HLM:

[0401] [Table 17]

[0402] Mechanism-based CYP3A4 Inhibition Assay (MBI 3A4): Time-dependent inhibition of CYP3A4 is assayed in human liver microsomes (0.02 mg / mL) using midazolam (15 μM) as substrate. Test compounds and water controls (wells without test compound) are preincubated with human liver microsomes (0.2 mg / mL) in the presence of NADPH (1 mM) at a concentration of 25 uM for 0 and 30 min. After preincubation, the incubation is diluted 1:10 and the substrate midazolam is added to the main incubation (15 min). The main incubation is quenched with acetonitrile and the formation of hydroxy-midazolam is quantified via LC / MS-MS. The formation of hydroxy-midazolam from the 30 min preincubation versus the 0 min preincubation is used as readout. Values ​​less than 100% mean that the substrate midazolam is metabolized to a lower extent during the 30 min preincubation compared to the 0 min preincubation. In general, a low effect upon 30 min preincubation is desirable (corresponding to values ​​close to 100% / no difference from values ​​determined with the water control).

[0403] Data obtained in the disclosed assays for a selection of compounds (I) according to the invention:

[0404] [Table 18]

[0405] Solubility measurement (DMSO solution precipitation method) A 10 mM DMSO stock solution of the test compound is used to determine its aqueous solubility. The DMSO solution is diluted in aqueous medium (McIlvaine buffer, pH=4.5 or 6.8) to a final concentration of 250 μM. After shaking for 24 hours at ambient temperature, any precipitate that may have formed is removed by filtration. The concentration of the test compound in the filtrate is determined by LC-UV method by calibrating the signal against that of a reference solution using complete dissolution of the test compound in acetonitrile / water (1:1) of known concentration.

[0406] Data obtained in the disclosed assays for a selection of compounds (I) according to the invention:

[0407] [Table 19]

[0408] Caco-2 assay This assay provides information on the ability of compounds to cross cell membranes, the extent of oral absorption, and whether compounds are actively transported by uptake and / or efflux transporters. It uses permeability measurements across polarized confluent Caco-2 cell monolayers grown on permeable filter supports (Corning, catalog #3391). A 10 μM solution of test compound in assay buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4, 0.41 mM NaH2PO4, 15 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), 20 mM glucose, pH 7.4) is added to the donor compartment of a cell chamber containing a monolayer of Caco-2 cells between the donor and receiver compartments. The receiver and donor compartments contain 0.25% bovine serum albumin (BSA) in assay buffer. Passive diffusion and / or active transport of compounds across the monolayer are measured in both apical to basolateral (ab) and basolateral to apical (ba) directions. Ab permeability (PappAB) represents drug absorption from the intestine to the blood via both passive permeation and active transport mechanisms mediated by efflux and uptake transporters expressed on Caco-2 cells, whereas ba permeability (PappBA) represents drug secretion from the blood back to the intestine. After preincubation at 37°C for 25-30 min, samples were taken from the receiver and donor compartments, respectively, at predefined time points (0, 30, 60 and 90 min). The concentration of the test compound in the samples was measured by HPLC / MS / MS, with samples from the donor compartment diluted 1:50 (v:v) in assay buffer and samples from the receiver compartment measured undiluted.

[0409] The apparent permeability in the two directions ab (PappAB) and ba (PappBA) is calculated according to the following formula:

number

[0410] The Caco-2 efflux ratio (ER) is calculated as the ratio of PappBA / PappAB.

[0411] Data obtained in the disclosed assays for a selection of compounds (I) according to the invention:

[0412] [Table 20]

[0413] The following formulation examples are illustrative of the present invention but are not intended to limit its scope:

[0414] Examples of pharmaceutical prescriptions A) Per tablet 100 mg of active substance according to formula (I) Lactose 140mg Corn starch 240mg Polyvinylpyrrolidone 15mg Magnesium stearate 5mg 500mg

[0415] The finely ground active substance, lactose and some of the corn starch are mixed. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and magnesium stearate are screened and mixed. The mixture is compressed to produce tablets of suitable shape and size.

[0416] B) Per tablet 80 mg of active substance according to formula (I) Lactose 55mg Corn starch 190mg Microcrystalline cellulose 35mg Polyvinylpyrrolidone 15mg Sodium carboxymethyl starch 23mg Magnesium stearate 2mg 400mg

[0417] The finely ground active substance, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is sieved, the remaining corn starch and water are treated to produce granules, which are dried and sieved, sodium carboxymethyl starch and magnesium stearate are added, mixed and the mixture is compressed to produce tablets of suitable size.

[0418] C) Per tablet 25 mg of active substance according to formula (I) Lactose 50mg Microcrystalline cellulose 24mg Magnesium stearate 1mg 100mg

[0419] The active substance, lactose and cellulose are mixed. The mixture is screened, then moistened with water, kneaded, wet granulated, dried or dry granulated, or final blended directly with magnesium stearate and compressed to tablets of suitable shape and size. If wet granulated, additional lactose or cellulose and magnesium stearate are added and the mixture is compressed to produce tablets of suitable shape and size.

[0420] D) Ampoules Liquid 50 mg of active substance according to formula (I) Sodium chloride 50mg Water for injection 5mL

[0421] The active substance is dissolved in water at its own pH or optionally at pH 5.5-6.5, and sodium chloride is added to make it isotonic. The resulting solution is filtered to make it pyrogen-free, and the filtrate is transferred under aseptic conditions into ampoules, which are then sterilized and melt-sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R １ａ and R １ｂ are each independently 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 selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; R ２ａ and R ２ｂ are each independently 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 selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; and / or optionally R １ａ or R １ｂ One of the two and R ２ａ or R ２ｂ together with the carbon atom to which they are attached form a cyclopropane ring; Z is -(CR ６ａ R ６ｂ ) ｎ - and; Each R ６ａ and R ６ｂ are independently 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 selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; Or, R ６ａ and R ６ｂ together with the carbon atoms to which they are attached form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; -L- is a bond or is one of -O-, -S- and -N(R １３ )-(wherein, R １３ is hydrogen or C １－６ alkyl); R ３ is substituted with E, and -L- is -O-, -S- and -N(R １３ )-, R ３ is C １－６ Alkyl, C １－６ selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 3- to 11-membered heterocyclyl, wherein C １－６ Alkyl, 5-10 membered heteroaryl, C １－６ All alkoxy and 3- to 11-membered heterocyclyl are optionally and independently selected from halogen, C １－６ Alkyl, —OH, —NH ２ , —NH(C １－４ alkyl), -N(C １－４ alkyl) ２ , C ３－５ substituted with one or more identical or different substituents selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; When -L- is a bond, R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ All aryls and 5- to 10-membered heteroaryls may optionally and independently be one or more of the same or different R ７ and / or R ８ is replaced by Each R ７ are independently halogen, —CN, —OH, C １－６ Alkoxy, —NR ８ R ８ , -C(=O)R ８ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , -NHC(=O)OR ８ and the divalent substituent =O; Each R ８ are independently hydrogen, C １－６ Alkyl, C ３－１０ selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 11-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl may all be substituted with one or more of the same or different R ９ and / or R １０ optionally substituted with; Each R ９ are independently -OR １０ and Each R １０ are independently hydrogen, C １－６ selected from the group consisting of alkyl, 3- to 11-membered heterocyclyl, and 5- to 10-membered heteroaryl; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R １１ ) = and R １１ is hydrogen, halogen and C １－４ alkoxy; Ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole, and triazole; Each R ４ is, if present, independently 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; p is selected from the group consisting of 0, 1, 2 and 3; R ５ represents one or more identical or different C １－６ Alkyl, C １－６ 3- to 11-membered heterocyclyl optionally substituted with alkoxy or 5- to 6-membered heterocyclyl, wherein C １－６ alkyl is optionally substituted with cyclopropyl; Or, R ５ is —O—C substituted with 3- to 11-membered heterocyclyl １－６ alkyl, wherein the 3- to 11-membered heterocyclyl is one or more of the same or different R １２ optionally substituted with; Each R １２ is C １－６ Alkyl, C １－６ selected from the group consisting of alkoxy, halogen, and 3- to 11-membered heterocyclyl; 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 )-selected from the group consisting of; Each R Ｇ１ are independently 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 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; Each R Ｈ１ are independently hydrogen, —OH, C １－６ Alkoxy, -CN and C １－６ 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, as well as 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 C optionally substituted with one or more identical or different substituents selected from the group consisting of alkoxy １－６ selected from the group consisting of alkyl; R Ｅ and R Ｆ are each independently R ａ２ and R ｂ２ selected from the group consisting of: R ａ２ is hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ All aryls and 5- to 10-membered heteroaryls may contain one or more of the same or different R ｂ２ and / or R ｃ２ optionally substituted with; Each R ｂ２ are independently -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; Each R ｃ２ are independently hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ４－１０ Cycloalkenyl, 3- to 11-membered heterocyclyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ４－１０ Cycloalkenyl, 3- to 11-membered heterocyclyl, C ６－１０ All 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 alicycle or a 4- to 7-membered unsaturated heterocycle, wherein the 4- to 7-membered unsaturated alicycle or the 4- to 7-membered unsaturated heterocycle is optionally 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 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 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 are not present together; 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 aryl and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ All aryls and 5- to 10-membered heteroaryls may contain one or more of the same or different R ｂ２ and / or R ｃ２ optionally substituted with; Each R ｂ２ are independently -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; Each R ｃ２ are independently 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 5-10 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 )-selected from the group consisting of; Each R Ｇ２ are independently 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 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; Each R Ｈ２ are independently hydrogen, —OH, C １－６ Alkoxy, -CN and C １－６ 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 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 )-selected from the group consisting of; Each R Ｇ３ are independently 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 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocyclyl; Each R Ｈ３ are independently hydrogen, —OH, C １－６ Alkoxy, -CN and C １－６ selected from the group consisting of alkyl; R Ｍ represents halogen, —CN and —O—C(═O)—C １－６ 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 selected from the group consisting of 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; Each R Ｎ are independently １－４ Alkyl, C １－４ Haloalkyl, vinyl, ethynyl, halogen, -CN, nitro and C １－４ alkoxy] A compound represented by the formula: or a salt thereof.

2. A compound represented by formula (Ia) or a salt thereof: 【Chemistry 9】 [In the formula, A, V, U, W, L, R ３ and R ５ is defined as in claim 1]

3. A compound represented by formula (Ib) or a salt thereof: 【Chemistry 10】 [In the formula, A, V, U, W, L, R ３ and R ５ is defined as in claim 1]

4. Ring A is 【Chemistry 11】 The compound or salt according to any one of claims 1 to 3, selected from:

5. R ５ but, 【Chemistry 12】 The compound or salt according to any one of claims 1 to 3, selected from the group consisting of:

6. R ５ but, 【Chemistry 13】 6. The compound or salt of claim 5, selected from the group consisting of:

7. W is nitrogen (-N=); V is nitrogen (-N=); U is =C(R １１ )- and; R １１ is hydrogen, halogen and C １－４ The compound or salt according to any one of claims 1 to 3, wherein the alkoxy is selected from the group consisting of alkoxy, ...

8. R ３ is substituted with E; -L- is a bond; R ３ is 3- to 11-membered heterocyclyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein 3- to 11-membered heterocyclyl, C ６－１０ The aryl and 5- to 10-membered heteroaryl may all optionally and independently be one or more of the same or different R ７ and / or R ８ is replaced by Each R ７ are independently selected from halogen, —CN, —OH, C １－６ Alkoxy, —NR ８ R ８ , -C(=O)R ８ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , -NHC(=O)OR ８ and the divalent substituent =O; Each R ８ are independently hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ All aryl and 5- to 10-membered heteroaryl may have one or more identical or different R ９ and / or R １０ and optionally substituted with Each R ９ But independently, -OR １０ selected from the group consisting of: Each R １０ are independently hydrogen, C １－６ Alkyl, C ３－１０ The compound or salt of any one of claims 1 to 3, wherein the compound or salt is selected from the group consisting of cycloalkyl, 3- to 11-membered heterocyclyl, and 5- to 10-membered heteroaryl.

9. R ３ is substituted with E; -L- is a bond; R ３ but, 【Chemistry 14】 【change】 selected from the group consisting of Each of these groups is attached to formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) at any ring position by removal of a hydrogen atom, and optionally and independently, one or more of the same or different R ７ and / or R ８ where: Each R ７ are independently -halogen, -CN, -OH, C １－６ Alkoxy, —NR ８ R ８ , -C(=O)R ８ , -C(=O)OR ８ , —C(═O)NR ８ R ８ , -NHC(=O)OR ８ and the divalent substituent =O; Each R ８ are independently hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 11-membered heterocyclyl, C ６－１０ All aryl and 5- to 10-membered heteroaryl may have one or more identical or different R ９ and / or R １０ optionally substituted with; Each R ９ is —OH or C １－６ is alkoxy; Each R １０ But independently, C １－６ The compound or salt of any one of claims 1 to 3, wherein the heteroaryl is selected from the group consisting of alkyl, 3- to 11-membered heterocyclyl, and 5- to 10-membered heteroaryl.

10. -L- is a bond; R ３ but, 【Chemistry 15】 The compound or salt according to any one of claims 1 to 3,

11. E, 【Chemistry 16】 and 【Chemistry 17】 represents a double bond; Q １ is —C(═O)—; R Ｄ But hydrogen, halogen, C １－６ selected from the group consisting of alkoxy; R Ｅ and R Ｆ are each independently R ａ２ and R ｂ２ selected from the group consisting of: R ａ２ But hydrogen, C １－６ Alkyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, wherein C １－６ Alkyl, C ６－１０ All aryl and 5- to 10-membered heteroaryl may have one or more identical or different R ｂ２ and / or R ｃ２ optionally substituted with; Each R ｂ２ But independently, -OR ｃ２ or a halogen; Each R ｃ２ are independently hydrogen, C １－６ alkyl, and 5- to 10-membered heteroaryl, wherein C １－６ The compound or salt of any one of claims 1 to 3, wherein the alkyl and the 5- to 10-membered heteroaryl are all optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen or -OH. 【Request Item 12】 【Chemistry 18】 【change】 【change】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

13. A pharmaceutical composition comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition of claim 13 for use in the treatment and / or prevention of cancer.

15. A pharmaceutical composition for use according to claim 14, wherein the compound or salt is administered in combination with one or more other pharmacologically active substances.

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