KRA decomposition compounds containing cyclized 2-amino-3-cyanothiophenes

Abstract

The present invention relates to compounds of formula (I) and derivatives which target KRAS and may be useful as drugs for treating and / or preventing cancer diseases.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a compound of formula (I): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 and R 7 have the meaning given to them in the claims and the specification. The present invention relates to compounds and derivatives of the formula:

[0002] 2. Background of the Invention V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small GTPase of the Ras family, and the protein exists in either a GTP- or GDP-bound state in cells (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, enhances 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). 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, including 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 activities, leading to an increase in the population of GTP-bound / active mutant Ras family proteins (McCormick et al., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). In turn, this leads to sustained activation of effector pathways downstream of mutant Ras family proteins (e.g., RAF / MEK / ERK, PI3K / AKT / mTOR, RalGDS pathways).

[0004] KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are found in a variety of human cancers, including lung, colon, and pancreatic cancers (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). In addition, alterations in Ras family proteins / Ras genes (e.g., mutations, overexpression, gene amplification) have also been reported as a mechanism of resistance 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).

[0005] In a subset of oncology indications, such as gastric, gastroesophageal junction, and esophageal cancers, significant amplification of the wild-type (WT) KRAS proto-oncogene acts as a driver alteration, and tumor models with this genotype become KRAS addicted in vitro and in vivo (Wong et al. Nat Med., 2018, 24(7):968-977). In contrast, WT cell lines with no KRAS amplification are KRAS-independent unless they have a secondary alteration in the gene that indirectly causes KRAS activation (Meyers et al., Nat Genet., 2017, 49:1779-1784). Based on these data, a therapeutic window is expected for KRAS-targeting agents with activity targeting KRAS WT.

[0006] For example, genetic changes affecting codon 12 of KRAS replace the glycine residue originally present at this position with a different amino acid, such as aspartic acid (G12D mutation or KRAS G12D), cysteine ​​(G12C mutation or KRAS G12C), valine (G12V mutation or KRAS G12V), etc. Similarly, mutations within codons 13, 61, and 146 of KRAS are commonly found in the KRAS gene. KRAS mutations are detectable in 35% of lung cancers, 45% of colon cancers, and up to 90% of pancreatic cancers (Herdeis et al., Curr Opin Struct Biol., 2021, 71:136-147).

[0007] Proteolytic targeting chimeras (PROTACs) bind to proteins and induce their ubiquitination, thereby causing their degradation. PROTACs are trimolecular or heterobifunctional molecules consisting of a part that binds to the protein to be degraded, a second part that can bind to and artificially recruit an E3 ubiquitin ligase, and a linker that connects the two parts. Upon formation of a trimeric complex consisting of the target protein, the PROTAC, and the ligase, the target protein is ubiquitinated due to the proximity of the ligase to the target. Ubiquitination serves as a post-translational modification of proteins, in particular leading to their recruitment to the proteasome, resulting in their proteolytic degradation. The multiubiquitin chains on the target protein are then recognized by the proteasome, and the target protein is degraded (Collins, I. et al., Biochem J., 2017, 474, 1127-1147; Hughes, SJ and Ciulli, A, Essays Biochem., 2017, 61, 505-516; Toure, M. and Crews, CM, Angew. Chem. Int. Ed. Engl., 2016, 55, 1966-1973).

[0008] In contrast to classical small molecule drugs, PROTAC-driven degradation operates in a substoichiometric manner, thus requiring low systemic exposure to achieve efficacy (Bondeson, DP et al., Nat. Chem. Bio., 2015, 11, 611; Winter, GE et al., Science, 2015, 348, 1376-1381). PROTACs have been shown to exhibit a higher degree of selectivity for protein degradation than the target ligand itself due to differences in complementarity at the protein-protein interaction interface of the ternary complex formed (Bondeson, DP et al., Cell Chemical Biology, 2018, 25, 78-87.e75;Gadd, MS et al. (2017), Nature Chemical Biology, 13, 514-521;Nowak, RP et al. (2018), Nat. Chem. Bio., 14(7):706-714;Zengerle, M. et al., ACS Chemical Biology, 2015, 10, 1770-1777). In addition, PROTACs are expected to expand the druggable proteome, as degradation is not functionally restricted to disease-causing protein domains. In the case of challenging multidomain proteins, traditionally considered difficult targets for drug development, the domains most amenable to ligand can be targeted for degradation, regardless of their functionality or vulnerability to small molecule blockade (Gechijian, LN et al., Nat. Chem. Bio., 2018, 14, 405-412).

[0009] Although irreversible in nature, triggered degradation of KRAS by recruitment of E3 ubiquitin ligases is expected to induce cellular effects comparable to irreversible inhibition. Moreover, because mutant KRAS is expected to still follow cycling between GTP-bound active and GDP-bound inactive states triggered by GEF / GAPs, triggered degradation of mutant KRAS by PROTACs that engage the GDP-bound state may gradually degrade a large portion of the total KRAS pool in cells. Thus, degradation of oncogenic KRAS mutants may inhibit downstream signaling in tumors, resulting in anticancer effects, as described for KRAS inhibition. Once the target is irreversibly degraded, restoration of downstream signaling activity is not only dependent on removal of the drug from the treated subject (e.g., by clearance), but is further limited by de novo resynthesis of the target protein by ribosomes. Irreversible inhibition has so far been restricted to KRAS G12C protein, which represents only a small fraction of the total KRAS mutant tumors. In contrast, induced degradation of KRAS has the potential to irreversibly inhibit KRAS signaling for most remaining tumor growth-driving KRAS mutations / alterations, provided that heterologous bifunctional degradation molecules can bind.

[0010] In summary, degraders of wild-type (eg, amplified or overexpressed) or mutant KRAS (eg, G12C, G12D, G12V, G13D) are expected to confer anti-cancer effects.

[0011] Thus, there remains a need for novel compounds capable of degrading KRAS in its wild-type or mutant form, which ideally are effective across a panel of protein forms. Such compounds would be useful in treating cancers dependent on or mediated by KRAS, particularly KRAS mutated at positions 12 or 13, and / or wild-type amplified KRAS-mediated cancers. The compounds also possess desirable pharmacological properties, including (but not limited to) metabolic stability, plasma protein binding, solubility, and permeability.

[0012] Detailed Description of the Invention compound It has now surprisingly been found that the compounds of the present invention have further advantages. In particular, the compounds of formula (I) as defined herein can act as degraders of KRAS. Surprisingly, the compounds described herein have been found to have antitumor activity. Advantageously, the compounds of the present invention are effective against wild-type (e.g., amplified or overexpressed) and mutant KRAS, such as G12C, G12D, G12V, G13D. In particular, the compounds of the present invention may be effective against a panel of KRAS mutants. Thus, the compounds of the present invention can be used, for example, for the treatment of diseases mediated by KRAS and / or characterized by excessive or abnormal cell proliferation.

[0013] In addition, compounds of the present invention advantageously possess desirable pharmacological properties including, but not limited to, metabolic stability, plasma protein binding, solubility and permeability.

[0014] Thus, the object of the present invention is to provide a compound of formula (I): [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 heterocycloalkyl; R 2a and R 2b 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 and / or selected from the group consisting of cycloalkyl and 3-5 membered heterocycloalkyl; In some cases, R 1a or R 1b One of the following and R 2a or R 2b together with the carbon atom to which they are attached form a cyclopropane ring, Z is -(CR 3a R 3b ) n - and Each R 3a and R 3b is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, C 3-5 independently selected from the group consisting of cycloalkyl and 3-5 membered heterocycloalkyl; R 3a and R 3b 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; R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -CN, C 3-5 selected from the group consisting of cycloalkyl and 3- to 5-membered heterocycloalkyl; Ring A is a 5-membered heteroarylene; R 5 If present, then each R 5 is 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 independently selected from the group consisting of cycloalkyl and 3-5 membered heterocycloalkyl; m is selected from the group consisting of 0, 1, 2 and 3; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R 11 )= R 11 is hydrogen, halogen and C 1-4 alkoxy; Ring B may contain one or more identical or different C 1-6 Alkyl, C 1-6 3- to 11-membered heterocycloalkylene optionally substituted by alkoxy or 5- to 6-membered heterocycloalkyl, where C 1-6 alkyl is optionally substituted with cyclopropyl; L is a bond, C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene and C 1-8 selected from the group consisting of alkoxylenes, X is -(CH2)- or -O-; Y is a 5-membered heteroarylene or -C(O)(NR 12 )-, wherein said 5-membered heteroarylene contains at least one nitrogen atom, and wherein said -C(O)(NR 12 )- is linked to X via a C atom, R 9 is C 1-4 is alkyl, R 10 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)R 12 and -C(O)OR 12 wherein said C is selected from the group consisting of 1-6 The alkyl is optionally substituted with -OH or -OP(O)(OH); Each R 12 are independently hydrogen or C 1-4 is alkyl, q is selected from the group consisting of 0, 1 and 2; R 6 If present, then each R 6 Each independently represents a halogen or C 1-3 is alkyl, R 7 is a halogen, C 1-3 is selected from the group consisting of alkyl, -CN, and 5-membered heteroaryl, wherein said 5-membered heteroaryl contains at least one nitrogen atom; R 8 and optionally substituted by R 8 is C 1-3 Alkyl or C 1-3 hydroxyalkyl] or a salt thereof.

[0015] In one embodiment, the compound or salt of formula (I) is * ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 and R 7 are as defined herein. This is shown by:

[0016] In another embodiment, the compound or salt of formula (I) is ** ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 and R 7 are as defined herein. This is shown by:

[0017] In another embodiment, the compound or salt of formula (I) is *** ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 and R 7 are as defined herein. This is shown by:

[0018] In another embodiment, the compound of formula (I) is **** ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4, ring A, R 5 , m, U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 and R 7 are as defined herein. This is shown by:

[0019] Formula (I * ), (I ** ), (I *** ) and (I **** It is to be understood that the configuration at the asymmetric carbon atom indicated in may be applied to any one or more of the aspects and / or preferred embodiments defined below.

[0020] In another embodiment, the compound of formula (I) has the formula (Ia): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 , R 7 and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (Ia) is * ), (I ** ), (I *** ) or (I **** )

[0021] In another embodiment, the compound of formula (I) has the formula (Ib): [ka] [In the formula, R 1a , R 1b , R 2a , R2b , Z, R 4 , U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 , R 7 and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (Ib) is * ), (I ** ), (I *** ) or (I **** )

[0022] In another embodiment, the compound of formula (I) has the formula (Ic): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 , R 7 and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (Ic) is * ), (I ** ), (I *** ) or (I **** )

[0023] In another embodiment, the compound of formula (I) has the formula (Id): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, ring B, L, X, Y, R 9, R 10 , q, R 6 , R 7 and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (Id) is * ), (I ** ), (I *** ) or (I **** )

[0024] In another embodiment, the compound of formula (I) has the formula (Ie): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, ring B, L, X, Y, R 9 , R 10 , q, R 6 , R 7 and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (Ie) is * ), (I ** ), (I *** ) or (I **** )

[0025] In another embodiment, the compound of formula (I) has the formula (If): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, ring B, L, X, R 9 , R 10 , q, R 6 , R7 and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (If) is as shown in formula (I * ), (I ** ), (I *** ) or (I **** )

[0026] In another embodiment, the compound of formula (I) has the formula (Ig): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, ring B, L, X, R 9 , R 10 , q, R 6 , R 7 and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (Ig) is * ), (I ** ), (I *** ) or (I **** )

[0027] In another embodiment, the compound of formula (I) has the formula (Ih): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, ring B, L, X, R 9 , R 10 , q, R 6 , R 7and stereochemistry is as defined herein. Preferably, the stereochemistry of the chiral center in formula (Ih) is * ), (I ** ), (I *** ) or (I **** )

[0028] Formula (I * ), (I ** ), (I *** ), (I **** Each of the compounds represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih) is understood to be a subset of the compounds represented by formula (I). Any reference to a compound represented by formula (I) is understood to be a reference to a compound represented by formula (I) unless otherwise specified. * ), (I ** ), (I *** ), (I **** The present invention also refers to and is meant to include compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih). * ), (I ** ), (I *** ), (I **** ), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih), individually or collectively, may be referred to as a "subformula" or "subformulas" of formula (I).

[0029] Formula (I), (I * ), (I ** ), (I *** ), (I **** In one embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), R 1a or R 1b One of the groups is hydrogen.

[0030] Formula (I), (I * ), (I **), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a and R 1b is hydrogen.

[0031] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 2a or R 2b One of the groups is hydrogen.

[0032] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 2a and R 2b is hydrogen.

[0033] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen.

[0034] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 3a or R 3b One of the groups is hydrogen.

[0035] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 3a and R 3b is hydrogen.

[0036] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a , R 2b , R 3a and R 3b is hydrogen.

[0037] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), n is 1.

[0038] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), Z is -CH2-.

[0039] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R1a , R 1b , R 2a and R 2b is hydrogen and Z is -CH2-.

[0040] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 4 and the carbon atom to which ring A is attached is in the (S) configuration.

[0041] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 4 is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Cyano-C 1-3 Alkyl, halogen, -OH, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, -CN, C 3-4 It is selected from the group consisting of cycloalkyl and 3-4 membered heterocycloalkyl.

[0042] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 4 is C 1-6 It is an alkyl.

[0043] Formula (I), (I * ), (I ** ), (I *** ), (I**** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 4 is C 1-3 It is an alkyl.

[0044] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 4 is methyl.

[0045] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl.

[0046] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, R 4 and the carbon atom to which ring A is attached is in the (S) configuration.

[0047] Formula (I), (I * ), (I ** ), (I *** ), (I ****In another embodiment of the compounds of formula (I), (If), (Ig), or (Ih), Ring A is selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, and triazole.

[0048] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds represented by formula (I), (If), (Ig) or (Ih), Ring A is selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, oxadiazole and thiadiazole.

[0049] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds represented by formula (I), (If), (Ig) or (Ih), ring A is selected from the group consisting of isoxazole, isothiazole and oxadiazole.

[0050] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (I), (If), (Ig) or (Ih), ring A is [ka] is selected from the group consisting of:

[0051] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (I), (If), (Ig) or (Ih), ring A is [ka] is selected from the group consisting of:

[0052] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), at any occurrence, the oxadiadiol is [ka] is selected from the group consisting of:

[0053] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), at any occurrence, the oxadiadiol is [ka] It is.

[0054] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), in any occurrence, the isoxazole is [ka] It is.

[0055] Formula (I), (I * ), (I ** ), (I *** ), (I ****In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), in any occurrence, the isothiazole is [ka] It is.

[0056] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (I), (If), (Ig), or (Ih), m is 0.

[0057] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 11 is hydrogen.

[0058] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), U, V and W are each independently =N- or =C(H)-.

[0059] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), at least one of V or W is =N-.

[0060] Formula (I), (I * ), (I ** ), (I *** ), (I**** In another embodiment of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), one of V or W is =N-.

[0061] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), V and W are both =N-.

[0062] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), W is =N-.

[0063] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), U is ═N—, V is ═C(H)— and W is ═N—.

[0064] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), U is ═C(H)—, V is ═N— and W is ═N—.

[0065] Formula (I), (I * ), (I ** ), (I *** ), (I ****In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl and W is =N-.

[0066] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, W is =N, and R 4 and the carbon atom to which ring A is attached is in the (S) configuration.

[0067] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, U is =N-, V is =C(H)-, and W is =N-.

[0068] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, U is =C(H)-, V is =N-, and W is =N-.

[0069] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, U is =N-, V is =C(H)-, W is =N-, and R 4 and the carbon atom to which ring A is attached is in the (S) configuration.

[0070] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, U is =C(H)-, V is =N-, W is =N-, and R 4 and the carbon atom to which ring A is attached is in the (S) configuration.

[0071] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B contains at least one nitrogen atom.

[0072] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B contains two nitrogen atoms.

[0073] (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is selected from the group consisting of one C 1-6 substituted with alkyl, optionally with one or more of the same or different C 1-6 Alkyl, C 1-6 3- to 11-membered heterocycloalkylene further substituted by alkoxy or 5- to 6-membered heterocycloalkyl, where C 1-6 Any of the alkyls is optionally and independently substituted by cyclopropyl, preferably wherein said 3- to 11-membered heterocycloalkylene contains at least one nitrogen atom or wherein said 3- to 11-membered heterocycloalkylene contains two nitrogen atoms.

[0074] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is one or more identical or different C 1-3 Alkyl, C 1-3 5-8 membered heterocycloalkylene optionally substituted by alkoxy or 5-6 membered heterocycloalkyl, where C 1-3Alkyl is optionally substituted by cyclopropyl, preferably wherein said 5-8 membered heterocycloalkylene contains at least one nitrogen atom or wherein said 5-8 membered heterocycloalkylene contains two nitrogen atoms.

[0075] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is selected from the group consisting of one C 1-3 substituted with alkyl, optionally with one or more of the same or different C 1-3 Alkyl, C 1-3 and 5- to 8-membered heterocycloalkylene further substituted by alkoxy or 5- to 6-membered heterocycloalkyl, preferably wherein said 5- to 8-membered heterocycloalkylene contains at least one nitrogen atom or wherein said 5- to 8-membered heterocycloalkylene contains two nitrogen atoms.

[0076] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is [ka] [In the formula, r is 0, 1 or 2; s is 0, 1, 2, 3 or 4; R 13 is C 1-6 alkyl, and each R 14 are each independently 1-6 Alkyl, C 1-6 alkoxy or 5-6 membered heterocycloalkyl, C 1-6 Any of the alkyls is optionally substituted with cyclopropyl. It is.

[0077] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is [ka] [In the formula, r is 0, 1 or 2; s is 0, 1, 2, 3 or 4; R 13 is C 1-3 alkyl, and each R 14 are each independently 1-3 Alkyl, C 1-3 alkoxy or 5-6 membered heterocycloalkyl. It is.

[0078] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is [ka] [In the formula, r is 0, 1 or 2; s is 0, 1 or 2; R 13 is C 1-3 alkyl, and each R 14 are each independently the same or different C 1-3 is alkyl] It is.

[0079] Preferably, R 13 The carbon atom to which is attached is in the (S) configuration.

[0080] Preferably, r is 0 or 1. Preferably, r is 0. Preferably, r is 1.

[0081] Preferably, s is 0, 1 or 2. Preferably, s is 0, and preferably, s is 1. Preferably, s is 2.

[0082] Preferably, R 13 is methyl.

[0083] Preferably, R 14 If exists, R 14 is methyl.

[0084] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is [ka] wherein p is selected from the group consisting of 0, 1, 2 and 3. It is.

[0085] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is [ka] wherein p is 1 or 2 and the chiral carbon atom is in the (S) configuration. It is.

[0086] Formula (I), (I * ), (I ** ), (I *** ), (I ****In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is [ka] is selected from the group consisting of:

[0087] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), ring B is [ka] is selected from the group consisting of:

[0088] It is to be understood that "(C)" and "(L)" represent the atom or substituent of formula (I) to which Ring B is attached.

[0089] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), L is C 1-8 Alkylene, C 2-8 Alkenylene and C 1-8 The alkoxylenes are selected from the group consisting of:

[0090] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), L is C 1-6 Alkylene, C 2-6 Alkenylene and C 1-6 The alkoxylenes are selected from the group consisting of:

[0091] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)6-, [ka] is selected from the group consisting of:

[0092] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)6-, [ka] is selected from the group consisting of:

[0093] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)6-, [ka] is selected from the group consisting of:

[0094] Formula (I), (I * ), (I ** ), (I *** ), (I**** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), L is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)6-, [ka] is selected from the group consisting of:

[0095] It should be understood that "(B)" and "(Y)" represent the substituents of formula (I) to which L is attached.

[0096] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), X is -(CH2)-.

[0097] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), X is -O-.

[0098] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is a 5-membered heteroarylene or -C(O)(NH)-, wherein the 5-membered heteroarylene contains at least one nitrogen atom, and wherein the -C(O)(NH)- is linked to X via a C atom.

[0099] Formula (I), (I * ), (I ** ), (I *** ), (I**** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole and -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X via a C atom, preferably where R 12 is hydrogen.

[0100] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is selected from the group consisting of pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole and triazole.

[0101] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is isoxazole, triazole or -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X via a C atom.

[0102] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound of formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is isoxazole, triazole or -C(O)(NH)-, where -C(O)(NH)- is linked to X via a C atom.

[0103] Formula (I), (I* ), (I ** ), (I *** ), (I **** In another embodiment of the compound of formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is -C(O)(NH)-, where -C(O)(NH)- is linked to X via a C atom.

[0104] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is isoxazole or triazole.

[0105] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is isoxazole.

[0106] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is triazole.

[0107] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is [ka] is selected from the group consisting of:

[0108] Formula (I), (I * ), (I ** ), (I*** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is [ka] is selected from the group consisting of:

[0109] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is [ka] is selected from the group consisting of:

[0110] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is [ka] It is.

[0111] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), Y is [ka] It is.

[0112] Formula (I), (I * ), (I ** ), (I *** ), (I**** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), at any occurrence, the triazole is [ka] is selected from the group consisting of:

[0113] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), Y is -C(O)(NR 12 )-, X is -(CH2)-, where said -C(O)(NR 12 )- is linked to X via a C atom.

[0114] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is -C(O)(NR 12 )- or X is -(CH2)- or -O- and Y is a 5-membered heteroarylene containing at least one nitrogen atom, wherein said -C(O)(NR 12 )- is linked to X via a C atom.

[0115] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X via a C atom.

[0116] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X through a C atom, and L is C 1-8 Alkylene or C 1-8 It is an alkoxylene.

[0117] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X through a C atom, and L is C 1-6 Alkylene or C 1-4 It is an alkoxylene.

[0118] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)- or -O- and Y is a 5-membered heteroarylene containing at least one nitrogen atom.

[0119] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is a 5-membered heteroarylene containing at least one nitrogen atom.

[0120] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)-, Y is a 5-membered heteroarylene containing at least one nitrogen atom, and L is C 1-8 It is alkylene.

[0121] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -O- and Y is a 5-membered heteroarylene containing at least one nitrogen atom.

[0122] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound of formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is selected from the group consisting of pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, and triazole.

[0123] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)-, Y is selected from the group consisting of pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, and triazole, and L is C. 1-8 It is alkylene.

[0124] Formula (I), (I * ), (I** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -O- and Y is selected from the group consisting of pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole and triazole.

[0125] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is isoxazole or triazole.

[0126] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)-, Y is isoxazole or triazole, and L is C 1-8 It is alkylene.

[0127] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)- and Y is triazole.

[0128] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)-, Y is triazole, and L is C 1-8 It is alkylene.

[0129] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH2)-, Y is triazole, and L is C 1-6 It is alkylene.

[0130] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -O- and Y is isoxazole or triazole.

[0131] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -O- and Y is isoxazole.

[0132] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -O- and Y is triazole.

[0133] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)- and Y is [ka] is selected from the group consisting of:

[0134] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)- and Y is [ka] and L is selected from the group consisting of C 1-8 It is alkylene.

[0135] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -O- and Y is [ka] is selected from the group consisting of:

[0136] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)- and Y is [ka] is selected from the group consisting of:

[0137] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)- and Y is [ka] and L is selected from the group consisting of C 1-8 It is alkylene.

[0138] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -O- and Y is [ka] is selected from the group consisting of:

[0139] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH)- and Y is a 5-membered heteroarylene or -C(O)(NR 12 )-, wherein said 5-membered heteroarylene contains at least one nitrogen atom, and wherein said -C(O)(NR 12 )- is linked to X via a C atom or X is -O- and Y is a 5-membered heteroarylene containing at least one nitrogen atom.

[0140] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH)- and Y is a 5-membered heteroarylene containing at least one nitrogen atom or -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X via a C atom.

[0141] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH)- and Y is a 5-membered heteroarylene containing at least one nitrogen atom or -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X through a C atom, and L is C 1-8 It is alkylene.

[0142] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)- and Y is selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole and -C(O)(NR 12 or X is -O- and Y is selected from the group consisting of pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, and triazole, wherein said -C(O)(NR 12 )- is linked to X via a C atom.

[0143] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH2)- and Y is selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole and -C(O)(NR 12 )-, wherein said -C(O)(NR 12)- is linked to X via a C atom.

[0144] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), or (Ie), X is -(CH)- and Y is triazole or -C(O)(NR 12 )- or X is -O- and Y is triazole or isoxazole, where the -C(O)(NR 12 )- is linked to X via a C atom.

[0145] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH)- and Y is triazole or -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X via a C atom.

[0146] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), X is -(CH)- and Y is triazole or -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X through a C atom, and L is C 1-8 It is alkylene.

[0147] Formula (I), (I * ), (I ** ), (I *** ), (I ****In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), (B)-L-X-Y-(C) is [ka] is selected from the group consisting of:

[0148] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), (B)-L-X-Y-(C) is [ka] is selected from the group consisting of:

[0149] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 9 is a branched chain C 1-4 It is an alkyl.

[0150] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 9 is isopropyl or tert-butyl.

[0151] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R9 is isopropyl.

[0152] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9 is isopropyl, and Y is a 5-membered heteroarylene containing at least one nitrogen atom.

[0153] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9 is isopropyl, and Y is pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, and -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X via a C atom, preferably where R 12 is hydrogen.

[0154] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9 is isopropyl and Y is isoxazole or triazole.

[0155] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9 is isopropyl and Y is [ka] is selected from the group consisting of:

[0156] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9 is isopropyl and Y is [ka] is selected from the group consisting of:

[0157] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9 is tert-butyl.

[0158] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9 is tert-butyl and Y is -C(O)(NR 12 )-, wherein said -C(O)(NR 12 )- is linked to X via a C atom.

[0159] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id) or (Ie), R 9is tert-butyl and Y is -C(O)(NH)-, where said -C(O)(NH)- is linked to X via a C atom.

[0160] Formula (I), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 9 The carbon atom to which is attached is in the (S) configuration.

[0161] Formula (I), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 9 The carbon atom to which is attached is in the (R) configuration.

[0162] Formula (I), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 9 is isopropyl, R 9 The carbon atom to which is attached is in the (S) configuration.

[0163] Formula (I), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 9 is isopropyl, R 9 The carbon atom to which is attached is in the (R) configuration.

[0164] Formula (I), (I * ), (I ** ), (I *** ), (I ****In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, W is =N-, and R 9 is isopropyl.

[0165] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, W is =N-, and R 9 is isopropyl, R 4 and the carbon atom to which ring A is attached is in the (S) configuration, R 9 The carbon atom to which is attached is in the (S) configuration.

[0166] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is hydrogen, C 1-6 Alkyl and -C(O)OR 12 wherein said C is selected from the group consisting of 1-6 The alkyl is optionally substituted with -OH or -OP(O)(OH).

[0167] Formula (I), (I * ), (I ** ), (I *** ), (I ****In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is hydrogen.

[0168] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is C 1-6 Alkyl and -C(O)OR 12 wherein said C is selected from the group consisting of 1-6 The alkyl is optionally substituted with -OH or -OP(O)(OH).

[0169] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is hydrogen, C 1-4 Alkyl and -C(O)OR 12 wherein said C is selected from the group consisting of 1-4 The alkyl is optionally substituted with -OH or -OP(O)(OH).

[0170] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is hydrogen, C 1-4 Alkyl and -C(O)OR 12 wherein said C is selected from the group consisting of 1-4 The alkyl is optionally substituted with -OH.

[0171] Formula (I), (I* ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is not hydrogen, but R 10 The carbon atom to which is attached is in the (S) configuration.

[0172] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is not hydrogen, but R 10 The carbon atom to which is attached is in the (R) configuration.

[0173] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 10 is hydrogen, methyl, -CH2OH, -CH2CH2OH, [ka] , -CH2CH2OP(O)(OH)2, -C(O)OCH3 and -C(O)OH.

[0174] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 12 is hydrogen or methyl.

[0175] Formula (I), (I *), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 12 is hydrogen.

[0176] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 12 is methyl.

[0177] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), q is 0. When q is 0, R 6 is to be understood to be hydrogen.

[0178] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), q is 1. When q is 1, R 6 is R 7 It may be meta or ortho to R. 6 R 7 If it is in meta for R 6a It is labeled as R 6 R 7 If it is orthogonal to R 6b and is labeled.

[0179] If q is 1, then R 6a and R 6bare each independently hydrogen, halogen, or C 1-3 When q is 1, R 6a or R 6b It is to be understood that one of is hydrogen.

[0180] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), q is 2. When q is 2, two R 6 There exists. R 7 R in meta against 6 is R 6a It is labeled as R 7 R in ortho 6 is R 6b and is labeled.

[0181] If q is 2, then R 6a and R 6b Each independently represents a halogen or C 1-3 It is an alkyl.

[0182] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), q is 0 or 1.

[0183] Preferably, R 6a is hydrogen or halogen.

[0184] Preferably, R 6a is hydrogen or fluorine.

[0185] Preferably, R 6a is hydrogen.

[0186] Preferably, R6a is fluorine.

[0187] Preferably, R 6b is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

[0188] Preferably, R 6a is hydrogen or halogen, R 6b is hydrogen, halogen or C 1-3 It is an alkyl.

[0189] Preferably, R 6a is hydrogen and R 6b is hydrogen, halogen and C 1-3 It is an alkyl.

[0190] Preferably, R 6a and R 6b are each independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

[0191] Preferably, R 6a is hydrogen or fluorine, R 6b is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

[0192] Preferably, R 6a is hydrogen and R 6b is selected from the group consisting of fluorine, chlorine and methyl.

[0193] Preferably, R 6a and R 6b is hydrogen.

[0194] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 7is selected from the group consisting of chlorine, bromine, isopropyl, -CN, thiazole, triazole, and imidazole, wherein said thiazole, triazole, or imidazole is selected from the group consisting of R 8 is optionally replaced by

[0195] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 7 is a halogen, C 1-3 is selected from the group consisting of alkyl, -CN, thiazole, triazole and imidazole, wherein the thiazole is R 8 has been replaced by

[0196] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 7 is a halogen, C 1-3 It is selected from the group consisting of alkyl, -CN, thiazole, triazole and imidazole, wherein said thiazole is substituted with methyl or -CH2OH.

[0197] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 7 is selected from the group consisting of chlorine, bromine, isopropyl, -CN, thiazole, triazole, and imidazole, wherein said thiazole is substituted with methyl or -CHOH.

[0198] Formula (I), (I * ), (I** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 7 is chlorine, bromine, isopropyl, -CN, [ka] is selected from the group consisting of:

[0199] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 8 is methyl or -CHOH.

[0200] Formula (I), (I * ), (I ** ), (I *** ), (I **** In another embodiment of the compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih), R 8 is methyl.

[0201] Preferred embodiments of the compounds of formula (I) are represented by the compounds of formulas I-1 to I-48 defined below, including any stereoisomers thereof.

[0202] It is to be understood that any two or more aspects and / or preferred embodiments of formula (I) or subformulas thereof may be combined in any manner that results in a chemically stable structure to provide further aspects and / or preferred embodiments of formula (I) or subformulas thereof.

[0203] Further, the present invention relates to a compound represented by formula (I), * ), (I ** ), (I *** ), (I**** The present invention relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih) (including all aspects and preferred embodiments thereof).

[0204] For example, the formula (I), (I * ), (I ** ), (I *** ), (I **** The compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih) (including all aspects and preferred embodiments thereof) are potential prodrugs in which the ester is cleaved under physiological conditions and are also part of the present invention.

[0205] Further, the present invention relates to a compound represented by formula (I), * ), (I ** ), (I *** ), (I **** The present invention relates to a pharma- ceutically acceptable salt of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih) (including all aspects and preferred embodiments thereof).

[0206] A further object of the present invention is to provide a compound of formula (II): [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 heterocycloalkyl; R 2a and R 2bare 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 3-5 membered heterocycloalkyl; In some cases, R 1a or R 1b One of the following and R 2a or R 2b together with the carbon atom to which they are attached form a cyclopropane ring, Z is -(CR 3a R 3b ) n - and Each R 3a and R 3b is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, C 3-5 independently selected from the group consisting of cycloalkyl and 3-5 membered heterocycloalkyl; R 3a and R 3b 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; R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -CN, C 3-5selected from the group consisting of cycloalkyl and 3- to 5-membered heterocycloalkyl; Ring A is selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, and triazole; R 5 If present, then each R 5 is 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 independently selected from the group consisting of cycloalkyl and 3-5 membered heterocycloalkyl; m is selected from the group consisting of 0, 1, 2 and 3; U, V and W are each independently =N- or =C(H)-; p is selected from the group consisting of 0, 1, 2 and 3; L is a bond, C 1-6 Alkylene, C 2-6 Alkenylene and C 1-6 selected from the group consisting of alkoxylenes, q is selected from the group consisting of 0, 1 and 2; R 6 If present, then each R 6 Each independently represents a halogen or C 1-3 is alkyl, R 7 is a halogen, C 1-3 is selected from the group consisting of alkyl, -CN, and 5-membered heteroaryl, wherein said 5-membered heteroaryl contains at least one nitrogen atom; R 8 and optionally substituted by R 8 is C 1-3 Alkyl or C 1-3 hydroxyalkyl] or a salt thereof.

[0207] In one embodiment, the compound or salt of formula (II) is * ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0208] In another embodiment, the compound or salt of formula (II) is ** ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0209] In another embodiment, the compound or salt of formula (II) is *** ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, p, L, q, R6 and R 7 are as defined herein. This is shown by:

[0210] In another embodiment, the compound of formula (II) is **** ): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0211] Formula (II * ), (II ** ), (II *** ) and (II **** It is to be understood that the configuration at the asymmetric carbon atom indicated in may be applied to any one or more of the aspects and / or preferred embodiments defined below.

[0212] In one embodiment, the compound of formula (II) has the formula (IIa): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0213] Preferably, it is of the formula (II * A): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0214] In another embodiment, the compound of formula (II) has the formula (IIb): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0215] Preferably, it is of the formula (II * b): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0216] In another embodiment, the compound of formula (II) has the formula (IIc): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0217] Preferably, it is of the formula (II * c): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0218] In another embodiment, the compound of formula (II) has the formula (IId): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0219] Preferably, it is of the formula (II * d): [ka] [In the formula, R 1a , R 1b , R2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0220] In another embodiment, the compound of formula (II) has the formula (IIe): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0221] Preferably, it is of the formula (II * e): [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , U, V, W, p, L, q, R 6 and R 7 are as defined herein. This is shown by:

[0222] Formula (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II *Each of the compounds represented by formula (IIe) or (IIf) is a subset of the compounds represented by formula (II), and any reference to a compound represented by formula (II) is a reference to the compound represented by formula (IIe) or (IIf), unless otherwise specified. * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * It is understood that the compounds of formula (II e) and (IIf) are also mentioned and are meant to be included in these compounds. * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * e) and (IIf) are sometimes referred to as "subformulas" of formula (II).

[0223] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In one embodiment of the compound represented by e) or (IIf), R 1a or R 1b One of them is hydrogen.

[0224] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II *a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 1a and R 1b is hydrogen.

[0225] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 2a or R 2b One of them is hydrogen.

[0226] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 2a and R 2b is hydrogen.

[0227] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II* In another embodiment of the compound represented by e) or (IIf), R 1a , R 1b , R 2a , R 2b is hydrogen.

[0228] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 3a or R 3b One of them is hydrogen.

[0229] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 3a and R 3b is hydrogen.

[0230] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 1a , R1b , R 2a , R 2b , R 3a and R 3b is hydrogen.

[0231] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), n is 1.

[0232] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), Z is -CH2-.

[0233] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 1a , R 1b , R 2a and R 2b is hydrogen and Z is -CH2-.

[0234] Formula (II), (II *** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 4 and the carbon atom to which ring A is attached is in the (S) configuration.

[0235] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 4 is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Cyano-C 1-3 Alkyl, halogen, -OH, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, -CN, C 3-4 It is selected from the group consisting of cycloalkyl and 3-4 membered heterocycloalkyl.

[0236] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R4 is C 1-6 It is an alkyl.

[0237] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 4 is C 1-3 It is an alkyl.

[0238] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 4 is methyl.

[0239] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl.

[0240] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl, R 4 and the carbon atom to which ring A is attached is in the (S) configuration.

[0241] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of a compound represented by e) or (IIf), Ring A is selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and thiadiazole.

[0242] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II *In another embodiment of the compounds represented by e) or (IIf), Ring A is selected from the group consisting of isoxazole, isothiazole, and oxadiazole.

[0243] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), ring A is [ka] is selected from the group consisting of:

[0244] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), A is [ka] is selected from the group consisting of:

[0245] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II* d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), the oxadiadiol is [ka] is selected from the group consisting of:

[0246] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), the oxadiadiol is [ka] It is.

[0247] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), the isoxazole is [ka] It is.

[0248] Formula (II), (II * ), (II ** ), (II *** ), (II ****), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), the isothiazole is [ka] It is.

[0249] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), m is 0.

[0250] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), at least one of V or W is =N-.

[0251] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II *c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), one of V or W is =N-.

[0252] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), V and W are both =N-.

[0253] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), W is =N-.

[0254] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of a compound represented by e) or (IIf), U is ═N—, V is ═C(H)—, and W is ═N—.

[0255] Formula (II), (II* ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of a compound represented by e) or (IIf), U is ═C(H)—, V is ═N—, and W is ═N—.

[0256] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 1a , R 1b , R 2a and R 2b is hydrogen, Z is -CH2-, and R 4 is methyl and W is =N-.

[0257] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), p is 1 or 2.

[0258] Formula (II), (II * ), (II ** ), (II *** ), (II**** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), p is 1.

[0259] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), p is 2.

[0260] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), L is C 1-6 Alkylene, C 2-6 Alkenylene and C 1-6 Preferably, the C is selected from the group consisting of alkoxylenes. 1-6 Alkylene, C 2-6 Alkenylene and C 1-6 The alkoxylenes are linear.

[0261] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II *a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), L is a bond, C 1-4 Alkylene, C 2-4 Alkenylene and C 1-4 Preferably, the C is selected from the group consisting of alkoxylenes. 1-4 Alkylene, C 2-4 Alkenylene and C 1-4 The alkoxylenes are linear.

[0262] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), L is C 1-4 Alkylene, C 2-4 Alkenylene and C 1-4 The alkoxylenes are selected from the group consisting of:

[0263] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), L is C 1-5 Alkylene, C3 alkenylene and C 3-4 The alkoxylenes are selected from the group consisting of:

[0264] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), L is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)5-, [ka] is selected from the group consisting of:

[0265] It should be understood that "(N)" and "(C)" indicate the atom of formula (I) to which L is attached.

[0266] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 6 If present, then each R 6 Each independently represents a halogen or C 1-3 It is an alkyl.

[0267] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II* In another embodiment of the compounds represented by e) or (IIf), q is 0. When q is 0, R 6 is to be understood to be hydrogen.

[0268] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), q is 1. When q is 1, R 6 is R 7 It may be meta or ortho to R. 6 R 7 If it is in meta for R 6a It is labeled as R 6 R 7 If it is orthogonal to R 6b and is labeled.

[0269] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), when q is 1, R 6a and R 6b are each independently hydrogen, halogen, or C 1-3 When q is 1, R 6a or R 6b It is to be understood that one of is hydrogen.

[0270] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), q is 2. When q is 2, two R 6 There exists. R 7 R in meta against 6 is R 6a It is labeled as R 7 R in ortho 6 is R 6b and is labeled.

[0271] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), when q is 2, R 6a and R 6b are each independently a halogen or C 1-3 It is an alkyl.

[0272] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II *In another embodiment of the compounds represented by e) or (IIf), q is 0 or 1.

[0273] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compounds represented by e) or (IIf), p is 1 or 2 and q is 0 or 1.

[0274] In another embodiment, the compound of formula (II) is represented by formula (IIf) [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , Z, R 4 , ring A, R 5 , m, U, V, W, p, L and R 7 is as defined herein, and R 6a and R 6b are each independently hydrogen, halogen, or C 1-3 alkyl] This is shown by:

[0275] In one embodiment of the compound of formula (IIf), R 6a is hydrogen or halogen.

[0276] In another embodiment of the compound of formula (IIf), R 6a is hydrogen or fluorine.

[0277] In another embodiment of the compound of formula (IIf), R 6a is hydrogen.

[0278] In another embodiment of the compound of formula (IIf), R 6a is fluorine.

[0279] In another embodiment of the compound of formula (IIf), R 6b is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

[0280] In another embodiment of the compound of formula (IIf), R 6a is hydrogen or halogen, R 1b is hydrogen, halogen or C 1-3 It is an alkyl.

[0281] In another embodiment of the compound of formula (IIf), R 6a is hydrogen and R 6b is hydrogen, halogen and C 1-3 It is an alkyl.

[0282] In another embodiment of the compound of formula (IIf), R 6a and R 6b are each independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

[0283] In another embodiment of the compound of formula (IIf), R 6a is hydrogen or fluorine, R 6b is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

[0284] In another embodiment of the compound of formula (IIf), R 6a is hydrogen and R 6b is selected from the group consisting of fluorine, chlorine and methyl.

[0285] In another embodiment of the compound of formula (IIf), R 1a and R 1b is hydrogen.

[0286] Formula (II), (II * ), (II **), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 7 is selected from the group consisting of chlorine, bromine, isopropyl, -CN, thiazole, triazole, and imidazole, wherein said thiazole, triazole, or imidazole is selected from the group consisting of R 8 is optionally replaced by

[0287] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 7 is a halogen, C 1-3 is selected from the group consisting of alkyl, -CN, thiazole, triazole and imidazole, wherein the thiazole is R 8 has been replaced by

[0288] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 7 is a halogen, C 1-3It is selected from the group consisting of alkyl, -CN, thiazole, triazole and imidazole, wherein said thiazole is substituted with methyl or -CH2OH.

[0289] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 7 is selected from the group consisting of chlorine, bromine, isopropyl, -CN, thiazole, triazole, and imidazole, wherein said thiazole is substituted with methyl or -CHOH.

[0290] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 7 is chlorine, bromine, isopropyl, -CN, [ka] is selected from the group consisting of:

[0291] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II *b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 8 is methyl or -CHOH.

[0292] Formula (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * In another embodiment of the compound represented by e) or (IIf), R 8 is methyl.

[0293] Preferred embodiments of the compounds of formula (I) or (II) are represented by the compounds of formulas I-1 to I-27 defined below, including any stereoisomers thereof.

[0294] The present invention also refers to a method for preparing a compound of formula (II) by the process of Scheme 3 or 4.

[0295] Scheme 3 [ka]

[0296] Scheme 4 [ka]

[0297] Further objects of the present invention are to provide [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0298] The present invention further relates to a compound represented by formula (II), * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * The present invention relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of the compounds of formula (e) or (IIf) (including all aspects and preferred embodiments thereof).

[0299] The present invention further relates to a compound represented by formula (II), * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * e) or (IIf) (including all aspects and preferred embodiments thereof) of the compound.

[0300] The present invention further relates to a compound represented by formula (II), * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * e) or (IIf) (including all aspects and preferred embodiments thereof) of the solvates thereof.

[0301] For example, the formula (II) having an ester group, * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * Compounds of formula e) or (IIf) (including all aspects and preferred embodiments thereof) are potential prodrugs in which the ester is cleaved under physiological conditions and are also part of the present invention.

[0302] The present invention further relates to a compound represented by formula (II), * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * e) or (IIf) and a pharma- ceutically acceptable salt thereof, including all aspects and preferred embodiments thereof.

[0303] Medical Use - Treatment Method Indications – Patient Population The present invention is directed to compounds which inhibit or degrade KRAS, preferably KRAS mutated at residue 12, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A and KRAS G12R inhibitors, preferably inhibitors of KRAS G12C and / or KRAS G12D or inhibitors selective for KRAS G12D, as well as compounds which inhibit KRAS wild type, preferably amplified, KRAS mutated at residue 13, such as KRAS G13D or KRAS mutated at residue 61, such as KRAS Q61H. In particular, the compounds of the present invention may be useful for the treatment and / or prevention of diseases and / or conditions that depend on or are mediated by KRAS, preferably KRAS mutated at residue 12, e.g., KRAS G12C, KRAS G12D, KRAS G12V, more preferably, G12D or an amplification of KRAS wild type or KRAS mutated at residue 13, e.g., KRAS G13D or KRAS mutated at residue 61, e.g., KRAS Q61H.

[0304] 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 a medicament.

[0305] 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.

[0306] 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 treating and / or preventing a disease and / or condition mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12C, KRAS G12D, KRAS G12V, more preferably by G12D or by amplification of KRAS wild type or by KRAS mutated at residue 13, e.g. KRAS G13D.

[0307] 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 a disease and / or condition mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12C, KRAS G12D, KRAS G12V, more preferably by G12D or by amplification of KRAS wild type or by KRAS mutated at residue 13, e.g. KRAS G13D.

[0308] In a further aspect, the present invention relates to a method for treating and / or preventing diseases and / or conditions mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12C, KRAS G12D, KRAS G12V, more preferably by G12D or by amplification of KRAS wild type or by KRAS mutated at residue 13, e.g. KRAS G13D, which comprises administering to a human a therapeutically effective amount of a compound of the invention or a pharma- ceutically acceptable salt thereof.

[0309] 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 treating and / or preventing cancer.

[0310] 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.

[0311] 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 treating and / or preventing cancer.

[0312] 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.

[0313] Preferably, the cancer as defined herein (above or below) comprises a KRAS mutation. In particular, the KRAS mutation comprises, for example, a mutation of the KRAS gene and KRAS protein, such as an overexpression of KRAS, an amplification of 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 show one or more of these mutations / alterations.

[0314] Preferably, the cancer as defined herein (above or below) comprises, in addition to or alternatively to 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.

[0315] Preferably, cancer as defined herein (above or below) comprises, in addition to or alternatively to KRAS mutations, mutations in receptor tyrosine kinases (RTKs), including EGFR, MET and ERBB2 mutations.

[0316] 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 treating and / or preventing 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.

[0317] 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 treating and / or preventing 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.

[0318] 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 present invention or a pharma- ceutically acceptable salt thereof, wherein the cancer comprises a KRAS mutation, said KRAS mutation 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.

[0319] In a further aspect, the present invention relates to a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein said cancer comprises a KRAS G12D mutation.

[0320] In a further aspect, the present invention relates to a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein said cancer comprises a KRAS G12V mutation.

[0321] In a further aspect, the present invention relates to a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein said cancer comprises a KRAS G13D mutation.

[0322] In a further aspect, the present invention relates to a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein said cancer comprises KRAS wild-type amplification.

[0323] 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 inhibiting or degrading KRAS, wherein KRAS may be wild-type, mutated or amplified, as defined herein.

[0324] In a further aspect, the 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 use in a method of inhibiting or degrading KRAS, wherein KRAS may be wild-type, amplified or mutated, as defined herein.

[0325] In a further aspect, the present invention relates to a method for inhibiting or degrading KRAS, which may be wild-type, amplified or mutated as defined herein, comprising administering to a human a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt thereof.

[0326] 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 degrading or inducing the degradation of KRAS, wherein KRAS may be wild-type, amplified or mutated, as defined herein above.

[0327] In a further aspect, the 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 use in a method of degrading or inducing the degradation of KRAS, wherein KRAS may be wild-type, amplified or mutated, as defined herein.

[0328] In a further aspect, the present invention relates to a method for degrading or inducing the degradation of KRAS, where KRAS may be wild-type, amplified or mutated as defined herein, comprising administering to a human a therapeutically effective amount of a compound of the invention or a pharma- ceutically acceptable salt thereof.

[0329] Another embodiment is based on identifying a relationship between the KRAS status of a patient and the potential sensitivity to treatment with a compound of the present invention or a pharma- ceutically acceptable salt thereof. KRAS inhibitors or decomposers, such as the compounds of the present invention or a pharma- ceutically acceptable salt thereof, can then be advantageously used to treat patients with diseases dependent on KRAS that may be resistant to other treatments. This therefore provides opportunities, methods and tools for selecting patients, in particular cancer patients, for treatment with the compounds of the present invention. This selection is based on whether the tumor cells to be treated have a wild type, preferably an amplified or mutated KRAS gene at residue 12, preferably G12C, G12D or G12V, or a mutated KRAS gene at residue 13, preferably G13D. Thus, the status of the KRAS gene can be used as a biomarker to indicate that it may be advantageous to select treatment with a compound of the present invention.

[0330] According to one aspect, there is provided a method for selecting a patient for treatment with a compound of the invention, or a pharma- ceutically acceptable salt thereof, the method comprising: 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 mutated (cysteine, aspartic acid, valine, alanine or arginine at position 12, aspartic acid at position 13, amplified and / or overexpressed) KRAS protein; selecting patients for treatment with said compound based thereon; Includes.

[0331] The method may or may not include the step of isolating an actual patient sample.

[0332] In one embodiment, if the tumor cell DNA has a mutated KRAS gene, the patient is selected for treatment with a compound of the invention, or a pharma- ceutically acceptable salt thereof.

[0333] 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 which have a KRAS mutation or an amplification of KRAS wild type.

[0334] 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 with a G12C mutant, a G12D mutant, a G12V mutant or a G13D mutant KRAS gene, or an amplification of the KRAS wild type.

[0335] 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 have a G12D mutated KRAS gene.

[0336] 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 have a G12V mutated KRAS gene.

[0337] 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 have a G13D mutated KRAS gene.

[0338] 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 which have KRAS wild-type amplification or overexpression of KRAS.

[0339] According to another aspect, there is provided a method of treating cancer having tumor cells with a G12C mutant, a G12D mutant, a G12V mutant, a G12A mutant, a G13D mutant or a G12R mutant KRAS gene, or an amplification of the KRAS wild-type gene, comprising administering to a human an effective amount of a compound of the invention or a pharma- ceutically acceptable salt thereof.

[0340] According to another aspect, there is provided a method of treating cancer having tumor cells with a G12C mutant, a G12D mutant, a G12V mutant, a G12A mutant, a G13D mutant or a G12R mutant KRAS gene, or an amplification of the KRAS wild-type gene, comprising administering an effective amount of a compound of the invention or a pharma- ceutical acceptable salt thereof.

[0341] Determining whether a tumor or cancer contains a 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 a putative KRAS mutant protein. The nucleotide 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) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for KRAS mutations by real-time PCR. In real-time PCR, fluorescent probes specific for KRAS mutations can be used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, direct sequencing of specific regions (e.g., exon 2 and / or exon 3) in the KRAS gene is used to identify KRAS mutations. 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 and may be applied to identify the presence of mutated / altered KRAS at baseline, as well as to monitor response to treatment, in particular treatment-related depletion of WT or mutant KRAS from tumor samples. These methods include, but are not limited to, detection of mutant KRAS using binding agents (e.g., antibodies) that may also be specific for mutant proteins, detection of wild-type or mutant KRAS by protein electrophoresis, Western blotting, direct peptide sequencing, and mass spectrometry-based approaches.

[0342] In the method for determining whether a tumor or cancer contains a KRAS mutation, various samples can be used. 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, where a test is performed on a blood sample to look for cancer cells from the tumor circulating in the blood or to look for fragments of DNA from tumor cells in the blood.

[0343] Preferably, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by 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, colon cancer, bile duct cancer, appendix cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, esophageal cancer, gastroesophageal cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0344] Preferably, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by 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.

[0345] In another aspect, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by the compound of the present invention or its 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 (preferably pancreatic ductal adenocarcinoma (PDAC)), lung cancer (preferably non-small cell lung cancer (NSCLC)), gastric cancer, bile duct cancer and colon cancer (preferably colon adenocarcinoma). Preferably, said pancreatic cancer, lung cancer, bile duct cancer, colon cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) or colon adenocarcinoma comprises a KRAS mutation, in particular a KRAS G12D or KRAS G12V mutation. Preferably (alternatively or in combination with the previous preferred embodiment), said non-small cell lung cancer (NSCLC) comprises a mutation (in particular a loss-of-function mutation) in the NF1 gene.

[0346] In another aspect, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by 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 gastric cancer, ovarian cancer or esophageal cancer, said gastric cancer or esophageal cancer is 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 a KRAS mutation or an amplification of wild-type KRAS.

[0347] Particularly preferably, the cancers to be treated / prevented by 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 cancer (NSCLC)) with at least one KRAS mutation, in particular with an amplification of the KRAS wild type, colon adenocarcinoma with at least one KRAS mutation, in particular with amplification of the wild-type KRAS; pancreatic adenocarcinoma (preferably pancreatic ductal adenocarcinoma (PDAC)) with at least one KRAS mutation, in particular with an amplification of the KRAS wild type, gastric cancer with at least one KRAS mutation, in particular with amplification of the wild type KRAS, esophageal cancer with at least one KRAS mutation, in particular with amplification of the wild-type KRAS; Gastroesophageal junction cancer with at least one KRAS mutation, particularly amplification of the wild-type KRAS is selected from the group consisting of:

[0348] Preferably, as used herein (above or below), "cancer" 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 or below) that is resistant to treatment with a KRAS G12C inhibitor.

[0349] 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.

[0350] In another aspect, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by 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 preferably a RASopathy selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML) (also called 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.

[0351] Furthermore, the following cancers, tumors and other proliferative diseases (including but not limited to) can be treated with the compounds of the present invention or their pharma- ceutically acceptable salts. Preferably, the methods of treatment, methods, uses, compounds for use and pharmaceutical compositions for use disclosed herein (above and below) are applied to the treatment of diseases / conditions / cancers / tumors (i.e., cells) that have been identified as having a KRAS mutation (including those at position 12 (preferably G12C, G12D, G12V, G12A, G12R mutations) or an amplification of KRAS wild type), alternatively as having a KRAS mutation at position 12 (preferably G12C, G12D, G12V, G12A, G12R mutations) or an amplification of KRAS wild type as described and / or mentioned herein.

[0352] Cancers / tumors / carcinomas of the head and neck: e.g. tumors / carcinomas of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, recurrent ridge, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsils, tonsillar foramen, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands);

[0353] 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, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma);

[0354] 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, lymphangioma, lymphangiopericytoma, lymphangioleiomyoma);

[0355] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g. tumors / carcinomas / cancers of the esophagus (e.g. esophageal cancer, gastroesophageal junction cancer), stomach (gastric cancer), pancreas, liver and biliary tract (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcomatous HCC, sclerosing HCC, hepatoblastoma, cholangiocarcinoma, cholangiocellular carcinoma, hepatic cystadenocarcinoma, angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatzkin's tumor), gallbladder , extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colon cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms tumor), renal epithelioma, Grawitz tumor, ureter, bladder, e.g., urinary tract carcinoma, urothelial carcinoma, urethra, e.g., distal, bulbar, prostatic, prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis);

[0356] Cancer / tumor / carcinoma of the testis: e.g. seminoma, non-seminoma,

[0357] Gynaecological cancers / tumours / carcinomas: for example, tumours / carcinomas / cancer of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus);

[0358] Breast cancer / tumour / carcinoma: e.g. breast cancer (invasive ductal carcinoma, colloid carcinoma, lobular carcinoma, tubular carcinoma, adenocystic carcinoma, papillary carcinoma, medullary carcinoma, mucinous carcinoma), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast;

[0359] Cancers / tumors / carcinomas of the endocrine system: e.g. tumors / carcinomas / carcinomas of the endocrine glands, thyroid (thyroid carcinoma / tumor; papillary, follicular, anaplastic, medullary), parathyroid (parathyroid carcinoma / tumor), adrenal cortex (adrenal cortical carcinoma / tumor), pituitary gland (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;

[0360] 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, plexus sarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, anaplastic small cell tumor;

[0361] Sarcomas of bone: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcomas), 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;

[0362] Mesothelioma: e.g. pleural mesothelioma, peritoneal mesothelioma;

[0363] Cancers of the skin: e.g. basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, lentigo acuminata, nodular, and intraocular melanoma), actinic keratosis, and eyelid cancer;

[0364] Neoplasms of the central nervous system and brain: for example, astrocytoma (cerebral, cerebellar, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, germ cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, schwannoma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g. acoustic), spinal axis tumor;

[0365] Lymphomas and leukemias: e.g., B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma) (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 (C TLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-predominant HD, and lymphocyte-deficient HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myelogenous / myeloid (m yeloid) leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0366] carcinoma of unknown primary site (CUP);

[0367] All cancers / tumors / carcinomas referred to above that are characterized by a particular location / origin within the body are meant to include both the primary tumor and any metastatic tumors derived therefrom.

[0368] All the above mentioned cancers / tumors / carcinomas can be further differentiated by histopathological classification.

[0369] Epithelial carcinomas, such as squamous cell carcinoma (SCC) (in situ, superficial invasive carcinoma, warty carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well differentiated, mucinous, papillary, pleomorphic giant cell, tubular, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acicular cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid), oncocytic carcinoma;

[0370] 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.

[0371] The compounds of the invention may be used in therapeutic regimens for first line, second line or any further line of treatment.

[0372] The compounds of the invention can be used for the prevention, short-term treatment or long-term treatment of the above mentioned diseases / conditions / cancers / tumours, optionally in combination with radiation therapy and / or surgery.

[0373] The methods of treatment, methods, uses and compounds for use disclosed herein (above and below) may be carried out using any compound of the invention and any pharmaceutical composition or kit comprising a compound of the invention as disclosed or defined herein.

[0374] Combination treatment The compounds of the present invention or pharma- ceutically acceptable salts thereof and pharmaceutical compositions containing such compounds or salts can also be co-administered with other pharmacologically active substances, such as other anti-neoplastic compounds (e.g., chemotherapy) or used as adjuvants in combination with other treatments, such as radiation or surgical intervention, either pre- or post-operatively. Preferably, the pharmacologically active substance for co-administration is an anti-neoplastic compound.

[0375] Therefore, in a further aspect, the present invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof, for the above-defined uses, wherein said compound is administered before, after or together with one or more other pharmacologically active substances.

[0376] In a further aspect, the invention relates to a compound of the invention or a pharma- ceutically acceptable salt thereof, for the above-defined uses, wherein said compound is administered in combination with one or more other pharmacologically active substances.

[0377] In a further aspect, the present invention relates to the use of a compound of the invention as defined above or a pharma- ceutically acceptable salt thereof, wherein said compound is administered before, after or together with one or more other pharmacologically active substances.

[0378] In a further aspect, the present invention relates to a method as defined above (e.g. a method for treatment and / or prevention), wherein a compound according to 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.

[0379] In a further aspect, the present invention relates to a method as defined above (e.g. a method for treatment and / or prevention), wherein a compound according to 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.

[0380] In a further aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need of said treatment and / or prevention 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, concurrently, sequentially, alternately or separately with the one or more other pharmacologically active substances.

[0381] In a further aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need of said treatment and / or prevention 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.

[0382] In a further aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need of said treatment and / or prevention a therapeutically effective amount of a KRAS inhibitor or degrader (preferably a pan-KRAS inhibitor or degrader) and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the KRAS inhibitor or degrader (preferably a pan-KRAS inhibitor or degrader) is administered in combination with one or more other pharmacologically active substances.

[0383] 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 treating and / or preventing cancer, wherein the compound of the present invention or a pharma- ceutically acceptable salt thereof is administered simultaneously, simultaneously, sequentially, consecutively, alternatingly or separately with one or more other pharmacologically active substances.In a further aspect, the present invention relates to a KRAS inhibitor or degrader (preferably a pan-KRAS inhibitor or degrader) for use in treating and / or preventing cancer, wherein the KRAS inhibitor or degrader (preferably a pan-KRAS inhibitor or degrader) is administered in combination with one or more other pharmacologically active substances.

[0384] In a further aspect, the present invention relates to an inhibitor or decomposer of amplified or overexpressed wild type KRAS, or a pharma- ceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein said inhibitor or decomposer, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more other pharmacologically active substances.

[0385] In a further aspect, the present invention provides a method for treating and / or preventing cancer, comprising: 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; wherein the first pharmaceutical composition is administered simultaneously, simultaneously, sequentially, consecutively, alternatingly or separately with the second and / or additional pharmaceutical compositions or dosage forms.

[0386] In one embodiment, such kit for said use comprises a third pharmaceutical composition or dosage form comprising a third pharmaceutical composition or dosage form comprising a further pharmacologically active substance and optionally one or more pharma- ceutically acceptable excipients.

[0387] In a further embodiment of the invention, the components (i.e. combination partners) of the combination, kit, use, method and compound for use according to the invention (including all embodiments) are administered simultaneously.

[0388] 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 concurrently.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] In a further embodiment of the invention, the components (i.e. combination partners) of the combination, kit, use, method of the invention (including all embodiments) and the compounds for use are administered separately.

[0393] The pharmacologically active substance to be used in conjunction / combination with the compound of the invention or a pharma- ceutically acceptable salt thereof or in the medical applications, uses, methods of treatment and / or methods of prophylaxis, 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):

[0394] 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, canatinib, neratinib, avitinib, poziotinib, AV412, PF-6274484, HKI357, olmutinib, osimertinib, almonatinib, nazartinib, lazertinib, pelitinib; b. Reversible inhibitors: e.g., erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW583340; c. Anti-EGFR antibodies: e.g., necitumumab, panitumumab, cetuximab, amivantamab; d. Anti-HER2 antibodies: e.g., pertuzumab, trastuzumab, trastuzumab emtansine; e. Inhibitors of mutant EGFR; f. Inhibitors of HER2 with exon 20 mutations; g. Afatinib, the preferred irreversible inhibitor; h. The preferred anti-EGFR antibody, cetuximab.

[0395] 2. Inhibitors of MEK and / or its mutants For example, trametinib, cobimetinib, binimetinib, selumetinib, rifametinib; b. Preferably, trametinib c. MEK inhibitors disclosed in WO 2013 / 136249; d. MEK inhibitors disclosed in WO 2013 / 136254.

[0396] 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 interfering with the protein-protein interaction between SOS1 and a (mutated) Ras protein, for example KRAS). For example, BAY-293; b. SOS1 inhibitors disclosed in WO 2018 / 115380; c. SOS1 inhibitors disclosed in WO 2019 / 122129; d. SOS1 inhibitors disclosed in WO 2020 / 180768, 2020 / 180770, 2018 / 172250 and 2019 / 201848.

[0397] 4. Inhibitors of YAP1, WWTR1, TEAD1, TEAD2, TEAD3 and / or TEAD4 a. Reversible inhibitors of TEAD transcription factors (e.g., those disclosed in WO 2018 / 204532); b. Irreversible inhibitors of TEAD transcription factors (e.g., those disclosed in WO 2020 / 243423); c. Protein-protein interaction inhibitors of the YAP / TAZ::TEAD interaction (e.g., those disclosed in WO 2021 / 186324); d. TEAD palmitoylation inhibitor.

[0398] 5. Oncolytic viruses

[0399] 6. RAS Vaccine For example, TG02 (Targovax).

[0400] 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. Preferably, palbociclib and abemaciclib; iii. Most preferably, abemaciclib b. For example, vinca alkaloids i. For example, vinorelbine c. For example, inhibitors of Aurora kinase and / or any mutants thereof i. For example, alisertib, barasertib.

[0401] 8. Inhibitors of PTK2 (=FAK) and / or any mutants thereof For example, TAE226, BI853520.

[0402] 9. Inhibitors of SHP2 and / or any mutant thereof a.For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0403] 10. Inhibitors of PI3 kinase (=PI3K) and / or any mutants thereof For example, an inhibitor of PI3K alpha and / or any mutant thereof i. For example, alpelisib, ceravelisib, GDC-0077, HH-CYH33, AMG511, bupallisib, dactolisib, pictilisib, taselisib.

[0404] 11. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutants thereof For example, ponatinib, infigratinib, nintedanib.

[0405] 12. Inhibitors of AXL and / or any mutant thereof

[0406] 13. Taxanes For example, paclitaxel, nab-paclitaxel, docetaxel; b. Preferably, paclitaxel.

[0407] 14.Platinum-containing compounds For example, cisplatin, carboplatin, oxaliplatin b. Preferably, oxaliplatin.

[0408] 15. Antimetabolites For example, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, trifluridine in combination with tipiracil (=TAS102); b. Preferably, 5-fluorouracil.

[0409] 16. Immunotherapeutic agents 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. Preferably, an anti-PD1 mAb; iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab; iv. Preferably, nivolumab, pembrolizumab, ezabenlimab and PDR-001 (= spartalizumab); v. Most preferably, ezabenlimab, pembrolizumab and nivolumab.

[0410] 17. Topoisomerase inhibitors a. For example, irinotecan, liposomal irinotecan (nal-IRI), topotecan, etoposide; b. Most preferably, irinotecan and liposomal irinotecan (nal-IRI).

[0411] 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 in WO 2014 / 151616), LxH254, sorafenib, LY-3009120 (= Example 1 in WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265.

[0412] 19. mTOR inhibitors For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, torin 1, dactolisib, GDC-0349, VS-5584, bistosertib, AZD8055.

[0413] 20. Epigenetic regulators For example, BET inhibitors i. For example, JQ-1, GSK525762, OTX-015, CPI-0610, TEN-010, OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601, CC-90010, AZD5153, I-BET151, BI894999.

[0414] 21. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutants thereof a. For example, xentuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (=dusigitumab), linsitinib.

[0415] 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, SU6656, WH-4-023.

[0416] 23. Apoptosis regulators a. For example, an MDM2 inhibitor, such as an inhibitor of the interaction between p53 (preferably functional p53, most preferably wtp53) 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. Preferably, 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.

[0417] 24. Inhibitors of c-MET and / or any of its mutants For example, savolitinib, cabozantinib, foretinib; b.MET antibodies, e.g., emibetuzumab, amivantamab.

[0418] 25. Inhibitors of ERK and / or any mutant thereof For example, ulixertinib, LTT462.

[0419] 26. Inhibitors of farnesyltransferase and / or any mutant thereof For example, tipifarnib.

[0420] In a further embodiment of the (combined) uses and methods described above (e.g. methods for treatment and / or prevention), one other pharmacologically active substance is administered before, after or together with the compound of the invention, 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 inhibitor.

[0421] In a further embodiment of the (combined) uses and methods (e.g. methods for treatment and / or prevention) described above, one other pharmacologically active substance is administered in combination with a compound or a pharma- ceutically acceptable salt of the invention, 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 inhibitor.

[0422] In a further embodiment of the (combined) uses and methods described above (e.g. methods for treatment and / or prevention), two other pharmacologically active substances are administered before, after or together with the compound of the invention, wherein said two other pharmacologically active substances are MEK inhibitors and SOS1 inhibitors or Trametinib and SOS1 inhibitors or an anti-PD-1 antibody (preferably, ezabenlimab) and an anti-LAG-3 antibody, or Anti-PD-1 antibody (preferably, ezabenlimab) and 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 TEAD palmitoylation inhibitors or -SOS1 inhibitor and YAP / TAZ::TEAD inhibitor.

[0423] In a further embodiment of the (combined) uses and methods (e.g. methods for treatment and / or prevention) described above, two other pharmacologically active substances are administered in combination with a compound of the invention, wherein said two other pharmacologically active substances are MEK inhibitors and SOS1 inhibitors or Trametinib and SOS1 inhibitors or an anti-PD-1 antibody (preferably, ezabenlimab) and an anti-LAG-3 antibody, or Anti-PD-1 antibody (preferably, ezabenlimab) and 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 TEAD palmitoylation inhibitors or -SOS1 inhibitor and YAP / TAZ::TEAD inhibitor.

[0424] Additional pharmacologically active substances which may also be used together / in combination with the compounds of the invention or their pharma- ceutically acceptable salts or in the medical applications, uses, methods of treatment and / or prevention, pharmaceutical compositions, kits defined herein (above and below) include hormones, hormone analogs and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxetine ... xymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, leuprolide), growth factors and / or 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. inhibitors of HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors (e.g. (anti)growth factor antibodies, (anti)growth factor receptor antibodies and tyrosine kinase inhibitors such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab), antimetabolites (e.g. folate antagonists such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), ribonucleosides and deoxyribonuclease inhibitors such as ribonuclease inhibitors (RIB), ... Ribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues, e.g., mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (araC), fludarabine), antitumor antibiotics (e.g., anthracyclines, e.g., doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myoset (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin),Platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin), alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, e.g., carmustine and lomustine, thiotepa, etc.), antimitotic agents (e.g., vinca alkaloids, e.g., vinblastine, vindesine, vinorelbine, and vincristine, etc., and taxanes, e.g., paclitaxel, docetaxel), angiogenesis inhibitors (e.g., thiazides, tetracycline ... skinimod), tubulin inhibitors, DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, etc.), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors , PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimetics, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g., venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, SCR inhibitors, rc inhibitors, rapamycin analogues (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g., carfilzomib), immunotherapeutics such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab, etc.),These include, but are not limited to, ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers (BiTEs®, e.g., CD3xBCMA, CD3xCD33, CD3xCD19, PSMAxCD3, etc.), tumor vaccines, immune modulators such as STING agonists, and various chemotherapeutic agents such as amifostine, anagrelide, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer.

[0425] It is to be understood that the combinations, compositions, kits, methods, uses, pharmaceutical compositions or compounds for use of the present invention may envisage simultaneous, concurrent, sequential, consecutive, alternating or separate administration of the active ingredients or components. The compounds of the present invention and one or more other pharmacologically active substances may be administered in a combination, either dependent or independent. For example, it will be understood that the compounds of the present invention and one or more other pharmacologically active substances may be administered either as part of the same pharmaceutical composition / dosage form or, preferably, in separate pharmaceutical compositions / dosage forms.

[0426] In this context, "combination" or "combined" in the sense of the present invention includes, but is not limited to, products resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed (e.g., free) combinations (including kits) and uses, such as simultaneous, simultaneous, sequential, consecutive, alternating or separate use of the ingredients or components. 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, either simultaneously, simultaneously or sequentially, without any specific time restrictions, where such administration provides a therapeutically effective level of the compound in the patient's body.

[0427] The administration of the compound of the invention and one or more other pharmacologically active substances can be carried out by co-administration of the active ingredients or components, such as by administering them simultaneously or simultaneously in a single or two or more separate formulations or dosage forms. Alternatively, the administration of the compound of the invention and one or more other pharmacologically active substances can be carried out by administering the active ingredients or components sequentially or alternatingly, such as by administering them in two or more separate formulations or dosage forms.

[0428] For example, simultaneous administration includes administration at substantially the same time. Such dosage forms can also be referred to as "concurrent" administration. Simultaneous administration includes administration of active agents within the same general time period, e.g., on the same day, but not necessarily at the same time. Alternating administration includes administration of one agent for a period, e.g., several days or a week, followed by administration of the other agent for a subsequent period, e.g., several days or a week, and then repeating this pattern for one or more cycles. Sequential or consecutive administration includes administration of one agent during a first period (e.g., several days or a week) using one or more doses, followed by administration of the other agent during a second and / or additional period (e.g., several days or a week) using one or more doses. Overlapping schedules can also be utilized, which do not necessarily follow a regular order, and include administration of active agents on different days over the treatment period. Modifications of these general guidelines can also be utilized, for example, depending on the agents used and the condition of the subject.

[0429] Pharmaceutical Compositions - Kits 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.

[0430] 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.

[0431] Suitable pharmaceutical compositions for administering the compounds of the present invention will be clear to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, suspensions, in particular solutions, suspensions or other mixtures for parenteral administration (sc, iv, im, etc...) and infusions (injections), 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 wt%, preferably 0.5-50 wt%, based on the total composition, i.e., an amount sufficient to achieve the dose ranges specified below. The specified doses can be given several times a day as needed.

[0432] 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 may also comprise multiple layers.

[0433] Coated tablets can be prepared by coating a core, prepared similarly to tablets, with excipients commonly used in tablet coating, such as Kollidon or shellac, gum arabic, talc, titanium dioxide or sugars. The core may also consist of multiple layers to achieve delayed release or to prevent incompatibility. Similarly, tablet coatings may consist of multiple layers to achieve delayed release and may use the excipients mentioned above for tablets.

[0434] Syrups or elixirs containing one or more compounds of the invention or combinations with one or more other pharma- ceutically active substances may further contain excipients such as sweeteners, e.g., saccharin, cyclamate, glycerol or sugars and flavor enhancers, e.g., flavorings, e.g., vanillin or orange extract. Syrups or elixirs may also contain excipients such as suspension adjuvants or thickeners, e.g., sodium carboxymethylcellulose, wetting agents, e.g., condensation products of fatty alcohols with ethylene oxide, or preservatives, e.g., p-hydroxybenzoates.

[0435] Solutions for injection and infusion are prepared in the usual manner by adding excipients such as isotonicity agents, preservatives, e.g., p-hydroxybenzoates or stabilizers, e.g., alkali metal salts of ethylenediaminetetraacetic acid, and optionally using emulsifiers and / or dispersants, and when water is used as diluent, e.g., organic solvents can optionally be used as solvating agents or solubilizing agents, and transferred into injection vials or ampoules or infusion bottles.

[0436] Capsules containing one or more compounds of the present invention or a combination with one or more other pharma- ceutically active substances can be prepared, for example, by mixing the compounds / active substances with inert excipients, such as lactose or sorbitol, and filling them into gelatin capsules.

[0437] Suitable suppositories can be prepared, for example, by mixing with excipients provided for this purpose, such as neutral fats or polyethylene glycol or a derivative thereof.

[0438] Excipients which may be used include, for example, water, pharma-ceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. lignin, spent sulfite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0439] The pharmaceutical composition is administered by conventional methods, preferably by oral or transdermal route, most preferably by oral route.For oral administration, tablets may naturally contain additional excipients, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various excipients, such as starch, preferably potato starch, gelatin, etc., apart from the excipients mentioned above.In addition, lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, can be used at the same time for the tableting process.For aqueous suspensions, active substances can be combined with various flavor enhancers or colorants in addition to the excipients mentioned above.

[0440] For parenteral application, solutions of the active substance and a suitable liquid excipient can be used.

[0441] The daily applicable dose range of the compound of the present invention is usually 1 mg to 2000 mg, preferably 250 mg to 1250 mg.

[0442] 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 timing or interval at which the drug is administered (continuous or intermittent treatment with one or more doses per day). For this reason, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When larger amounts are administered, it may be advisable to administer them in several small portions over the course of a day.

[0443] Therefore, in a further aspect, the present invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of the present invention or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0444] The compounds of the present invention and pharmaceutical compositions containing such compounds and salts can 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 above under Combination Treatments).

[0445] The elements of such combinations, when used as monotherapy, can be administered in a manner conventional to those skilled in the art, 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 (whether sequential or independent), and can be formulated, either alone or together, into appropriate dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.

[0446] The combination can be administered in a therapeutically effective single daily dose or in divided doses. The active ingredients of the combination can be administered in a therapeutically effective dose in monotherapy or in a dose lower than that used in monotherapy, but which, in combination, results in the desired (jointly) therapeutically effective amount.

[0447] However, when the combination of two or more active substances or principles results in a synergistic effect, it may also be possible to reduce the amount of one, more or all of the substances or principles 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 substances or principles when used in their normal amounts, while still obtaining the desired pharmacological or therapeutic effect.

[0448] In yet a further aspect, the present invention relates to a pharmaceutical preparation 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.

[0449] Also for this reason, in a further aspect, the present invention 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.

[0450] The co-administered or combined pharmaceutical compositions can also be provided in the form of a kit.

[0451] And therefore, in a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: a first pharmaceutical composition or dosage form comprising a compound of the invention 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; The present invention relates to a kit comprising:

[0452] In one embodiment, such a kit further comprises a third pharmaceutical composition or dosage form comprising another pharmacologically active agent and optionally one or more pharma- ceutically acceptable excipients.

[0453] definition Terms not specifically defined herein should be given the meaning that would be ascribed to them by those of ordinary skill in the art in light of the present disclosure and the context. However, when used herein, unless otherwise specified, the following terms have the indicated meanings and the following conventions are adhered to.

[0454] Prefix C x-y (where x and y each represent a positive integer (x < y)) is used in direct reference and indicates that the chain or ring structure being referred to may consist of a maximum of y and a minimum of x carbon atoms.

[0455] The indication of the member number of a group containing one or more heteroatoms (e.g., heterocycloalkyl, ring, etc.) relates to the total number of atoms of all ring members or the total of all ring members and carbon chain members.

[0456] In groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., those of ordinary skill in the art may be able to determine the point of attachment of the group to the molecule from the free valence of the group itself.

[0457] When the compounds described herein are represented by chemical names and formulas, in case of any contradiction, the formula shall be given precedence.

[0458] The expression "the compounds of the present invention" and its grammatical variations refer to the compounds of formula (I), (I * ), (I ** ), (I *** ), (I **** ), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II *The compounds of the present invention include compounds of formula (I), (Id), and (IIf), as well as compounds I-49, I-50, and I-51, including all salts, aspects, and preferred embodiments thereof as defined herein. * ), (I ** ), (I *** ), (I **** ), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (II * ), (II ** ), (II *** ), (II **** ), (IIa), (II * a), (IIb), (II * b), (IIc), (II * c), (IId), (II * d), (IIe), (II * Any reference to compounds designated e) and (IIf) is intended to include reference to the respective (sub) aspects and embodiments.

[0459] Dashed line [ka] or wavy line [ka] can be used in a subformula to indicate the atoms or bonds attached to the defined core molecule. In certain cases, a substituent of the core molecule to which the subformula is attached can be specifically designated on the side of the dashed or wavy line opposite to that of the subformula.

[0460] "C 1-x The term "alkyl" (wherein x is an integer selected from 2, 3, 4, 5 or 6, preferably 3, 4 or 6), either alone or in combination with another group, denotes an acyclic, saturated, branched or straight chain hydrocarbon group having 1 to x C atoms. For example, C 1-6The term alkyl encompasses groups such as HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-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-C(CH)-, HC-CH-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)-CH-, HC-CH-CH(CH)-CH-, HC-CH-CH(CH)-CH 1-x Alkyl refers to methyl, isopropyl or tert-butyl.

[0461] "C 1-x The term "alkylene" (wherein x is an integer selected from 2, 3, 4, 5, 6, 7 or 8, preferably 3, 4 or 6), either alone or in combination with another group, denotes an acyclic, saturated, branched or straight chain, divalent alkyl group containing 1 to x C atoms. For example, C 1-4 The term alkylene includes -CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -C(CH)-, -CH(CHCH)-, -CH(CH)-CH-, -CH-CH(CH)-, -CH-CH-CH-CH-, -CH-CH-CH(CH)-, -CH-CH-CH-CH-, -CH-CH-CH(CH)-, -CH(CH)-CH-CH-, -CH-CH(CH)-CH-, -CH-C(CH)-, -C(CH)-CH-, -CH(CH)-CH(CH)-, -CH-CH(CH)-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -CH(CHCH)-CH-, -C(CH)(CHCH)-, and the like.

[0462] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like, without further definition, refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, wherein all isomers are included.

[0463] The above definition of alkyl also includes the fact that alkyl is part of another (linked) group, e.g., cyano-C 1-6 Alkylamino or C x-y This also applies to alkyloxy etc. x-y Alkyloxy is C x-y It may also be abbreviated as alkoxy.

[0464] The term "alkoxylene" refers to a divalent alkoxy group.

[0465] Unlike alkyl, alkenyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are connected by a CC double bond, and a carbon atom may only be part of one CC double bond. In the above defined alkyl having at least two carbon atoms, when two hydrogen atoms on adjacent carbon atoms are formally removed to saturate the free valences and form a second bond, the corresponding alkenyl is formed.

[0466] 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.

[0467] The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc., without further definition, 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.

[0468] Alkenyls may optionally be in the cis or trans or E or Z orientation about the double bond.

[0469] The above definition of alkenyl also applies when the alkenyl is part of another (linked) group, e.g., C x-y Alkenylamino or C x-y This also applies to the case of alkenyloxy and the like.

[0470] Unlike alkylene, alkenylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are connected by a CC double bond, and a carbon atom may only be part of one CC double bond. In the above defined alkylene having at least two carbon atoms, when two hydrogen atoms at adjacent carbon atoms are formally removed to saturate the free valences and form a second bond, the corresponding alkenylene is formed.

[0471] 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.

[0472] The generic terms propenylene, butenylene, pentenylene, hexenylene, etc., without further definition, 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.

[0473] Alkenylene may optionally be in the cis or trans or E or Z orientation about the double bond.

[0474] The above definition of alkenylene also applies when the alkenylene is part of another (linked) group, e.g., HO-C x-y Alkenyleneamino or H2N-C x-y This also applies to the case where the group is alkenyleneoxy.

[0475] Unlike alkyl, alkynyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are linked by a C-C triple bond; in the above defined alkyl having at least two carbon atoms, when two hydrogen atoms at each adjacent carbon atom are formally removed to saturate the free valences and form two additional bonds, the corresponding alkynyl is formed.

[0476] 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.

[0477] The generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc., without further definition, 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.

[0478] If the hydrocarbon chain has both at least one double bond and at least one triple bond, then by definition it belongs to an alkynyl subgroup.

[0479] The above definition of alkynyl also applies when the alkynyl is part of another (linked) group, e.g., C x-y Alkynylamino or C x-y This also applies to the case where it is alkynyloxy.

[0480] Unlike alkylene, alkynylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are linked by a CC triple bond. In the above defined alkylene having at least two carbon atoms, when two hydrogen atoms at each adjacent carbon atom are formally removed and the free valences are saturated to form two additional bonds, the corresponding alkynylene is formed.

[0481] 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.

[0482] The generic terms propynylene, butynylene, pentynylene, hexynylene, etc., without further definition, 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.

[0483] The above definition of alkynylene also applies when the alkynylene is part of another (linked) group, e.g., HO-C x-y Alkynyleneamino or H2N-C x-y This also applies to the case where alkynyleneoxy is used.

[0484] Heteroatoms means oxygen, nitrogen and sulfur atoms.

[0485] A haloalkyl is derived from an alkyl as defined above by independently replacing one or more hydrogen atoms in the hydrocarbon chain with halogen atoms, which may be the same or different.

[0486] Examples of haloalkyl 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.

[0487] Halogen refers to fluorine, chlorine, bromine and iodine.

[0488] C 3-k Cycloalkyl, where k is 4 or 5, alone or in combination with other groups, denotes a cyclic, saturated, unbranched hydrocarbon group having 3 to k C atoms. For example, 3-5 The term cycloalkyl includes cyclopropyl, cyclobutyl and cyclopentyl. 3-k The cycloalkyl may be linked to the molecule as a substituent via any suitable position of the ring system.

[0489] The above definition of cycloalkyl also applies when cycloalkyl is part of another (linked) group, e.g., C x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y This also applies when the radical is cycloalkylalkyl.

[0490] Heterocycloalkyl means a saturated or unsaturated monocyclic or polycyclic ring system of the specified number of atoms, optionally including an aromatic ring, containing one or more heteroatoms selected from N, O, S, SO, or SO2, where the heteroatoms are not part of an aromatic ring (if present). The term "heterocycloalkyl" is intended to include all possible isomers.

[0491] Unsaturated means that there is at least one double bond in the ring system, but no (hetero)aromatic system is formed.

[0492] When a heterocycloalkyl is substituted, the substitutions may occur independently at all hydrogen-bearing carbon and / or nitrogen atoms, each in the form of mono- or polysubstitution. The heterocycloalkyl itself may be linked to the molecule as a substituent through any suitable position of the ring system. Substituents on a heterocycloalkyl are not counted in the member count of the heterocycloalkyl.

[0493] Thus, the term "heterocycloalkyl" includes the following exemplary structures (each of which is not depicted as a group because it is optionally attached via a covalent bond to any atom as long as appropriate valences are maintained):

[0494] [ka] TIFF2024542692000081.tif186165TIFF2024542692000082.tif49165

[0495] The term heterocycloalkylene is also derived from the heterocycloalkyl defined above. Heterocycloalkylene, unlike heterocycloalkyl, is bivalent and requires two binding partners. Formally, this bivalency is obtained by removing a hydrogen atom from heterocycloalkylene. Corresponding groups include, for example, piperidinyl and [ka] It is.

[0496] The term heteroaryl refers to a monocyclic or polycyclic ring system of 5 to 14 ring atoms containing at least one aromatic ring and containing one or more heteroatoms selected from N, O, S, SO, or SO2, where at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all possible isomers.

[0497] Thus, the term "heteroaryl" includes the following exemplary structures (not shown as groups because each form is optionally attached via a covalent bond to any atom as long as appropriate valences are maintained):

[0498] [ka]

[0499] In particular, heteroarylene refers to pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole and triazole, all of which, including all possible isomers, may be attached to the molecule as a substituent via any suitable position of the ring system.

[0500] The term heteroarylene is also derived from heteroaryl as defined above. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, this bivalency is obtained by removing a hydrogen atom from heteroaryl. Corresponding groups include, for example, pyrrole and [ka] It is.

[0501] The above definition of heteroarylene also applies when heteroarylene is part of another (linked) group, for example HO-heteroaryleneamino or H2N-heteroaryleneoxy.

[0502] As used herein, the term "substituted" means that one or more hydrogens on the specified atom are replaced with a group selected from a defined group of substituents, provided that the replacement does not exceed the normal valence of the specified atom and that the replacement results in a stable compound. Similarly, the term "substituted" can be used in connection with a chemical moiety in place of a single atom, such as, for example, "substituted alkyl."

[0503] Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc...) and racemates thereof, as well as mixtures of different ratios of the separate enantiomers, mixtures of diastereomers or mixtures of any of the aforementioned forms, when such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof, such as salts including solvates and hydrates of the free compounds or solvates and hydrates of the salts of the compounds.

[0504] Unless otherwise specified, "pharmaceutically acceptable salts", as defined in more detail below, are also intended to encompass solvates thereof, such as, for example, hydrates.

[0505] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. Methods for preparing optically active forms are known in the art, for example, by separation of racemic forms or, for example, by synthesis starting from optically active starting materials and / or by use of chiral reagents.

[0506] Enantiomerically pure compounds or intermediates of the invention can be prepared, for example, by asymmetric synthesis, by preparation and subsequent separation of suitable diastereomeric compounds or intermediates which can be separated by known methods (e.g., by chromatographic separation or crystallization) and / or by using chiral reagents, e.g., chiral starting materials, chiral catalysts or chiral auxiliaries.

[0507] Furthermore, methods for preparing enantiomerically pure compounds from the corresponding racemic mixtures are known to the skilled artisan, for example by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases (this also applies to other mixtures of stereoisomers, e.g. mixtures of diastereomers, atropisomers, etc.) or by resolution of the racemic mixtures using suitable resolving agents, for example by forming diastereomeric salts of the racemates with optically active acids or bases, followed by resolution of these salts and release of the desired compounds from these salts, or by derivatization of the corresponding racemates with optically active chiral auxiliary reagents, followed by separation of the diastereomers and removal of the chiral auxiliary, or by dynamic resolution of the racemates (for example by enzymatic resolution), enantioselective crystallization from a conglomerate of mirror image crystals under suitable conditions or (partial) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0508] As used herein, the phrase "pharmacologically acceptable" is used to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0509] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by forming an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines, alkali or organic salts of acidic residues, such as carboxylic acids, and the like.

[0510] 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.

[0511] 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.

[0512] 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.

[0513] For example, salts of acids other than those mentioned above that are useful for purifying or isolating the compounds of the invention (eg, trifluoroacetates) also form part of this invention.

[0514] for example, [ka] In such expressions, the letter A functions as a ring designator, for example, to more easily show the attachment of that ring to another ring.

[0515] For divalent groups which may be useful in determining which adjacent groups are attached and at what valency, the following representation may be used, where necessary for clarification: [ka] Or (R 2 )-C(=O)NH- or (R 2 The corresponding binding partner can be shown at the end of the dashed line or in brackets, such as -NHC(=O)-.

[0516] In the absence of such specification, divalent groups can be attached in both directions, for example -C(=O)NH- also includes -NHC(=O)- and vice versa.

[0517] Groups or substituents are often referred to as corresponding group designations, e.g., R a , R b etc.) It is pointed out that when such a group is used repeatedly in defining a compound of the invention in different parts of the molecule, the various uses are considered to be entirely independent of each other.

[0518] For purposes of this invention, a therapeutically effective amount means an amount of a substance capable of avoiding symptoms of the disease or preventing or alleviating these symptoms or prolonging the survival of the treated patient.

[0519] Working Example Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.

[0520] [Table 1] TIFF2024542692000089.tif230161 TIFF2024542692000090.tif110161

[0521] Examples of Chemical Substances 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 thereon are carried out under protective gas (nitrogen or argon).

[0522] When a compound is represented by both a structural formula and its nomenclature, in the event of a conflict, the structural formula takes precedence.

[0523] Chromatography Thin layer chromatography is performed on Merck pre-made glass-on-glass silica gel 60 TLC plates (with fluorescent indicator F-254).

[0524] Preparative high performance chromatography (RPHPLC) of the example compounds of the present invention is carried out on an Agilent or Gilson system equipped with a Waters column (designation: SunFire™ Prep C18, OBD™ 10 μm, 50×150 mm or SunFire™ Prep C18, OBD™ 5 μm, 30×50 mm or XBridge™ Prep C18, OBD™ 10 μm, 50×150 mm or XBridge™ Prep C18, OBD™ 5 μm, 30×150 mm or XBridge™ Prep C18, OBD™ 5 μm, 30×50 mm) and a YMC column (designation: Actus-Triart Prep C18, 5 μm, 30×50 mm) and a Chiralpak IE (5 μm, 250×20 mm).

[0525] Compounds were eluted using different gradients of HO / acetonitrile, whereas for the Agilent system, 5% acidity modifier (20 mL HCOOH per L HO / acetonitrile (1 / 1)) was added to the water (acidic conditions), and for the Gilson system, 0.1% HCOOH was added.

[0526] For chromatography under basic conditions on the Agilent system, a H2O / acetonitrile gradient was also used, while the water was made alkaline by adding 5% basic modifier (50 g NH4HCO3 + 50 mL NH3 (25% in H2O) with H2O to 1 L). For the Gilson system, the water was made alkaline as follows: 5 mL of NH4HCO3 solution (158 g in 1 L H2O) and 2 mL of NH3 (28% in H2O) made up to 1 L with H2O. The Gilson system was also used under isocratic conditions (60% EtOH / 40% EtOH + 0.1% DEA).

[0527] Supercritical fluid chromatography (SFC) of the intermediates and example compounds of the present invention was carried out using an Agilent 1260SFC system, a JASCO SFC system, a Sepiatec SFC system, a Waters Thar SFC system, or a Waters UPC 2 -Made using the MSSFC system.

[0528] Use the following columns: Chiralcel OJ (250 x 20 mm, 5 μm), Chiralpak AD-H (21 x 250 mm), 5 μm, Chiralpak AD (250 x 20 mm, 5 μm), Chiralpak AS (250 x 20 mm, 5 μm), Chiralpak IC (250 x 20 mm, 5 μm), Chiralpak IA (250 × 20 mm, 5 μm), Chiralcel OJ (250 × 20 mm, 5 μm), Chiralcel OD (250 × 20 mm, 5 μm), Chiralcel OX-3 (150 × 4.6 mm, 3 μm), Phenomenex Lux C2 (250 × 20 mm, 5 μm).

[0529] Analytical SFC / UV spectroscopy SFC method: SFC-1 SFC Agilent1260 (Binary Pump) SFC Column Chiralpak AD-H (250×4,6mm), 5μm Flow rate 2mL / min Mobile phase A:CO2+B:MeOH ABPR 120Bar Temp 37.5℃ UV 220nm Gradient: 80% A + 20% B (uniform concentration) Downtime 10 minutes

[0530] Analytical HPLC (reaction control) of intermediates and final compounds is performed using Waters columns (name: XBridge™ C18, 2.5 μm, 2.1×20 mm or XBridge™ C18, 2.5 μm, 2.1×30 mm or Aquity UPLC BEH C18, 1.7 μm, 2.1×50 mm), YMC columns (name: Triart C18, 3.0 μm, 2.0×30 mm) and Phenomenex columns (name: Luna C18, 5.0 μm, 2.0×30 mm). Each analytical instrument is also equipped with a mass detector.

[0531] HPLC-Mass Spectrometry / UV Spectroscopy Retention Time / MS-ESI for Characterizing Example Compounds of the Invention + is generated using an HPLC-MS instrument (high performance liquid chromatography with mass detector). Compounds eluting in the injection peak are identified with retention times t Ret =0.00.

[0532] Method A HPLC Agilent 1100 System MS 1200 Series LC / MSD (API-ES + / -3000V, quadrupole, G6140) MSD Signal Settings Scan Positive / Negative 120~1500m / z Detection signal: 315 nm (bandwidth 170 nm, reference off) Spectral range: 230-400nm Peak width <0.01 min Column: Waters, XBridge C18, 2.5 μm, 2.1 x 20 mm column Column temperature: 60℃ Solvent A: 20mM NH4HCO3 / NH3 aqueous solution pH 9 B: ACN HPLC grade Flow rate 1.00mL / min Gradient 0.00~1.50 min 10% to 95% B 1.50~2.00 minutes 95% B 2.00-2.10 min 95% to 10% B

[0533] Method B HPLC Agilent 1260 Series MS Agilent LC / MSD Quadrupole Detection MS: positive and negative modes Mass range: 100-1200m / z Column: Waters X-Bridge BEH C18, 2.5 μm, 2.1 × 30 mm 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 to 95% B 1.00~1.30 minutes: 95% B

[0534] Method C HPLC Agilent 1100 / 1200 system MS 1200 Series LC / MSD (MM-ES+APCI + / -3000V, quadrupole, G6130B) MSD Signal Settings Scan Positive / Negative 150~750 Detection signal: UV254nm, 230nm, 214nm (bandwidth 8, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (response time 0.063 sec, 80 Hz) Column: Waters, part number 186003389, XBridge BEH C18, 2.5 μm, 2.1 x 30 mm) 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 0.0~1.0 min 15% to 95% B 1.0~1.1 minutes 95% B Downtime: 1.3 minutes

[0535] Method D HPLC Agilent 1100 / 1200 system MS 1200 Series LC / MSD (API-ES + / -3000 / 3500V, quadrupole, G6140A) MSD Signal Settings Scan Positive / Negative 150~750 Detection signal: UV254nm, 230nm, 214nm (bandwidth 10, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (response time 0.063 sec, 80 Hz) Column YMC; Part number TA12S03-0302WT; Triart C18, 3μm, 12nm; 30×2.0mm 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 0.0~1.0 min 15% to 95% B 1.0~1.1 minutes 95% B Downtime 1.23 minutes

[0536] Method E UPLC-MS Waters Acquity-UPLC-SQ Detector-2 MSD Signal Settings Scan Positive / Negative 100~1500 Source voltage: Capillary voltage (kV) -3.50, Cone (V): 50 Source Temp: Desolvation Temp (℃): 350 Source 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, 2.1×50mm Column temperature: 35℃ Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water Flow rate 0.6mL / min Gradient 0.0~0.30 min 97% B 0.30~2.20 min 97% to 2% B 2.20~3.30 minutes 2% B 3.30~4.50 min 2% to 97%B 4.50~4.51 minutes 97% B

[0537] Method F UPLC-MS Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2 MSD Signal Settings Scan Positive / Negative 100~1500 Source voltage: Capillary voltage (kV) -3.50, Cone (V): 50 Source Temp: Desolvation Temp (℃): 350 Source 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, 2.1×50mm Column temperature: 35℃ Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water Flow rate 0.6mL / min Gradient 0.0~0.40min 97% B 0.40-2.50 min 97% to 2% B 2.50~3.40 minutes 2% B 3.40-3.50 min 2% to 97%B 3.50~4.0 minutes 97% B

[0538] Method G UPLC-MS Shimadzu series LC-MS2020 system with photodiode array detector MSD signal settings APCI and ESI positive / negative 100-1000m / z Detection signal Photodiode array Spectral range: 200-400 nm, detection wavelength: 254 nm Sampling rate: 40Hz Column: Hypersil Gold column, particle size 1.9 μm, 2.1 x 50 mm Column temperature: 40℃ Solvent A: 0.1% FA in HO; B: 0.1% FA in MeCN B: 0.07% formic acid in water Flow rate 0.8mL / min Gradient 0.0~3.0 min: 5% to 95% B

[0539] Method H HPLC Agilent 1100 / 1200 system MS 1200 Series LC / MSD (MM-ES+APCI + / -3000V, quadrupole, G6130B) MSD Signal Settings Scan Positive 700~1350 Column: Waters, part number 186003389, XBridge BEH C18, 2.5 μm, 2.1 x 30 mm column Eluent A: 5mM NH4HCO3 / 18mM NH3(pH=9.2) B: Acetonitrile (HPLC grade) Detection signal: UV254nm, 230nm, 214nm (bandwidth 8, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (response time 0.063 sec, 80 Hz) Injection 0,5μL standard injection Flow rate 1.4mL / min Column temperature: 45℃ Gradient 0.0~1.0 min 15%→95% B 1.0~1.1 minutes 95% B Downtime 1.3 minutes

[0540] HPLC / UV spectroscopy Method I HPLC Agilent 1100 / 1200 system Column: Chiralpak; Part No. 85394; IE, 5 μm; 150 x 2.1 mm Eluent A: n-heptane B: EtOH + 0.1% DEA Detection signal: UV315nm (bandwidth 170, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (response time 0.063 sec, 80 Hz) Injection 0,5μL standard injection Flow rate 1.2mL / min Column temperature: 45℃ Uniform concentration 70% B Downtime 5 minutes

[0541] Method J HPLC Agilent 1100 / 1200 system MS 1200 Series LC / MSD (API-ES + / -3000 / 3500V, quadrupole, G6140A) MSD Signal Settings Scan Positive / Negative 700~1350 Detection signal: UV254nm, 230nm, 214nm (bandwidth 10, reference off) Spectral range: 190~400nm; slit: 4nm Peak width >0.0031 min (response time 0.063 sec, 80 Hz) Column YMC; Part number TA12S03-0302WT; Triart C18, 3μm, 12nm; 30×2.0mm 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 0.0~1.0 min 15% to 95% B 1.0~1.1 minutes 95% B Downtime 1.23 minutes

[0542] Method K UPLC-MS Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2 MSD Signal Settings Scan Positive / Negative 100~1500 Source voltage: Capillary voltage (kV) -3.50, Cone (V): 50 Source Temp: Desolvation Temp (℃): 350 Source gas flow rate: Desolvation (L / Hr): 700, 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, 2.1×50mm Column temperature: 35℃ Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water Flow rate 0.6mL / min Gradient 0.0~0.40min 97% B 0.40-2.50 min 97% to 2% B 2.50~3.40 minutes 2% B 3.40-3.50 min 2% to 97%B 3.50~4.0 minutes 97% B

[0543] Method L UPLC-MS Waters Aquity H Class LC system coupled with Waters ZQ / 3100 / SQD2 mass spectrometer MSD Signal Settings Scan Positive / Negative 100~1500 Detection signal Diode array Spectral range: 190~400nm; resolution: 1.2nm Column: YMC triart C18 column (3 μm, 33 × 2.1 mm) Column temperature: 30℃ Solvent A: 5 mM ammonium acetate in water / 0.05% formic acid in water B: 5 mM ammonium acetate in acetonitrile:water (90:10) / 0.05% formic acid in water Flow rate 1mL / min Gradient 0.0~0.75min 2% B 0.75~1.00 min 2% to 10% B 1.00~2.00 min 10% to 98% B 2.00~2.50 minutes 98%B 2.50~2.90 min 98% to 2% B 2.90~3.00 minutes 2% B

[0544] Method M HPLC-MS: Agilent 1200 HPLC with diode array detector; MS: Agilent 6130 ESI mass spectrometer MSD signal settings: ESI positive, 100-1000 m / z Column: Waters XBridge C18 column, 2.1 x 50 mm, particle size 3.5 μm Solvent A: 0.1% formic acid in water, B: 0.1% formic acid in ACN Detection signal 254 nm, reference off Spectral range: 190-400nm Peak width <0.01 min Injection 4.0μL standard injection Column temperature: 35℃ Flow rate 0.7mL / min Gradient: 5 to 95% B, 3 divisions

[0545] Method N HPLC-MS Agilent 1100 Series; Bruker Microtof MSD signal setting ESI positive 100~1200m / z Column: Waters XBridge C18 column, 2.1 x 50 mm, particle size 3.5 μm Solvent A: 0.1% formic acid in water, B: 0.1% formic acid in ACN Detection signal 254 nm, reference off Spectral range: 190-400nm Peak width <0.01 min Injection 3.0μL standard injection Column temperature: 35℃ Flow rate 0.6mL / min Gradient: 5 to 95% B, 8 divisions

[0546] The compounds of the present invention and intermediates thereof can be obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis.Preferably, the compounds are obtained in a manner similar to the preparation methods described more fully below. In said methods, the substituents of the general formulae have the meanings given above. These methods are intended to be illustrative of the present invention, without limiting the scope of the subject matter and the compounds claimed to these examples.In some cases, the order of carrying out the reaction steps can be changed.Variants of the reaction methods known to those skilled in the art but not described in detail here can also be used.

[0547] In cases where the preparation of the starting compounds is not described, they are commercially available or their synthesis is described in the prior art or they can be prepared analogously to known prior art compounds or methods described herein, i.e., 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. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again at an appropriate stage in the reaction sequence using methods familiar to those skilled in the art. In cases where the following chemical structures are shown, for example, without the exact configuration of the stereocenters of asymmetrically substituted carbon atoms, both configurations shall be considered as included and disclosed in such representations. The representation of a stereocenter in a racemate shall always be considered as including and disclosing both enantiomers (if no other defined stereocenter exists) or all other possible diastereomers and enantiomers (if additional defined or undefined stereocenters exist).

[0548] Scheme 1 [ka] Scheme 2 [ka]

[0549] Synthesis experimental procedure for K-1a [ka] To a solution of ethyl 1-methyl-2-oxocyclohexane-1-carboxylate (108.00 g, 586.2 mmol) in toluene (1.03 L) is added malononitrile (58.04 g, 879.3 mmol, 1.5 eq.), followed by ammonium acetate (9.04 g, 117.2 mmol, 0.2 eq.) and acetic acid (13.41 mL, 234.5 mmol, 0.4 eq.) at rt. The mixture is stirred at 110° C. for 16 h. After complete conversion, the mixture is diluted with EtOAc, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give crude product K-1a. The crude material is used in the next step without further purification (see also Naumann et al., Pharmazie 51 (1996), 4).

[0550] [Table 2]

[0551] Synthesis experiment procedure for K-2a [ka] To a solution of K-1a (250.0 g, 1.1 mol) in DMF (3.0 L) is added sulfur (68.9 g, 2.2 mol, 2.0 eq.) and L-proline (24.8 g, 0.22 mol, 0.2 eq.) and the resulting mixture is stirred at 80° C. for 12 h. After complete conversion, the mixture is partitioned between EtOAc and water and the organic layer is collected. The aqueous layer is further extracted with EtOAc and the combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography to afford K-2a.

[0552] [Table 3]

[0553] Synthesis experiment procedure for K-3a [ka] K-2a (78.0 mg, 0.3 mmol, 1.0 eq) is dissolved in EtOH (1.5 mL) and potassium hydroxide (4 M in water, 0.37 mL, 1.5 mmol, 5.0 eq) is added. The mixture is stirred at 78 °C for 16 h. After complete conversion, water and EtOAc are added to the reaction mixture, the pH of the aqueous phase is set to pH 4 using KHSO4 solution (10% in water) and the product is extracted using EtOAc. The combined organic layers are dried, filtered and concentrated. The crude product is purified by acidic reverse phase chromatography (gradient elution: 20% to 90% acetonitrile in water) to yield K-3a.

[0554] The enantiomers can be separated by preparative SFC chromatography. For example, K-3a can be separated into K-3b and its enantiomer (Analytical SFC Method SFC-1:t ret = 4.9 min for K-3b and 7.9 min for the other enantiomer).

[0555] [Table 4]

[0556] Synthesis Experimental Procedure for K-4a [ka] To a solution of K-3b (22.00 g, 93.11 mmol, 1.0 eq) in THF (300 mL) is added CDI (17.12 g, 102.42 mmol, 1.1 eq) and the mixture is stirred at 50 °C for 1 h. The mixture is cooled to rt and sodium borohydride (10.78 g, 279.32 mmol, 3.0 eq) suspended in 5 mL water is added slowly to the reaction mixture (exothermic reaction). After addition, the mixture is stirred for 1 h and subsequently quenched by slow addition of water (250 mL). THF is removed under vacuum and the resulting mixture is extracted with EtOAc (3 x 120 mL). The combined organic layers are washed with water (3 x 100 mL) and the organic layer is dried over MgSO4. The solvent is removed under vacuum and the crude product K-4a is used in the next step without further purification.

[0557] The following intermediates K-4 (Table 4) are accessible in a similar manner starting from the different intermediates K-3: The crude products K-4 are purified by chromatography if necessary.

[0558] [Table 5]

[0559] K-5a synthesis experimental procedure [ka] K-4a (21.10 g, 75.93 mmol, 80% purity, 1.0 eq) is mixed with N,N-dimethylformamide dimethyl acetal (57.6 g, 454.37 mmol, 94% purity, 6.0 eq) and irradiated in an ultrasonic bath for 15 min until the mixture becomes a clear solution. Water (200 mL) is added and the reaction mixture is stirred at rt for 30 min until a precipitate forms. The precipitate is filtered and water (100 mL) is added. The mixture is irradiated in an ultrasonic bath for 15 min and the precipitate is filtered. The precipitate is washed with isopropanol (25 mL) and dried under vacuum at 45 °C overnight to give K-5a, which is used in the next step without further purification.

[0560] The following intermediate K-5 (Table 4 * ) is accessible in an analogous manner starting from the different intermediate K-4. The crude product K-5 is purified by chromatography if necessary.

[0561] [Table 6]

[0562] Synthesis procedure for K-6a [ka] A solution of oxalyl chloride (12.2 mL, 144.20 mmol, 2.5 eq.) in DCM (120 mL) is cooled to -78 °C. A solution of anhydrous DMSO (18.44 mL, 259.57 mmol, 4.5 eq.) in DCM (60 mL) is added dropwise to the reaction mixture (exothermic reaction). The mixture is stirred at -78 °C for 30 min. K-5a (16.00 g, 57.68 mmol, 1.0 eq.) is added slowly to the reaction mixture. The mixture is stirred at -78 °C for 30 min and trimethylamine (71.96 mL, 519.32 mmol, 9.0 eq.) is added dropwise. The reaction mixture is slowly warmed to rt and stirred for a further 2 h. Water and DCM are added to the mixture and the phases are separated. The aqueous layer is extracted twice with DCM and the combined organic layers are washed three times with water. The organic layer is dried over MgSO4 and the solvent is removed in vacuo to give crude intermediate K-6a, which is used in the next step without further purification.

[0563] The following intermediates K-6 (Table 5) are accessible in a similar manner starting from the different intermediates K-5: The crude products K-6 are purified by chromatography if necessary.

[0564] [Table 7]

[0565] Synthesis Experimental Procedure for K-7a [ka] A mixture of K-6a (15.90 g, 57.75 mmol, 1.0 eq.), Cs2CO3 (22.58 g, 69.26 mmol, 1.2 eq.) and MeOH (120 mL) is cooled to 0 °C and a solution of Bestmann-Ohira reagent (dimethyl (1-diazo-2-oxopropyl)phosphonate; 12.20 g, 63.52 mmol, 1.1 eq.) in MeOH (5 mL) is added dropwise to the reaction mixture. After 3 h at 0 °C, the reaction mixture is slowly warmed to rt. After complete conversion, MeOH is removed under vacuum and water (500 mL) and EtOAc (500 mL) are added to the mixture. The phases are separated and the aqueous layer is extracted twice with EtOAc. The combined organic layers are washed three times with water, dried over MgSO4 and the solvent is removed under vacuum. The residue is mixed with diethyl ether and stirred for 30 min at rt. The mixture is cooled to 0° C. and stirred for an additional 30 min, then filtered and washed with a small amount of cold diethyl ether. The precipitate is dried under vacuum at 45° C. to give intermediate K-7a, which is used in the next step without further purification.

[0566] The following intermediates K-7 (Table 6) are accessible in a similar manner starting from the different intermediates K-6: The crude products K-7 are purified by chromatography if necessary.

[0567] [Table 8]

[0568] K-20a synthesis experimental procedure [ka] To a stirred solution of (2S)-2-{benzyl[(tert-butoxy)carbonyl]amino}propanoic acid (24.00 g, 85.92 mmol, 1.0 eq) in DCM (200 mL) is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.71 g, 128.88 mmol, 1.5 eq.), 1-hydroxybenzotriazole (19.74 g, 128.88 mmol, 1.5 eq.) and NEt3 (47.81 mL, 343.67 mmol, 4.0 eq.). The reaction mixture is stirred at rt for 5 min. 3-Amino-3-methyl-butyric acid ethyl ester hydrochloride (23.41 g, 128.88 mmol, 1.5 eq.) is added and the reaction mixture is stirred at rt for 16 h. After complete conversion, the reaction mixture is diluted with DCM and washed with water. The organic layer is washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by column chromatography to give K-20a.

[0569] [Table 9]

[0570] Synthesis procedure for K-21a [ka] To a stirred solution of K-20a (16.00 g, 39.36 mmol, 1.0 eq.) in THF (40 mL) and water (20 mL) is added lithium hydroxide (2.48 g, 59.04 mmol, 1.5 eq.) and the reaction mixture is stirred at rt for 16 h. After complete conversion, the reaction mixture is diluted with water and the organic layer is separated. The aqueous layer is washed with EtOAc. The aqueous layer is acidified with citric acid and extracted with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product K-21a is used in the next step without further purification.

[0571] [Table 10]

[0572] K-22a synthesis experimental procedure [ka] To a stirred solution of intermediate K-21a (20.00 g, 52.84 mmol, 1.0 eq.) in DCM (100 mL) is added HCl (200 mL, 4N in 1,4 dioxane) and the reaction mixture is stirred at rt for 4 h. After complete conversion, the volatiles are removed under reduced pressure to give the crude product. The crude product is triturated with pentane to give intermediate K-22a, which is used in the next step without any further purification.

[0573] [Table 11]

[0574] Synthesis procedure for K-23a [ka] To a stirred suspension of TBTU (25.95 g, 80.83 mmol, 1.5 eq.) in DCM (800 mL) is slowly added a solution of intermediate K-22a (15.00 g, 53.89 mmol, 1.0 eq.) and DIPEA (28.73 mL, 161.67 mmol, 3.0 eq.) in DCM (800 mL) at 0 °C, and the reaction mixture is warmed to rt and stirred for 16 h. The reaction mixture is quenched with water. The organic layer is separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography to give intermediate K-23a.

[0575] [Table 12]

[0576] Synthesis Experimental Procedure for K-24a [ka] To a stirred solution of intermediate K-23a (9.00 g, 34.57 mmol, 1.0 eq.) in THF (50.00 mL) is added lithium aluminum hydride solution (5.26 mL, 138.28 mmol, 4.0 eq, 1M in THF) at 0° C. and the reaction mixture is warmed to rt and stirred at rt for 10 min. The reaction mixture is heated to 80° C. and stirred for 16 h. The reaction mixture is cooled to 0° C. and carefully quenched by slow addition of saturated Na2SO4 solution. The phases are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude is purified by column chromatography to afford intermediate K-24a.

[0577] [Table 13]

[0578] K-25a synthesis experiment procedure [ka] To a stirred solution of intermediate K-24a (1.00 g, 4.13 mmol, 1.0 eq.) in DCM (10 mL) is added NEt3 (3.43 mL, 24.78 mmol, 6.0 eq.) and Boc anhydride (2.00 g, 9.08 mmol, 2.2 eq.). The reaction mixture is stirred at rt for 16 h. The reaction mixture is concentrated under reduced pressure, dissolved in acetonitrile, and purified by chromatography to give intermediate K-25a.

[0579] [Table 14]

[0580] K-26a synthesis experimental procedure [ka] To a solution of intermediate K-25a (846 mg, 2.545 mmol, 1.0 eq) in MeOH (40 mL) in a hydrogenation reactor, Pd / C (10%, 150.00 mg) is added. The reaction mixture is stirred under a pressure of 5 bar H2 for 3 h. After complete conversion, the reaction mixture is filtered and the solvent is removed under reduced pressure to give intermediate K-26a.

[0581] [Table 15]

[0582] K-9a synthesis experiment procedure [ka] To a solution of (S)-tert-butyl-3-methyl-1,4-diazepane-1-carboxylate (846.0 mg, 214.30 mmol, 1.0 eq) and 2-chloropyrimidine-4-carbonitrile (528.9 mg, 139.54 mmol, 1.0 eq) in DMSO (4 ml, 4.5 V) is added TEA (1.1 ml, 101.19 mmol, 2.0 eq) at rt. The reaction mixture is stirred at 80° C. for 1 h. After complete conversion, the reaction mixture is cooled to rt and water and EtOAc are added. The phases are separated. The organic layer is washed with water, dried over sodium sulfate, then filtered and concentrated under reduced pressure to give the crude product, which is purified by chromatography to give K-9a.

[0583] The following intermediates K-9 (Table 14) can be obtained by a similar method using different nitriles or amines, such as K-26a, to prepare K-9d. The crude product K-9 is purified by chromatography if necessary.

[0584] [Table 16] TIFF2024542692000123.tif70165

[0585] K-10a synthesis experimental procedure [ka] To a solution of K-9a (33.85 g, 106.65 mmol, 1.0 eq) in EtOH (270 ml) is added a 50% solution of hydroxylamine in water (13.05 mL, 213.30 mmol, 2.0 eq) at rt. The reaction mixture is stirred at 60° C. for 1 h. After complete conversion, the reaction mixture is concentrated under reduced pressure to give K-10a, which is used in the next step without further purification.

[0586] The following intermediates K-10 (Table 15) are accessible in an analogous manner using different nitriles K-9: The crude products K-10 are purified by chromatography if necessary.

[0587] [Table 17] TIFF2024542692000126.tif117165

[0588] Synthesis procedure for K-11a [ka] To a stirred solution of K-3b (2.53 g, 10.70 mmol, 1.0 eq) in DMSO (10 ml) is added TEA (2.17 g, 21.40 mmol, 2.0 eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU, 4.27 g, 11.24 mmol, 1.10 eq.) at rt. The mixture is stirred at rt for 15 min. K-10a (3.75 g, 10.70 mmol, 1.0 eq) is added at rt and stirred overnight. After complete conversion, the reaction mixture is diluted with water and EtOAc. The phases are separated. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material is purified by column chromatography to give K-11a.

[0589] The following intermediate K-11 (Table 16) is accessible in an analogous manner using the different intermediate K-10: The crude product K-11 is purified by chromatography if necessary.

[0590] [Table 18]

[0591] K-12a synthesis experimental procedure [ka] To a stirred solution of K-11a (2.00 g, 3.51 mmol, 1.0 eq) in THF (40 mL) is added DBU (1.98 mL, 14.04 mmol, 4.0 eq) at rt. The reaction mixture is stirred at 70° C. overnight. After complete conversion, the reaction mixture is concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography to give K-12a.

[0592] The following intermediate K-12 (Table 17) is accessible in a similar manner using different intermediate K-11. The crude product K-12 is purified by chromatography if necessary.

[0593] [Table 19] TIFF2024542692000131.tif42165

[0594] K-13a synthesis experimental procedure [ka] To a stirred solution of K-12a (20.00 g, 34.52 mmol, 1.0 eq.) in MeOH (350 mL) is added concentrated HCl (32.88 mL, 345.21 mmol, 10.0 eq.) at rt. The reaction mixture is stirred at 50° C. for 2 h. After complete conversion, the reaction mixture is concentrated under reduced pressure and diluted with water. The aqueous phase is extracted with DCM. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure to give K-13a, which is used in the next step without further purification.

[0595] The following intermediate K-13 (Table 18) can be obtained in a similar manner using different intermediate K-12. The crude product K-13 is purified by chromatography if necessary.

[0596] [Table 20] TIFF2024542692000134.tif122165

[0597] K-14a synthesis experimental procedure [ka] To a solution of K-9a (534 mg, 1.68 mmol, 1.0 eq.) in EtOH (4.0 ml), sodium hydroxide (4M in water, 1.00 ml, 40.0 mmol, 2.4 eq.) is added and stirred under reflux for 1 h. The reaction mixture is cooled to rt and acidified with citric acid (5% in water). Water and EtOAc are added and the phases are separated. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product K-14a (Table 19), which is used in the next step without further purification.

[0598] [Table 21]

[0599] K-15a synthesis experiment procedure [ka] To a stirred solution of K-14a (481.0 mg, 1.43 mmol, 1.0 eq) in anhydrous THF (3.0 mL, 7.5 V), DIPEA (1.27 mL, 7.15 mmol, 5.0 eq) and HATU (598 mg, 1.57 mmol, 1.1 eq) are added and stirred at rt for 15 min. N,O-Dimethylhydroxylamine hydrochloride (278.9 mg, 2.86 mmol, 2.0 eq) is added and stirred at rt for 1 h. After complete conversion, the reaction mixture is diluted with water and EtOAc and the phases are separated. The organic layer is washed with water, dried over sodium sulfate and concentrated under reduced pressure to give crude K-15a (Table 20). The crude is purified by chromatography.

[0600] [Table 22]

[0601] K-16a synthesis experimental procedure [ka] To a solution of K-7a (230 mg, 0.85 mmol, 1.0 eq.) and K-15a (389.0 mg, 1.025 mmol, 1.2 eq.) in THF (7 mL) is added LiHMDS (3.39 mL, 3.39 mmol, 4.00 eq., 1M in THF) dropwise at -78 °C and stirred for 10 min at -78 °C. After complete conversion, the reaction is warmed to rt, quenched with water and diluted with EtOAc. The phases are separated and the aqueous layer is extracted three times with EtOAc. The combined organic layers are concentrated under reduced pressure. The residue is dissolved in acetonitrile and water and purified by chromatography to give the desired product K-16a (Table 21).

[0602] [Table 23]

[0603] K-17a synthesis experimental procedure [ka] To a stirred solution of K-16a (100 mg, 0.17 mmol, 1.0 eq.) in EtOH (1 mL) is added hydroxylamine hydrochloride (60.1 mg, 0.85 mmol, 5.0 eq.) and stirred at rt for 2 h. After complete conversion, the reaction is quenched with saturated aqueous sodium bicarbonate solution and stirred at rt for 2 h. The mixture is diluted with acetonitrile and water, filtered and purified by chromatography to give the desired intermediate K-17a (Table 22).

[0604] [Table 24]

[0605] Synthesis Experimental Procedure for K-18a [ka] To a stirred solution of K-16a (45 mg, 0.076 mmol, 1.0 eq.) in ACN (0.5 mL) is added hydroxylamine solution (50% in water, 70.14 μL, 1.145 mmol, 15.0 eq.) and the reaction mixture is stirred at rt for 30 min. After complete conversion, the reaction mixture is diluted with acetonitrile and water, filtered and purified by chromatography to give the desired intermediate K-18a (Table 23).

[0606] [Table 25]

[0607] K-17b synthesis experimental procedure [ka] To a solution of K-16a (85.0 mg, 0.144 mmol, 1.0 eq.) in methanol (2 mL) is added hydroxylamine-O-sulfonic acid (32.6 mg, 0.288 mmol, 2.0 eq.). The reaction mixture is stirred for 40 min. Sodium bicarbonate (30.3 mg, 0.360 mmol, 2.5 eq.) and sodium hydrogen sulfide (20.2 mg, 0.360 mmol, 2.5 eq.) are added to the reaction mixture and stirred for 18 h. Additional sodium bicarbonate (36.3 mg, 0.432 mmol, 3.0 eq.) and sodium hydrogen sulfide (24.2 mg, 0.432 mmol, 3.0 eq.) are added and the reaction mixture is stirred at 60° C. for 2 h. The reaction mixture is diluted with DCM and saturated aqueous sodium bicarbonate solution. The phases are separated and the aqueous layer is extracted with DCM (5 times). The organic layers are combined and the solvent is removed under reduced pressure. The crude product is purified by chromatography to give intermediate K-17b (Table 24).

[0608] [Table 26]

[0609] Synthesis experiment procedure for K-13d [ka] To a stirred solution of K-17a (114.0 mg, 0.19 mmol, 1.0 eq.) in THF (1 mL) is added HCl (2 M in water, 0.94 mL, 1.89 mmol, 10.0 eq.) at rt. The reaction mixture is stirred at 65° C. for 2 h. After complete conversion, the reaction mixture is concentrated under reduced pressure, diluted with water and acetonitrile, and brought to alkaline pH by adding 2 M NaOH. It is purified by reverse phase chromatography using basic conditions to afford K-13d.

[0610] The following intermediate K-13 (Table 25) can be obtained in an analogous manner using the different intermediate K-17. The crude product K-17 is purified by chromatography if necessary.

[0611] [Table 27]

[0612] Synthesis experiment procedure for K-13f [ka] To a stirred solution of K-18a (40.0 mg, 0.06 mmol, 1.0 eq.) in THF (0.5 mL) is added HCl (2 M in water, 0.32 mL, 0.64 mmol, 10.0 eq.) at rt. The reaction mixture is stirred at 65° C. for 3 h. After complete conversion, the reaction mixture is concentrated under reduced pressure, diluted with water and acetonitrile, and basified by adding NaOH (2 M in water). The mixture is purified by chromatography to afford K-13f (Table 26).

[0613] [Table 28]

[0614] Synthesis experimental procedure for A-1a [ka] To a stirred solution of 4-bromo-3-fluorobenzonitrile (100 mg, 0.50 mmol, 1.0 eq.) and 4-methyl-thiazole (100 mg, 1.00 mmol, 2.0 eq.) in N,N-dimethylacetamide (1.00 mL) are added potassium acetate (99 mg, 1.00 mmol, 2.0 eq.) and palladium(II) acetate (11 mg, 0.05 mmol, 0.1 eq.) at rt and the mixture is purged with argon for 15 min. The mixture is stirred and heated by microwave irradiation at 150° C. for 30 min. After complete conversion, the reaction mixture is cooled to room temperature, diluted with water and EtOAc and stirred for 15 min. The phases are separated and the aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with saturated aqueous NaCl and the solvent is removed under reduced pressure. The crude product is purified by chromatography to give A-1a.

[0615] The following intermediates A-1 (Table 27) can be obtained in an analogous manner by using other corresponding bromides as starting materials. The crude product A-1 is purified by chromatography if necessary.

[0616] [Table 29]

[0617] Synthesis experimental procedure for A-2a [ka] To a stirred solution of A-1a (530 mg, 2.43 mmol, 1.0 eq) in anhydrous THF (20.0 mL) is added lithium aluminum hydride (2 M in THF, 3.64 mL, 7.29 mmol, 3.0 eq) dropwise at 0° C. The reaction mixture is slowly warmed to RT and stirred overnight. After complete conversion, the reaction mixture is cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution, then treated with saturated aqueous sodium potassium tartrate solution and stirred for 2 h. Aqueous NaOH (2 M) and EtOAc are added, the mixture is filtered through celite and the phases are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography to afford A-2a.

[0618] The following intermediates A2 (Table 28) are accessible in an analogous manner starting from the different intermediates A1: The crude products A2 are purified by chromatography if necessary.

[0619] [Table 30]

[0620] Experimental procedure for synthesis of A-2d [ka] [4-({[(tert-butoxy)carbonyl]amino}methyl)phenyl]boronic acid (500 mg, 1.991 mmol), ethyl 5-bromo-1,3-thiazole-4-carboxylate (630 mg, 2.589 mmol, 1.3 eq.), sodium carbonate (848 mg, 7.965 mmol, 4.0 eq.) and tetrakis-(triphenylphosphine)-palladium (232 mg, 0.199 mmol, 0.1 eq.) are dissolved in dimethoxylethane (5 mL) and water (1.5 mL). The mixture is flushed with argon at rt for 5 min and then stirred at 90° C. for 2 h. Water (0.5 mL) is added to the reaction mixture, which is stirred at 90° C. for a further 2 h. The reaction mixture is diluted with DCM and water and the phases are separated. The aqueous layer is extracted twice with DCM and the combined organic layers are concentrated under reduced pressure to dryness and purified by chromatography to give ethyl 5-[4-({[(tert-butoxy)carbonyl]amino}methyl)phenyl]-1,3-thiazole-4-carboxylate (HPLC Method A:t ret =1.25 minutes, [M+H] + =363).

[0621] [ka] To a stirred solution of 5-[4-({[(tert-butoxy)carbonyl]amino}methyl)phenyl]-1,3-thiazole-4-carboxylate (580 mg, 1.60 mmol, 1.0 eq) in anhydrous THF (5.0 mL) is added lithium borohydride (2 M in THF, 1.6 mL, 3.20 mmol, 2.0 eq) portionwise at 0° C. The reaction mixture is stirred at rt for 6 h. After complete conversion, the reaction mixture is diluted with ice-cold water and extracted with EtOAc. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product is purified by column chromatography to give tert-butyl N-({4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}methyl)carbamate (HPLC method A:t ret =1.09 minutes, [M+H] + =321).

[0622] [ka] tert-Butyl N-({4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}methyl)carbamate (32 mg, 0.1 mmol, 1.0 eq.) is dissolved in methanol (0.32 mL) and HCl (4 M in dioxane, 0.12 mL) is added at 0° C. The reaction mixture is stirred at rt for 2 h. After complete conversion, the reaction mixture is concentrated to dryness under reduced pressure to give crude A-2d as the HCl salt (Table 29), which is used without further purification.

[0623] [Table 31]

[0624] Synthesis experimental procedure for A-5a [ka] To a stirred solution of 4-(4-methylthiazol-5-yl)benzaldehyde (1.10 g, 5.41 mmol, 1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (0.98 g, 8.12 mmol, 1.50 eq.) in anhydrous THF (10 mL), Cs2CO3 (4.41 g, 13.5 mmol, 2.50 eq.) is added and the resulting mixture is stirred at 50° C. for 3 h. The reaction mixture is quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers are dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography to give intermediate A-5a (Table 30).

[0625] [Table 32]

[0626] Synthesis procedure of A-6a [ka] To a stirred solution of intermediate A-5a (1.00 g, 3.263 mmol, 1.0 eq.) in THF (5 mL) at 0° C. is added allylmagnesium bromide (4.89 mL, 4.8945 mmol, 1.5 eq. 1.0 M in Et2O). The reaction is warmed to rt and stirred for 16 h. The reaction mixture is diluted with ice water (10 mL) and the resulting precipitate is filtered and washed with water. The filtrate is extracted with DCM (2×10 mL) and the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by chromatography to give intermediate A-6a (Table 31).

[0627] [Table 33]

[0628] Synthesis experimental procedure for A-7a [ka] A stirred solution of SmI2 (0.1 M in THF, 27.4 mL, 2.74 mmol, 3.0 eq) is cooled to -78 °C and a solution of A-5a (280 mg, 0.91 mmol, 1.0 eq.) and 10 drops of acetaldehyde in anhydrous tBuOH (171.5 μL, 1.83 mmol, 2.0 eq) and anhydrous THF (11.0 mL) is added portionwise over 0.5 h at -78 °C and stirring is continued for 2 h at -78 °C. The reaction mixture is quenched with 10% aqueous sodium thiosulfate and DCM is added. A white precipitate forms which is filtered through Celite. The phases are separated and the aqueous phase is extracted three times with DCM. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography to give A-7a (78% purity) as the major product (Table 32). This is improved to 98% by chiral chromatography.

[0629] [Table 34]

[0630] Synthesis experimental procedure for A-8a [ka] A stirred solution of intermediate A-6a (1.00 g, 2.869 mmol, 1.0 eq.) in MeOH (10 mL) at -78 °C is purged with ozone gas for 30 min. Sodium borohydride (0.370, 10.042 mmol, 3.5 eq.) is added at -78 °C and the mixture is allowed to warm to rt overnight. The reaction mixture is quenched with ice-cold water and extracted with DCM. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by chromatography to give intermediate A-8a (Table 33).

[0631] [Table 35]

[0632] Synthesis Experimental Procedure of A-9a [ka] To a stirred mixture of intermediate A-7a (105 mg, 0.298 mmol, 1.0 eq.) in THF (1.2 mL) is added HCl (0.6 mL, 2M in HO). The mixture is stirred at rt for 3 h. The reaction is diluted with MeOH and purified by ion exchange column chromatography (Isolute SPE 1 g column, SCX-2) to give intermediate A-9a.

[0633] The following intermediate A-9 (Table 34) is accessible in an analogous manner starting from the different intermediates A-7 or A-8.

[0634] [Table 36]

[0635] A-10a synthesis experimental procedure [ka] To a stirred solution of intermediate A-9b (600 mg, 2.11 mmol, 1.0 eq.) in 1,4 dioxane (6 mL) and HO (6 mL) is added NEt3 (1.5 mL, 10.5 mmol, 5.0 eq.) and Boc anhydride (0.73 mL, 3.16 mmol, 1.50 eq.) and the mixture is stirred at rt for 3 h. The reaction mixture is quenched with ice-cold water and extracted with DCM. The organic layer is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by chromatography to give intermediate A-10a (Table 35).

[0636] [Table 37]

[0637] A-11a synthesis experimental procedure [ka] To a stirred solution of intermediate A-10a (100 mg, 0.274 mmol, 1.0 eq.) and NEt3 (475 μL, 3.289 mmol, 12 eq.) in anhydrous THF (2 mL) is slowly added a solution of phosphoroxychloride (250 μL, 2.741 mmol, 10 eq.) in anhydrous THF (1 mL) at 0° C. The reaction mixture is stirred for 30 min at 0° C. The mixture is quenched with water at 0° C. and warmed to rt. The mixture is diluted with acetonitrile and water, filtered, and purified by reverse phase chromatography to give intermediate A-11a (Table 36).

[0638] [Table 38]

[0639] Synthesis experimental procedure for A-2e [ka] To a stirred solution of intermediate A-11a (15 mg, 0.035 mmol, 1.0 eq.) in MeOH (1 mL) at rt, HCl (1 mL, 4N in 1,4 dioxane) is added and the mixture is stirred for 1 h. The reaction mixture is concentrated under reduced pressure and the crude intermediate A-2e (Table 37) is used in the next step without further purification.

[0640] [Table 39]

[0641] A-12a synthesis experimental procedure [ka] To a stirred solution of tert-butyl N-[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate (500 mg, 1.42 mmol, 1.0 eq) in THF (3.3 mL) is added Dess-Martin periodinane (723 mg, 1.70 mmol, 1.2 eq) under argon atmosphere and stirred at rt for 1 h to form the intermediate tert-butyl N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-2-oxoethyl]carbamate, which was not isolated. The reaction mixture is filtered and cooled to -78°C under argon. Isopropyl-magnesium bromide (0.8 M in THF, 10.65 mL, 8.52 mmol, 6.0 eq.) is added dropwise over 1 h. The reaction mixture is stirred at -78°C for 1 h. After conversion, the reaction mixture is quenched with water, DCM is added and the mixture is filtered. The phases are separated and the organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography to give intermediate A-12a (Table 38).

[0642] [Table 40]

[0643] Synthesis experimental procedure for A-2f [ka] To a stirred mixture of A-12a (78 mg, 0.207 mmol, 1.0 eq) in THF (0.8 mL) is added HCl (259 μL, 1.04 mmol, 4.0 M in dioxane, 5.0 eq.) and the mixture is stirred at 60° C. for 2 h. Additional HCl (259 μL, 1.04 mmol, 4.0 M in dioxane, 5.0 eq.) is added and the mixture is stirred at 60° C. for an additional 3 h. The mixture is cooled to rt and stirred at rt for 18 h. The volatiles are removed under reduced pressure and the residue is dissolved in acetonitrile and H2O and lyophilized. The crude product is purified by ion exchange chromatography (Isolute SPE 1 g column, SCX-2) to give intermediate A-2f (Table 39).

[0644] [Table 41]

[0645] Experimental procedure for synthesis of A-2g [ka] Methyl (2R)-2-amino-2-(4-bromophenyl)acetate hydrochloride (250 mg, 0.847 mmol, 1.0 eq), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (397 mg, 1.693 mmol, 2.0 eq.), XPhos Pd G3 (73 mg, 0.085 mmol, 0.1 eq.) and cesium carbonate (1.3 g, 4.233 mmol, 5.0 eq.) in DME (2 mL) and HO (0.4 mL) are heated to 80° C. for 90 min under microwave irradiation. The reaction mixture is purified by chromatography to give intermediate A-2g (Table 40).

[0646] [Table 42]

[0647] Synthesis experimental procedure for A-3a [ka] To a stirred solution of A-2a (85 mg, 0.382 mol, 1.0 eq) in DMF (1 mL) is added (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (100 mg, 0.421 mmol, 1.1 eq), HATU (163 mg, 0.4210 mol, 1.1 eq) and DIPEA (0.27 mL, 1.53 mmol, 4.0 eq) at rt and the mixture is stirred at rt for 1 h. After complete conversion, the reaction mixture is diluted with acetonitrile, filtered and purified by column chromatography to afford A-3a.

[0648] The following intermediate A3 (Table 41) is accessible in an analogous manner starting from the different intermediate A2.

[0649] [Table 43] TIFF2024542692000183.tif84165

[0650] Synthesis experimental procedure for A-4a [ka] To a stirred solution of A-3a (105 mg, 0.24 mmol, 1.0 eq) in THF (1.5 mL) is added HCl (2 M in water, 0.36 mL, 3.0 mmol, 3.0 eq) and stirred at 65° C. for 1 h. After complete conversion, the reaction mixture is concentrated under reduced pressure, diluted with ACN and carefully neutralized with aqueous sodium hydroxide (2 M). The mixture is purified by RP-chromatography to give A-4a.

[0651] The following intermediate A-4 (Table 42) is accessible in an analogous manner starting from the different intermediate A-3.

[0652] [Table 44] TIFF2024542692000186.tif205165

[0653] Synthesis procedure for E-1a [ka] To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (15.00 g, 0.08 mol, 1.0 eq.) in DMF (75.0 mL) is added potassium carbonate (31.17 g, 0.23 mol, 3.0 eq.) at 0° C. 1,3-dibromopropane (15.20 g, 0.08 mol, 1.0 eq.) is added dropwise and the reaction mixture is stirred at 0° C. for 9 h. After complete conversion, the reaction mixture is quenched with water and extracted with EtOAc. The organic layer is washed with ice water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The resulting crude compound is purified by chromatography to yield E-1a.

[0654] The following intermediates E-1 (Table 43) are available in an analogous manner: The crude product E-1 is purified by chromatography if necessary.

[0655] [Table 45] TIFF2024542692000189.tif34165

[0656] Synthesis procedure for E-6a [ka] To a stirred solution of 4-[(tert-butyldimethylsilyl)oxy]butan-1-ol (20.00 g, 0.10 mol, 1.0 eq.) in THF (200 ml) is added sodium hydride (2.81 g, 0.12 mol, 1.2 eq.) at 0° C. and stirred at rt for 1 h. The reaction mixture is cooled to 0° C. and trichloroethylene (15.38 g, 0.12 mol, 1.2 eq.) is added at 0° C. The reaction mixture is warmed to rt and stirred for 48 h. The reaction mixture is quenched with ice-cold water and the aqueous solution is extracted with EtOAc (3×). The combined organic layers are washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product is purified by chromatography to yield E-6a.

[0657] The following intermediates E-6 (Table 44) can be obtained in a similar manner using different alcohols as starting materials. The crude products E-6 (Table 44) are purified by chromatography if necessary.

[0658] [Table 46] TIFF2024542692000192.tif30165 * Intermediates E-6c and E-6d are obtained as a 3.5:1 mixture when butane-1,3-diol is used as the starting material and are used as a mixture in the next step.

[0659] Synthesis Experimental Procedure for E-7a [ka] To a stirred solution of intermediate E-6a (40.00 g, 0.13 mol, 1.0 eq.) in THF (800 ml) is added n-butyllithium solution (13 mL, 0.33 mol, 2.5 eq, 2.5 M in hexane) at -78°C and stirred at -40°C for 2 h. After complete conversion, the mixture is quenched with saturated ammonium chloride solution and diluted with ice-cold water. The aqueous solution is extracted with EtOAc (3x). The combined organic layers are washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product is purified by column chromatography to yield intermediate E-7a.

[0660] The following intermediate E-7 (Table 45) is accessible in a similar manner using the different intermediate E-6. The crude product E-7 is purified by chromatography if necessary.

[0661] [Table 47] TIFF2024542692000195.tif64165 * Intermediates E-7c and E-7d were obtained as a 3.5:1 mixture when a mixture of E-6c and E-6d (3.5:1) was used as the starting material and were used as a mixture in the next step.

[0662] Synthesis procedure for E-8a [ka] To a stirred solution of intermediate E-7a (5.81 g, 25.44 mmol, 1.0 eq.) in DMF (20 ml) and water (20 ml) is added methyl (2R)-2-azido-3-methylbutanoate (4.00 g, 25.44 mmol, 1.0 eq.), sodium L-ascorbate (2.52 g, 12.73 mmol, 0.5 eq) and copper(II) sulfate pentahydrate (0.88 g, 2.54 mmol, 0.1 eq) at rt. The reaction mixture is heated to 80° C. and stirred for 3 h. The reaction mixture is poured into water and the aqueous layer is extracted with EtOAc (3×). The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product is purified by chromatography to yield intermediate E-8a.

[0663] The following intermediates E-8 (Table 46) are accessible in an analogous manner using different intermediates E-7 and / or azides. The crude product E-8 is purified by chromatography if necessary.

[0664] [Table 48] TIFF2024542692000198.tif157165 * Intermediates E-8c and E-8d are obtained as a 3.5:1 mixture when a mixture of E-7c and E-7d (3.5:1) is used as the starting material and are used as a mixture in the next step.

[0665] Synthesis Experimental Procedure of E-9a [ka] Intermediate E-8a (1.85 g, 4.70 mmol, 1.0 eq.) is dissolved in MeOH (18.5 mL) and HCl (1.76 mL, 7.06 mmol, 1.5 eq, 4N solution in 1,4 dioxane) is added. The reaction mixture is stirred at 45° C. for 30 min and the reaction mixture is concentrated to dryness. The crude product is purified by chromatography to give intermediate E-9a.

[0666] The following intermediates E-9 (Table 47) are accessible in a similar manner using different intermediates E-8: The crude product E-9 is purified by chromatography if necessary.

[0667] [Table 49]

[0668] Synthesis procedure of E-9d [ka] To a stirred solution of E-8e (60.0 g, 129.96 mmol, 1.0 eq.) in THF at 10 °C, HF-pyridine (38.6 g, 389.88 mmol, 3.0 eq.) is added and the mixture is stirred at 10-20 °C for 2 h. To the mixture, aqueous NaHCO3 (1 M, 1.5 L) is added and the pH is adjusted to pH 7-8. The phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. The crude product is purified by column chromatography to give intermediate E-9d.

[0669] [Table 50]

[0670] Synthesis Experimental Procedure for E-10a and E-10b [ka] To a stirred solution of a mixture of E-8c and E-8d (258 mg, 0.71 mmol, 1.0 eq, 3.5:1) in DCM (0.5 mL) is added Dess-Martin periodinane (302.7 mg, 0.71 mmol, 1.0 eq) and stirred at rt for 1 h. The reaction mixture is filtered and concentrated under reduced pressure. The crude product is purified by column chromatography to give intermediates E-10a and E-10b.

[0671] The following intermediate E-10 (Table 48) is accessible in an analogous manner using the different intermediates E-8 or E-9. The crude product E-10 is purified by chromatography if necessary.

[0672] [Table 51]

[0673] Synthesis procedure for E-9c [ka] To a stirred solution of methyl 2-bromo-3-methylbutanoate (5.00 g, 0.026 mol, 1.0 eq.) in DMSO (50 mL) at 0° C., sodium azide (1.666 g, 0.026 mol, 1.0 eq.) is added. The mixture is warmed to rt and stirred for 16 h. The mixture is cooled to 0° C. and water (100 mL), sodium ascorbate (0.51 g, 0.03 mol, 0.1 eq.), copper(II) sulfate pentahydrate (1.28 g, 0.225 mol, 0.2 eq.) and hepta-6-yn-1-ol (2.871 g, 0.026 mmol, 1.0 eq.) are added. The mixture is warmed to rt and stirred for 16 h. The reaction mixture is poured into water (500 mL) and the mixture is extracted with ethyl acetate (3×400 mL). The combined organic layers are washed with saturated aqueous NaHCO3 (2 x 200 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography to give intermediate E-9c (Table 49).

[0674] [Table 52]

[0675] Synthesis Experimental Procedure for E-11a [ka] To a stirred solution of E-9a (1.95 g, 7.19 mmol, 1.0 eq.) and Et3N (2.00 mL, 14.37 mmol, 2.0 eq.) in dichloroethane (20.0 mL) is slowly added methanesulfonyl chloride (0.97 mL, 12.46 mmol, 1.70 eq.) at 0° C. and the reaction mixture is stirred at rt for 20 min. The reaction mixture is quenched with water and diluted with DCM. The layers are separated and the aqueous layer is extracted with DCM, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude compound is purified by chromatography using DCM and MeOH as solvents to yield E-11a.

[0676] The following intermediate E-11 (Table 50) is accessible in a similar manner starting from the different intermediate E-9: The crude product E-11 is purified by chromatography if necessary.

[0677] [Table 53] TIFF2024542692000209.tif54165

[0678] Synthesis Experimental Procedure for E-2a [ka] To a stirred solution of K-13a (4.50 g, 9.99 mmol, 1.0 eq.) and E-1a (3.72 g, 11.03 mmol, 1.1 eq.) in acetonitrile (45.0 mL) is added potassium carbonate (2.76 g, 19.98 mmol, 2.0 eq.) and the mixture is stirred under argon at 60° C. for 22 h. After complete conversion, the reaction mixture is cooled to rt, filtered and the solid is washed with acetonitrile. The combined solution is concentrated under reduced pressure and purified by chromatography to give E-2a.

[0679] The following intermediates E-2 (Table 51) are accessible in a similar manner starting from different intermediates K-13 and E-1 or alternative bromides. The crude product E-2 is purified by chromatography if necessary.

[0680] [Table 54] TIFF2024542692000212.tif227165 TIFF2024542692000213.tif228165 TIFF2024542692000214.tif232165

[0681] E-2m synthesis experiment procedure [ka] To a stirred solution of K-13a (500 mg, 1.11 mmol, 1.0 eq.) and E-11a (659 mg, 1.89 mmol, 1.7 eq.) in acetonitrile (45.0 mL) is added DIPEA (0-97 mL, 5.55 mmol, 5.0 eq.) and the mixture is stirred under argon at 65° C. for 18 h. After complete conversion, the reaction mixture is cooled to rt, diluted with water and purified by RP chromatography to give E-2m.

[0682] The following intermediate E-2 (Table 52) is accessible in a similar manner starting from the different intermediates K-13 and E-11. The crude product E-2 is purified by chromatography if necessary.

[0683] [Table 55] TIFF2024542692000217.tif104165

[0684] Experimental procedure for synthesis of E-2p [ka] To a stirred solution of K-13a (200 mg, 0.444 mmol, 1.0 eq.) and sodium triacetoxyborohydride (235 mg, 1,110 mmol, 2.5 eq.) in DMF (3 mL) at RT is slowly added a solution of E-10c (153 mg, 0.444 mmol, 1.0 eq.) in DMF (1 mL). The reaction is stirred for 30 min and then quenched by the addition of water. The solvent is removed under reduced pressure and the crude product is purified by chromatography to give E-2p.

[0685] The following intermediate E-2 (Table 53) is accessible in a similar manner starting from the different intermediates K-13 and E-10. The crude product E-2 is purified by chromatography if necessary.

[0686] [Table 56]

[0687] Synthesis Experimental Procedure for E-3a [ka] To a stirred solution of E-2a (4.26 g, 6.18 mmol, 1.0 eq.) in methanol (21.0 mL), sodium hydroxide solution (2 M in water, 6.18 mL, 12.35 mmol, 2.0 eq.) is added and the reaction mixture is stirred at 45° C. for 1 h. After complete conversion, the reaction mixture is concentrated under reduced pressure. The crude product is purified by chromatography to give E-3a.

[0688] The following intermediates E-3 (Table 54) are accessible in a similar manner starting from the different intermediates E-2: The crude products E-3 are purified by chromatography if necessary.

[0689] [Table 57] TIFF2024542692000222.tif224165 TIFF2024542692000223.tif218165 TIFF2024542692000224.tif191165

[0690] Synthesis procedure for E-3p [ka] To a solution of intermediate E-2p (1.33 g, 1.705 mmol, 1.0 eq.) in MeOH (25 mL) in a hydrogenation reactor, Pd / C (10%, 350.00 mg) is added. The reaction mixture is stirred under a pressure of 8 bar H2 for 8 h. After complete conversion, the reaction mixture is filtered and the solvent is removed under reduced pressure to give intermediate E-3p.

[0691] The following intermediates E-3 (Table 55) are accessible in a similar manner starting from the different intermediates E-2: The crude products E-3 are purified by chromatography if necessary.

[0692] [Table 58]

[0693] Synthesis Experimental Procedure for E-4a [ka] To a stirred solution of E-3a (4.38 g, 6.48 mmol, 1.0 eq.) and methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (1.61 g, 8.43 mmol, 1.3 eq.) and HATU (3.27 mg, 8.43 mmol, 1.3 eq.) in acetonitrile (35 mL) and DMSO (9.00 mL), DIPEA (5.66 mL, 32.41 mmol, 5.0 eq.) is added and stirred at rt for 30 min. After complete conversion, the reaction mixture is diluted with water and EtOAc. The layers are separated and the organic layer is washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product. The crude product is purified by chromatography to afford E-4a.

[0694] The following intermediates E-4 (Table 56) are accessible in an analogous manner starting from different intermediates E-3 and / or different protected pyrrolidines. The crude product E-4 is purified by chromatography if necessary.

[0695] [Table 59] TIFF2024542692000229.tif205165

[0696] E-5a synthesis experiment procedure [ka] To a stirred solution of E-4a (4.47 g, 5.57 mmol, 1.0 eq.) in methanol (22.0 mL), sodium hydroxide solution (2 M in water, 6.00 mL, 12.00 mmol, 2.2 eq.) is added and the reaction mixture is stirred at 45° C. for 1 h. After complete conversion, the reaction mixture is concentrated under reduced pressure. The crude product is purified by chromatography to give E-5a.

[0697] The following intermediates E-5 (Table 57) are accessible in a similar manner starting from the different intermediates E-4: The crude products E-5 are purified by chromatography if necessary.

[0698] [Table 60] TIFF2024542692000232.tif153165

[0699] E-5e synthesis experiment procedure [ka] To a solution of intermediate E-4e (66 mg, 0.074 mmol, 1.0 eq.) in MeOH (2 mL) in a hydrogenation reactor, Pd / C (10%, 50.00 mg) is added. The reaction mixture is stirred under a pressure of 8 bar H2 for 3 h. After complete conversion, the reaction mixture is filtered and the solvent is removed under reduced pressure to give intermediate E-5e (Table 58).

[0700] [Table 61]

[0701] Synthesis procedure for I-1 [ka] To a stirred solution of E-3a (219 mg, 0.32 mmol, 1.0 eq), (2S,4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (113 mg, 0.36 mmol, 1.1 eq.) and HATU (184 mg, 0.48 mmol, 1.3 eq.) in DMF (1.0 mL) is added DIPEA (0.16 mL, 0.97 mmol, 3.0 eq.) and the reaction mixture is stirred at rt for 30 min. After complete conversion, the reaction mixture is quenched with water, diluted with acetonitrile and purified by chromatography.

[0702] The following compounds I (Table 59) are available in a similar manner starting from the different intermediates E-3 and A-4.

[0703] [Table 62] TIFF2024542692000237.tif192165 TIFF2024542692000238.tif199165 TIFF2024542692000239.tif230165 TIFF2024542692000240.tif232165 TIFF2024542692000241.tif152165

[0704] Experimental procedure for the synthesis of I-17 [ka] To a stirred solution of E-5b (25 mg, 0.032 mmol, 1.0 eq.), 4-(aminomethyl)benzonitrile hydrochloride (10 mg, 0.059 mmol, 1.8 eq.) and HATU (35 mg, 0.091 mmol, 2.8 eq.) in DMSO (1.0 mL) is added TEA (26 μL, 0.187 mmol, 5.8 eq.) and the reaction mixture is stirred at rt for 20 min. After complete conversion, the reaction mixture is diluted with ACN and purified by chromatography to yield I-16.

[0705] The following compounds I (Table 60) are available in a similar manner starting from the different intermediates E-5 and A-2.

[0706] [Table 63] TIFF2024542692000244.tif228165 TIFF2024542692000245.tif228165 TIFF2024542692000246.tif51165

[0707] Chiral separation of compound I by chiral column chromatography When compound I is obtained as a mixture of diastereomers, they can be separated into single stereoisomers by chiral chromatography. For example, as shown, I-1 was separated to give I-24 and I-25. I-3 was separated to give I-26 and I-27. I-35 was separated to give I-40 and I-41. I-36 was separated to give I-42 and I-43. I-37 was separated to give I-44 and I-45 (Table 61).

[0708] [Table 64] TIFF2024542692000248.tif204165 TIFF2024542692000249.tif226165 TIFF2024542692000250.tif143165

[0709] Experimental procedure for the synthesis of I-46 [ka] To a stirred solution of I-33 (25 mg, 0.024 mmol, 1.0 eq) in THF (1 mL) is added LiOH solution (18 μL, 0.036, 1.5 eq., 2N in HO) and the reaction mixture is stirred for 48 h. The reaction mixture is acidified with 2N HCl and purified by chromatography to give I-46 (Table 62).

[0710] [Table 65]

[0711] Experimental procedure for synthesis of I-47 [ka] To a solution of E-2s (43 mg, 0.073 mmol, 1.0 eq) in THF (2.0 mL) and water (2 mL) is added LiOH HO (15 mg, 0.36 mmol) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is neutralized using 4 M HCl in water and concentrated under reduced pressure. The crude acid intermediate is dissolved in DMF (2.0 mL). HATU (50 mg, 0.13 mmol, 1.8 eq.), HOAt (18 mg, 0.13 mmol, 1.8 qe.), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (43 mg, 0.073 mmol, 1.8 eq.) and DIPEA (35 μL, 0.21 mmol, 2.9 eq.) are added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography to give I-47.

[0712] The following compounds I (Table 63) are available in an analogous manner starting from the different intermediate E-2.

[0713] [Table 66]

[0714] Compounds I-49, I-50 and I-51 of the present invention can also be obtained similarly using the corresponding building blocks according to the procedures described herein.

[0715] The following examples describe the biological activity of the compounds of the invention without limiting the invention to these examples.

[0716] Biological Examples HiBit degradation assay A HiBit protein detection tag (amino acid sequence VSGWRLFKKIS, SEQ ID NO:1) was introduced immediately downstream of the initiation methionine codon at the endogenous KRAS locus (Ensembl gene ID ENSG00000133703.7) in GP5d cells (ECACC Cat. No. 95090715) by CRISPR-based genome engineering using a KRAS(G12D) mutant donor construct encoding the HiBit tag. This resulted in the introduction of an N-terminally HiBit-tagged version of KRAS(G12D) heterozygously to the KRAS(WT) allele. Correct modification of the KRAS locus was assessed by PCR-based genotyping and Sanger sequencing of isolated PCR products. The resulting cell line is referred to as GP5d-HiBit-KRAS(G12D).

[0717] To evaluate PROTAC-mediated degradation of KRAS(G12D), GP5d-HiBit-KRAS(G12D) cells were seeded in white-bottom opaque 96-well plates (Perkin Elmer, cat.no.5680) at 25000 cells per well in 100 μL of Dulbecco's modified Eagle's medium (Sigma, cat.no.D6429) supplemented with 10% fetal bovine serum. Plates were incubated overnight at 37°C in a 5% CO2 humidified incubator to allow cells to adhere. Test compounds (10 mM stock in DMSO) were added in a log dose series using an HP Digital Dispenser D300 (Tecan) and normalized to DMSO added. Plates were incubated for an additional 18 h at 37°C. After incubation, 100 μL of Promega Nano-Glo HiBit Lytic Detection Reagent Mix (Promega Nano-Glo HiBit Lytic Detection System #N3050) prepared according to the kit manufacturer's instructions was added per well. To ensure sufficient cell lysis, plates were incubated on an orbital shaker for 15 minutes and then at room temperature for an additional 30 minutes. After cell lysis was complete, luminescence was measured using an Envision plate reader using the Ultrasensitive Luminescence Protocol for 96-well plates. Luminescence levels were normalized by those obtained with DMSO-treated samples and plotted as % DMSO control. DC 50 Values ​​were calculated using a four-parametric logistic model. Dmax values ​​represent the maximum extent of degradation observed and are reported as % control (% Ctrl.) treatment. DC 50 and Dmax are reported in Table 64 for representative compounds of the invention.

[0718] [Table 67] TIFF2024542692000256.tif93165

[0719] HiBit KRAS4B Mutant Spectral Resolution Assay Therapeutically relevant mutant KRAS constructs (WT, G12C, G12D, G12V, G13D) were obtained by site-directed mutagenesis using the KRAS4B WT cDNA construct as a template. GP5d cells (ECACC Cat. No. 95090715) were transduced with a lentiviral vector expressing mutant KRAS4B cDNA under the control of the CMV promoter. Stably transduced cells were selected using the neomycin selection marker encoded by the construct.

[0720] To evaluate PROTAC-mediated degradation of various KRAS mutants, GP5d cells stably transduced with the KRAS4B constructs described above were seeded in white-bottom opaque 96-well plates (Perkin Elmer, cat.no.5680) at 25000 cells per well in 100 μL of Dulbecco's modified Eagle's medium (Sigma, cat.no.D6429) supplemented with 10% fetal bovine serum. Plates were incubated overnight at 37°C in a 5% CO2 humidified incubator to allow cells to adhere. Test compounds (10 mM stock in DMSO) were added in a logarithmic dose series using a HP Digital Dispenser D300 (Tecan) and normalized to the DMSO added. Plates were incubated for a further 18 h at 37°C. After incubation, 100 μL of Promega Nano-Glo HiBit Lytic Detection Reagent Mix (Promega Nano-Glo HiBit Lytic Detection System #N3050) prepared according to the kit manufacturer's instructions was added per well. To ensure sufficient cell lysis, plates were incubated on an orbital shaker for 15 minutes and then at room temperature for an additional 30 minutes. After cell lysis was complete, luminescence was measured using an Envision plate reader using the Ultrasensitive Luminescence Protocol for 96-well plates. Luminescence levels were normalized by those obtained with DMSO-treated samples and plotted as % DMSO control. DC 50 Values ​​were calculated using a four-parametric logistic model and are reported in nM in Table 65 for representative Example (Ex.) compounds of the present invention. Dmax values ​​represent the maximum extent of degradation observed and are reported as % Control (% Ctrl.) treatment in Table 66 for representative Example (Ex.) compounds of the present invention.

[0721] [Table 68]

[0722] [Table 69]

[0723] Additional proliferation assays using mutant cancer cell lines NCI-H358 CTG proliferation assay (120 hours) (NSCLC, G12C) NCI-H358 cells (ATCC No. CRL-5807) are dispensed into white bottom opaque 96 well plates (PerkinElmer cat no. 5680) at a density of 2000 cells per well in 100 μL of RPMI-1640 ATCC-Formulation (Gibco #A10491) + 10% FCS (fetal bovine serum) (assay 1) or into flat bottom clear black 384 well plates (Greiner, PNr. 781091) at a density of 200 cells per well in 60 μL of RPMI-1640 ATCC-Formulation (Gibco #A10491) + 10% FCS (fetal bovine 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), including a DMSO control, 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 to the added DMSO. 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 (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50 Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0724] ·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 RL-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 of RPMI ATCC + 10% FCS + Penstrep in a flat-bottomed clear 384-well plate (Greiner, PNr. 781091). Cells are then incubated in the plate overnight at 37°C in a CO2 incubator. On day 1, compounds (10 mM stock in DMSO) are added with an ECHO acoustic liquid handler system (Beckman Coulter), 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 (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50 Values ​​can be determined from viability measurements by non-linear regression using a four-parameter model.

[0725] ·GP2D proliferation assay (120 hours) (Colon cancer, G12D) GP2D cells (ATCC No. CRL-5807) are dispensed into white flat-bottom 384-well plates (PerkinElmer, 6007680) at a density of 500 cells per well in 40 μL of DMEM (Sigma, D6429) + 1× GlutaMAX (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), including DMSO controls, are added in a log dose series using a HP Digital Dispenser D300 (Tecan) (assay 1) and normalized to the DMSO added. 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 (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50 Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0726] ·SAS CTG proliferation assay (120 hours) (HNSCC, wt amplified type) SAS cells (JCRB0260) are dispensed into flat-bottom clear 384-well plates (Greiner, PNr.781091) at a density of 300 cells per well in 60 μL of DMEM:F12 (Gibco 31330-038) + 10% fetal bovine serum (HycClone, PNr.:SH30084.03) and incubated overnight at 37°C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) are added, including a DMSO control, with an ECHO acoustic liquid handler system (Beckman Coulter). Plates are incubated for 120 hours and cell viability is measured using the CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50 Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0727] ·SK-CO-1 CTG proliferation assay (120 hours) (CRC, G12V) SK-CO-1 cells (ATCC HTB-39) are dispensed into flat-bottom clear 384-well plates (Greiner, PNr.781091) at a density of 500 cells per well in 60 μL of EMEM (Sigma M5650) + 10% fetal bovine serum (HycClone, PNr.:SH30084.03) and incubated overnight at 37 °C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) are added, including a DMSO control, with an ECHO acoustic liquid handler system (Beckman Coulter). Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the cells in the DMSO control. I C 50Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0728] LOVO CTG proliferation assay (120 hours) (CRC, G13D) LOVO cells (ATCC CCL-229) are dispensed into flat-bottom clear 384-well plates (Greiner, PNr.781091) at a density of 1000 cells per well in 60 μL of DMEM (Sigma D6429) + 10% fetal bovine serum (HycClone, PNr.:SH30084.03) and incubated overnight at 37 °C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) are added, including a DMSO control, with an ECHO acoustic liquid handler system (Beckman Coulter). Plates are incubated for 120 hours and cell viability is measured using CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the cells in the DMSO control. I C 50 Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0729] ·GP5d cell proliferation assay (colon cancer, G12D) GP5d cells (ECACC 95090715) are dispensed into white bottom opaque 96 well plates at a density of 5000 cells per well in 100 μL of DMEM (BioWhittaker, Cat# BE12-605F) supplemented with 10% FCS. Cells are incubated overnight at 37° C. in a humidified tissue culture incubator with 5% CO2. Compounds (10 mM stocks in DMSO) are added in a log dose series using a HP Digital Dispenser D300 (Tecan) and normalized to the DMSO added. For TO time point measurements, untreated cells are analyzed at the time of compound addition. Plates are incubated for 5 days and cell viability is measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50 Values ​​were calculated from relative survival values ​​using a four-parameter logistic model.

[0730] ·SW620 cell proliferation assay (colon cancer, G12V) SW620 cells (ATCC CCL-227) are dispensed into white bottom opaque 96-well plates at a density of 2000 cells per well in 100 μL of DMEM (BioWhittaker, Cat# BE12-605F) supplemented with 10% FCS. Cells are incubated overnight at 37° C. in a humidified tissue culture incubator with 5% CO2. Compounds (10 mM stocks in DMSO) are added in a log dose series using a HP Digital Dispenser D300 (Tecan) and normalized to the DMSO added. For TO time point measurements, untreated cells are analyzed at the time of compound addition. Plates are incubated for 5 days and cell viability is measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50Values ​​are calculated from the relative survival values ​​using a four parameter model.

[0731] A375 CTG proliferation assay (120 hours) (melanoma, wt, B-Raf mutant, negative control) A375 cells (ATCC CRL-1619) are dispensed into flat-bottom clear 384-well plates (Greiner, PNr.781091) at a density of 300 cells per well in 60 μL of DMEM (Sigma D6429) + 10% fetal bovine serum (HycClone, PNr.:SH30084.03) and incubated overnight at 37°C in a CO2 incubator. The following day, compounds (10 mM stocks in DMSO) are added in a logarithmic dose series, including a DMSO control, using an HP Digital Dispenser D300 (Tecan). Plates are incubated for 120 hours and cell viability is measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (listed as % control) is defined as the relative luminescence units (RLU) of each well divided by the RLU of the DMSO control cells. IC 50 Values ​​are determined from viability measurements by non-linear regression using a four-parameter model.

[0732] IC of representative compounds of the invention measured by these assays in the indicated cell lines 50 The values ​​are shown in Table 67.

[0733] [Table 70] TIFF2024542692000260.tif57165

[0734] combination The following formulation examples illustrate the invention without limiting its scope.

[0735] Examples of pharmaceutical preparations A) Tablets Per tablet 100mg of active substance of formula (I) Lactose 140mg Cornstarch 240mg Polyvinylpyrrolidone 15mg Magnesium stearate 5mg 500mg

[0736] The finely ground active substance, lactose and a portion 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.

[0737] B) Tablets Per tablet 80mg of active substance of formula (I) Lactose 55mg Cornstarch 190mg Microcrystalline cellulose 35mg Polyvinylpyrrolidone 15mg Sodium carboxymethyl starch 23mg Magnesium stearate 2mg 400mg

[0738] The finely ground active substance, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together. The mixture is screened, the remaining corn starch and water are added to form granules. The granules are dried and screened. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of suitable size.

[0739] C) Tablets Per tablet 25mg of active substance of formula (I) Lactose 50mg Microcrystalline cellulose 24mg Magnesium stearate 1mg 100mg

[0740] The active substance, lactose and cellulose are mixed together. The mixture is screened, then either moistened with water, kneaded, wet granulated, dried or dry granulated or final blended directly with magnesium stearate and compressed into tablets of suitable shape and size. In the case of wet granulation, additional lactose or cellulose and magnesium stearate are added and the mixture is compressed to produce tablets of suitable shape and size.

[0741] D) Ampoule solution 50mg of active substance of formula (I) Sodium chloride 50mg Water for injection 5mL

[0742] 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, and the filtrate is transferred under aseptic conditions into ampoules. The ampoules are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims

1. Formula (I): 【Chemistry 153】 [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 heterocycloalkyl; 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 and / or selected from the group consisting of cycloalkyl and 3- to 5-membered heterocycloalkyl; In some cases, R １ａ or R １ｂ and one of R ２ａ or R ２ｂ together with the carbon atoms to which they are attached form a cyclopropane ring, Z is -(CR ３ａ R ３ｂ ) ｎ - and Each R ３ａ and R ３ｂ 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 heterocycloalkyl; R ３ａ and R ３ｂ 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; R ４ is hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, cyano-C １－６ Alkyl, halogen, —OH, —NH ２ , —NH(C １－４ alkyl), -N(C １－４ alkyl) ２ , -CN,C ３－５ selected from the group consisting of cycloalkyl and 3- to 5-membered heterocycloalkyl; Ring A is a 5-membered heteroarylene; R ５ If there is a ５ are independently １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, cyano-C １－６ Alkyl, halogen, —OH, —NH ２ , —NH(C １－４ alkyl), -N(C １－４ alkyl) ２ , -CN,C ３－５ selected from the group consisting of cycloalkyl and 3- to 5-membered heterocycloalkyl; m is selected from the group consisting of 0, 1, 2 and 3; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R １１ ) = R １１ is hydrogen, halogen and C １－４ alkoxy; Ring B may be one or more of the same or different C １－６ Alkyl, C １－６ 3- to 11-membered heterocycloalkylene optionally substituted by alkoxy or 5- to 6-membered heterocycloalkyl, wherein C １－６ alkyl is optionally substituted with cyclopropyl; L is a bond, C １－８ Alkylene, C ２－８ Alkenylene, C ２－８ Alkynylene and C １－８ selected from the group consisting of alkoxylenes; X is -(CH ２ )- or -O-; Y is a 5-membered heteroarylene or —C(O)(NR １２ )-, wherein said 5-membered heteroarylene contains at least one nitrogen atom, and wherein said -C(O)(NR １２ )- is linked to X via a C atom, R ９ is C １－４ is alkyl, R １０ is hydrogen, C １－６ Alkyl, C １－６ Alkoxy, —C(O)R １２ and -C(O)OR １２ wherein said C １－６ Alkyl is —OH or —OP(O)(OH) ２ and optionally substituted by Each R １２ are independently hydrogen or C １－４ is alkyl, q is selected from the group consisting of 0, 1 and 2; R ６ If there is a ６ are each independently a halogen or C １－３ is alkyl, R ７ is a halogen, C １－３ is selected from the group consisting of alkyl, —CN, and 5-membered heteroaryl, wherein said 5-membered heteroaryl contains at least one nitrogen atom; R ８ and optionally substituted by R ８ is C １－３ Alkyl or C １－３ is hydroxyalkyl] A compound represented by the formula: or a salt thereof.

2. 2. The compound or salt according to claim 1, wherein m is 0.

3. Formula (I ＊ ), (I ＊＊ ), (I ＊＊＊ ) or (I ＊＊＊＊ ): 【Chemistry 154】 【change】 [In the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , Z, R ４ , ring A, R ５ , m, U, V, W, ring B, L, X, Y, R ９ , R １０ , q, R ６ and R ７ is as defined in claim 1 or 2] 3. The compound or salt according to claim 1 or 2, which is represented by:

4. 3. The compound or salt according to claim 1, wherein ring A is selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole and triazole.

5. 3. The compound or salt according to claim 1, wherein ring A is selected from the group consisting of isoxazole, isothiazole and oxadiazole.

6. Formula (Ia), (Ib), (Ic), (Id) or (Ie): 【Chemistry 155】 【change】 【change】 [In the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , Z, R ４ , U, V, W, ring B, L, X, Y, R ９ , R １０ , q, R ６ , R ７ and the stereochemistry is as defined in claim 1 or 2.

3. The compound or salt according to claim 1 or 2, which is represented by:

7. -X is -(CH ２ )—, and Y is a 5-membered heteroarylene or —C(O)(NR １２ )-, wherein said 5-membered heteroarylene contains at least one nitrogen atom, and wherein said -C(O)(NR １２ )- is linked to X via a C atom, or 3. The compound or salt according to claim 1, wherein -X is -O- and Y is a 5-membered heteroarylene containing at least one nitrogen atom.

8. 3. The compound or salt according to claim 1, wherein Y is isoxazole or triazole.

9. Formula (If): 【Chemistry 156】 [In the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , Z, R ４ , ring A, R ５ , m, U, V, W, ring B, L, X, R ９ , R １０ , q, R ６ , R ７ and the stereochemistry is as defined in claim 1 or 2.

3. The compound or salt according to claim 1 or 2, which is represented by:

10. Formula (Ig): 【Chemistry 157】 [In the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , Z, R ４ , ring A, R ５ , m, U, V, W, ring B, L, X, R ９ , R １０ , q, R ６ , R ７ and the stereochemistry is as defined in claim 1 or 2.

3. The compound or salt according to claim 1 or 2, which is represented by:

11. Formula (Ih): 【Chemistry 158】 [In the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , Z, R ４ , ring A, R ５ , m, U, V, W, ring B, L, X, R ９ , R １０ , q, R ６ , R ７ and the stereochemistry is as defined in claim 1 or 2.

3. The compound or salt according to claim 1 or 2, which is represented by:

12. X is -(CH ２ 10. The compound or salt according to claim 9, wherein:

13. The compound or salt according to claim 10, wherein X is —(CH 2 )—.

14. 10. The compound or salt according to claim 9, wherein X is -O-.

15. The compound or salt according to claim 10, wherein X is —O—.

16. R １ａ , R １ｂ , R ２ａ and R ２ｂ is hydrogen and Z is -CH ２ The compound or salt according to claim 1 or 2, wherein

17. R ４ 3. The compound or salt according to claim 1 or 2, wherein is methyl.

18. 3. The compound or salt according to claim 1, wherein at least one of V or W is =N-.

19. Ring B is 【Chemistry 159】 [In the formula, r is 0, 1 or 2; s is 0, 1 or 2; R １３ But C １－３ is alkyl, Each R １４ are each independently the same or different C １－３ is alkyl, (C) and (L) represent the atom or substituent of formula (I) to which ring B is attached.

3. The compound or salt according to claim 1 or 2, wherein:

20. L is C １－６ Alkylene, C ２－６ Alkenylene and C １－６ 3. The compound or salt according to claim 1 or 2, selected from the group consisting of alkoxylenes.

21. R ９ is isopropyl and / or R ９ 3. The compound or salt according to claim 1, wherein the carbon atom to which is attached is in the (S) configuration.

22. R １０ But hydrogen, C １－６ Alkyl and —C(O)OR １２ wherein C is selected from the group consisting of １－６ The alkyl is —OH or —OP(O)(OH) ２ 3. The compound or salt of claim 1, optionally substituted by:

23. R １０ The compound or salt according to claim 1 or 2, wherein is hydrogen.

24. R ７ But chlorine, bromine, isopropyl, -CN, [Chemical 160] 3. The compound or salt according to claim 1 or 2, selected from the group consisting of:

25. below: 【Chemistry 161】 【change】 【change】 【change】 【change】 【change】 【Chemistry 162】 3. The compound or salt according to claim 1 or 2, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

26. below: 【Chemistry 163】 or a pharmaceutically acceptable salt thereof, compound.

27. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

28. A composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Pharmaceutical compositions.

29. 29. A pharmaceutical composition according to claim 28 for use in treating and / or preventing cancer.

30. 30. The pharmaceutical composition of claim 29, administered in combination with one or more other pharmacologically active substances.

31. 30. The pharmaceutical composition of claim 29, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colon 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, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, gastroesophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

32. 30. The pharmaceutical composition of claim 29, wherein the cancer comprises tumor cells with a KRAS mutation or an amplification of KRAS wild-type.

33. 33. The pharmaceutical composition of claim 32, wherein the KRAS mutation is selected from the group consisting of KRAS G12C, KRAS G12D, KRAS G12V, and KRAS G13D.

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