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

Abstract

The present invention relates to a compound represented by formula (V), 1a , R 1b , R 2a , R 2b , Z, R 4 , R 5 , R 14 , A, p, X, U, V and W have the meanings indicated in the claims and the specification), their use as inhibitors of KRAS, pharmaceutical compositions and formulations containing such compounds, and their medicinal / medical uses, in particular their use as agents for the treatment and / or prevention of neoplastic diseases. TIFF2024543975000189.tif43161

Description

[Technical field]

[0001] The present invention relates to a compound of formula (V): [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , R 5 , R 14 , A, p, X, U, V and W have the meanings as defined in the claims and the specification), their use as inhibitors of KRAS, pharmaceutical compositions and formulations containing such compounds and their medicinal / medical uses, in particular their use as agents for the treatment and / or prevention of oncological diseases, such as cancer. [Background technology]

[0002] V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small GTPase of the Ras family of proteins that exists in cells in either a GTP-bound or GDP-bound state (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Nimnual et al., Sci. STKE., 2002, 2002(145):pe36). 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 Sevenless1) 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 associate with 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 increased 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 variety of human cancers, including lung, colorectal, and pancreatic cancer (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Alterations in Ras family proteins / Ras genes (e.g., mutations, overexpression, gene amplification) have also been described as a resistance mechanism to anticancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 Jul;92(7):709-22) and the EGFR tyrosine kinase inhibitor osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 7 5(12):2489-500).

[0004] In a subset of oncology indications, such as gastric, gastroesophageal and esophageal cancer, significant amplification of the wild-type (WT) KRAS proto-oncogene acts as a driver alteration, rendering tumor models with this genotype addicted to KRAS in vitro and in vivo (Wong et al. Nat Med., 2018, 24(7):968-977). In contrast, non-amplified KRAS WT cell lines are KRAS independent unless they have a secondary genetic alteration that indirectly causes KRAS activation (Meyers et al., Nat Genet., 2017, 49:1779-1784). Based on these data, a therapeutic window is predicted for KRAS targeting agents with KRAS WT targeting activity.

[0005] For example, genetic alterations affecting codon 12 of KRAS replace the naturally occurring glycine residue at this position with various amino acids, including aspartic acid (G12D mutation or KRAS G12D), cysteine ​​(G12C mutation or KRAS G12C), valine (G12V mutation or KRAS G12V), among others. Similarly, mutations within codons 13, 61, and 146 of KRAS are commonly found in the KRAS gene. Overall, KRAS mutations are detectable in 35% of lung cancers, 45% of colorectal cancers, and up to 90% of pancreatic cancers (Herdeis et al., Curr Opin Struct Biol., 2021, 71:136-147).

[0006] In summary, binders / inhibitors of wild-type or mutant KRAS (eg, G12D, G12V and G12C) are expected to provide anti-cancer effects.

[0007] Thus, there is a need to develop new compounds that are effective in treating cancers mediated by KRAS, particularly KRAS mutated at positions 12 or 13, and / or wild-type amplified KRAS mediated cancers, and that also have desirable pharmacological properties (including, but not limited to, metabolic stability, plasma protein binding, solubility and permeability). Summary of the Invention

[0008] Now, surprisingly, a compound of formula (V): [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , R 5 , R 14 It has been found that compounds of the formula (wherein A, p, X, U, V and W have the meanings given below) act as inhibitors of KRAS and are involved in the control of cell proliferation. Thus, the compounds according to the invention can be used, for example, in the treatment of diseases characterized by excessive or abnormal cell proliferation.

[0009] Surprisingly, it has been found that the compounds described herein have antitumor activity and are useful for inhibiting uncontrolled cell proliferation resulting from malignant diseases.This antitumor activity is believed to result from, inter alia, the inhibition of KRAS mutated at position 12 or 13, preferably G12D, G12V or G13D mutant KRAS, or the inhibition of WT KRAS, particularly KRAS WT amplification.Advantageously, the compounds may be selective for a particular KRAS mutant, preferably KRAS G12D, or may be effective against a panel of KRAS mutants, including amplified KRAS wild type.

[0010] Moreover, compounds of the present invention advantageously possess desirable pharmacological properties, including, but not limited to, metabolic stability, plasma protein binding, solubility and permeability.

[0011] Thus, in a first aspect, the present invention provides a compound of formula (V): [ka] (In the formula, R 1a and R 1b are each independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C1~4 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- 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, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 3~5 and / or selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; 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- 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; X is =C(R 15 )-or-N(R 15)-and R 14 and R 15 together with the atoms to which they are attached, C 5~7 cycloalkyl or 5-7 membered heterocyclyl containing oxygen or sulfur, 5~7 Cycloalkyl and 5- to 7-membered heterocyclyl may optionally have one or more identical or different R 3a and / or R 3b is replaced by R 3a and R 3b are each independently 1~4 Alkyl, C 1~4 selected from the group consisting of haloalkyl and halogen; W is -N= or -CH=; V is -N= or -CH=; U is -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, oxazole, isoxazole, thiazole, isothiazole, and triazole; Each R 4 If present, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, Cyano-C 1~6 Alkyl, halogen, -OH, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, -CN, C 3~5 selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; p is selected from the group consisting of 0, 1, 2 and 3; R 5 is a halogen or, optionally, one or more of the same or different C 1~6 Alkyl, C 1~6 Alkoxy, -C(O)-OC 1~63- to 11-membered heterocyclyl substituted with alkyl or 5- to 6-membered heterocyclyl, where C 1~6 The alkyl is optionally substituted with cyclopropyl or -OH, or R 5 is -OC substituted with 3-11 membered heterocyclyl 1~6 alkyl, where the 3- to 11-membered heterocyclyl is optionally represented by one or more of the same or different R 12 is replaced by Each R 12 is C 1~6 Alkyl, C 1~6 Alkoxy, -C(O)-OC 1~6 selected from the group consisting of alkyl, halogen and 3- to 11-membered heterocyclyl or a salt thereof.

[0012] In another aspect, the present invention relates to a compound of formula (V'): [ka] (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, -NH2, -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, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 3~5and / or selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl; 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- to 5-membered heterocyclyl; or R 6a or 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; X is =C(R 15 )-or-N(R 15 )-and R 14 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy and C 1~6 thioalkoxy; R 14 and R 15 together with the atoms to which they are attached, C 5~7 cycloalkyl or 5-7 membered heterocyclyl containing oxygen or sulfur, 5~7 Cycloalkyl and 5- to 7-membered heterocyclyl may optionally have one or more identical or different R 3a and / or R 3bis replaced by R 3a and R 3b are each independently 1~4 Alkyl, C 1~4 selected from the group consisting of haloalkyl and halogen; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R 11 )= Each 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(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 optionally one or more identical or different C 1~6 Alkyl, C 1~6 3- to 11-membered heterocyclyl substituted with alkoxy or 5- to 6-membered heterocyclyl, where C 1~6 The alkyl is optionally substituted with cyclopropyl, or R 5 is -OC substituted with 3-11 membered heterocyclyl 1~6 alkyl, where the 3- to 11-membered heterocyclyl is optionally represented by one or more of the same or different R 12 is replaced by Each R 12 is C1~6 Alkyl, C 1~6 selected from the group consisting of alkoxy, halogen and 3- to 11-membered heterocyclyl or a salt thereof.

[0013] It is to be understood that the following embodiments and aspects are applicable to formula (V) and formula (V') unless otherwise stated.

[0014] In another aspect, the present invention provides a compound of formula (I): [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 5 , A, p, U, V and W have the meanings given herein. The present invention relates to a compound of the formula:

[0015] 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 the present invention, wherein the compound is selected from the group consisting of alkyl, or a salt thereof.

[0016] In another aspect, the present invention provides a compound comprising R 2a and R 2b are each independently selected from the group consisting of hydrogen and halogen, or a salt thereof.

[0017] In another aspect, the present invention provides a compound comprising R 1a and R 1b are each independently selected from the group consisting of hydrogen and methyl, or a salt thereof.

[0018] In another aspect, the present invention provides a compound comprising R 2a and R 2b are each independently selected from the group consisting of hydrogen and fluorine, or a salt thereof.

[0019] 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.

[0020] In another aspect, the present invention relates to a compound in which Z is -(CR 6a R 6b ) n - and n is 0; or a salt thereof.

[0021] In another aspect, the present invention relates to a compound in which Z is -(CR 6a R 6b ) n where n is 1 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 The present invention relates to a compound of the formula (V), (V') or (I), or a salt thereof, wherein R is selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl.

[0022] In another aspect, the present invention relates to a compound of the present invention, or a salt thereof, wherein Z is -CH2-.

[0023] In another aspect, the present invention provides a compound comprising R 1a , R 1b , R 2a and R 2b is hydrogen and Z is -CH2-, or a salt thereof.

[0024] In another aspect, the present invention relates to a compound in which Z is -(CR 6a R 6b ) n where n is 2 and each R6a 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 of the present invention, or a salt thereof, which is selected from the group consisting of cycloalkyl and 3- to 5-membered heterocyclyl.

[0025] In another aspect, the present invention provides a compound according to the present invention, wherein X is ═C(R 15 )- and R 14 But, C 2~4 Alkyl, C 2~4 Alkoxy and C 2~4 or R is selected from the group consisting of thioalkoxy; 14 and R 15 together with the atoms to which they are bonded, C 5~7 cycloalkyl or 5-7 membered heterocyclyl containing oxygen or sulfur, 5~7 Cycloalkyl and 5- to 7-membered heterocyclyl may optionally have one or more identical or different R 3a and / or R 3b is replaced by R 3a and R 3b are each independently 1~4 Alkyl, C 1~4 The present invention relates to a compound of the present invention, wherein the compound is selected from the group consisting of haloalkyl and halogen, or a salt thereof.

[0026] In another embodiment, the present invention relates to a compound of the present invention, or a salt thereof, wherein p is 0.

[0027] In another embodiment, the present invention relates to a compound of the present invention, or a salt thereof, wherein p is 1.

[0028] In another aspect, the present invention provides a compound according to the present invention, wherein p is 1 and R 4 C 1~6 The present invention relates to a compound, or a salt thereof, in which R is an alkyl group.

[0029] In another aspect, the present invention provides a compound according to the present invention, wherein p is 1 and R 4 is methyl, or a salt thereof.

[0030] In another aspect, the present invention provides a compound of formula (Ia): [ka] (Wherein, A, V, U, W and R 5 is defined herein) or a salt thereof.

[0031] In another aspect, the present invention relates to a compound of formula (Ib): [ka] (Wherein, A, V, U, W and R 5 is defined herein) or a salt thereof.

[0032] In another embodiment, the present invention relates to the compound of the present invention, or a salt thereof, wherein ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole and triazole.

[0033] In another aspect, the present invention relates to a compound wherein ring A is: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0034] In another aspect, the present invention relates to a compound wherein ring A is: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the following:

[0035] In another aspect, the present invention relates to a compound wherein ring A is: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the following:

[0036] In another aspect, the present invention provides a compound wherein ring A is of the formula: [ka] The present invention relates to a compound of the present invention, or a salt thereof,

[0037] In another aspect, the present invention provides a compound of formula (Ic): [ka] (Wherein, V, U, W and R 5 is as defined herein) or a salt thereof.

[0038] In another aspect, the present invention provides a compound of formula (Id): [ka] (Wherein, V, U, W and R 5 is as defined herein) or a salt thereof.

[0039] In another aspect, the present invention provides a compound of formula (IIa): [ka] (Wherein, V, U, W and R 5 is as defined herein) or a salt thereof.

[0040] In another aspect, the present invention relates to a compound of formula (IIb): [ka] (Wherein, V, U, W and R 5 is as defined herein) or a salt thereof.

[0041] In another aspect, the present invention provides a compound of formula (IV): [ka] (Wherein, V, U, W and R 5 is as defined herein) or a salt thereof.

[0042] In another aspect, the present invention provides a compound of formula (IIc): [ka] (Wherein, V, U, W and R 5 is as defined herein) or a salt thereof.

[0043] In another aspect, the present invention relates to a compound of formula (IId): [ka] (Wherein, V, U, W and R 5 is as defined herein) or a salt thereof.

[0044] In another aspect, the present invention relates to a compound of formula (IIe): [ka] (Wherein, V, U, W and R 5 is as defined herein, and R 3a and R 3bare the same or different, halogen or C 1~4 alkyl) or a salt thereof.

[0045] In another aspect, the present invention provides a compound of formula (III): [ka] (Wherein, V, U, W and R 5 is as defined herein, and R 4 is hydrogen or C 1~4 (It is alkyl) or a salt thereof.

[0046] In another embodiment, the present invention relates to a compound of the present invention, or a salt thereof, wherein at least one of W, V and U is nitrogen.

[0047] In another aspect, the present invention provides a compound wherein W is nitrogen (-N=), V is nitrogen (-N=) and U is ═C(R 11 )- and R 11 However, hydrogen, halogens and C 1~4 alkoxy, or a salt thereof.

[0048] In another aspect, the present invention provides a compound wherein W is -CH=, V is nitrogen (-N=) and U is ═C(R 11 )- and R 11 However, hydrogen, halogens and C 1~4 alkoxy, or a salt thereof.

[0049] In another aspect, the present invention provides a compound according to the present invention, wherein V is -CH=, W is nitrogen (-N=) and U is ═C(R 11 )- and R 11 However, hydrogen, halogens and C 1~4 alkoxy, or a salt thereof.

[0050] In another aspect, the present invention provides a compound comprising R 11is selected from hydrogen, -F, -Cl and -O-CH3, or a salt thereof.

[0051] In another embodiment, the present invention relates to a compound of the present invention, wherein V is nitrogen (-N=), W is -CH= and U is nitrogen (-N=), or a salt thereof.

[0052] In another embodiment, the present invention relates to a compound of the present invention, wherein W is nitrogen (-N=), V is -CH= and U is nitrogen (-N=), or a salt thereof.

[0053] In another embodiment, the present invention relates to a compound of the present invention, or a salt thereof, wherein W is CH=, V is -CH=, and U is nitrogen (-N=).

[0054] In another embodiment, the present invention relates to a compound of the present invention, wherein W is nitrogen (-N=), V is nitrogen (-N=) and U is nitrogen (-N=), or a salt thereof.

[0055] In another aspect, the present invention provides a method for producing a composition comprising: R 5 optionally one or more identical or different C 1~6 Alkyl, C 1~6 3- to 11-membered heterocyclyl substituted with alkoxy or 5- to 6-membered heterocyclyl; 1~6 The 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 optionally represented by one or more of the same or different R 12 is replaced by Each R 12 But, C 1~6 Alkyl, C 1~6 selected from the group consisting of alkoxy, halogen and 3- to 11-membered heterocyclyl; The present invention relates to a compound or a salt thereof. In another aspect, the present invention provides a compound comprising R 5is chlorine, or a salt thereof.

[0056] In another aspect, the present invention provides a compound comprising R 5 is halogen or optionally one or more of the same or different C 1~6 Alkyl, C 1~6 Alkoxy, -C(O)-OC 1~6 6- to 11-membered heterocyclyl substituted with alkyl or 5- to 6-membered heterocyclyl; C 1~6 The present invention relates to a compound of the present invention, or a salt thereof, wherein alkyl is optionally substituted with cyclopropyl or -OH.

[0057] In another aspect, the present invention provides a compound comprising R 5 optionally one or more identical or different C 1~6 Alkyl, C 1~6 6- to 11-membered heterocyclyl substituted with alkoxy or 5- to 6-membered heterocyclyl; 1~6 The present invention relates to a compound of the present invention, or a salt thereof, wherein alkyl is optionally substituted with cyclopropyl.

[0058] In another aspect, the present invention provides a compound comprising R 5 optionally one or more independently selected C 1~4 The present invention relates to a compound of the present invention, wherein the compound is selected from the group consisting of 6-membered nitrogen-containing heterocyclyl substituted with alkyl, or a salt thereof.

[0059] In another aspect, the present invention provides a compound comprising R 5 optionally one or more independently selected C 1~4 7-membered heterocyclyl substituted with alkyl, or a salt thereof.

[0060] In another aspect, the present invention provides a compound comprising R 5 -OC substituted with 5-9 membered heterocyclyl 1~6 alkyl, and the 5- to 9-membered heterocyclyl is optionally represented by one or more of the same or different R 12 Each R 12 But, C1~6 Alkyl, C 1~6 Alkoxy, -C(O)-OC 1~6 The present invention relates to a compound of the present invention, wherein the aryl group is selected from the group consisting of alkyl, halogen and 5-membered heterocyclyl, or a salt thereof.

[0061] In another aspect, the present invention provides a method for producing a composition comprising: R 5 -OC substituted with 5-9 membered heterocyclyl 1~6 alkyl, and the 5- to 9-membered heterocyclyl is optionally represented by one or more of the same or different R 12 is replaced by Each R 12 But, C 1~6 Alkyl, C 1~6 selected from the group consisting of alkoxy, halogen and 5-membered heterocyclyl; The present invention relates to a compound or a salt thereof.

[0062] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0063] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0064] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0065] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0066] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0067] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0068] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof, selected from the group consisting of:

[0069] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof,

[0070] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof,

[0071] In another aspect, the present invention provides a compound comprising R 5 But the following: [ka] The present invention relates to a compound of the present invention, or a salt thereof,

[0072] In another aspect, the present invention provides a compound wherein W is nitrogen (-N=), V is -CH=, U is nitrogen (-N=), and R 5 optionally one or more independently selected C 1~4 The present invention relates to a compound of the present invention, wherein the compound is selected from the group consisting of 6-membered nitrogen-containing heterocyclyl substituted with alkyl, or a salt thereof.

[0073] Preferred embodiments of the present invention are exemplary compounds Ia-1, IIa-1, Ib-1, Ib-2, Ib-3, IIb-1, IIb-2, Ib-4, IIb-3, IIb-4, IIb-5, IIb-6, IIb-7, IIIa-1, IIIb-1, Id-1, Id-2, IId-1, Ie-1, Ie-2, IIe-1, Ie-3, Ie-4, Ie-5, If-1, IIf-1, If-2, Ig-1, Ig-2, Ig-4, IIg-1, Ih-1, IVa-1, and any subset thereof.

[0074] It is to be understood that any two or more aspects and / or preferred embodiments of Formulas (V), (V'), (I), (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IV), (IIc), (IId), (IIe) and (III) - or subformulas thereof - may be combined in any manner that results in a chemically stable structure to obtain further aspects and / or preferred embodiments of Formulas (V), (V'), (I), (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IV), (IIc), (IId), (IIe) and (III) - or subformulas thereof.

[0075] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of the compounds of the present invention, including all embodiments thereof.

[0076] The present invention further relates to hydrates of the compounds of the present invention, including all embodiments thereof.

[0077] The present invention further relates to solvates of the compounds of the present invention, including all embodiments thereof.

[0078] For example, compounds of the present invention (including all embodiments thereof) having an ester group may be prodrugs in which the ester is cleaved under physiological conditions and are also part of the present invention.

[0079] The present invention further relates to pharma- ceutically acceptable salts of the compounds of the present invention, including all embodiments thereof.

[0080] The present invention further relates to pharma- ceutically acceptable salts of the compounds of the present invention (including all embodiments thereof) with an inorganic or organic acid or base.

[0081] Pharmaceutical Compositions A further object of the invention is a pharmaceutical composition comprising a compound of the invention or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0082] 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.

[0083] Suitable pharmaceutical compositions for administering the compounds according to the invention are clear to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, suspensions (especially solutions, suspensions or other mixtures (injectables) for injection (subcutaneous, intravenous, intramuscular) and infusion), elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. The content of the compound of the present invention 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 range specified below. The specified dose may be given several times a day, if necessary.

[0084] Suitable tablets can be obtained, for example, by mixing the compounds of the present invention with known pharma- ceutically acceptable excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. Tablets can also include several layers.

[0085] Coated tablets can be conveniently prepared by coating a core prepared similarly to tablets with excipients commonly used for tablet coating, such as Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar. The core can consist of multiple layers to achieve delayed release or to prevent incompatibility. Similarly, tablet coatings can consist of multiple layers to achieve delayed release, optionally using the excipients mentioned above for tablets.

[0086] Syrups or elixirs containing one or more compounds of the invention or a combination with one or more other pharma- ceutically active substances may further contain excipients such as sweeteners, such as saccharin, cyclamate, glycerol or sugar, and flavour enhancers, e.g. flavourings, e.g. vanillin or orange extract, etc. They may also contain excipients such as suspension aids or thickeners, e.g. sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with ethylene oxide, or preservatives, e.g. p-hydroxybenzoates.

[0087] 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, optionally using emulsifiers and / or dispersants, but where water is used as diluent, for example, optionally using organic solvents as solvating or solubilizing agents, and may be transferred into injection vials or ampoules or infusion bottles.

[0088] Capsules containing one or more compounds of the present invention or a combination with one or more other pharma- ceutical active agents can be prepared, for example, by mixing the compounds / active agents with inert excipients such as lactose or sorbitol and filling them into gelatin capsules.

[0089] Suitable suppositories can be prepared by mixing with excipients provided for this purpose, such as, for example, neutral fats or polyethylene glycol or derivatives thereof.

[0090] Excipients that may be used include, for example, water, pharma- ceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., cane sugar, lactose and glucose), emulsifiers (e.g., lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0091] The pharmaceutical composition is administered by conventional methods, preferably by oral or transdermal route, most preferably by oral route.For oral administration, tablets may of course contain, apart from the above-mentioned excipients, various excipients, such as starch, preferably potato starch, gelatin, etc., as well as further excipients, such as sodium citrate, calcium carbonate and dicalcium phosphate.Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously in the tableting process.In the case of aqueous suspension, the active substance may be combined with various flavor enhancers or colorants in addition to the above-mentioned excipients.

[0092] For parenteral use, solutions of the active substances with suitable liquid excipients can be used.

[0093] The applicable daily dose range of the compound of the present invention is usually 1 mg to 2000 mg, preferably 250 to 1250 mg.

[0094] However, it may be necessary to deviate from the amounts specified, 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 more doses per day).Thus, in some cases it may be sufficient to use less 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 them into a number of smaller doses and distribute them over the day.

[0095] Therefore, in a further aspect, the present invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of the invention or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0096] The compounds of the invention, 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).

[0097] The elements of such combinations may be administered by methods conventional to those of skill in the art, and as 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 (dependently or independently), and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.

[0098] The combination may be administered in a single or divided therapeutically effective daily dose. The active ingredients of the combination may be administered in doses that are therapeutically effective in monotherapy or in doses that are lower than those used in monotherapy but which, when combined, provide the desired (combined) therapeutically effective amount.

[0099] However, when the combination of two or more active substances or principles produces a synergistic effect, it may be possible to reduce the amount of one, more or all of the substances administered while still achieving the desired therapeutic effect. This may be useful, for example, to avoid, limit or reduce any undesirable side effects associated with the use of one or more of the substances (when they are used in their usual amounts) while still obtaining the desired pharmacological or therapeutic effect.

[0100] Therefore, in a further aspect, the present invention also relates to a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0101] In a further aspect, the present invention also relates to a pharmaceutical formulation comprising a compound of the invention or a pharma- ceutically acceptable salt thereof and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0102] The pharmaceutical compositions for simultaneous administration or use in combination can also be provided in the form of a kit.

[0103] 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 the invention 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:

[0104] In one embodiment, such a kit comprises a third pharmaceutical composition or dosage form comprising an additional pharmacologically active substance and, optionally, one or more pharma- ceutically acceptable excipients.

[0105] Medical Use - Treatment Method Indications – Patient Population The present invention relates to compounds which inhibit KRAS, preferably KRAS mutated at residue 12, such as inhibitors of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A and KRAS G12R, preferably inhibitors of KRAS G12C and / or KRAS G12D, or inhibitors selective for KRAS G12D; and compounds which inhibit KRAS wild-type (preferably amplified), KRAS mutated at residue 13 (e.g. KRAS G13D), or KRAS mutated at residue 61 (e.g. KRAS Q61H). In particular, the compounds of the present invention (including all embodiments thereof) are potentially useful for the treatment and / or prevention of diseases and / or conditions mediated by KRAS, preferably KRAS mutated at residue 12, such as KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D, or by amplification of KRAS wild type, or by KRAS mutated at residue 13, such as KRAS G13D, or by KRAS mutated at residue 61, such as KRAS Q61H.

[0106] Therefore, in a further aspect, the present invention relates to a compound of the present invention, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0107] In a further aspect, the present invention relates to a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in a method of treatment of the human or animal body.

[0108] In a further aspect, the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of diseases and / or conditions mediated by KRAS, preferably by KRAS mutated at residue 12, such as KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D, or by amplification of KRAS wild type, or by KRAS mutated at residue 13, such as KRAS G13D.

[0109] In a further aspect, the present invention relates to the use of a compound of the invention 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 KRAS, preferably by KRAS mutated at residue 12, such as KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D, or by amplification of KRAS wild type, or by KRAS mutated at residue 13, such as KRAS G13D.

[0110] In a further aspect, the present invention relates to a method for the treatment and / or prevention of diseases and / or conditions mediated by KRAS, preferably KRAS mutated at residue 12, such as KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D, or by amplification of KRAS wild type, or by KRAS mutated at residue 13, such as KRAS G13D, comprising administering to a human a therapeutically effective amount of a compound of the invention or a pharma- ceutically acceptable salt thereof.

[0111] In a further aspect, the present invention relates to a compound of the present invention, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer.

[0112] In a further aspect, the present invention relates to a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in a method for the treatment and / or prevention of cancer in the human or animal body.

[0113] In a further aspect, the present invention relates to the use of a compound of the invention or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing cancer.

[0114] In a further aspect, the present invention relates to a method for treating and / or preventing cancer comprising administering to a human a therapeutically effective amount of a compound of the invention or a pharma- ceutically acceptable salt thereof.

[0115] Preferably, the cancer defined herein (above or below) comprises KRAS mutation. In particular, KRAS mutation comprises, for example, mutation of KRAS gene and KRAS protein, such as overexpressed KRAS, amplified KRAS or KRAS, KRAS mutated at residue 12, KRAS mutated at residue 13, KRAS mutated at residue 61, KRAS mutated at residue 146, in particular KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G13C, KRAS G13D, KRAS G13V, KRAS Q61H, KRAS Q61E, KRAS Q61P, KRAS A146P, KRAS A146T, KRAS A146V. KRAS may present one or more of these mutations / alterations.

[0116] Preferably, the cancers defined herein (above or below) contain, in addition to or instead of a KRAS mutation, a BRAF mutation, in particular a class III BRAF mutation, as defined, for example, in Z. Yao, Nature, 2017, 548, 234-238.

[0117] Preferably, the cancers defined herein (above or below) comprise, in addition to or instead of KRAS mutations, mutations in receptor tyrosine kinases (RTKs), including EGFR, MET and ERBB2 mutations.

[0118] In a further aspect, the present invention relates to a compound of the present invention or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS mutation, said KRAS mutation being preferably selected from the group consisting of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; or amplification of KRAS wild type, amplification of the KRAS gene or overexpression of KRAS.

[0119] In a further aspect, the present invention relates to the use of a compound of the present invention or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS mutation, said KRAS mutation being preferably selected from the group consisting of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; or amplification of KRAS wild type, amplification of the KRAS gene or overexpression of KRAS.

[0120] 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 the present invention or a pharma- ceutically acceptable salt thereof, wherein the cancer comprises a KRAS mutation, said KRAS mutation being preferably selected from the group consisting of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; or amplification of KRAS wild type, amplification of the KRAS gene or overexpression of KRAS.

[0121] In a further aspect the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G12D mutation.

[0122] In a further aspect the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G12V mutation.

[0123] In a further aspect the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS G13D mutation.

[0124] In a further aspect, the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer, wherein the cancer comprises a wild-type amplified KRAS.

[0125] Another aspect is based on identifying a correlation between the KRAS status of a patient and their potential sensitivity to treatment with the compounds of the present invention. Thus, KRAS inhibitors such as the compounds of the present invention can be advantageously used to treat patients with KRAS-dependent diseases that may be resistant to other therapies. This therefore provides an opportunity, method and tool for selecting patients, particularly cancer patients, for treatment with the compounds of the present invention. Selection is based on whether the tumor cells to be treated have (preferably amplified) wild type or KRAS mutated at residue 12 (preferably G12C, G12D or G12V genes), or KRAS mutated at residue 13 (preferably G13D genes). Thus, the status of the KRAS gene can be used as a biomarker to indicate that it may be advantageous to select treatment with the compounds of the present invention.

[0126] According to one embodiment, there is provided a method for selecting a patient for treatment with a compound of the invention, comprising the steps of: providing a tumor cell-containing sample from a patient; determining whether the KRAS gene in the patient's tumor cell-containing sample encodes a wild-type (glycine at position 12) or mutant (cysteine, aspartic acid, valine, alanine or arginine at position 12, aspartic acid at position 13, amplified and / or overexpressed) KRAS protein; - based thereon, selecting patients for treatment with the compounds of the invention; A method is provided, comprising:

[0127] The method may include or exclude the actual patient sample isolation step.

[0128] According to another aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating a cancer associated with tumour cells harbouring a KRAS mutation or an amplification of KRAS wild-type.

[0129] According to another aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating a cancer having tumor cells carrying an amplification of a G12C, G12D, G12V, G12A, G13D or G12R mutant KRAS gene or of the KRAS wild type.

[0130] According to another aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating a cancer having tumor cells carrying an amplification of a G12C, G12D, G12V or G13D mutant KRAS gene, or of the KRAS wild type.

[0131] According to another aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating a cancer having tumour cells harbouring a G12D mutated KRAS gene.

[0132] According to another aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating a cancer having tumour cells harbouring a G12V mutated KRAS gene.

[0133] According to another aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating a cancer having tumour cells harbouring a G13D mutated KRAS gene.

[0134] According to another aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating a cancer having tumour cells which harbour wild-type amplified KRAS or overexpressed KRAS.

[0135] According to another aspect, there is provided a method of treating cancer having tumor cells carrying an amplification of a G12C, G12D, G12V, G12A or G12R mutant KRAS gene or a wild-type KRAS gene, comprising administering to a human an effective amount of a compound of the invention or a pharma- ceutically acceptable salt thereof.

[0136] According to another aspect, there is provided a method of treating a cancer having tumor cells carrying an amplification of a G12C, G12D, G12V, G12A, G13D or G12R mutant KRAS gene or a wild-type KRAS gene, comprising administering an effective amount of a compound of the invention or a pharma- ceutically acceptable salt thereof.

[0137] Determining whether a tumor or cancer contains a G12C KRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS protein, by evaluating the amino acid sequence of the KRAS protein, or by evaluating the characteristics of the putative KRAS mutant protein. The sequence of wild-type human KRAS is known in the art. Methods for detecting mutations in KRAS 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 an embodiment, the sample is evaluated for the G12C KRAS mutation by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRAS G12C mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In one embodiment, the KRAS G12C mutation is identified using direct sequencing of a specific region (e.g., exon 2 and / or exon 3) of the KRAS gene. This technique will identify all possible mutations in the sequenced region. Methods for detecting mutations in KRAS protein are known to those skilled in the art. These methods include, but are not limited to, detection of KRAS mutations using binding agents (e.g., antibodies) specific to mutant proteins, protein electrophoresis, Western blotting, and direct peptide sequencing.

[0138] The method of determining whether a tumor or cancer contains a G12C KRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In some embodiments, the sample is a liquid biopsy and tests are performed on a blood sample to look for cancer cells from the tumor circulating in the blood, or pieces of DNA from tumor cells in the blood.

[0139] Similarly, it can be determined whether a tumor or cancer contains KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D and KRAS G12R mutations, or whether KRAS is wild type, preferably amplified.

[0140] Preferably, the disease / condition / cancer / tumor / cancer cell to be treated / prevented with the compounds of the present invention or their pharma- ceutically acceptable salts, according to the methods and uses defined and disclosed herein (above and below), is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, 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.

[0141] Preferably, the disease / condition / cancer / tumor / cancer cell to be treated / prevented with the compounds of the present invention or their pharma- ceutically acceptable salts according to the methods and uses defined and disclosed herein (above and below) is selected from the group consisting of pancreatic cancer, lung cancer, ovarian cancer, colorectal cancer (CRC), gastric cancer, gastroesophageal junction cancer (GEJC) and esophageal cancer.

[0142] In another aspect, the disease / condition / cancer / tumor / cancer cell to be treated / prevented with the compound of the present invention or its pharma- ceutically acceptable salt according to the methods and uses defined and disclosed herein (above and below) is selected from the group consisting of pancreatic cancer (preferably pancreatic ductal adenocarcinoma (PDAC)), lung cancer (preferably non-small cell lung cancer (NSCLC)), gastric cancer, bile duct cancer and colorectal cancer (preferably colorectal adenocarcinoma). Preferably, the pancreatic cancer, lung cancer, bile duct cancer, colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) or colorectal adenocarcinoma comprises a KRAS mutation, in particular a KRAS G12D or KRAS G12V mutation. Preferably (alternatively or in combination with the previous preferred embodiments), the non-small cell lung cancer (NSCLC) comprises a mutation (in particular a loss-of-function mutation) in the NF1 gene.

[0143] In another aspect, the disease / condition / cancer / tumor / cancer cell to be treated / prevented with the compounds of the invention or their pharma- ceutically acceptable salts according to the methods and uses defined and disclosed herein (above and below) is gastric cancer, ovarian cancer or esophageal cancer, said gastric cancer or esophageal cancer being preferably selected from the group consisting of gastric adenocarcinoma (GAC), esophageal adenocarcinoma (EAC) and gastroesophageal junction cancer (GEJC). Preferably, said gastric cancer, ovarian cancer, esophageal cancer, gastric adenocarcinoma (GAC), esophageal adenocarcinoma (EAC) or gastroesophageal junction cancer (GEJC) comprises KRAS mutation or wild type amplified KRAS.

[0144] Particularly preferably, the cancers to be treated / prevented with the compounds of the invention or their pharma- ceutically acceptable salts, according to the methods and uses defined and disclosed herein (above and below), are: lung adenocarcinoma (preferably non-small cell lung carcinoma (NSCLC)) with a KRAS mutation at position 12 (preferably G12C, G12D, G12V, G12A, G12R mutation), at position 13 (preferably G13D) or with an amplification of KRAS wild type, colorectal adenocarcinoma with KRAS mutations at position 12 (preferably G12C, G12D, G12V, G12A, G12R mutations), at position 13 (preferably G13D) or with amplification of KRAS wild type, pancreatic adenocarcinoma (preferably pancreatic ductal adenocarcinoma (PDAC)) with an amplification of a RAS mutation at position 12 (preferably KRAS, preferably G12C, G12D, G12V, G12A, G12R mutation), at position 13 (preferably G13D) or KRAS wild type is selected from the group consisting of:

[0145] Preferably, "cancer" as used herein (above or below) includes drug-resistant cancers and cancers that have failed one, two or more lines of monotherapy or combination therapy with one or more anti-cancer drugs. In particular, "cancer" (and any embodiment thereof) refers to any cancer (particularly the cancer types defined above and below) that is resistant to treatment with a KRAS G12C inhibitor.

[0146] Various resistance mechanisms have already been reported. For example, the following papers describe resistance in patients after treatment with KRAS G12C inhibitors: (i) Awad MM, Liu S, Rybkin, II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS(G12C)inhibition in cancer. N Engl J Med 2021;384:2382-93 and (ii) Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, et al. Clinical acquired resistance to KRAS(G12C)inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov 2021;11:1913-22.

[0147] In another embodiment, the disease / condition / cancer / tumor / cancer cell to be treated / prevented with the compounds of the present invention or their pharma- ceutically acceptable salts, according to the methods and uses defined and disclosed herein (above and below), is a RASopathy, preferably selected from the group consisting of Neurofibromatosis Type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML) (also known as LEOPARD syndrome), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome (also known as NF1-like syndrome) and Hereditary Gingival Fibromatosis.

[0148] Furthermore, the following cancers, tumors and other proliferative diseases may be treated with the compounds of the present invention or pharma- ceutically acceptable salts thereof, without being limited thereto. Preferably, the methods of treatment, methods, uses, compounds for use and pharmaceutical compositions for use as disclosed herein (above and below) are applied in the treatment of the following diseases / conditions / cancers / tumors (i.e., the respective cells) having a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation) or an amplification of KRAS wild type, or which have been identified as having a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation) or an amplification of KRAS wild type, as described and / or referenced herein:

[0149] Cancers / tumours / carcinomas of the head and neck: e.g. 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 ciliary bodies, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); Lung cancer / tumor / 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, lymphangiohemangioma, lymphangiopericytoma, lymphangioleiomyoma); Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., esophagus, stomach (gastric cancer), gastroesophageal junction cancer, pancreas, liver and bile duct (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, composite 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, Clark's tumor), gallbladder, extrahepatic bile duct, small intestine (duodenum, bladder ... intestine, including ileum), large intestine (cecum, colon, rectum, anus; including colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (kidney, e.g. renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal tumor, Grabitz tumor; ureter; bladder, e.g. urinary tract carcinoma, urothelial carcinoma; urethra, e.g. distal, bulbar, prostate; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis); tumors / cancers / carcinomas of gastric cancer; Cancer / tumor / carcinoma of the testis: e.g. seminoma, non-seminoma, Gynaecological cancers / tumors / carcinomas: for example, tumors / tumors / carcinomas of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, basalis); Cancers / tumors / carcinomas of the breast: e.g., breast cancer (infiltrating ductal, colloid, lobular infiltrating, tubular, glandular 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: e.g., tumors / tumors of endocrine glands, thyroid (thyroid carcinoma / tumor; papillary, follicular, anaplastic, medullary), parathyroid (parathyroid carcinoma / tumor), adrenal cortex (adrenal cortical carcinoma / tumor), 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 the soft tissue: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, neurosarcoma, neuroblastoma, glioblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal tumor, alveolar sarcoma, epithelioid sarcoma, extrarenal rhabdomyosarcoma, 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, high-grade superficial, small cell, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, and chondroblastoma; Mesothelioma: e.g. pleural mesothelioma, peritoneal mesothelioma; Cancers of the skin: 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: for example, astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, round cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., auditory nerve), spinal axis tumor; Lymphomas and leukemias: e.g., B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid 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 (ATL) / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), Cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosis HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, lymphocyte-depleted HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myelogenous leukemia (CML), acute myeloma (ACMD), myeloid / myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphoblastic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML); carcinoma of unknown primary site (CUP); All of the above cancers / tumors / carcinomas characterised by their specific location / origin within the body are meant to include both the primary tumour and any metastatic tumours derived therefrom.

[0150] All the above cancers / tumors / carcinomas can be further differentiated by their histopathological classification. Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, verrucous, pseudosarcoma, undifferentiated, transitional cell, lymphoid epithelium), adenocarcinoma (AC) (well differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell) spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cyst), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumor (small cell carcinoma, paraganglioma, carcinoid); carcinoma cell 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, hematological neoplasms, mixed and undifferentiated carcinomas;

[0151] The compounds of the invention may be used in a treatment regimen in connection with first line, second line, or any further line of treatment.

[0152] 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 in combination with radiotherapy and / or surgery.

[0153] The methods of treatment, methods, uses and compounds for use as disclosed herein (above and below) may be carried out using any compound of the invention or a pharma- ceutically acceptable salt thereof, as disclosed or defined herein, and any pharmaceutical composition or kit comprising a compound of the invention or a pharma- ceutically acceptable salt thereof (each of which includes any individual embodiment or generic subset of the compounds of the invention).

[0154] Combination treatment The compounds of the present invention or their pharma- ceutically acceptable salts 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 in combination with other treatments, such as radiation or surgical intervention, either as pre- or post-operative adjuvants. Preferably, the pharmacologically active substance for co-administration is an anti-neoplastic compound.

[0155] Therefore, in a further aspect, the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof for use as hereinbefore defined, wherein said compound is administered before, after or together with one or more other pharmacologically active substances.

[0156] In a further aspect, the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof for use as hereinbefore defined, wherein said compound is administered in combination with one or more other pharmacologically active substances.

[0157] In a further aspect, the present invention relates to the use of a compound of the invention or a pharma- ceutically acceptable salt thereof as hereinbefore defined, wherein said compound is administered before, after or together with one or more other pharmacologically active substances.

[0158] In a further aspect, the present invention relates to a method (e.g. a method for treatment and / or prevention) as defined herein above, wherein a compound of the invention 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.

[0159] In a further aspect, the present invention relates to a method (e.g. a method for treatment and / or prevention) as defined herein above, wherein a compound of the invention or a pharma- ceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substances.

[0160] In a further aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the compound of the present invention, or a pharma- ceutically acceptable salt thereof, is administered simultaneously, in parallel, sequentially, subsequently, alternatingly or separately from the one or more other pharmacologically active substances.

[0161] 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 an inhibitor of KRAS mutated at residue 12 or 13, such as a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D and / or KRAS G12R inhibitor, preferably a KRAS G12C, KRAS G12D or selective KRAS G12D inhibitor or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the inhibitor or a pharma- ceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0162] 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 an inhibitor of amplified or overexpressed wild type KRAS, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the inhibitor or a pharma- ceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0163] In a further aspect, the present invention relates to a compound of the present invention or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the compound of the present invention or a pharma- ceutically acceptable salt thereof is administered simultaneously, in parallel, sequentially, subsequently, alternatingly or separately with one or more other pharmacologically active substances.

[0164] In a further aspect the present invention relates to an inhibitor of KRAS mutated at residue 12 or 13, such as a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D and / or KRAS G12R inhibitor, preferably a KRAS G12C, KRAS G12D or selective KRAS G12D inhibitor or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the inhibitor or a pharma- ceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0165] In a further aspect, the present invention relates to an inhibitor of amplified or overexpressed wild type KRAS, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the inhibitor or a pharma- ceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0166] 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 the invention or a pharma- ceutically acceptable salt thereof, and optionally one or more pharma- ceutically acceptable excipients; a second pharmaceutical composition or dosage form comprising another pharmacologically active substance, and optionally one or more pharma- ceutically acceptable excipients; and A kit for use in the treatment and / or prevention of cancer, comprising: The first pharmaceutical composition is administered simultaneously, in parallel, sequentially, subsequently, alternatingly or separately from the second and / or additional pharmaceutical compositions or dosage forms; Regarding the kit.

[0167] In one embodiment, the kit for such use comprises a third pharmaceutical composition or dosage form, including a third pharmaceutical composition or dosage form comprising a further pharmacologically active substance and, optionally, one or more pharma- ceutically acceptable excipients.

[0168] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered simultaneously.

[0169] In a further embodiment of the invention, the components (ie combination partners) of the combinations, kits, uses, methods and compounds according to the invention (including all embodiments) are administered in parallel.

[0170] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered sequentially.

[0171] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered sequentially.

[0172] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered alternately.

[0173] In a further embodiment of the invention, the components (i.e. combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered separately.

[0174] The pharmacologically active substance to be used together / in combination with the compounds of the invention or pharma- ceutically acceptable salts thereof (including any individual embodiment or generic subset of compounds), or in the medical applications, methods of use, treatment and / or prevention, pharmaceutical compositions defined herein (above and below), may be selected from any one or more of the following (preferably there are one or two additional pharmacologically active substances used in all these embodiments):

[0175] 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutants thereof a. Irreversible inhibitors: for example, afatinib, dacomitinib, canertinib, neratinib, avitinib, pozotinib, AV412, PF-6274484, HKI357, olmutinib, osimertinib, almonertinib, nazartinib, lazertinib, pelitinib; b. Reversible inhibitors: e.g., erlotinib, gefitinib, icotinib, sapitinib, lapatinib, balitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW583340; c. Anti-EGFR antibodies: e.g., necitumumab, panitumumab, cetuximab, amivantamab; d. Anti-HER2 antibodies: e.g., pertuzumab, trastuzumab, trastuzumab emtansine; e. Inhibitors of mutant EGFR; f. Inhibitors of HER2 with exon 20 mutations; g. The preferred irreversible inhibitor is afatinib; h. A preferred anti-EGFR antibody is cetuximab.

[0176] 2. Inhibitors of MEK and / or its mutants For example, trametinib, cobimetinib, binimetinib, selumetinib, refametinib; b. Trametinib is preferred c. MEK inhibitors disclosed in WO 2013 / 136249; d. MEK inhibitors disclosed in WO 2013 / 136254

[0177] 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 preventing protein-protein interaction between SOS1 and (mutated) Ras proteins, such as KRAS). a. For example, BAY-293; b. SOS1 inhibitors as disclosed in WO 2018 / 115380; c. SOS1 inhibitors as disclosed in WO 2019 / 122129; d. SOS1 inhibitors such as those disclosed in WO 2020 / 180768, WO 2020 / 180770, WO 2018 / 172250 and WO 2019 / 201848

[0178] 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.

[0179] 5. Oncolytic viruses

[0180] 6. RAS Vaccine For example, TG02 (Targovax).

[0181] 7. 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 For example, vinorelbine. c. Inhibitors of, for example, Aurora kinase and / or any mutants thereof i. For example, alisertib, barasertib.

[0182] 8. Inhibitors of PTK2 (=FAK) and / or any mutants thereof For example, TAE226, BI853520.

[0183] 9. Inhibitors of SHP2 and / or any mutant thereof a.For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0184] 10. Inhibitors of PI3 kinase (=PI3K) and / or any mutant thereof a. Inhibitors of, for example, PI3K alpha and / or any mutant thereof i. For example, alpelisib, ceravelisib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactolisib, pictilisib, taselisib.

[0185] 11. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutants thereof a.For example, ponatinib, infigratinib, nintedanib.

[0186] 12. Inhibitors of AXL and / or any of its mutants

[0187] 13. Taxanes For example, paclitaxel, nab-paclitaxel, docetaxel; b. Preferred is paclitaxel.

[0188] 14.Platinum-containing compounds For example, cisplatin, carboplatin, oxaliplatin b. Preferred is oxaliplatin.

[0189] 15.Antimetabolites For example, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, trifluridine in combination with tipiracil (=TAS102); b. Preferred is 5-fluorouracil.

[0190] 16. Immunotherapeutic agents a. For example, immune checkpoint inhibitors i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb; ii. Anti-PD1 mAb is preferred; iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab; iv. Nivolumab, pembrolizumab, ezabenlimab and PDR-001 (= spartalizumab) are preferred; v. Most preferred are ezabenlimab, pembrolizumab and nivolumab.

[0191] 17. Topoisomerase inhibitors a. For example, irinotecan, liposomal irinotecan (nal-IRI), topotecan, etoposide; b. Most preferred are irinotecan and liposomal irinotecan (nal-IRI).

[0192] 18. 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 of WO 2014 / 151616), LXH254, sorafenib, LY-3009120 (= Example 1 of WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265.

[0193] 19. mTOR inhibitors For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin 1, dactolisib, GDC-0349, VS-5584, bistosertib, AZD8055.

[0194] 20. Epigenetic Regulators 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;

[0195] 21. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutants thereof For example, xentuzumab (antibody 60833 of WO 2010 / 066868), MEDI-573 (=dusigitumab), linsitinib.

[0196] 22. 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.

[0197] 23. Apoptosis regulators a. For example, an MDM2 inhibitor, such as an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 and / or any 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; iii. MDM2 inhibitors disclosed in WO 2015 / 155332; iv. MDM2 inhibitors disclosed in WO 2016 / 001376; v. MDM2 inhibitors disclosed in WO 2016 / 026937; vi. MDM2 inhibitors disclosed in WO 2017 / 060431; b. For example, PARP inhibitors; c. For example, MCL-1 inhibitors; i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0198] 24. Inhibitors of c-MET and / or any of its mutants For example, savolitinib, cabozantinib, foretinib; b.MET antibodies, e.g., emibetuzumab, amivantamab;

[0199] 25. Inhibitors of ERK and / or any mutant thereof For example, ulixertinib, LTT462;

[0200] 26. Inhibitors of farnesyltransferase and / or any mutant thereof a. For example, tipifarnib; In a further embodiment of the (combined) uses and methods (e.g. methods for treatment and / or prevention) as described hereinbefore, one other pharmacologically active substance is administered before, after or together with a compound of the invention 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; or Inhibitors of TEAD palmitoylation; or YAP / TAZ::TEAD inhibitors

[0201] In a further embodiment of the (combined) 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 the invention 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; or Inhibitors of TEAD palmitoylation; or YAP / TAZ::TEAD inhibitors

[0202] In a further embodiment of the (combined) 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 the invention 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 MEK inhibitors and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants thereof; or an inhibitor selected from the group consisting of SOS1 inhibitors and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants 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; or SOS1 inhibitors and inhibitors of TEAD palmitoylation; or ·SOS1 inhibitors and YAP / TAZ::TEAD inhibitors.

[0203] In a further embodiment of the (combined) 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 the invention 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 MEK inhibitors, and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants thereof; or an inhibitor selected from the group consisting of SOS1 inhibitors and EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutants 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; or SOS1 inhibitors and inhibitors of TEAD palmitoylation; or ·SOS1 inhibitors and YAP / TAZ::TEAD inhibitors.

[0204] Additional pharmacologically active substance(s) that may be used together / in combination with the compounds of the present invention or pharma- ceutically acceptable salts thereof (including any individual embodiment or generic subset of the compounds of the present invention), or that may also be used in the medical applications, uses, methods of treatment and / or prevention, pharmaceutical compositions, kits defined herein (above and below), include, but are not limited to, the following: hormones, hormone analogs and antihormones (e.g., tamoxifen, toremifene, raloxifene, phenytoin, 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, luprolide), growth factors and / or or inhibitors of their corresponding receptors (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), etc., and / or their corresponding receptors) (inhibitors include, e.g., (anti-)growth factor antibodies, (anti-)growth factor receptor antibodies and tyrosine kinase inhibitors, e.g., cetuximab, gefitinib, anti-metabolites (e.g., antifolates 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 (ara C), fludarabine);Antitumor antibiotics (e.g., doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride), myocet (non-pegylated liposomal doxorubicin), anthracyclines such as 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); mitotic inhibitors (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. PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, aurora kinase inhibitors, kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC 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, tetanus, musirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g., carfilzomib), immunotherapeutic agents such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibody, anti-CD37 antibodies, anti-CD20 antibodies), t-cell engagers (e.g., bispecific T-cell engagers (BiTEs®), such as CD3xBCMA, CD3xCD33, CD3xCD19, PSMAxCD3), tumor vaccines, immunomodulatory agents, such as STING agonists, and various chemotherapeutic agents, including amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer);

[0205] It is to be understood that the combinations, compositions, kits, methods, uses, pharmaceutical compositions or compounds for use according to the present invention may envisage simultaneous, parallel, sequential, subsequent, alternating or separate administration of the active ingredients or components. It will be understood that the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances may be administered or formulated dependently or independently, for example, the compound of the present invention 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, may be administered in separate pharmaceutical compositions / dosage forms.

[0206] In this context, "combination" or "combined" within the meaning of the present invention results from the mixing or combination of two or more active ingredients, and includes, but is not limited to, both fixed and non-fixed (e.g., free) combinations (including kits) and uses, such as products that include simultaneous, parallel, sequential, subsequent, alternating or separate use of the ingredients. The term "fixed combination" means that the active ingredients are administered to a patient at the same time 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 restrictions, such administration providing a therapeutically effective level of the compound in the patient's body.

[0207] The administration of the compound of the formula of the present invention or a pharma- ceutically acceptable salt thereof and one or more other pharmacologically active substances can be carried out by simultaneous administration of the active ingredients, for example by administering them simultaneously or in parallel in one single or two or more separate formulations or dosage forms. Alternatively, the administration of the compound of the present invention or a pharma- ceutically acceptable salt thereof and one or more other pharmacologically active substances can be carried out by administering the active ingredients sequentially or alternatingly, for example in two or more separate formulations or dosage forms.

[0208] For example, co-administration includes administering substantially simultaneously, which may also be referred to as "parallel" administration. Co-administration includes administering the active agents within the same general period, e.g., on the same day, but does not necessarily require simultaneous administration. Alternating administration includes administering one agent for a period, e.g., several days or one week, followed by administering another agent for a subsequent period, e.g., several days or one week, and then repeating that pattern for one or more cycles. Sequential or consecutive administration includes administering a first period (e.g., over several days or one week) of one or more doses of one agent, followed by a second and / or additional period (e.g., over several days or one week) of one or more doses of another agent(s). A repeating schedule can also be used, which includes administering the active agents on different days over the treatment period, not necessarily in a regular order. For example, variations of these general guidelines can also be used, depending on the agents used and the condition of the subject.

[0209] Definitions Terms not specifically defined herein should be given the meaning that would be ascribed to them by one of ordinary skill in the art in light of the present disclosure and the context. However, as used herein, unless otherwise specified, the following terms have the indicated meanings and the following rules are adhered to.

[0210] Prefix C x~y (wherein x and y each represent positive integers (x < y)) is used to indicate that the chain or ring structure, or combination of chain and ring structures, directly referred to and mentioned, can consist of a maximum of y and a minimum of x carbon atoms in total.

[0211] The indication of the number of members of a group containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total number of atoms of all ring members, or the total number of all rings and carbon chain members.

[0212] References to the number of carbon atoms in groups consisting of a combination of carbon chain and carbocyclic structures (e.g., cycloalkylalkyl, arylalkyl) refer to the total number of carbon atoms in all the carbocyclic and carbon chain members. Obviously, the ring structure has at least three members.

[0213] Generally, for groups containing two or more subgroups (e.g., heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, arylalkyl), the last named subgroup is the point of attachment of the radical, e.g., the substituent aryl-C 1~6 Alkyl is an aryl group having C 1~6 It means that it is attached to an alkyl group, which in turn is attached to a core or group to which a substituent is attached.

[0214] For groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, one skilled in the art can tell from the free valence of the group itself the point of radical attachment to the molecule.

[0215] The phrase "compounds of the invention" and grammatical variations thereof include compounds of formula (V), (V'), (I), (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IV), (IIc), (IId), (IIe) and / or (III) (including all salts, aspects and preferred embodiments thereof as defined herein). Any reference to a compound of the invention or a compound of formula (V), (V'), (I), (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IV), (IIc), (IId), (IIe) and / or (III) is intended to include a reference to each (sub)aspect and embodiment.

[0216] Alkyl denotes a univalent 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.

[0217] "C 1~5The 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-CH-, HC-CH-CH-CH-CH-, HC-CH-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)-.

[0218] 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( CH3)CH2CH(CH3)2), 3-Methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-Methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-Dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-Dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3-Dimethyl-1-butyl (-CH2C H(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.;

[0219] Without further definition, the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms.

[0220] The above definition of alkyl means that alkyl can be combined with another group, e.g. C x~y Alkylamino or C x~y This also applies when the aryl group is part of an alkyloxy group, and the latter is C x~y Abbreviated as alkoxy.

[0221] C x~yt Thioalkyloxy or C x~y Thioalkoxy is C x~y It means that at least one atom of the alkyl group is replaced with a sulfur atom.

[0222] The term alkylene can also be derived from alkyl. Unlike alkyl, alkylene is divalent and requires two bond 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.

[0223] "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)-.

[0224] 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.

[0225] Without further definition, the general terms propylene, butylene, pentylene, hexylene, etc., refer to all possible isomers 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.

[0226] The above definition of alkylene means that alkylene may be combined with another group, e.g. HO-C x~y Alkyleneamino or H2N-C x~y This also applies when it is a part of alkyleneoxy.

[0227] Unlike alkyl, alkenyl consists of at least two carbon atoms, at least two adjacent carbon atoms are bonded together by a CC double bond, and one carbon atom can only be part of one CC double bond. In an alkyl as defined 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.

[0228] 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.

[0229] Without further definition, the general terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc., refer to all possible isomers 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.

[0230] The alkenyl may optionally be in the cis or trans or E or Z orientation about the double bond.

[0231] The above definition for alkenyl applies when alkenyl is part of another (combined) group, e.g. C x~y Alkenylamino or C x~y This also applies to alkenyloxy.

[0232] Unlike alkylene, alkenylene consists of at least two carbon atoms, at least two adjacent carbon atoms are bonded to each other by a CC double bond, and one carbon atom can only be part of one CC double bond. In an alkylene as defined 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.

[0233] 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.

[0234] Without further definition, the general terms propenylene, butenylene, pentenylene, hexenylene, etc., refer to all possible isomers with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene, butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.

[0235] Alkenylene may optionally be in the cis or trans or E or Z orientation about the double bond.

[0236] The above definition of alkenylene applies when alkenylene is part of another (combined) group, e.g., HO-C x~y Alkenyleneamino or H2N-C x~y This also applies to alkenyleneoxy.

[0237] Unlike alkyl, alkynyl consists of at least two carbon atoms, at least two adjacent carbon atoms are linked together by a CC triple bond. In the alkyl as defined above having at least two carbon atoms, if two hydrogen atoms on adjacent carbon atoms are in each case formally removed and the free valences are saturated to form two further bonds, the corresponding alkynyl is formed.

[0238] 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.

[0239] Without further definition, the general terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc., refer to all possible isomers 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.

[0240] If the hydrocarbon chain contains both at least one double bond and at least one triple bond, then by definition it belongs to the alkynyl subgroup.

[0241] The above definition of alkynyl applies when alkynyl is part of another (combined) group, e.g. C x~y Alkynylamino or C x~y This also applies to alkynyloxy.

[0242] Unlike alkylene, alkynylene consists of at least two carbon atoms, at least two adjacent carbon atoms being linked to each other by a CC triple bond. If in the above-defined alkylene having at least two carbon atoms two hydrogen atoms on adjacent carbon atoms are in each case formally removed and the free valences are saturated to form two further bonds, the corresponding alkynylene is formed.

[0243] 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.

[0244] Without further definition, the general terms propynylene, butynylene, pentynylene, hexynylene, etc., refer to all possible isomers 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.

[0245] The above definition of alkynylene applies when alkynylene is part of another (combined) group, e.g., HO-C x~y Alkenyleneamino or H2N-C x~y This also applies to alkenyleneoxy.

[0246] Heteroatoms means oxygen, nitrogen and sulfur atoms.

[0247] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the alkyl (alkenyl, alkynyl) defined above by replacing, independently of one another, one or more hydrogen atoms of the hydrocarbon chain with halogen atoms, which may be the same or different. If haloalkyl (haloalkenyl, haloalkynyl) is further substituted, the substitutions may be carried out independently of one another in the form of mono- or polysubstitutions, in each case on all the hydrogen-bearing carbon atoms.

[0248] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, and the like.

[0249] From the haloalkyl (haloalkenyl, haloalkynyl) defined above, the term haloalkylene (haloalkenylene, haloalkynylene) is also derived. Unlike haloalkyl (haloalkenyl, haloalkynyl), haloalkylene (haloalkenylene, haloalkynylene) is divalent and requires two bond partners. Formally, the second valency is formed by removing a hydrogen atom from the haloalkyl (haloalkenyl, haloalkynyl).

[0250] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F, etc.

[0251] The above definitions also apply if the corresponding halogen-containing groups are part of another (combined) group.

[0252] Halogen denotes fluorine, chlorine, bromine and / or iodine atoms.

[0253] Cycloalkyl consists of the subgroups monocyclic cycloalkyl, bicyclic cycloalkyl and spiro-cycloalkyl. The ring system is saturated and is formed by the bonded carbon atoms. In bicyclic cycloalkyl, the two rings are bonded to each other so that they have at least two carbon atoms in common. In spiro-cycloalkyl, one carbon atom (spiro atom) belongs simultaneously to both rings.

[0254] 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-bearing carbon atoms. The cycloalkyl itself may be linked as a substituent to the molecule via any suitable position of the ring system.

[0255] 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.

[0256] The above definition for cycloalkyl applies when cycloalkyl is part of another (combined) group, e.g., C x~y Cycloalkylamino, C x~y Cycloalkyloxy or C x~y The same also applies to cycloalkylalkyl.

[0257] If the free valence of a cycloalkyl is saturated, an alicyclic ring is obtained.

[0258] Thus, the term cycloalkylene can be derived from cycloalkyl as defined above. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two bond partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups include, for example: Cyclohexyl, [ka] It is.

[0259] The above definition of cycloalkylene also applies when cycloalkylene is part of another (combined) group, e.g. HO-C x~y Cycloalkyleneamino or H2N-C x~y The same also applies to cycloalkyleneoxy.

[0260] Cycloalkenyl is composed of the subgroups monocyclic cycloalkenyl, bicyclic cycloalkenyl and spiro-cycloalkenyl. However, these systems are unsaturated, i.e., there is at least one C-C double bond, but no aromatic system. In the cycloalkyl as defined herein above, when two hydrogen atoms on adjacent ring carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding cycloalkenyl is obtained.

[0261] 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-bearing carbon atoms. The cycloalkenyl itself may be linked as a substituent to the molecule via any suitable position of the ring system.

[0262] 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.

[0263] The above definition for cycloalkenyl applies when cycloalkenyl is part of another (combined) group, e.g. C x~y Cycloalkenylamino, C x~y Cycloalkenyloxy or C x~y The same applies to cycloalkenylalkyl.

[0264] If the free valence of a cycloalkenyl is saturated, an unsaturated alicyclic ring is obtained.

[0265] Thus, the term cycloalkenylene can be derived from cycloalkenyl as defined above. Unlike cycloalkenyl, cycloalkenylene is divalent and requires two bond partners. Formally, the second valency is obtained by removing a hydrogen atom from cycloalkenyl. Corresponding groups include, for example: Cyclopentenyl, [ka] It is.

[0266] The above definition of cycloalkenylene applies when cycloalkenylene is part of another (combined) group, e.g., HO-C x~y Cycloalkenyleneamino or H2N-C x~y This also applies to cycloalkenyleneoxy.

[0267] Aryl denotes a monocyclic, bicyclic or tricyclic carbocycle having at least one aromatic carbocycle. Preferably, it denotes 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 ring with a 5-membered ring), in which the second ring may be aromatic but may also be partially saturated.

[0268] 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-bearing carbon atoms. The aryl itself may be linked as a substituent to the molecule via any suitable position of the ring system.

[0269] 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.

[0270] The above definition of aryl also applies when aryl is part of another (combined) group, such as, for example, arylamino, aryloxy or arylalkyl.

[0271] If the free valence of an aryl is saturated, an aromatic group results.

[0272] The term arylene can also be derived from aryl as defined above. Unlike aryl, arylene is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups include, for example: Phenyl, [ka] Naphthyl and [ka] It is.

[0273] The above definition of arylene also applies if arylene is part of another (combined) group, such as, for example, HO-aryleneamino or H2N-aryleneoxy.

[0274] Heterocyclyl denotes a ring system derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the -CH2- groups in the hydrocarbon ring, independently of one another, with the group -O-, -S- or -NH-, or by replacing one or more of the =CH- groups with the group =N-, where a total of up to 5 heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between 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.

[0275] A direct consequence of derivatization from cycloalkyl, cycloalkenyl and aryl is the formation of the subgroups of heterocyclyl, which may exist in saturated or unsaturated form: monocyclic heterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl and spiro-heterocyclyl.

[0276] Unsaturated means that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In a bicyclic heterocyclyl, the two rings are linked together so that they have at least two (hetero)atoms in common. In a spiro-heterocyclyl, one carbon atom (spiro atom) belongs simultaneously to both rings.

[0277] If 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-bearing carbon and / or nitrogen atoms. The heterocyclyl itself may be linked as a substituent to the molecule via any suitable position of the ring system. Substituents on a heterocyclyl are not included in the number of members of the heterocyclyl.

[0278] 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-dihydroazet, 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.

[0279] Further examples are the structures shown below, which can be bonded (with hydrogen exchange) through each hydrogen-bearing atom: [ka] TIFF2024543975000037.tif234165 TIFF2024543975000038.tif77165

[0280] Preferred monocyclic heterocyclyls are 4-7 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0281] Preferred monocyclic heterocyclyls are piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl and azetidinyl.

[0282] Preferred bicyclic heterocyclyls are 6-10 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0283] Preferred tricyclic heterocyclyls are 9-membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0284] Preferred spiro-heterocyclyls are 7-11 membered and have 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0285] The above definition of heterocyclyl also applies if heterocyclyl is part of another (combined) group, for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl.

[0286] If the free valence of a heterocyclyl is saturated, a heterocyclic ring is obtained.

[0287] The term heterocyclylene is also derived from heterocyclyl as defined above. Unlike heterocyclyl, heterocyclylene is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups include, for example: Piperidinyl, [ka] 2,3-dihydro-1H-pyrrolyl, [ka] It is.

[0288] The above definition of heterocyclylene also applies if heterocyclylene is part of another (combined) group, for example in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy.

[0289] Heteroaryl denotes a monocyclic heteroaromatic ring or a polycyclic ring having at least one heteroaromatic ring, which, in comparison with the corresponding aryl or cycloalkyl(alkenyl), contains one or more identical or different heteroatoms selected independently from among nitrogen, sulfur and oxygen instead of one or more carbon atoms, and the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is the heteroatom and the heteroaromatic system.

[0290] When heteroaryl is substituted, the substitutions can be carried out independently of one another on all hydrogen-bearing carbon and / or nitrogen atoms, in the form of monosubstitution or polysubstitution in each case.Heteroaryl itself can be linked to the molecule as a substituent through all suitable positions of the ring system, both carbon and nitrogen.Substituents on heteroaryl are not included in the number of members of heteroaryl.

[0291] 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, benzyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benzyl Examples of such an oxide include benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, and benzimidazolyl-N-oxide.

[0292] Further examples are the structures shown below, which can be bonded (with hydrogen exchange) through each hydrogen-bearing atom: [ka]

[0293] Preferably, the heteroaryl is a 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring having 1 to 4 heteroatoms each independently selected from oxygen, nitrogen and sulfur.

[0294] The above definition of heteroaryl also applies if heteroaryl is part of another (combined) group, for example in heteroarylamino, heteroaryloxy or heteroarylalkyl.

[0295] When the free valence of a heteroaryl is saturated, a heteroaromatic group is obtained.

[0296] The term heteroarylene 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 include, for example: Pyrrolyl and [ka] It is.

[0297] The above definition of heteroarylene also applies if heteroarylene is part of another (combined) group, for example in HO-heteroaryleneamino or H2N-heteroaryleneoxy.

[0298] Substituted means that the hydrogen atom directly bonded to the atom under consideration is replaced by another atom or a group of other atoms (substituents). Depending on the starting conditions (number of hydrogen atoms), single or multiple substitutions can occur for an atom. Substitution with a specific substituent is only possible if the allowed valencies of the substituent and the atom to be substituted 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).

[0299] Divalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, etc. can only be substituents on carbon atoms, but the divalent substituents =O and =NR can also be substituents on sulfur. In general, substitution with divalent substituents can only take place on ring systems and requires the replacement of two geminal hydrogen atoms, i.e. hydrogen atoms attached to the same carbon atom that is saturated before the substitution. Thus, substitution with divalent substituents is 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).

[0300] Stereochemistry / Solvates / Hydrates: Unless otherwise 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.) and their racemates, as well as mixtures of the separate enantiomers in various ratios, mixtures of diastereomers, or mixtures of any of the aforementioned forms when such isomers and enantiomers exist, as well as salts (including pharma- ceutically acceptable salts) and solvates thereof, such as hydrates (including solvates and hydrates of the free compound or solvates and hydrates of a salt of the compound).

[0301] 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 using stereochemically pure starting materials, and / or by stereoselective synthesis. It is well known in the art how to prepare optically active forms, for example, by resolution of racemates or by synthesis (e.g., starting from optically active starting materials and / or by using chiral reagents).

[0302] Enantiomerically pure compounds or intermediates of the invention may be prepared by asymmetric synthesis, for example by the preparation and subsequent separation of appropriate diastereomeric compounds or intermediates, which may be separated by known methods (e.g., by chromatographic separation or crystallization), and / or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.

[0303] Furthermore, methods for the preparation of enantiomerically pure compounds from the corresponding racemic mixtures are known to the person skilled in the art, 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 an optically active acid or base followed by resolution of the salts and release of the desired compound from the salts, or by derivatization of the corresponding racemate with an optically active chiral auxiliary reagent followed by diastereomeric separation and removal of the chiral auxiliary, or by kinetic resolution of the racemates (for example by enzymatic resolution), by enantioselective crystallization from a consortium of enantiomeric crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary, etc.).

[0304] Salts: 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 commensurate with a reasonable benefit / risk ratio.

[0305] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where 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.

[0306] 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.

[0307] 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.

[0308] 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 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.

[0309] Salts of acids other than those mentioned above, for example those useful for purifying or isolating the compounds of the invention (eg trifluoroacetates), are also part of the invention.

[0310] For example, [ka] In expressions such as: the letter A has the function of ring designation, for example to make it easy to indicate the attachment of the ring in question to other rings.

[0311] In the case of divalent groups where it is important to determine which adjacent group they are bonded to and with which valency, the corresponding bond partners are shown in parentheses, if necessary, for the sake of clarity, as in the following representation: [ka] Or (R 2 )-C(=O)NH- or (R 2 )-NHC(=O)-.

[0312] Unless such specification is made, divalent groups can be attached in both directions, i.e., for example, -C(=O)NH- also includes -NHC(=O)- and vice versa.

[0313] A group or substituent may be replaced with a corresponding group designation (e.g., R a , R b etc.) are often selected from among a number of alternative groups / substituents. It is pointed out that when such groups are used repeatedly in different parts of a molecule to define a compound according to the invention, the various uses are to be considered completely independent of each other.

[0314] A therapeutically effective amount for purposes of this invention means an amount of a substance that is capable of eliminating symptoms of a disease or preventing or alleviating these symptoms or prolonging the survival of the treated patient.

[0315] List of abbreviations [Table 1] TIFF2024543975000046.tif236165 TIFF2024543975000047.tif200165

[0316] Working Example Other 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.

[0317] Preparation of compounds according to the invention general Unless otherwise stated, all reactions are carried out with 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 therewith are carried out under protective gas (nitrogen or argon).

[0318] When a compound is represented by both a structural formula and its nomenclature, in the event of a conflict, the structural formula is determinative.

[0319] Microwave reactions are carried out in an initiator / reactor from Biotage, or in an Explorer from CEM, or in a Synthos 3000 or Monowave 3000 from Anton Paar, in a closed vessel (preferably 2, 5 or 20 mL), preferably with stirring.

[0320] Chromatography Thin layer chromatography is performed on precast silica gel 60 TLC plates on glass from Merck (with fluorescent indicator F-254).

[0321] Preparative high pressure chromatography (RP HPLC) of the exemplary compounds according to the invention is carried out on Agilent or Gilson systems using columns from Waters (name: SunFire™ Prep C18, OBD™ 10 μm, 50x150mm or SunFire™ Prep C18, OBD™ 5 μm, 30x50mm or XBridge™ Prep C18, OBD™ 10 μm, 50x150mm or XBridge™ Prep C18, OBD™ 5 μm, 30x150mm or XBridge™ Prep C18, OBD™ 5 μm, 30x50mm) and YMC (name: Actus-Triart Prep C18, 5 μm, 30x50mm).

[0322] Different gradients of HO / acetonitrile are used to elute the compounds, whereas for the Agilent system, 5% acidic modifier (20 mL HCOOH to 1 L HO / acetonitrile (1 / 1)) is added to the water (acidic conditions); for the Gilson system, 0.1% HCOOH is added to the water.

[0323] For chromatography under basic conditions on the Agilent system, a H2O / acetonitrile gradient is also used, but the water is made alkaline by adding 5% basic modifier (50 g NH4HCO3 + 50 mL NH3 (25% in H2O) with H2O up to 1 L). 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) are added to 1 L H2O.

[0324] Supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a JASCO SFC system with the following columns: Chiralcel OJ (250x20mm, 5μm), Chiralpak AD (250x20mm, 5μm), Chiralpak AS (250x20mm, 5μm), Chiralpak IC (250x20mm, 5μm), Chiralpak IA (250x20mm, 5μm), Chiralcel OJ (250x20mm, 5μm), Chiralcel OD (250x20mm, 5μm), Phenomenex Lux C2 (250x20mm, 5μm).

[0325] Analytical HPLC (reaction control) of intermediates and final compounds is carried out using columns from Waters (name: XBridge™ C18, 2.5 μm, 2.1x20 mm or XBridge™ C18, 2.5 μm, 2.1x30 mm or Aquity UPLC BEH C18, 1.7 μm, 2.1x50 mm) and YMC (name: Triart C18, 3.0 μm, 2.0x30 mm) and Phenomenex (name: Luna C18, 5.0 μm, 2.0x30 mm). The analytical equipment is also equipped with a mass detector in each case.

[0326] HPLC mass spectrometry / UV spectroscopy Retention Time / MS-ESI for Characterizing Exemplary Compounds According to the Invention + is generated using an HPLC-MS instrument (high performance liquid chromatography with mass detector). Compounds eluting in the injection peak have retention times t Ret. =0.00.

[0327] Method A HPLC Agilent 1100 System MS 1200Series LC / MSD(API-ES+ / -3000V,Quadrupol,G6140) MSD signal settings scan pos / neg120-900m / z Detection signal 315 nm (bandwidth 170 nm, reference off) Spectral range: 230-400nm Peak width <0.01 min Column: Waters, XBridge C18, 2.5μm, 2.1x20mm column Column temperature: 60℃ Solvent A: 20mM NH4HCO3 / NH3 in H2O pH 9 B: ACN HPLC grade Flow rate 1.00mL / min Gradient 0.00~1.50min 10%~95%B 1.50~2.00 minutes 95%B 2.00~2.10 minutes 95%~10%B

[0328] Method B HPLC Agilent 1260 System MS 1200 Series LC / MSD (MM-ES+APCI+ / -3000V, Quadrupol, G6130) Detection UV: 254 nm (bandwidth 8, reference off) UV: 230nm (bandwidth 8, reference off) UV spectrum range: 190~400nm; step: 4nm MS: positive and negative modes Mass range: 100-800m / z Column Waters; No. 186003389; XBridge BEH C18, 2, 5μm, 30x2.1mm Column temperature: 45℃ Solvent A: 5mM NH4HCO3 / 19mM NH3 in H2O; B: ACN (HPLC grade) Flow rate 1.40mL / min Gradient 0.00~1.00 min: 5%B~100%B 1.00~1.37 minutes: 100%B 1.37~1.40 minutes: 100%B~5%B

[0329] Method C HPLC Agilent 1260 Series MS Agilent LC / MSD Quadrupole Detection MS: positive and negative modes Mass range 100~750m / z Column: Waters X-Bridge BEH C18, 2.5μm, 2.1x30mm XP Column temperature: 45℃ Solvent A: 20mM NH4HCO3 / 30mM NH3 in H2O; B: ACN (HPLC grade) Flow rate 1.40mL / min Gradient 0.00-1.00 min: 15%B-95%B 1.00~1.30 minutes: 95%B

[0330] Method D HPLC Agilent 1100 / 1200 Systems MS 1200 Series LC / MSD (MM-ES+APCI+ / -3000V, Quadrupol, G6130B) MSD signal setting scan pos 150~750 Detection signal: UV 254nm, 230nm, 214nm (bandwidth 8, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (0.063 sec response time, 80 Hz) Column: Waters, No. 186003389, XBridge BEH C18, 2.5μm, 2.1x30mm) column Column temperature: 45℃ Solvent A: 5mM NH4HCO3 / 18mM NH3 in H2O (pH=9.2) B: ACN (HPLC grade) Flow rate 1.4mL / min Gradient 0.0~1.0min 15%~95%B 1.0~1.1 minutes 95%B Downtime: 1.3 minutes

[0331] Method E HPLC Agilent 1100 / 1200 Systems MS 1200 Series LC / MSD (MM-ES+APCI+ / -3000V, Quadrupol, G6130B) MSD signal setting scan pos / neg150~750 Detection signal: UV 254nm, 230nm, 214nm (bandwidth 8, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (0.063 sec response time, 80 Hz) Column: Waters, No. 186003389, XBridge BEH C18, 2.5μm, 2.1x30mm) column Column temperature: 45℃ Solvent A: 5mM NH4HCO3 / 18mM NH3 in H2O (pH=9.2) B: ACN (HPLC grade) Flow rate 1.4mL / min Gradient 0.0~1.0min 15%~95%B 1.0~1.1 minutes 95%B Downtime: 1.3 minutes

[0332] Method F HPLC Agilent 1100 / 1200 Systems MS 1200 Series LC / MSD(API-ES+ / -3000 / 3500V, Quadrupol, G6140A) MSD signal setting scan pos / neg150~750 Detection signal: UV 254nm, 230nm, 214nm (bandwidth 10, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (0.063 sec response time, 80 Hz) Column YMC; No. TA12S03-0302WT; Triart C18, 3μm, 12nm; 30x2.0mm column Column temperature: 45℃ Solvent A: H2O + 0.11% formic acid B: ACN + 0.1% formic acid (HPLC grade) Flow rate 1.4mL / min Gradient 0.0~1.0min 15%~95%B 1.0~1.1 minutes 95%B Downtime: 1.23 minutes

[0333] Method G UPLC-MS Waters Acquity-UPLC-SQ Detector-2 MSD signal setting scan pos&Neg100~1500, Power supply voltage: Capillary Vol (kV) -3.50, Cone (V): 50 Power supply temperature: Desolvation temperature (℃): 350 Feed gas flow rate: Desolvation (L / Hr): 750, Cone (L / Hr): 50 Detection signal: Diode array Spectral range: 200~400nm; resolution: 1.2nm Sampling rate: 10 points / sec Column: AQUITY UPLC BEH C18 1.7μm, 2.1x50mm Column temperature: 35℃ Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water Flow rate 0.6mL / min Gradient 0.0~0.30min 97%B 0.30~2.20 minutes 97%~2%B 2.20~3.30 minutes 2%B 3.30~4.50 minutes 2%~97%B 4.50~4.51 minutes 97%B

[0334] Method H UPLC-MS Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2 MSD signal setting scan pos&Neg100~1500, Power supply voltage: Capillary Vol (kV) -3.50, Cone (V): 50 Power supply temperature: Desolvation temperature (℃): 350 Feed gas flow rate: Desolvation (L / Hr): 750, Cone (L / Hr): 50 Detection signal: Diode array Spectral range: 200~400nm; resolution: 1.2nm Sampling rate: 10 points / sec Column: AQUITY UPLC BEH C18 1.7μm, 2.1x50mm Column temperature: 35℃ Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water Flow rate 0.6mL / min Gradient 0.0-0.40 min 97%B 0.40~2.50 minutes 97%~2%B 2.50~3.40 minutes 2%B 3.40~3.50 minutes 2%~97%B 3.50~4.0 minutes 97%B

[0335] Method I LC-MS Waters Arc-HPLC-SQ Detector-2 MSD signal settings ESI scan pos&neg Capillary voltage 3.50Kv Cone voltage 30V Desolvation gas 750L / hr Desolvation temperature 350℃ Column: X-Bridge C18, 4.6x75mm, 3.5μ Column temperature: 35℃ Solvent A: 10 mM ammonium acetate in water B:ACN Flow rate 1.0mL / min Gradient 0.0~0.75min 5%B 0.75~1.50 minutes 5%~40%B 1.50~5.0 minutes 40%~98%B 5.0~7.0 minutes 98%B

[0336] Method J LC-MS Waters Acquity-UPLC-SQ Detector-2 MSD signal settings ESI scan pos&neg Capillary voltage 3.50Kv Cone voltage 50V Desolvation gas 750L / h Desolvation temperature 350℃ Column: Waters Acquity-UPLC-SQ Detector-2 Column temperature: 35℃ Solvent A: 0.05% TFA in ACN B: 0.05% TFA in water Flow rate 0.6mL / min Gradient 0.0-0.3 min 97%B 0.3~2.2 minutes 97%~2%B 2.2~3.3 minutes 2%B

[0337] Method K LC-MS Waters Arc-HPLC-SQ Detector-2 MSD signal settings ESI scan pos&neg Capillary voltage 3.50Kv Cone voltage 30V Desolvation gas 750L / hr Desolvation temperature 350℃ Column: X-Bridge C18, 4.6x50mm, 3.5μ Column temperature: 35℃ Solvent A: 10 mM ammonium acetate in water B:ACN Flow rate 2.0mL / min Gradient 0.0~0.2min 10%B 0.2~2.50 minutes 10%~75%B 2.50~3.0 minutes 75%~100%B 3.0~4.8 minutes 100%B

[0338] Method L HPLC Agilent 1260 Series MS Agilent LC / MSD Quadrupole Detection MS: positive and negative modes Mass range: 550-1200m / z Column: Waters X-Bridge BEH C18, 2.5μm, 2.1x30mm XP Column temperature: 45℃ Solvent A: 20mM NH4HCO3 / 30mM NH3 in H2O; B: ACN (HPLC grade) Flow rate 1.40mL / min Gradient 0.00-1.50 min: 50%B-95%B 1.50~2.00 minutes: 95%B

[0339] Method M HPLC Agilent 1260 Series MS Agilent LC / MSD Quadrupole Detection MS: positive and negative modes Mass range: 550-1200m / z Column: Waters X-Bridge BEH C18, 2.5μm, 2.1x30mm XP Column temperature: 45℃ Solvent A: 20mM NH4HCO3 / 30mM NH3 in H2O; B: ACN (HPLC grade) Flow rate 1.40mL / min Gradient 0.00-1.00 min: 50%B-95%B 1.00~1.30 minutes: 95%B

[0340] Method N HPLC Agilent 1260 Series MS Agilent LC / MSD Quadrupole Detection MS: positive and negative modes Mass range 100~750m / z Column: YMC-Triart C18, 3μm, 12nm, 2.0x30mm Column temperature: 45℃ Solvent A: H2O + 0.11% formic acid; B: ACN (HPLC grade) + 0.1% formic acid Flow rate: 1.40mL / min Gradient: 0.00-1.00 min: 15%B-95%B 1.00~1.30 minutes: 95%B

[0341] Method O HPLC Waters-Alliance 2996 Detection signal PDA Detector Spectral range: 200~400nm; resolution: 1.2nm Sampling rate: 1 point / sec ELSD parameters Gas pressure: 50 PSI, Drift tube temperature: 50°C, Gain: 500 Column: Atlantis T3 (4.6x250mm) 5.0μm Column temperature Ambient Solvent A: 10 mM ammonium acetate in water B:ACN Flow rate 0.7mL / min Gradient 0.0~1.20min 2%B 1.2~10.0 minutes 2%~98%B 10.0~12.0 minutes 98%B 12.0~14.0 minutes 97%~2%B 14.0~16.0 minutes 2%B

[0342] Method P UPLC-MS Waters Acquity-UPLC-SQ Detector-2 MSD signal settings scan positive & negative 100~1500, Power supply voltage: Capillary voltage (kV) -3.50, Cone (V): 50 Power supply temperature: Desolvation temperature (℃): 350 Raw material gas flow rate: Desolvation (L / Hr): 650 Detection signal: Diode array Spectral range: 200~400nm; resolution: 1.2nm Sampling rate: 10 points / sec ELSD parameters: GAS: 2.0 SLM, nebulizer temperature: 40°C, evaporation temperature: 45°C Column: AQUITY UPLC BEH C18 1.7μm, 2.1x50mm Column temperature: 50℃ Solvent A: 0.05% formic acid in water B: 0.05% formic acid in ACN Flow rate 0.6mL / min Gradient 0.0~2.20min 3%~98%B 2.20~3.20 minutes 98%B 3.20~3.50 minutes 98%~3%B 3.50~4.20 minutes 2%B

[0343] Method Q HPLC-MS 2998PDA Detector and Waters Arc-HPLC with SQ Detector-2 MSD signal setting Scan Pos&Neg 100~1500, Power supply voltage: Capillary volume (kV) -3.50, Cone (V): 30 Power supply temperature: Desolvation temperature (℃): 350 Raw material gas flow rate: Desolvation (L / h): 750 Detection signal PDA Detector Spectral range: 200~400nm; resolution: 1.2nm Sampling rate: 10 points / sec Column: X-Bridge C18, 4.6x50mm, 3.5μm Column temperature: 35℃ Solvent A: 10 mM ammonium acetate in water B:ACN Flow rate 1.0mL / min Gradient 0.0~0.75min 5%B 0.75~1.50 minutes 5%~40%B 1.50~5.0 minutes 40%~98%B 5.0~7.0 minutes 98%B 7.0~9.0 minutes 98%~5%B 9.0~10.01 minutes 5%B

[0344] Method R HPLC Agilent 1200 System Column: Chiralpak IE, 5.0 μm, 2.1 x 150 mm column Column temperature: 40℃ Solvent EtOH / heptane 1:1 + 0.1% diethylamine (isocratic) Flow rate 0.60mL / min GCMS

[0345] Method U Agilent Technologies-7890B GC System Auto Sampler with GC 7693 and 5977A MSD Injection temperature 230℃ Column flow rate: 2.0 mL / min Solvent delay 1.5 min Split ratio 10:01 Column oven temperature program: 100°C / 1 min, 20°C / min / 310° / 5 min Total driving time: 16 minutes Interface temperature 150℃ Ion source temperature: 230℃ Gas He Column and column dimensions: ZB-5MS (30m x 0.32mm; 1μm) MSD scan range 50-900

[0346] Method V Agilent Technologies-7890B GC System Auto Sampler with GC 7693 and 5977A MSD Injection temperature 230℃ Column flow rate: 2.0 mL / min Solvent delay 1.5 min Split ratio 10:01 Column oven temperature program: 40°C / 2 min, 15°C / min / 200° / 1 min, 25°C / min / 310° / 0 min, Total driving time: 18 minutes Interface temperature 150℃ Ion source temperature: 230℃ Gas He Column and column dimensions: ZB-5MS (30m x 0.32mm; 1μm) MSD scan range 50-900

[0347] Method W Agilent Technologies-7890B GC System Auto Sampler with GC 7693 and 5977A MSD Injection temperature 230℃ Column flow rate: 2.0 mL / min Solvent delay 1.5 min Split ratio 10:01 Column oven temperature program: 60°C / 3 min, 20°C / min / 310° / 2 min Total driving time: 18 minutes Interface temperature 150℃ Ion source temperature: 230℃ Gas He Column and column dimensions: ZB-5MS (30m x 0.32mm; 1μm)

[0348] Method SFC-1 Manufacturing Waters UPC 2 -MS Software Empower3 MS QDa Column: CHIRALCEL OX-3 (4.6x150MM) 3μm A-solvent CO2 Solvent B: ACN Total flow rate: 3g / min % of co-solvent 15 ABPR 1500psi Temperature 30℃ PDA range 200nm~400nm Resolution 1.2nm MS parameters- QDa MS scan range 100Da~1000Da Cone Voltage Positive scan 20V Negative scan 15V

[0349] The compounds and intermediates according to the invention are prepared by the synthetic methods described below, where the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as illustrations of the invention, without limiting the scope of the subject matter of the invention and the compounds claimed in these examples. If the preparation of the starting compounds is not described, they are commercially available, their synthesis is described in the prior art, or they can be prepared analogously to known prior art compounds or methods described herein, i.e., 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. If the chemical structures below are shown without the exact configuration of a stereocenter, such as an asymmetrically substituted carbon atom, both configurations are considered to be included and disclosed in such representation. The representation of a racemic stereocenter shall always be considered to include and disclose both enantiomers (if no other defined stereocenter exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined stereocenters exist).

[0350] Synthesis of spiroketone intermediate A Experimental procedure for the synthesis of A-2a [ka] To a suspension of 5-chloropentanenitrile (22.9 g, 195 mmol, 1.00 equiv) in EtOH (136 mL) was added acetyl chloride (111 mL, 1.56 mol, 8.00 equiv) dropwise at 0 °C. The reaction mixture was allowed to warm to 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 (HPLC method: A; t ret =1.03 minutes; [M+H] + =164).

[0351] Experimental procedure for the synthesis of A-3a [ka] Crude A-2a (HCl salt) (28.0 g, 140 mmol, 1.00 equiv) and ethylene glycol (7.38 g, 119 mmol, 0.90 equiv) were dissolved in DCM (300 mL) and stirred at room temperature for 6 days. 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 KOH solution (2 M in water, 150 mL). The intact phase was kept and the mixture was stirred at room temperature overnight. The phases were separated, the aqueous phase was extracted with DCM (2x) and the combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude orthoester A-3a was used in the next step without further purification. (HPLC method: A; t ret =1.37 minutes; [M+H] + =163).

[0352] Experimental procedure for the synthesis of A-5a [ka] To a stirred solution of tetrahydro-thiopyran-4-one (20.0 g, 0.172 mol, 1.0 equiv.) in n-hexane (240 mL) was added a solution of sodium iodide (31.0 g, 0.207 mol. 1.2 equiv.) in ACN (160 mL) under nitrogen atmosphere. Then, triethylamine (28.8 mL, 0.207 mol, 1.2 equiv.) was added dropwise and cooled to 0° C. Then, chloro-trimethyl-silane (21.7 mL, 0.189 mol, 1.1 equiv.) was added dropwise and the mixture was stirred at room temperature for 3 days until TLC showed complete conversion. The reaction mixture was filtered through Celite and washed with hexane (200 mL). From the two layers formed, the hexane layer was removed, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by NP chromatography to give A-5a.

[0353] The following intermediates A-5 (Table 1) are obtained in an analogous manner using various ketones A4: The crude products A-5 are purified by chromatography if necessary. [Table 2]

[0354] Experimental procedure for the synthesis of A-4a [ka] Crude A-3a (22.3 g, 107 mmol, 1.00 equiv), 1-cyclohexenyloxytrimethylsilane (16.4 mL, 82.3 mmol, 0.80 equiv) and zinc chloride (10.2 g, 74.8 mmol, 0.70 equiv) were dissolved in DCM (120 mL) and stirred at room temperature for 5 h. The reaction mixture was treated with the addition of saturated sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by NP chromatography to give the desired compound A-6a.

[0355] The following intermediates A-6 (Table 2) are obtained in an analogous manner from A-3a and the appropriate intermediate A-5: The crude product is purified by chromatography if necessary. [Table 3]

[0356] Experimental procedure for the synthesis of A-8a [ka] A-6a (14.9 g, 57.1 mmol, 1.0 equiv) and sodium iodide (26.0 g, 171 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-7a was used in the next step without further purification.

[0357] A-7a (30 g, 85.0 mmol, 1.0 equiv.) was dissolved in THF. The mixture was treated with potassium tert.-butoxide (28.7 g, 256 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 by the addition of 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 to give (racemic) compound A-8a (the reaction sequence A-1a → A-8a is based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., Eur. J. Org. Chem. 2004, 19:3962-3967).

[0358] The desired enantiomer A-8b can then be obtained after chiral separation by SFC using the following conditions: Column: Lux; Cellulose-4 (250 mm x 30 mm x 5 μm), 90% CO2, 10% ACN, Flow rate: 90 g / min, Temperature: 30 °C, Desired enantiomer A-8b (SFC-Method: SFC-1, t ret = 2.99 min), as peak 2 after the undesired enantiomer elutes.

[0359] The following intermediates A-8 (Table 3) are obtained in an analogous manner using various ketones A-6 via intermediate A-7. The crude products are purified by chromatography if necessary. [Table 4]

[0360] Experimental procedure for the synthesis of A-10a [ka] To a stirred solution of 4-bromo-3,6-dihydro-2H-pyran (10.0 g, 0.061 mol, 1.0 equiv) in THF (150 mL) under argon, n-butyllithium solution (2.5 M in hexanes, 49.1 mL, 0.123 mol, 2.0 equiv) was added slowly over 10 min at −78° C. The mixture was stirred at −78° C. for 0.5 h. Cyclopentanone (5.16 g, 0.061 mol, 1.0 equiv) in dry THF (40 mL) was then added and the mixture was stirred at −78° C. for 0.5 h. The mixture was allowed to warm to room temperature. The reaction was quenched by the addition of water (100 mL) and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was then purified by flash chromatography on neutral alumina to yield A-10a.

[0361] Experimental procedure for the synthesis of A-11a [ka] To a stirred solution of A-10a (5.00 g, 0.030 mol, 1.0 equiv) in benzene (100 mL) under argon, vanadyl acetylacetonate (0.788 g, 0.003 mol, 0.1 equiv) was added slowly at 0° C., followed by dropwise addition of t-BuOOH (10.7 g, 0.036 mol, 1.2 equiv). Benzene (100 mL) was added and the mixture was stirred at 0° C. for 2 h. The mixture was allowed to warm to room temperature. A saturated aqueous solution of NaHCO3 (2×100 ml) was added, followed by extraction with EtOAc, and the organic layer was dried, filtered, and concentrated. The crude product was purified by NP chromatography to yield A-11a.

[0362] Experimental procedure for the synthesis of A-12a [ka] To a stirred solution of A-11a (4.00 g, 0.022 mol, 1.0 equiv) in dry DCM (400 mL) at -78 °C under argon, a solution of BF3.OEt2 (2.68 mL, 0.022 mol, 1.0 equiv) diluted with DCM (20 mL) was added dropwise, and the mixture was then stirred at -78 °C for 3 h until TLC showed complete conversion. The mixture was then concentrated, and the crude mixture was purified by NP chromatography to give A-12a (HPLC method: H; t ret =1.21 minutes; [M+H] + =185).

[0363] A-13a Experimental procedure for the synthesis of [ka] To a stirred solution of A-12a (3.10 g, 0.017 mol, 1.0 equiv.) in benzene (62 mL) at room temperature, p-TsOH (960 mg, 0.005 mol, 0.3 equiv.) and ethane-1,2-diol (9.49 mL, 0.17 mol, 10.0 equiv.) were added, the mixture was stirred at room temperature for 10 min, then the reaction was heated to 80-90 °C by use of a Dean-Stark apparatus and stirred for 20 h until TLC showed complete conversion. The reaction mixture was cooled to room temperature, quenched with 5% aqueous NaHCO3 (60 mL), and extracted with EtOAc. The organic layer was separated, dried, concentrated under reduced pressure, and the crude mixture was purified by NP chromatography to give A-13a (HPLC method: H; t ret =1.47 minutes; [M+H] + =229).

[0364] Experimental procedure for the synthesis of A-14a [ka] To a stirred solution of A-13a (1.35 g, 0.006 mol, 1.0 equiv.) in dry DCM (54 mL) at 0 °C, Dess-Martin periodinane (2.76 g, 0.007 mol, 1.1 equiv.) was added and the mixture was stirred at room temperature for 1 h until TLC showed complete conversion. The reaction mixture was quenched with 5% NaHCO3 (20 mL), washed with water, the organic layer was dried and concentrated under reduced pressure, and the crude mixture was purified by NP chromatography to give A-14a (HPLC method: C; t ret =0.426 minutes; [M+H] + =227).

[0365] Synthesis of alcohol- and amine-intermediates B Experimental Procedure for the Synthesis of B-2 (Method I) [ka] B-1a (4.92 g, 19.1 mmol, 1.00 equiv), N,N-carbonyldiimidazole (5.14 g, 28.6 mmol, 1.50 equiv) and molecular sieves (3A, 500 mg) were dissolved in DCM (29.5 mL) and stirred at room temperature for 40 min. After complete activation, N,O-dimethylhydroxylamine hydrochloride (2.79 g, 28.6 mmol, 1.50 equiv) was added and the reaction was stirred again at room temperature for 2 h. After complete reaction was observed, water (100 mL) and DCM (150 mL) were added, the phases were separated and the aqueous phase was extracted with DCM (2×). The combined organic phase was washed with brine and concentrated under reduced pressure. The residue was purified by NP chromatography to give product B-2a.

[0366] The following intermediates B-2 (Table 4) are obtained in an analogous manner using various acids. The crude products are purified by chromatography if necessary. [Table 5]

[0367] Experimental Procedure for the Synthesis of B-2d (Method II) [ka] To a stirred solution of (S)-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (10.0 g, 43.6 mmol, 1.0 equiv.) in DCM (100 mL), DIPEA (47.7 mL, 261.7 mmol, 6.0 equiv.) and N,O-dimethylhydroxylamine hydrochloride (10.2 g, 104 mmol, 2.4 equiv.) were added at 0° C. Then, T3P (109 mL, 1.6 mol / L, 174 mmol, 4.0 equiv.) was added dropwise at the same temperature. The resulting mixture was stirred at reflux temperature for 2 days. After complete conversion, the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The crude compound was purified by NP chromatography to yield B-2d (HPLC method: G; t ret =2.07 minutes; [M+H] + =273).

[0368] Experimental procedure for the synthesis of B-3a [ka] B-2a (4.88 g, 16.9 mmol, 1.00 equiv) was dissolved in THF (15 mL) under argon atmosphere and cooled to -10°C. Bromo(methyl)magnesium (3.4 M in MeTHF, 6.46 mL, 22.0 mmol, 1.3 equiv) was added and stirred at -10°C for 1 h. After complete conversion, the reaction mixture was cooled to -20°C and quenched by addition of brine. The resulting mixture was extracted with DCM (3x). The combined organic phase was concentrated under reduced pressure to give B-3a.

[0369] The following intermediates B-3 (Table 5) are obtained in an analogous manner from the corresponding starting materials B-2. The crude products are purified by chromatography if necessary. [Table 6]

[0370] Experimental Procedure for the Synthesis of B-4 (Method I) [ka] (R)-Methyl oxazaborolidine (0.99 g, 3.3 mmol, 0.20 equiv) was dissolved in THF (2 mL) under argon atmosphere and cooled to -5°C. Borane-dimethylsulfide complex (1.0 M, 22 mL 22 mmol, 1.3 equiv) was added. The mixture was stirred at room temperature for 30 min. The mixture was cooled to -5°C and B-3a (4.1 g, 17 mmol, 1 equiv) was added dropwise slowly. The reaction was stirred at room temperature for 1 h. After complete conversion of the starting material, the reaction was cooled to -10°C and quenched by addition of MeOH. The mixture was concentrated under reduced pressure. The residue was dissolved in water (150 mL) and formic acid (0.5 mL) and extracted with DCM (3x). The combined organic phase was concentrated under reduced pressure and purified by NP chromatography to give product B-4a.

[0371] The following intermediates B-4 (Table 6) are obtained in an analogous manner from the corresponding starting materials B-3. The crude products are purified by chromatography if necessary. [Table 7]

[0372] Experimental Procedure for the Synthesis of B-4 (Method II) [ka] To a stirred solution of (R)-(+)-2 methyl-CBS-oxazaborolidine (787 mg, 2.84 mmol, 0.2 equiv) in THF (20 mL) at 0° C., borane THF complex (1 M in THF, 18.5 mL, 18.5 mmol, 1.3 equiv) was added and stirred for 1 h. The reaction mixture was cooled to 0° C. again and B-3c (3.20 g, 14.2 mmol, 1.0 equiv) was added and stirred at room temperature for 3 h. After complete conversion, the reaction mixture was cooled to 0° C., MeOH was added slowly and stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. The crude compound was purified by NP chromatography to yield B-4c.

[0373] The following intermediates B-4 (Table 7) are obtained in an analogous manner from the corresponding starting materials B-3. The crude products are purified by chromatography if necessary. [Table 8]

[0374] Experimental procedure for the synthesis of B-5a [ka] B-4a (306 mg, 12.5 mmol, 1.00 equiv) was dissolved in THF, (30.6 mL) under argon atmosphere. Lithium aluminum hydride (1 M in THF, 24.9 mL, 25.0 mmol, 2.00 equiv) was added slowly. The reaction was stirred at 60° C. for 1 h. After complete conversion, the reaction was cooled to room temperature, Rochelle's salt solution and KOH were added, and stirred for 1 h. The existing suspension was extracted with DCM (3×) and the combined organic phase was concentrated under reduced pressure to yield B-5a.

[0375] The following intermediates B-5 (Table 8) are obtained in an analogous manner from the corresponding starting materials B-4. The crude products are purified by chromatography if necessary. [Table 9]

[0376] Experimental procedure for the synthesis of B-8a [ka] 1,7-Dichloro-heptan-4-one (6.00 g, 32.8 mmol, 1.0 equiv.) and 2-amino-2-methyl-propionitrile (8.27 g, 98.3 mmol, 3.0 equiv.) were added to ammonia (7 M in MeOH, 46.8 mL, 328 mmol, 10.0 equiv.) at 0° C., the mixture was allowed to reach room temperature and stirred for 24 h. After complete conversion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by NP chromatography to produce B-8a (HPLC method: H; t ret =0.23 minutes; [M+H] + =137).

[0377] Experimental procedure for the synthesis of B-9a [ka] To a stirred solution of B-8a (300 mg, 2.21 mmol, 1.0 equiv) in dry THF (5.0 mL) at -78 °C, methyllithium (1.6 M in diethyl ether, 4.13 mL, 6.61 mmol, 3.0 equiv) was added and stirred at -78 °C for 2 h. After complete conversion, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by NP chromatography to yield B-9a (HPLC method: H; t ret =0.28 minutes; [M+H] + =154).

[0378] The reaction sequence B-6a → B-9a is based on Oka et al., J. Heterocyclic Chem. 2003, 40, 177-180.

[0379] Experimental procedure for the synthesis of B-10a [ka] To a stirred solution of B-9a (1.00 g, 6.53 mmol, 1.0 equiv) in MeOH (10.0 mL) at 0° C., sodium borohydride (297 mg, 8.48 mmol, 1.3 equiv) was added and stirred at room temperature for 3 h. After complete conversion, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The organic layer was dried, filtered, and concentrated under reduced pressure to give B-10a (HPLC method: H; t ret =0.38 minutes; [M+H] + =156).

[0380] Experimental procedure for the synthesis of B-12a [ka] N-(tert-butoxycarbonyl)-L-prolinal (3.60 g, 18.1 mmol, 1.0 equiv.) was dissolved in DCM (150 mL) and N-benzylhydroxylamine hydrochloride (2.88 g, 18.1 mmol, 1.0 equiv.) and MgSO4 (2.17 g, 18.1 mmol, 1.0 equiv.) were added. The mixture was cooled to 0° C. and triethylamine (2.52 mL, 18.1 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred at room temperature for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure and purified by NP chromatography to produce B-12a (HPLC method: C; t ret =0.49 minutes; [M+H] + =305).

[0381] Experimental procedure for the synthesis of B-13a [ka] B-12a (4.94 g, 16.2 mmol, 1.0 equiv) was dissolved in dry THF (80 mL) and cooled to -60°C. Methylmagnesium bromide (3 M, 11.0 mL, 32.5 mmol, 2.0 equiv) was then added dropwise. The reaction mixture was stirred at -60°C for 5 h. After complete conversion of the starting material was observed, the mixture was quenched with saturated NH4Cl solution and extracted with DCM / water. The combined organic phase was concentrated under reduced pressure and purified by NP chromatography to yield B-13a (HPLC method: C; t ret =0.84 minutes; [M+H] + =321).

[0382] Experimental procedure for the synthesis of B-14a [ka] To a stirred solution of B-13a (11.5 g, 35.9 mmol, 1.0 equiv) in methanol (230 mL) and DCM (230 mL) at room temperature, palladium hydroxide (20% on charcoal, 4.20 g) was added and the mixture was stirred under hydrogen atmosphere for 7-8 h. After complete conversion, the reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The crude compound was purified by NP chromatography to yield B-14a (HPLC method: G; t ret =1.43 minutes; [M+H] + =215).

[0383] Experimental procedure for the synthesis of B-15a [ka] To a stirred solution of B-14a (4.0 g, 18.7 mmol, 1.0 equiv) in THF (20 mL) and water (20 mL) at room temperature, sodium bicarbonate (2.35 g, 28.0 mmol, 1.5 equiv) was added and stirred for 10 min. Then, 2-nitrobenzenesulfonyl chloride (4.54 g, 20.5 mmol, 1.1 equiv) was added and the reaction mixture was stirred at room temperature for 16 h. After complete conversion, the reaction mixture was diluted with EtOAc (200 mL), washed with water and brine, dried, filtered, and concentrated under reduced pressure. The crude compound was purified by NP chromatography to yield B-15a (HPLC method: H; t ret =2.12 minutes; [M+H] + =300).

[0384] Experimental procedure for the synthesis of B-16a [ka] To a stirred solution of B-15a (1.10 g, 2.75 mmol, 1.00 equiv) in DCM (8 ml) at room temperature was added HCl solution (4 M in dioxane, 2.75 ml, 11.0 mmol, 4.00 equiv). After 16 h, the reaction mixture was concentrated under reduced pressure to yield B-16a, which was used directly in the next step without purification.

[0385] Experimental procedure for the synthesis of B-17a [ka] To a stirred solution of B-16a (3.10 g, 9.23 mmol, 1.0 equiv) in toluene (30.0 mL) at room temperature, potassium carbonate (5.10 g, 36.9 mmol, 4.0 equiv) was added and stirred for 10 min. Then, 3-bromo 1-propanol (1.61 mL, 18.5 mmol, 2.0 equiv) was added and the reaction mixture was stirred at 80 °C for 2-4 h. After complete conversion of the starting material was observed, the mixture was cooled to room temperature, filtered through a Celite pad, and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by NP chromatography to produce B-17a (HPLC method: G; t ret =1.42 minutes; [M+H] + =358).

[0386] Experimental procedure for the synthesis of B-18a [ka] To a stirred solution of B-17a (3.0 g, 8.39 mmol, 1.0 equiv) in DCM (83 mL) at 0° C., triphenylphosphine (3.30 g, 12.6 mmol, 1.50 equiv) and diisopropyl azodicarboxylate (2.44 mL, 12.6 mmol, 1.50 equiv) were added. The reaction mixture was stirred at room temperature for 4-5 h. After complete conversion, the reaction mixture was diluted with DCM (150 mL), washed with water and brine, dried, filtered and concentrated. The crude compound was purified by NP chromatography to yield B-18a (HPLC method: G; t ret =1.47 minutes; [M+H] + =340).

[0387] Experimental procedure for the synthesis of B-19a [ka] To a stirred solution of B-18a (900 mg, 2.65 mmol, 1.0 equiv) in ACN (13.5 mL) at room temperature, potassium hydroxide (0.45 g, 7.95 mmol, 3.0 equiv) was added and stirred for 10 min. Then, thiophenol (0.73 g, 6.63 mmol, 2.50 equiv) was added and the reaction mixture was heated at 65 °C for 2 h. After complete conversion, the reaction mixture was cooled to room temperature and the solid was removed by filtration. The filtrate was concentrated and the residue was triturated with n-pentane. The remaining solid was discarded and the n-pentane fraction was concentrated to give the crude compound. The crude compound was dissolved in DCM (4.5 mL), HCl (4 M in dioxane, 0.36 mL, 10.7 mmol, 4.0 equiv) was added at 0 °C and the reaction mixture was stirred at room temperature for 1-2 h.

[0388] The reaction mixture was concentrated under reduced pressure, then the crude compound was triturated with diethyl ether and dried to give the desired product B-19a (HPLC method: O; t ret =2.31 minutes; [M+H] + =155).

[0389] Experimental procedure for the synthesis of B-21a [ka] (1R,2R)-1,2-Bis(2-hydroxyphenyl)ethylenediamine (408 mg, 1.59 mmol, 1.0 equiv) was dissolved in toluene (5 mL), then acetaldehyde (232 μL, 4.11 mmol, 2.59 equiv) was added and the mixture was stirred under nitrogen atmosphere at room temperature for 18 h and at 115° C. for an additional 20 h. After complete conversion, the reaction mixture was concentrated under reduced pressure and purified by RP chromatography to give B-21a (HPLC method: A; t ret =1.46 minutes; [M+H] + =297).

[0390] Experimental procedure for the synthesis of B-23a [ka] B-21a (224 mg, 0.72 mmol, 1.0 equiv) was dissolved in THF (3.5 mL) and concentrated hydrochloric acid (175 μL, 2.11 mmol, 2.94 equiv) was added. The mixture was stirred at 50° C. under nitrogen atmosphere for 3 h. After complete conversion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in isopropanol and stirred for 20 min. The precipitate was collected by filtration to yield B-22a, which was used in the next step without purification. B-22a (116 mg, 0.68 mmol, 1.0 equiv) was dissolved in diethyl ether (2 mL) and water (3 mL) and 4-methylbenzene-1-sulfonyl chloride (268 mg, 3.09 mmol, 4.53 equiv) was added at room temperature. The mixture was then cooled to 0° C. and sodium hydroxide (128 mg, 3.09 mmol, 4.53 equiv) was added dropwise. The mixture was allowed to slowly reach room temperature and stirred for 3 h. After complete conversion, the mixture was filtered and washed with water and diethyl ether. The precipitate was dissolved in water and ACN and lyophilized to give B-23a (HPLC method: A; t ret =1.24 minutes; [M+H] + =397).

[0391] Experimental procedure for the synthesis of B-24a [ka] B-23a (183 mg, 0.46 mmol, 1.0 equiv) was dissolved in DMF (1.5 mL) and potassium carbonate (136 mg, 0.97 mmol, 2.10 equiv) was added. The mixture was stirred at room temperature for 30 min. Then, 1,3-dibromopropane (50.0 μL, 0.49 mmol, 1.05 equiv) was added and stirred at 50° C. under nitrogen atmosphere for 48 h. After complete conversion, water was added and stirred for 10 min. The precipitate was collected by filtration and the residue was dissolved in DMF and purified by RP chromatography to give B-24a (HPLC method: C; t ret =0.81 minutes; [M+H] + =437).

[0392] Experimental procedure for the synthesis of B-25a [ka] B-24a (122 mg, 0.22 mmol, 1.0 equiv.) was dissolved in acetic acid (4 mL) and hydrobromic acid (33%, 130 μL, 0.74 mmol, 3.32 equiv.) was added. The reaction mixture was stirred overnight at 115° C. under nitrogen atmosphere. After complete conversion, the reaction mixture was extracted with toluene / water. The aqueous phase was lyophilized to give pure compound B-25a (HPLC method: C; t ret =0.08 minutes; [M+H] + =129).

[0393] Synthesis of pyrimidine derivative C Experimental procedure for the synthesis of C-2a [ka] To a stirred solution of 2,4-dichloro-1,3,5-triazine (9.00 g, 60 mmol, 1.0 equiv.) in ACN (100 mL), (S)-3-methyl-1,4-diazepane-1-carboxylic acid tert.butyl ester (10.9 g, 0.51 mmol, 0.85 equiv.) and DIPEA (11.6 g, 90 mmol, 1.5 equiv.) were added at 0° C., the mixture was allowed to reach room temperature and stirred for 2 h. After complete conversion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water, dried, filtered, concentrated under reduced pressure and the crude product was purified by NP chromatography to yield C-2a (HPLC method: G; t ret =2.23 minutes; [M+H] + =328).

[0394] Experimental procedure for the synthesis of C-4a [ka] To a stirred solution of (S)-1-((S)-1-methyl-pyrrolidin-2-yl)-ethanol (3.02 g, 23.4 mmol, 0.9 equiv.) in THF (20 mL), sodium tert-butoxide solution (1 M, 31.2 mL, 31.2 mmol, 1.2 equiv.) was added at 0° C., and then the mixture was stirred at the same temperature for 15 min. The mixture was cooled to −78° C. 4-Chloro-2-methanesulfonyl-pyrimidine (2.0 g, 10.4 mmol, 1 equiv.) in THF (20 mL) was cooled to −78° C. The above solution was added dropwise. After addition, the reaction mixture was stirred at −78° C. for 2 h. After complete conversion, the reaction mixture was quenched with water at −78° C. and extracted with EtOAc. The combined organic phase was concentrated under reduced pressure and purified by NP chromatography to yield C-4a (HPLC method: A; t ret =0.51 minutes; [M+H] + =242).

[0395] Synthesis of esters and acids D Experimental procedure for the synthesis of D-2a [ka] To a stirred solution of (S)-1-((S)-1-methyl-pyrrolidin-2-yl)-ethanol (11.2 g, 86.9 mmol, 1.50 equiv.) in DMSO (120 mL) was added 2-chloro-pyrimidine-4-carboxylic acid methyl ester (10.0 g, 58.0 mmol, 1.0 equiv.) dissolved in DMSO (30 mL) and DIPEA (24.1 mL, 145 mmol, 2.5 equiv.). The resulting mixture was stirred at 70° C. for 48 h. After complete conversion, the reaction mixture was extracted with EtOAc / water. The organic phase was washed with brine, dried, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography to yield D-2a.

[0396] The following intermediates D-2 (Table 9) can be obtained in an analogous manner from the corresponding aryl chloride and the appropriate alcohol or amine as nucleophile. The crude product is purified by chromatography if necessary. [Table 10]

[0397] Experimental procedure for the synthesis of D-3a [ka] D-2a (5.00 g, 18.1 mmol, 1.0 equiv) was dissolved in THF (100 mL) and NaOH (1 M in water, 27.1 mL, 27.1 mmol, 1.50 equiv) was added. The resulting mixture was stirred at room temperature for 1 h. After complete conversion, the solvent was removed under reduced pressure and the crude product was purified by RP chromatography to yield D-3a.

[0398] The following intermediate D-3 (Table 10) is obtained in an analogous manner: The crude product is purified by chromatography if necessary. [Table 11]

[0399] Experimental procedure for the synthesis of D-4a [ka] To a stirred solution of C-2a (11.0 g, 33.6 mmol, 1.0 equiv) in methanol (140 mL) in a steel bomb, sodium acetate (3.02 g, 36.9 mmol, 1.1 equiv) was added. The reaction mixture was then purged with argon for 15 min. 1,1-bis(diphenylphosphino)ferrocene (93.0 mg, 0.17 mmol, 0.01 equiv) and palladium(II) acetate (452 ​​mg, 0.67 mmol, 0.02 equiv) were added. The reaction mixture was charged with carbon monoxide gas (120 psi) and heated at 90° C. for 16 h. After complete conversion, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with DCM. The filtrate was concentrated under reduced pressure to give crude D-4a (HPLC method: G; t ret =1.99 minutes; [M+H]+ =352).

[0400] Synthesis of diketone E Experimental procedure for the synthesis of E-1a [ka] A-8b (5.08 g, 28.3 mmol, 1.01 equiv) and magnesium bromide diethyl etherate (8.01 g, 30.7 mmol, 1.6 equiv) were dissolved in dry DCM (50 mL) and stirred at room temperature for 5 min. DIPEA (7.5 mL, 0.04 mol, 1.53 equiv) was added, followed 5 min later by D-1a (6.62 g, 28.1 mmol, 1 equiv). The reaction was stirred at room temperature for 16 h. After complete conversion of the starting material was observed, 1M HCl was added and the mixture was stirred for 30 min. The mixture was extracted with DCM / water and the organic phase was concentrated under reduced pressure and purified by RP chromatography to yield E-1a.

[0401] The following intermediates E-1 (Table 11) are obtained in an analogous manner: The crude products are purified by chromatography if necessary. [Table 12]

[0402] Experimental procedure for the synthesis of E-2 [ka] A-8b (4.91 g, 21.9 mmol, 1.10 equiv) was dissolved in DCM (15 mL) cooled to 0° C., and magnesium bromide ethyl etherate (7.72 g, 29.9 mmol, 1.50 equiv) was added. The mixture was stirred at room temperature for 10 min. The mixture was cooled to 0° C., and then DIPEA (6.90 mL, 39.8 mmol, 2.0 equiv) and D-4a (7.0 g, 19.9 mmol, 1.0 equiv) were added slowly. The mixture was stirred at 30° C. for 48 h. After complete conversion was observed, the reaction mixture was poured into cold 2M HCl solution and extracted with DCM. The combined organic layers were washed with brine and concentrated under reduced pressure. The crude compound was purified by NP chromatography to yield E-2a.

[0403] The following intermediates E-2 (Table 12) are obtained in an analogous manner from the corresponding esters. The crude products are purified by chromatography if necessary. [Table 13]

[0404] Experimental procedure for the conversion of D-3 to E-4 (Method I) [ka] To a stirred solution of D-3b (1.50 g, 4.47 mmol, 1.0 equiv) in THF (20 mL) was added 1,1'-carbonyldiimidazole (872 mg, 5.38 mmol, 1.20 equiv) at room temperature and the reaction was stirred at room temperature for 2 h. Water and EtOAc were added, the organic layer was separated, dried, filtered and concentrated. The resulting residue was dissolved in DCM (5 mL) and added under nitrogen to a mixture of A-8b (1.50 g, 6.71 mmol, 1.50 equiv), magnesium bromide diethyl etherate (3.46 g, 13.4 mmol, 3.0 equiv) and DIPEA (2.47 mL, 13.4 mmol, 3.0 equiv) in DCM (5 mL) and the resulting mixture was stirred at room temperature for 16 h. After complete conversion, the reaction mixture was poured into cold 1M aqueous HCl, diluted with water and extracted with DCM. The combined organic layers were washed with brine and concentrated under reduced pressure. The crude compound was purified by NP chromatography to give E-4a (HPLC method: H; t ret =2.50 / 2.57 / 2.87 minutes; [M+H] + =542).

[0405] Experimental Procedure for the Conversion of D-3 to E-4 (Method II) [ka] Under argon, D-3a (333 mg, 1.33 mmol, 1.0 equiv) and 1,1'-carbonyldiimidazole (236 mg, 1.46 mmol, 1.1 equiv) were dissolved in dry THF (3 mL) and stirred at room temperature for 1 h. After complete activation of the acid, a solution of A-8a (297 mg, 1.33 mmol, 1.0 equiv) and LiHMDS (1 M in THF, 3.97 mL, 3.98 mmol, 3.0 equiv) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 3 days. After complete conversion, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic phases were combined, dried, filtered, and concentrated under reduced pressure to give the crude product. The crude product was dissolved in ACN and water, filtered, and purified by basic RP chromatography to give the desired product E-4b.

[0406] The following intermediates E-4 (Table 13) are obtained in an analogous manner from the corresponding acids D and ketones A. The crude products are purified by chromatography if necessary. [Table 14] TIFF2024543975000101.tif88161

[0407] Experimental procedure for the synthesis of E-5a [ka] E-1b (184 mg, 0.50 mmol, 1.0 equiv) was dissolved in dry DMSO (500 μL) and (1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethanol (96.8 mg, 0.67 mmol, 1.43 equiv) and DIPEA (176 μL, 1.01 mmol, 2.0 equiv) were added and stirred at 70° C. for 18 h. After complete conversion, the reaction mixture was filtered and purified by RP chromatography to give E-5a (HPLC method: C; t ret =0.74 / 0.80 minutes; [M+H] + =458).

[0408] Synthesis of azole intermediate F Experimental procedure for the synthesis of F-2a [ka] E-1a (1.02 g, 2.78 mmol, 1.0 equiv) was dissolved in pyridine (86 mL) and hydroxylamine hydrochloride (238 mg, 3.43 mmol, 1.23 equiv) was added. The reaction was stirred at room temperature overnight. After complete conversion, the mixture was acidified with 1M HCl and extracted with DCM. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to yield F-1a.

[0409] F-1a (335 mg, 0.88 mmol, 1.0 equiv) was dissolved in THF (4.0 mL) and aqueous HCl (4 M, 4.0 ml, 16.0 mmol, 18.1 equiv) and stirred at room temperature for 2 days. After complete conversion, the mixture was concentrated under reduced pressure. The precipitate was collected by filtration and dried under reduced pressure to give F-2a (HPLC method: A; t ret =1.33 / 1.13 minutes; [M+H] + =318).

[0410] Experimental procedure for the synthesis of F-4a [ka] E-1a (2.25 g, 6.15 mmol, 1.0 equiv) was dissolved in dioxane (10 mL) and hydroxylamine solution (50% in water, 390 μL, 6.36 mmol, 1.03 equiv) was added. The reaction was stirred overnight under nitrogen atmosphere. After complete conversion, the reaction mixture was concentrated under reduced pressure. The crude compound was dissolved in EtOAc and DCM, filtered, and purified by NP chromatography to yield F-3a.

[0411] F-3a (453 mg, 1.19 mmol, 1.0 equiv) was dissolved in dry DCM (5 mL) and DIPEA (483 μL, 2.77 mmol, 2.32 equiv) and methanesulfonyl chloride (95 μL, 1.22 mmol, 1.02 equiv) were added. The resulting solution was stirred at room temperature until complete conversion was observed. The reaction was evaporated and extracted with DCM and water. The organic solvent was evaporated and the resulting residue was purified by NP chromatography to yield F-4a (HPLC method: A; t ret =1.60 minutes; [M+H] + =362).

[0412] Experimental procedure for the synthesis of F-6 [ka] E-4e (333 mg, 0.48 mmol, 1 equiv) was dissolved in dioxane (3.0 mL) and hydroxylamine (50% in water, 32.0 μL, 0.52 mmol, 1.10 equiv) and formic acid (17.9 μL 0.48 mmol, 1.0 equiv) were added. The reaction was stirred at room temperature for 18 h. After complete conversion, the reaction mixture was extracted with DCM / NaHCO3 and the combined organic phase was concentrated under reduced pressure to yield crude F-5a.

[0413] F-5a (273 mg, 0.47 mmol, 1.0 equiv) was dissolved in dioxane (4.0 mL) and HCl (4 M in dioxane, 474 μL, 1.90 mmol, 4.0 equiv) was added. The reaction was stirred at 80° C. for 1 h. Then, water (2 mL) was added and stirred again at 80° C. for 1 h. After complete conversion, the reaction mixture was extracted with DCM / saturated aqueous NaHCO3. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to yield F-6a.

[0414] The following intermediate F-6 (Table 14) is obtained in an analogous manner: The crude product is purified by chromatography if necessary. [Table 15]

[0415] Experimental procedure for the synthesis of F-8a [ka] E-4d (100 mg, 0.18 mmol, 1.0 equiv) was dissolved in dioxane (0.5 mL) and hydroxylamine (50% in water, 12.4 μL, 0.20 mmol, 1.10 equiv) and formic acid (6.93 μL 0.18 mmol, 1.0 equiv) were added. The reaction was stirred at room temperature for 18 h. After complete conversion, when starting material was observed, the reaction was extracted with DCM / saturated aqueous NaHCO3 and the combined organic phase was concentrated under reduced pressure to yield crude F-7a.

[0416] F-7a (127 mg, 227 μmol, 1.0 equiv) was dissolved in trifluoroacetic acid (0.8 mL). The reaction was stirred at 80° C. for 18 h. After complete conversion, the mixture was extracted with DCM / saturated aqueous NaHCO3. The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give F-8a (HPLC method: A; t ret =1.19 minutes; [M+H] + =398).

[0417] Experimental procedure for the synthesis of F-11a and F-12a [ka] E-2b (361 mg, 0.79 mmol, 1.0 equiv) and hydroxylamine hydrochloride (224 mg, 3.22 mmol, 4.08 equiv) were dissolved in ethanol (2.5 ml) and stirred at room temperature overnight. After complete conversion, the solvent was evaporated. The reaction was basified with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was evaporated. The residue was purified by RP chromatography to give F-9a and F-10a.

[0418] The regioisomers were dissolved in acetic anhydride (500 μL) and stirred at 80° C. for 3 days. Then, water (125 μL) was added and the mixture was stirred at 80° C. overnight. After complete conversion, the mixture was cooled to room temperature and extracted with EtOAc and saturated aqueous NaHCO3. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to yield F-11a and F-12a (Table 15). [Table 16]

[0419] Experimental procedure for the synthesis of F-14a [ka] E-4c (5.26 g, 8.76 mmol, 1.0 equiv) and hydroxylamine hydrochloride (1.44 g, 20.7 mmol, 2.36 equiv) were dissolved in pyridine (25 mL). The reaction was stirred at 80° C. for 4 h. After complete conversion, water and DCM were added, the organic layer was separated, washed with 1M aqueous HCl, dried, filtered and concentrated. The crude product was purified by NP chromatography to yield F-13a.

[0420] F-13a (1.73 mg, 3.09 mmol, 1.0 equiv) was dissolved in THF (26 mL) and aqueous HCl (4 M, 19.3 mL, 77.3 mmol, 25 equiv) was added. The mixture was stirred at 60° C. for 3 h. After complete conversion, the mixture was extracted with DCM / saturated aqueous NaHCO3. The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give F-14a (HPLC method: A; t ret =1.28 minutes; [M+H] + =396).

[0421] Experimental procedure for the synthesis of F-16a [ka] E-4a (2.50 g, 4.62 mmol, 1.0 equiv) was dissolved in dioxane (25 mL) and hydroxylamine (50% in water, 3.66 g, 55.4 mmol, 12.0 equiv) was added. The reaction was stirred at 50° C. for 16 h. After complete conversion, the reaction mixture was concentrated under reduced pressure, water and DCM were added, the organic layer was separated, dried, filtered, and concentrated. The crude product was purified by NP chromatography to give F-15a, which was dissolved in acetic acid (15 mL) and stirred at room temperature for 16 h. After complete conversion, the reaction mixture was cooled to 0° C., saturated aqueous NaHCO3 and EtOAc were added, the organic layer was separated, dried, filtered, and concentrated. The crude product was purified by NP chromatography to give F-16a (HPLC method: H; t ret =2.75 minutes; [M+H] + =539).

[0422] Experimental procedure for the synthesis of F-18a [ka] E-2a (3.0 g, 5.52 mmol, 1 equiv.) was dissolved in dioxane (2 mL) and hydroxylamine solution (50% in water, 0.72 mL, 22.1 mmol, 4 equiv.) was added. The reaction was stirred overnight at 80° C. under nitrogen. After complete conversion, the reaction mixture was concentrated under reduced pressure. The crude compound was poured into cold water and extracted with DCM. The combined organic layers were washed with brine, dried and concentrated under reduced pressure to yield crude F-17a.

[0423] Crude F-17a (2.30 g, 4.12 mmol, 1.0 equiv) was dissolved in DCM (23 mL) and DIPEA (1.78 mL, 10.3 mmol, 2.5 equiv) and methanesulfonyl chloride (0.64 mL, 8.23 ​​mmol, 2.0 equiv) were added. The resulting solution was stirred at room temperature until complete conversion was observed. The reaction was evaporated and extracted with DCM / water. The organic solvent was evaporated and the resulting residue was purified by NP chromatography to yield F-18a (HPLC method: H; t ret =2.48 minutes; [M+H] + =541).

[0424] Experimental procedure for the synthesis of F-20 [ka] E-4g (941 mg, 1.63 mmol, 1.0 equiv) was dissolved in dioxane (5.0 mL) and hydroxylamine solution (50% in water, 110 μL, 1.79 mmol, 1.1 equiv) and formic acid (61.4 μL, 1.63 mmol, 1.2 equiv) were added. The reaction was stirred at room temperature for 18 h. After complete conversion, the reaction was extracted with DCM / saturated aqueous NaHCO3 and the combined organic phase was concentrated under reduced pressure to yield crude F-19a.

[0425] F-19a (965 mg, 1.63 mmol, 1.0 equiv) was dissolved in dioxane (2.0 mL) and HCl (4 M in dioxane, 1.63 μL, 6.50 mmol, 4.0 equiv) was added. The reaction was stirred at 80° C. for 1 h. Then, water (2 mL) was added and stirring was continued at 80° C. for 1 h. After complete conversion, the reaction mixture was extracted with DCM / saturated aqueous NaHCO3. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to yield F-20a.

[0426] The following intermediate F-20 (Table 16) is obtained in an analogous manner: The crude product is purified by chromatography if necessary. [Table 17]

[0427] Experimental procedure for the synthesis of F-23a [ka] To E-4b (119 mg, 0.26 mmol, 1.0 equiv) was added hydrazine (1.0 M in THF, 273 μL, 0.27 mmol, 1.05 equiv) and the reaction was stirred at room temperature for 14 h and then at 55° C. for 8 h. After complete conversion, acetic acid (1.0 mL) and water (1.0 mL) were added and the mixture was stirred again at 40° C. for 18 h and then at 75° C. for 20 h. After complete deprotection was observed, the reaction was basified with saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were concentrated under reduced pressure and purified by RP chromatography to yield F-23a (HPLC method: C; t ret =0-59 minutes; [M+H] + =410).

[0428] Experimental procedure for the synthesis of F-24a [ka] Hydrazine hydrate (20.8 mg, 0.42 mmol, 1.1 equiv) was dissolved in methanol (2 mL) and E-4h (200 mg, 0.38 mmol, 1.0 equiv) was added. The mixture was stirred at 70° C. for 2 days. After complete conversion, the mixture was concentrated under reduced pressure and purified by RP chromatography to give F-24a (HPLC method: A; t ret =1.55 minutes; [M+H] + =525).

[0429] Experimental procedure for the synthesis of F-25a [ka] F-4a (67.0 mg, 0.17 mmol, 1.0 equiv) was dissolved in dry DMSO (600 μL) and B-25a (99.7 mg, 0.34 mmol, 2.0 equiv) and DIPEA (70 μL, 0.40 mmol, 2.38 equiv) were added. The reaction was stirred at 90° C. for 19 h. After complete conversion of the starting material was observed, water and ACN were added and the mixture was filtered and purified by RP chromatography to give F-25a (HPLC method: C; t ret =0.86 minutes; [M+H] + =454).

[0430] Experimental procedure for the synthesis of F-27a [ka] F-4a (2.20 g, 6.09 mmol, 1.0 equiv) was dissolved in THF (8 mL) and aqueous HCl (2 M, 2.30 mL, 4.60 mmol, 0.76 equiv) was added and stirred at 70 °C for 18 h. After complete conversion, the reaction mixture was cooled to room temperature and the precipitate was collected by filtration, dissolved in DCM and washed with saturated aqueous NaHCO3. The organic phase was concentrated under reduced pressure to give F-27a (HPLC method: A; t ret =1.35 minutes; [M+H] + =318).

[0431] Experimental procedure for the synthesis of F-28 [ka] F-18a (300 mg, 0.52 mmol, 1.0 equiv) was dissolved in THF (2.0 mL), aqueous HCl (4 M, 2.0 mL, 8.0 mmol, 15.31 equiv) was added, and the reaction was stirred for 18 h at 50° C. After complete conversion, the reaction mixture was concentrated under reduced pressure and purified by RP chromatography to afford F-28a.

[0432] The following ketones F-28 (Table 17) are obtained in an analogous manner from the corresponding ketals. The crude products are purified by chromatography if necessary. [Table 18]

[0433] Experimental procedure for the synthesis of F-29a [ka] Sodium hydride (60% in mineral oil, 37.9 mg, 0.95 mmol, 3.5 equiv.) was dissolved in dry THF (1 mL), F-24a (142 mg, 0.27 mmol, 1 equiv.) was added, and the mixture was stirred under reflux for 1 h. Iodomethane (134 mg, 0.95 mmol, 3.5 equiv.) was added and stirred again under reflux for 1 h. After complete conversion, the reaction mixture was cooled to room temperature and extracted with DCM / water. The combined organic phases were dried, filtered, and concentrated under reduced pressure to yield F-29a (HPLC method: A; t ret =1.68 minutes; [M+H] + =539).

[0434] Experimental procedure for the synthesis of F-30a [ka] F-29a (176 mg, 0.26 mmol, 1.0 equiv) was dissolved in dioxane (2.0 mL) and HCl (4 M in dioxane, 327 μL, 1.31 mmol, 5.0 equiv) was added and stirred at room temperature over the weekend. After completion, the reaction mixture was basified with DIPEA, concentrated under reduced pressure, and purified by RP chromatography to give F-30a (HPLC method: A; t ret =1.12 minutes; [M+H] + =395).

[0435] Synthesis of aminocyanothiophenes G, I, II, and III Experimental procedures for the synthesis of Ia-1 and IIa-2 [ka] To a solution of F-27a (804 mg, 2.53 mmol, 1.0 equiv.) and molecular sieves (3 Å) in anhydrous isopropanol (16 mL) under argon atmosphere, malononitrile (341 mg, 5.06 mmol, 2.0 equiv.), sulfur (162 mg, 5.06 mmol, 2.0 equiv.) and β-alanine (451 mg, 5.06 mmol, 2 equiv.) were added. The reaction mixture was stirred at 90° C. overnight. After complete conversion, the reaction mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO3. The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in ACN and water and purified by basic RP chromatography to yield Ia-1.

[0436] The following compounds I and II (Table 18) are obtained in an analogous manner from the corresponding ketones. The crude products are purified by chromatography if necessary. [Table 19]

[0437] Experimental procedure for the conversion of ketone F to I (Method I) [ka] To a solution of F-11a (115 mg, 0.28 mmol, 1.0 equiv) and molecular sieves (3 Å) in absolute ethanol (235 μL) under argon atmosphere, malononitrile (64.8 mg, 0.98 mmol, 3.5 equiv), sulfur (35.9 mg, 1.12 mmol, 4.0 equiv) and L-proline (96.8 mg, 0.84 mmol, 3 equiv) were added. The reaction mixture was stirred at 80 °C overnight. After complete conversion, the reaction mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO3. The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in ACN and water and purified by RP chromatography to give the desired product Ib-1.

[0438] The following compounds I and II (Table 19) are obtained in an analogous manner from the corresponding ketone F. The crude products are purified by chromatography if necessary. [Table 20]

[0439] Experimental procedure for the conversion of ketone F to II (Method II) [ka] To a solution of F-20b (532 mg, 1.30 mmol, 1.0 equiv) and molecular sieves (3 Å) in anhydrous methanol (8 mL) under argon atmosphere was added malononitrile (136 mg, 1.95 mmol, 1.5 equiv), sulfur (62.5 mg, 1.95 mmol, 1.5 equiv) and β-alanine (146 mg, 1.56 mmol, 1.2 equiv). The reaction mixture was stirred at 80° C. overnight. After complete conversion, the reaction mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO3. The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in ACN and water and purified by RP chromatography to give the desired product IIb-1.

[0440] The following compounds I and II (Table 20) are obtained in an analogous manner from the corresponding ketone F. The crude products are purified by chromatography if necessary. [Table 21]

[0441] Experimental procedure for the conversion of ketone F to I and II (Method III) [ka] To a solution of F-28a (70.0 mg, 0.18 mmol, 1.0 equiv) and molecular sieves (3 Å) in absolute ethanol (2 mL) under argon atmosphere, malononitrile (61.38 mg, 0.88 mmol, 5.0 equiv), sulfur (17.0 mg, 0.53 mmol, 3 equiv) and β-alanine (49.7 mg, 0.53 mmol, 3 equiv) were added. The reaction mixture was stirred at 80° C. overnight. After complete conversion, the reaction mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO3. The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in ACN and water and purified by RP chromatography to give the desired product Ib-4.

[0442] The following compounds I and II (Table 21) are obtained in an analogous manner from the corresponding ketone F. The crude product is purified by chromatography if necessary. Traces of the other isoxazole regioisomer of IIb-5 are removed by SFC (Column: AmyC (30 mm x 250 mm, 5 μm), Column temperature: 40 °C, BPR: 100 bar, Eluent: 30:70 EtOH (0.2% v / v DEA):CO2, IIb-5 is collected as peak 2 after the other isomer). [Table 22]

[0443] Experimental procedure for the synthesis of IIIa-1 [ka] To a solution of F-23a (72.0 mg, 0.18 mmol, 1.0 equiv.) and molecular sieves (3 Å) in absolute ethanol (2.5 mL) under argon atmosphere, malononitrile (64.8 mg, 0.98 mmol, 3.5 equiv.), sulfur (35.9 mg, 1.12 mmol, 4 equiv.) and L-proline (82.6 mg, 703 μmol, 4.0 equiv.) were added. The reaction mixture was stirred at 90° C. overnight. After complete conversion, the mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO3. The organic phases were combined and concentrated under reduced pressure. The residue was purified by RP chromatography to give the desired product IIIa-1 (HPLC method: A; t ret =1.28 minutes; [M+H] + =490).

[0444] Experimental procedure for the synthesis of IIIb-1 [ka] To a solution of F-30a (58.0 mg, 0.15 mmol, 1.0 equiv.) and molecular sieves (3 Å) in absolute ethanol (1 mL) under argon atmosphere, malononitrile (69.4 mg, 1.03 mmol, 7.0 equiv.), sulfur (23.6 mg, 0.74 mmol, 5.0 equiv.) and β-alanine (65.9 mg, 0.74 mmol, 5.0 equiv.) were added. The reaction mixture was stirred at 80° C. overnight. After complete conversion, the mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO3. The organic phases were combined and concentrated under reduced pressure. The residue was purified by RP chromatography to give the desired product IIIb-1 (HPLC method: A; t ret =1.20 minutes; [M+H] + =475).

[0445] Experimental procedure for the synthesis of G-1a [ka] Ia-1 (500 mg, 1.26 mmol, 1.0 equiv) and N,N-dimethylformamide dimethyl acetal (255.5 μL, 1.88 mmol, 1.50 equiv) were dissolved in dry DMF (1.5 mL) and stirred at room temperature for 1 h. After complete conversion of the starting material was observed, the mixture was concentrated under reduced pressure and purified by RP chromatography to yield G-1a.

[0446] The following intermediates G-1 and G-2 (Table 22) are obtained in an analogous manner from the corresponding compounds Ia and IIa. The crude products are purified by chromatography if necessary. [Table 23]

[0447] Experimental procedure for the synthesis of Id-1 [ka] Ia-1 (50.0 mg, 0.13 mmol, 1.0 equiv), B-19a (66.8 mg, 0.25 mmol, 2.0 equiv), and DIPEA (43.8 μL, 0.25 mmol, 2.0 equiv) were dissolved in dry ACN (1 mL) and stirred at 90° C. for 2 days. After complete conversion, the mixture was concentrated under reduced pressure. The residue was dissolved in ACN / water, filtered, and purified by RP chromatography to yield Id-1.

[0448] The following compounds I (Table 23) are obtained in an analogous manner using the appropriate amines. The crude products are purified by chromatography if necessary. [Table 24]

[0449] Experimental procedure for the synthesis of IId-1 [ka] IIa-1 (150 mg, 0.377 mmol, 1.0 equiv), (3S)-3-methyl-1-piperazinecarboxylic acid tert-butyl ester (238 mg, 1.13 mmol, 3.0 equiv), and dry DIPEA (197 μL, 1.13 mmol, 3.0 equiv) were dissolved in dry ACN (3 mL) and stirred at 90 °C for 12 h. After complete conversion, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by RP chromatography to give IId-1 (HPLC method: A; t ret =1.64 minutes; [M+H] + =562).

[0450] Experimental procedure for the synthesis of G-3a [ka] The reaction was carried out in a glovebox under a nitrogen atmosphere. G-1a (180 mg, 0.38 mmol, 1.0 equiv), B-10a (156 mg, 0.60 mmol, 1.60 equiv), sodium tert-butoxide (54.4 mg, 0.57 mmol, 1.50 equiv) and [BrettPhos pd(crotyl)]OTf (32.0 mg, 0.04 mmol, 0.1 equiv) were dissolved in degassed dioxane (3.0 mL) and stirred at 60° C. for 16 h. After complete conversion, the reaction mixture was extracted with EtOAc / water and the combined organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by RP chromatography to give G-3a.

[0451] The following compounds G-3 and G-4 (Table 24) are obtained in an analogous manner using the appropriate alcohol B and chlorides G-1 and G-2, respectively. The crude products are purified by chromatography if necessary. [Table 25]

[0452] Experimental procedure for the synthesis of G-5a [ka] G-3b (525 mg, 0.82 mmol, 1.0 equiv.) was dissolved in DCM (8.0 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 3 h. After complete conversion, the reaction mixture was concentrated under reduced pressure to give G-5a (HPLC method: C; t ret =0.75 minutes; [M+H] + =544).

[0453] Experimental procedure for the synthesis of G-6a [ka] To sodium hydride (60% in mineral oil, 15.4 mg, 0.39 mmol, 4.0 equiv.) in dry NMP (0.5 mL) was added G-5a (150 mg, 0.10 mmol, 1.0 equiv.) and 2-iodoethane (608 mg, 3.86 mmol, 40 equiv.). The reaction mixture was stirred at room temperature for 18 h. After complete conversion, the mixture was filtered and purified by RP chromatography to give G-6a (HPLC method: C; t ret =0.90 minutes; [M+H] + =572).

[0454] Experimental Procedure for the Conversion of Intermediate G to Ie or IIe (Method I) [ka] G-3d (120 mg, 0.21 mmol, 1.0 equiv) was dissolved in ACN / water (1:1, 20 mL) and aqueous sodium hydroxide (2 M, 20.0 mL, 40 mmol, 190 equiv) was added. The reaction was stirred at 80° C. for 2 h. After complete conversion, the mixture was extracted with DCM. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to yield Ie-1.

[0455] The following compounds Ie (Table 25) are obtained in an analogous manner. The crude products are purified by chromatography if necessary. [Table 26]

[0456] Experimental Procedure for the Conversion of Intermediate G to Ie or IIe (Method II) [ka] G-4a (26.0 mg, 0.05 mmol, 1.0 equiv) was dissolved in ethanol (600 μL), and aqueous sodium hydroxide (2 M, 465 μL, 0.93 mmol, 20 equiv) was added and stirred at room temperature for 3 days. After complete conversion, water and ACN were added and the product was purified by RP chromatography to give IIe-1.

[0457] The following compounds Ie and IIe (Table 26) are obtained in an analogous manner. The crude products are purified by chromatography if necessary. [Table 27]

[0458] Experimental Procedure for the Conversion of Intermediate G to Ie or IIe (Method III) [ka] G-3a (12.0 mg, 21.0 μmol, 1.0 equiv) was dissolved in ethanol (0.5 mL), concentrated aqueous HCl (37.2%, 12.1 μL, 147 μL, 7.0 equiv) was added, and stirred at 90° C. for 2 h. After complete conversion, the mixture was concentrated under reduced pressure and purified by RP chromatography to give Ie-5 (HPLC method: A; t ret =1.40 minutes; [M+H] + =517).

[0459] Experimental procedure for the synthesis of If-1 [ka] Id-2 (2.33 g, 4.05 mmol, 1.0 equiv) was dissolved in DCM (20 mL), HCl in dioxane (12.1 mL, 48.6 mmol, 12.1 equiv) was added and the reaction was stirred at room temperature for 2 h. After complete conversion, the reaction was concentrated under reduced pressure, suspended in water, basified with DIPEA and extracted with DCM. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to yield If-1.

[0460] The following compounds If and IIf (Table 27) are obtained in an analogous manner from Id and IId. The crude products are purified by chromatography if necessary. [Table 28]

[0461] Experimental procedure for the synthesis of If-2 [ka] Ie-4 (28.0 mg, 0.05 mmol, 1.0 equiv) was dissolved in DCM (1.5 mL) and trifluoroacetic acid (0.06 mL, 0.76 mmol, 16 equiv) was added. The reaction was stirred at room temperature overnight. After complete conversion, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol and loaded onto an SCX-2 column and the product was eluted with NH3 (4 M in methanol) to give If-2 (HPLC method: C; t ret =0.69 minutes; [M+H] + =489).

[0462] Experimental procedure for the synthesis of Ig-1 [ka] If-1 (20.0 mg, 0.04 mmol, 1.0 equiv) was dissolved in dry DCM (1 mL) and cyclopropanecarboxaldehyde (2.95 mg, 0.04 mmol, 1.0 equiv) was added followed by sodium triacetoxyborohydride (36.7 mg, 0.17 mmol, 4.0 equiv). The solution was stirred at room temperature for 1 h. After complete conversion, the reaction mixture was quenched by addition of water. The aqueous phase was extracted with DCM (3×). The combined organic phases were filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by RP chromatography to give the desired product Ig-1.

[0463] The following compounds Ig (Table 28) are obtained in an analogous manner. The crude products are purified by chromatography if necessary. [Table 29]

[0464] Experimental procedure for the synthesis of Ig-4 [ka] (2R)-1,1-Dimethoxypropan-2-ol (30.3 mg, 0.25 mmol, 1.45 equiv) was dissolved in aqueous HCl (2 M, 130 μL, 0.26 mmol, 1.5 equiv) and stirred at room temperature overnight, then methanol (1 mL) and sodium acetate (22.8 mg, 0.28 mmol, 1.6 equiv) were added.

[0465] If-1 (82.5 mg, 0.17 mmol, 1.0 equiv) was dissolved in methanol (1.5 mL) and sodium cyanoborohydride (28.7 mg, 0.43 mmol, 2.50 equiv) was added. The aldehyde solution was added portionwise. After complete conversion, the reaction mixture was extracted with DCM / water and the combined organic phases were concentrated under reduced pressure and purified by RP chromatography to yield Ig-4 (HPLC method: A; t ret =1.46 minutes; [M+H] + =534).

[0466] Experimental procedure for the synthesis of IIg-1 [ka] IIb-5 (100 mg, 0.21 mmol, 1.0 equiv) was dissolved in DCM (5 mL) and tetrahydro-4H-pyran-4-one (1.05 g, 10.5 mmol, 50 equiv) was added and stirred for 15 min. Sodium triacetoxyborohydride (178 mg, 0.84 mmol, 4.0 equiv) was then added and the reaction was stirred at room temperature for 2 h. After complete conversion, the reaction mixture was concentrated under reduced pressure and purified by RP chromatography. Traces of the undesired isoxazole regioisomer were removed by SFC (column: AmyC (20 mm × 250 mm, 5 μm), column temperature: 40 °C, BPR: 125 bar, isocratic conditions: 30:70 EtOH:CO2 (0.2% v / v DEA), IIg-1 was collected as peak 2 after the alternative isomer) to produce IIg-1 (HPLC method: A; t ret =1.49 minutes; [M+H] + =560).

[0467] Experimental procedure for the synthesis of Ih-1 [ka] If-2 (22.0 mg, 0.05 mmol, 1.0 equiv.) was dissolved in dry THF (1 mL) and sodium hydride (60% in mineral oil, 3.60 mg, 0.09 mmol, 2.0 equiv.) was added and stirred at room temperature for 5 min. Then, iodomethane (12.8 mg, 0.09 mmol, 2.0 equiv.) was added and stirred at room temperature for 3 h. After complete conversion, the reaction mixture was filtered and purified by RP chromatography to produce Ih-1 (HPLC method: A; t ret =1.46 minutes; [M+H] + =503).

[0468] Synthesis of aminocyanothiophenes H and IV Experimental procedure for the synthesis of H-2a [ka] To a stirred solution of 2-oxo-cyclohexanecarboxylic acid ethyl ester (10.0 g, 58.8 mmol, 1.0 equiv.) in ethanol (50 mL) was added sulfur (1.88 g, 58.8 mmol, 1.0 equiv.), morpholine (5.12 g, 58.8 mmol, 1.0 equiv.) and malononitrile (3.88 g, 58.8 mmol, 1.0 equiv.). The reaction mixture was then stirred at 55° C. for 1 h. After complete conversion, the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organic phase was concentrated under reduced pressure and purified by NP chromatography to produce H-2a (HPLC method: C; t ret =0.54 minutes; [M+H] + =251).

[0469] Experimental procedure for the synthesis of H-3a [ka] H-2a (45.0 g, 180 mmol, 1.0 equiv) was dissolved in ethanol (300 mL) and sodium hydroxide (43.2 g, 1.08 mol, 6.0 equiv) dissolved in water (120 mL) was added. The resulting solution was heated to 60° C. and stirred for 1 h. After complete conversion, the mixture was cooled to room temperature, neutralized with 10% HCl, and extracted with EtOAc. The combined organic phase was washed with water and brine, then dried and concentrated under reduced pressure to give H-3a (HPLC method: N; t ret =0.36 minutes; [MH] - =221).

[0470] Experimental procedure for the synthesis of H-4a [ka] H-3a (1.00 g, 4.27 mmol, 1.0 equiv) was dissolved in dry DMSO and (dimethoxymethyl)dimethylamine (3.0 mL, 22.5 mmol, 5.26 equiv) was added slowly and stirred at 90° C. for 2 h. After complete conversion, the mixture was extracted with DCM / water. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to give H-4a (HPLC method: C; t ret =0.60 minutes; [M+H] + =292).

[0471] Experimental procedure for the synthesis of H-5a [ka] H-4a (711 mg, 2.44 mmol, 1.0 equiv) was dissolved in dry THF (3.95 mL) and degassed with argon. LiHMDS (1 M in THF, 2.56 mL, 2.56 mmol, 1.05 equiv) was added slowly and the mixture was stirred at room temperature for 5 min. Then, 5-bromopent-1-yne (359 mg, 2.44 mmol, 1.0 equiv) was added and the mixture was stirred at room temperature for 20 h. After complete conversion, water was added to the reaction, concentrated under reduced pressure, and then the mixture was extracted with DCM. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to yield H-5a (HPLC method: C; t ret =0.72 minutes; [M+H] + =358).

[0472] Experimental procedure for the synthesis of H-6a [ka] H-5a (824 mg, 2.31 mmol, 1.0 equiv) and Cs2CO3 (1502 mg, 11.5 mmol, 5.0 equiv) were dissolved in NMP (8.20 mL) and then thiophenol (1.18 mL, 11.5 mmol, 5.0 equiv) was added. The mixture was stirred at 80 °C for 7 h. Acetic acid (1 mL) was added and the mixture was extracted with DCM / water. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to give H-6a (HPLC method: C; t ret =0.40 minutes; [M+H] + =344).

[0473] Experimental procedure for the synthesis of H-7a [ka] H-6a (149 mg, 0.43 mmol, 1.0 equiv) was dissolved in dioxane (1.50 mL), DIPEA (113 μL, 0.65 mmol, 1.50 equiv) was added, and stirred at 60° C. for 2 h. In a separate vial, sodium hydride (60% in mineral oil, 52.0 mg, 1.30 mmol, 3.0 equiv) was flushed with argon. Allyl alcohol (590 μL, 8.67 mmol, 20 equiv) was added. After 10 min, diphenylphosphoryl azide (99.4 μL, 0.46 mmol, 1.05 equiv) was added. The second mixture was stirred for another 10 min. The above mixture was then added dropwise and stirred until complete conversion of the starting material was observed. The reaction mixture was concentrated under reduced pressure and extracted with DCM / water. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to give H-7a (HPLC method: C; t ret =0.73 minutes; [M+H] + =399).

[0474] Experimental procedure for the synthesis of H-8a [ka] C-4a (131 mg, 0.52 mmol, 1.24 equiv.) was dissolved in DMF (1.8 mL) and H-7a (168 mg, 0.42 mmol, 1.0 equiv.) was added. Then, bis(propan-2-yl)amine (1.60 mL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.6 mg, 0.03 mmol, 0.07 equiv.) and copper(I) iodide (8.0 mg, 0.04 mmol, 0.10 equiv.) were added. The mixture was stirred at 80° C. for 20 h. After complete conversion, the reaction mixture was extracted with DCM / water. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to give H-8a (HPLC method: A; t ret =1.39 minutes; [M+H] + =520).

[0475] Experimental procedure for the synthesis of H-9a [ka] H-8a (75.5 mg, 0.15 mmol, 1.0 equiv) was dissolved in methanol (3.7 mL) and degassed with argon. Imidazole-1-sulfonyl azide tetrafluoroborate (46.3 mg, 0.18 mmol, 1.22 equiv) and copper(II) sulfate (464 μg, 2.91 μmol, 0.02 equiv) were added. The mixture was heated to 60° C. After complete conversion, the reaction mixture was concentrated under reduced pressure and purified by RP chromatography to give H-9a (HPLC method: C; t ret =0.70 minutes; [M+H] + =546).

[0476] Experimental procedure for the synthesis of IVa-1 [ka] H-9a (30.5 mg, 0.06 mmol, 1.0 equiv) was dissolved in ethanol (2 mL) and aqueous HCl (2 M, 279.6 μL, 0.56 mmol, 10 equiv) was added. The reaction was stirred at 60° C. for 16 h. After complete conversion, the reaction mixture was concentrated under reduced pressure and purified by RP chromatography to give IVa-1 (HPLC method: A; t ret =1.21 minutes; [M+H] + =491).

[0477] The following examples describe the biological activity of the compounds according to the invention, without limiting the invention to these examples.

[0478] KRAS:SOS1 AlphaScreen binding assay This assay can be used to investigate the potency of compounds according to the invention that bind to (mutated) KRAS to inhibit the protein-protein interaction between SOS1 and (mutated) KRAS, e.g. KRAS WT, KRAS G12C, KRAS G12D, KRAS G12V or KRAS G13D. This inhibits the GEF functionality of SOS1 and locks the corresponding (mutated) KRAS protein in its inactive GDP-bound state. Low IC in this assay setting 50 The values ​​indicate a strong inhibition of the protein-protein interaction between SOS1 and KRAS:

[0479] Assay Description: These assays use Alpha Screen technology by Perkin Elmer to measure the inhibitory effect of compounds on KRAS mutant protein-protein interactions.

[0480] The following (mutant) enzymatic forms of KRAS and interacting proteins are used at the given concentrations in these assays: KRAS(G12D)1-169, N-terminal 6His tag, C-terminal avi tag (Xtal BioStructures, Inc.); 10 nM final assay concentration and SOS1 564-1049, N-terminal 229 GST tag, TEV cleavage site (Viva Biotech Ltd); 5 nM final assay concentration; KRAS(G12C)1-169, N-terminal 6His tag for purification, truncated, C-terminal avi tag, biotinylated, mutated: C51S, C80L, C118S (in-house); 7.5 nM final assay concentration and SOS1 564-1049, N-terminal 229GST tag, TEV cleavage site (Viva Biotech Ltd); 5 nM final assay concentration; KRAS(G12V)1-169, N-terminal 6His tag for purification, truncated, C-terminal avi tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loaded (in house); 10 nM final assay concentration and SOS1 564-1049, N-terminal 229 GST tag, TEV cleavage site (Viva Biotech Ltd); 10 nM final assay concentration; KRAS(G13D)1-169, N-terminal 6His tag for purification, truncated, C-terminal avi tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loaded (in house); 10 nM final assay concentration and SOS1 564-1049, N-terminal 229 GST tag, TEV cleavage site (Viva Biotech Ltd); 10 nM final assay concentration; KRAS (WT) 1-169, N-terminal 6His tag for purification, truncated, C-terminal avi tag, biotinylated, TEV cleavage site, mutated: C118S, GDP loaded (in house); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST tag, TEV cleavage site (Viva Biotech Ltd); 10 nM final assay concentration.

[0481] Test compounds dissolved in DMSO are dispensed into assay plates (Proxiplate 384 PLUS, white, PerkinElmer; 6008289) using an Access Labcyte Workstation equipped with a Labcyte Echo 55x. For the highest assay concentration selected of 100 μM, 150 nL of compound solution is transferred from the 10 mM DMSO compound stock solution. A series of 11-fold dilutions per compound are transferred to the assay plate and compound dilutions are tested in duplicate. DMSO is added as a backfill to bring the total volume to 150 nL.

[0482] The assay is performed in a dark room under 100 lux on a fully automated robotic system. Compound dilution: 150 nl, 10 μl of a mixture containing KRAS mutant protein, SOS1 (final assay concentrations see above) and GDP nucleotide (Sigma G7127; 10 μM final assay concentration) in assay buffer (1xPBS, 0.1% BSA, 0.05% Tween 20) is added to columns 1-24.

[0483] After a 30 minute incubation period, 5 μl of the Alpha Screen bead mixture in assay buffer is added to columns 1 to 23. The bead mixture consists of AlphaLISA Glutathione Acceptor Beads (PerkinElmer, Cat. No. AL109) and AlphaScreen Streptavidin Donor Beads (PerkinElmer Cat. No. 6760002) in assay buffer at 10 μg / ml final assay concentration, respectively.

[0484] Plates are kept at room temperature in a darkened incubator. After a further 60 min incubation period, signals are measured in a PerkinElmer Envision HTS Multilabel Reader using PerkinElmer's AlphaScreen specifications.

[0485] Each plate contains up to 16 wells of negative control (DMSO instead of test compound; KRAS mutant::SOS1 GDP mix and bead mix; column 23) and 16 wells of positive control (DMSO instead of test compound; KRAS mutant::SOS1 GDP mix without bead mix; column 24) depending on the dilution procedure (plate-wise or serial).

[0486] As an internal control, a known inhibitor of the KRAS mutant::SOS1 interaction can be measured on each compound plate.

[0487] IC50 values ​​are calculated and analyzed with Boehringer Ingelheim's MEGALAB IC50 application using a four parametric logistic model.

[0488] The table of exemplary compounds disclosed herein shows the IC 50 Contains values ​​(see Table 29). [Table 30]

[0489] Ba / F3 cell model generation and proliferation assay Ba / F3 cells are ordered from DSMZ (ACC300, lot 17) and grown in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10ng / mL IL-3 at 37°C in a 5% CO2 atmosphere. Plasmids containing KRASG12 mutants (i.e., G12D, G12C, G12V) are obtained from GeneScript. To generate a KRASG12-dependent Ba / F3 model, Ba / F3 cells are transduced with vector-containing retroviruses carrying KRASG12 isoforms. Platinum-E cells (Cell Biolabs) are used for packaging the retrovirus. Retroviruses are added to Ba / F3 cells. To ensure infection, 4μg / mL polybrene is added and the cells are disrupted. Infection efficiency is confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10%-20% are further cultured and puromycin selection at 1 µg / mL is initiated. As a control, parental Ba / F3 cells are used to demonstrate the selection condition. Selection is considered successful when the parental Ba / F3 cell culture dies. To evaluate the transforming potential of KRASG12 mutations, the growth medium is no longer supplemented with IL-3. Ba / F3 cells with an empty vector are used as a control. Approximately 10 days before performing the experiment, puromycin is excluded.

[0490] For proliferation assays, Ba / F3 cells were cultured at 1.5x10 in growth medium (RPMI-1640 + 10% FCS). 3Cells / 60 μL are seeded into 384-well plates. Compounds are added using an Access Labcyte Workstation equipped with a Labcyte Echo 550 or 555 acoustic dispenser. All treatments are performed in technical duplicates. Treated cells are incubated for 72 hours at 37° C. with 5% CO2. The viability stain AlamarBlue™ (ThermoFisher) is added and fluorescence is measured on a PerkinElmer Envision HTS Multilabel Reader. Raw data are imported and analyzed into Boehringer Ingelheim's proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0491] IC of representative compounds according to the invention measured in this assay 50 The values ​​are shown in Table 30. [Table 31]

[0492] Further 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 (PerkinElmer Cat. No. 5680) at a density of 2000 cells per well in 100 μL RPMI-1640 ATCC-Formulation (Gibco#A10491) + 10% FCS (fetal calf serum) (assay 1) or into black 384-well plates, flat clear bottom (Greiner, PNr. 781091) at a density of 200 cells per well in 60 μl RPMI-1640 ATCC-Formulation (Gibco#A10491) + 10% FCS (fetal calf serum) (assay 2). 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 an HP Digital Dispenser D300 (Tecan) (assay 1) or an ECHO acoustic liquid handler system (Beckman Coulter) (assay 2) and normalized for added DMSO, including a DMSO control. 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 (reported 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 nonlinear regression using a four-parameter model.

[0493] 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 ATCC+10% FCS+Penstrep RPMI 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 using an ECHO acoustic liquid handler system (Beckman Coulter) including DMSO controls. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (expressed 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 nonlinear regression using a four-parameter model.

[0494] ·AsPC-1 CTG proliferation assay (120 hours) (pancreatic cancer, G12D) The CTG assay is designed to quantitatively measure the proliferation of AsPC-1 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", 2000 AsPC-1 cells are seeded in 60 μL ATCC+10% FCS+Penstrep RPMI in a 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 using an ECHO acoustic liquid handler system (Beckman Coulter) including DMSO controls. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (expressed 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 nonlinear regression using a four-parameter model.

[0495] ·GP2D proliferation assay (120 hours) (colorectal cancer, G12D) GP2D cells (ATCC No. CRL-5807) are dispensed into white 384-well plates, flat white bottom (PerkinElmer, 6007680) at a density of 500 cells / well in 40 μl DMEM (Sigma, D6429) + 1xGlutaMAX (Gibco, 35050038) + 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 logarithmic dose series, including DMSO control and normalization for added DMSO, using a HP Digital Dispenser D300 (Tecan). 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 (expressed 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 nonlinear regression using a four-parameter model.

[0496] ·SAS CTG proliferation assay (120 hours) (HNSCC, wt amplified) SAS cells (JCRB0260) are dispensed into 384-well plates, flat clear bottom (Greiner, PNr.781091) at a density of 300 cells / well in 60 μL DMEM:F12 (Gibco 31330-038) + 10% fetal bovine serum (HyClone, PNr.:SH30084.03) and incubated overnight at 37 °C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) are added using a CHO acoustic liquid handler system (Beckman Coulter) with DMSO control. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (reported 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 nonlinear regression using a four-parameter model.

[0497] ·MKN1 CTG proliferation assay (120 hours) (gastric cancer, wt amplified) MKN1 cells (JCRB0252) are dispensed into white 384-well plates, flat white bottom (Corning Costar, PNr.:3570) at a density of 400 cells per well in 50 μl RPMI 1640 (PAN-Biotech, PNr.:P04-18047) + 10% FCS (HyClone, PNr.:SH30084.03) (Assay 1) or into black 384-well plates, flat clear bottom (Greiner, PNr.781091) at a density of 200 cells per well in 60 μl RPMI-1640 (Gibco#A10491) + 10% FCS (HyClone, PNr.:SH30084.03) + PenStrep (Gibco, PNr.15140-122) (Assay 2). 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 logarithmic dose series using an HP Digital Dispenser D300 (Tecan) (assays 1+2) or an ECHO acoustic liquid handler system (Beckman Coulter) (assay 3) (including DMSO control and normalization to added DMSO). Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (reported 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 nonlinear regression using a four-parameter model.

[0498] ·SK-CO-1 CTG proliferation assay (120 hours) (CRC, G12V) SK-CO-1 cells (ATCC HTB-39) are dispensed into 384-well plates, flat clear bottom (Greiner, PNr.781091) at a density of 500 cells / well in 60 μL EMEM (Sigma M5650) + 10% fetal bovine serum (HyClone, PNr.:SH30084.03) and incubated overnight at 37 °C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) are added using a CHO acoustic liquid handler system (Beckman Coulter) with DMSO control. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (reported 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 nonlinear regression using a four-parameter model.

[0499] LOVO CTG proliferation assay (120 hours) (CRC, G13D) LOVO cells (ATCC CCL-229) are dispensed into 384-well plates, flat clear bottom (Greiner, PNr.781091) at a density of 1000 cells / well in 60 μL DMEM (Sigma D6429) + 10% fetal bovine serum (HyClone, PNr.:SH30084.03) and incubated overnight at 37 °C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) are added using a CHO acoustic liquid handler system (Beckman Coulter) with DMSO control. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (reported 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 nonlinear regression using a four-parameter model.

[0500] A375 CTG proliferation assay (120 hours) (melanoma, wt, B-Raf mutant, negative control) A375 cells (ATCC CRL-1619) are dispensed into 384-well plates, flat clear bottom (Greiner, PNr.781091) at a density of 300 cells / well in 60 μL DMEM (Sigma D6429) + 10% fetal bovine serum (HyClone, PNr.:SH30084.03) and incubated overnight at 37 °C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) are added in a log dose series using a HP Digital Dispenser D300 (Tecan) including a DMSO control. Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (reported 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 nonlinear regression using a four-parameter model.

[0501] IC of representative compounds according to the invention measured in these assays in the indicated cell lines 50 The values ​​are shown in Tables 31 and 32. [Table 32] [Table 33]

[0502] ERK phosphorylation assay The ERK phosphorylation assay is used to examine the efficacy of compounds to inhibit KRAS G12C-mediated signaling in KRAS G12C mutant human cancer cell lines in vitro. This demonstrates the molecular mode of action of the compounds according to the present invention by disrupting the RAS G12C protein signaling cascade. The low IC in this assay setting50 The values ​​indicate the high potency of the compounds according to the present invention.The compounds according to the present invention are observed to exhibit an inhibitory effect on ERK phosphorylation in KRAS G12C mutant human cancer cell lines, thus confirming the molecular mode of action of the compounds on RASG 12C protein signaling.

[0503] ERK phosphorylation assays are performed using the following human cell lines: NCI-H358 (ATCC (ATCC CRL-5807): human lung cancer with KRAS G12C mutation (→ Assay 1) and NCI-H358_Cas9_SOS2, i.e., the same cell line in which SOS2 was knocked (→ Assay 2). Vectors containing designed DNA sequences for the production of gRNA for SOS2 protein knockout are obtained from Sigma Aldrich. To generate NCI-H358 SOS2 knockout cell lines, NCI-H358 cells expressing Cas9 endonuclease are transfected with XtremeGene9 reagent and the corresponding plasmid. Transfection efficiency is confirmed by measuring GFP-positive cells using a cell analyzer. GFP-positive cells are harvested and further expanded. These GFP-positive cell pools are subjected to single cell dilution and SOS2 knockout clones are identified by Western blot and genomic DNA sequencing analysis.

[0504] Materials used in the assay: RPMI-1640 Medium (ATCC® 30-2001™) Fetal Bovine Serum (FBS) from HyClone (SH30071.03) Non-essential amino acids from Thermo Fischer Scientific (11140035) Pyruvate (11360039) from Thermo Fischer Scientific Glutamax (35050061) from Thermo Fischer Scientific 384 plates (781182) from Greiner Bio-One Proxiplate™ 384 (6008280) from PerkinElmer Inc. AlphaLISA SureFire Ultra p-ERK1 / 2(Thr202 / Tyr204) Assay Kit(ALSU-PERK-A500) EGF (E4127) from Sigma Acceptor Mix: Protein A Acceptor Beads from PerkinElmer (6760137M) Donor Mix: AlphaScreen Streptavidin-coated Donor Beads (6760002) from PerkinElmer Trametinib Staurosporine (S6942) from Sigma Aldrich

[0505] Assay Setup: Cells are seeded at 40,000 cells per well in 60 μL of RPMI containing 10% FBS, non-essential amino acids, pyruvate and glutamax in Greiner TC 384 plates. Cells are incubated for 1 hour at room temperature and then 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 the addition of 20 μL of 1.6x lysis buffer from the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) Assay Kit supplemented with protease inhibitors, 100 nM trametinib + 100 nM staurosporine. After 20 min incubation at room temperature with shaking, 6 μL of each lysate sample is transferred to a 384-well Proxiplate and analyzed for pERK(Thr202 / Tyr204) using the AlphaLISA SureFire Ultra pERK1 / 2(Thr202 / Tyr204) Assay Kit. 3 μL of Acceptor Mix and 3 μL of Donor Mix are added under reduced light and incubated for 2 h at room temperature in the dark before the signal is measured on a PerkinElmer Envision HTS Multilabel Reader. Raw data is imported and analyzed into Boehringer Ingelheim's proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0506] Similarly, the assay described (pERK reduction; SureFire) can be performed on additional cell lines with various KRAS mutations or KRAS wild type, allowing for the measurement and determination of compound activity against various additional KRAS alleles in the cellular background.

[0507] 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. After a short preincubation period at 37°C, the reaction is started by the addition of 12 μL β-nicotinamide adenine dinucleotide phosphate reduced form (NADPH, 10 mM) and terminated after different time points (0, 5, 15, 30, 60 min) by transferring an aliquot into the solvent. Furthermore, NADPH-independent degradation is monitored by incubation without NADPH and terminated at the last time point by the addition of acetonitrile. 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.

[0508] 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 fitted to a first-order elimination rate constant as C(t)=C0*exp(-ke*t), where C(t) and C0 are the concentrations of unchanged test drug at incubation time t, and the preincubation concentration and ke are the elimination rate constants of unchanged drug. Then, CL int、インビトロ (μL minute -1 The amount of protein (quantity) is calculated by the formula CL int、インビボ =CL int、インビトロ Predicted CL in vivo from incubation parameters according to x (incubation volume (ml) / amount protein (mg)) x (amount protein (mg) / g liver tissue) x (liver weight / body weight) int、インビトロ (mL min. -1 ·kg -1 )

[0509] To allow for better interspecies comparisons, predicted clearance was calculated as the percent hepatic blood flow [%OH] (mL min ) in each individual species. -1 ·kg -1 ) In general, high stability of a compound across species (corresponding to a low %QH) is desired.

[0510] Table 33 shows metabolic stability data obtained in the disclosed assays of HLM for a selection of compounds according to the invention. [Table 34]

[0511] Plasma Protein Binding Assay (PPB) Binding of test compounds to plasma was determined using equilibrium dialysis (ED) and quantitative mass spectrometry interfaced with liquid chromatography (LC-MS). Briefly, ED was performed using a dialysis device consisting of two chambers separated by a semipermeable membrane with a molecular weight cutoff of 5-10 kg / mol. One chamber was filled with 10% FCS in PBS containing 1-10 μmol / L test compound, and the other chamber was filled with phosphate-buffered saline (PBS) with or without dextran. The dialysis chambers were incubated at 37°C for 3-5 h. After incubation, proteins were precipitated from an aliquot of each chamber and separated into the plasma-containing compartment (c 血清 ) and the buffer-containing compartment (c 緩衝液 The concentration of the test compound in the supernatant of the 100 ml of 10 ... u ) was calculated according to the following formula:

number

[0512] Table 34 shows metabolic stability data obtained in the disclosed assays for a selection of compounds according to the invention. [Table 35]

[0513] Mechanism-based inhibition of CYP3A4 assay (MBI3A4): 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 pre-incubated with human liver microsomes 25 uM concentration (0.2 mg / mL) in the presence of NADPH (1 mM) for 0 and 30 min. After pre-incubation, the incubation is diluted 1:10 and the substrate midazolam is added for the main incubation (15 min). The main incubation is quenched with acetonitrile and the formation of hydroxy-midazolam is quantified by LC / MS-MS. The formation of hydroxy-midazolam from 30 min pre-incubation versus 0 min pre-incubation is used as readout. Values ​​less than 100% mean that the substrate midazolam is metabolized to a lower extent in 30 min pre-incubation compared to 0 min pre-incubation. In general, a low effect upon 30 min preincubation is desirable (corresponding to values ​​close to 100% / not different from those determined in the water control).

[0514] Table 35 presents data obtained in the disclosed assays for a selection of compounds according to the invention. [Table 36]

[0515] Solubility measurement (DMSO solution precipitation method) A 10 mM DMSO stock solution of the test compound is used to determine its water solubility. The DMSO solution is diluted with aqueous medium (McIlvaine's buffer at pH=4.5 or 6.8) to a final concentration of 250 μM. After shaking for 24 hours at ambient temperature, any potentially formed precipitate is removed by filtration. The concentration of the test compound in the filtrate is determined by the LC-UV method by calibrating the signal to that of a reference solution in which the test compound is completely dissolved in acetonitrile / water (1:1) of known concentration.

[0516] Table 35 presents data obtained in the disclosed assays for a selection of compounds according to the invention. [Table 37]

[0517] Caco-2 assay This assay provides information on the possibility of compounds passing through cell membranes, the extent of oral absorption, and whether the 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, Cat. No. 3391). A 10 μM test compound solution 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) was 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, whereas ba permeability (PappBA) represents drug secretion from the blood back to the intestine via both passive permeability as well as active transport mechanisms mediated by efflux and uptake transporters expressed on Caco-2 cells. After preincubation for 25-30 min at 37 °C, samples were taken from the receptor 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.

[0518] The apparent transmittance in the ab (PappAB) and ba (PappBA) directions is calculated according to the following formula:

number

[0519] The Caco-2 efflux ratio (ER) is calculated as the ratio of PappBA / PappAB.

[0520] Table 37 presents data obtained in the disclosed assays for a selection of compounds according to the invention. [Table 38] The following formulation examples illustrate the invention without limiting its scope.

[0521] Examples of pharmaceutical preparations [Table 39]

[0522] The finely ground active substance, lactose and part of the corn starch are mixed together. 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 together. The mixture is compressed to produce tablets of suitable shape and size.

[0523] [Table 40]

[0524] The finely ground active substance, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remaining corn starch and water to form granules which are dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of suitable size.

[0525] [Table 41]

[0526] The active substance, lactose and cellulose are mixed together. The mixture is screened, then moistened with water, kneaded, wet granulated, dried, dry granulated, or directly final blended with magnesium stearate and compressed into tablets of suitable shape and size. When wet granulated, additional lactose or cellulose and magnesium stearate are added, and the mixture is compressed to produce tablets of suitable shape and size.

[0527] [Table 42]

[0528] 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 free of pyrogens, the filtrate is transferred under aseptic conditions into ampoules, which are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims

1. Formula (V): 【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 atoms 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; X is =C(R １５ )- or -N(R １５ ) - and R １４ and R １５ together with the atoms to which they are attached, ５～７ cycloalkyl or 5- to 7-membered heterocyclyl containing oxygen or sulfur, ５～７ Cycloalkyl and 5- to 7-membered heterocyclyl may optionally be one or more of the same or different R ３ａ and / or R ３ｂ and R ３ａ and R ３ｂ are each independently C １～４ Alkyl, C １～４ selected from the group consisting of haloalkyl and halogen; W is -N= or -CH=; V is -N= or -CH=; U is -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, oxazole, isoxazole, thiazole, isothiazole, and triazole; Each R ４ If present, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, cyano-C １～６ Alkyl, halogen, —OH, —NH ２ , —NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , -CN,C ３～５ independently 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 is a halogen or optionally one or more of the same or different C １～６ Alkyl, C １～６ Alkoxy, —C(O)—O—C １～６ a 3- to 11-membered heterocyclyl substituted with alkyl or a 5- or 6-membered heterocyclyl, １～６ The alkyl is optionally substituted with cyclopropyl or —OH; Or, R ５ is —O—C substituted with 3- to 11-membered heterocyclyl １～６ alkyl, and the 3- to 11-membered heterocyclyl optionally has one or more of the same or different R １２ is replaced by Each R １２ is C １～６ Alkyl, C １～６ Alkoxy, —C(O)—O—C １～６ selected from the group consisting of alkyl, halogen, and 3- to 11-membered heterocyclyl or a salt thereof.

2. Formula (I): 【Chemistry 2】 (In the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , Z, R ５ , A, p, U, V and W are as defined in claim 1.

2. The compound according to claim 1, or a salt thereof, having the formula:

3. Formula (Ia): 【Transformation 3】 (Wherein A, V, U, W and R ５ is as defined in claim 1) 2. The compound according to claim 1, or a salt thereof, having the formula:

4. 2. The compound or salt thereof according to claim 1, wherein ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole, and triazole.

5. Ring A is 【Chemistry 4】 The compound according to claim 1, or a salt thereof, selected from:

6. R ５ optionally one or more of the same or different C １～６ Alkyl, C １～６ 3- to 11-membered heterocyclyl substituted with alkoxy or 5- or 6-membered heterocyclyl, １～６ The alkyl is optionally substituted with cyclopropyl or Or, R ５ is substituted with 3- to 11-membered heterocyclyl; １～６ alkyl, and the 3- to 11-membered heterocyclyl optionally has one or more of the same or different R １２ is replaced by 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; The compound or salt thereof according to claim 1.

7. R ５ but, 【Transformation 5】 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of:

8. W is nitrogen (-N=), V is nitrogen (-N=), U is =C(R １１ ) - and R １１ is hydrogen, halogen and C １～４ alkoxy, The compound or salt thereof according to claim 1.

9. W is nitrogen (-N=), V is -CH=; U is nitrogen (-N=); The compound or salt thereof according to claim 1. 【Request Item 10】 【Chemistry 6】 【change】 【change】 2. The compound according to claim 1, or a salt thereof, selected from the group consisting of:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. 12. The pharmaceutical composition according to claim 11 for use in the treatment and / or prevention of cancer.

13. 13. The pharmaceutical composition of claim 12, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

14. The pharmaceutical composition of claim 12, wherein the cancer comprises tumor cells with a KRAS mutation or an amplification of the wild-type KRAS.

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