Field of the invention

The present invention relates to annulated 2-amino-3-cyano thiophenes and derivatives of formula (V): wherein R ^1a , R ^1b , R ^2a , R ^2b , Z, R ⁴ , R ⁵ , R ¹⁴ , A, p, X, U, V and W have the meanings given in the claims and specification, their use as inhibitors of KRAS, pharmaceutical compositions and preparations containing such compounds and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases, e.g. cancer.

Background of the invention

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small GTPase of the Ras family of proteins that exists in cells in either GTP-bound or GDP-bound states (McCormick et al., J. Mol. Med. (Berl). , 2016, 94(3):253-8; Nimnual eta!., Sci. STKE., 2002, 2002(145):pe36). Binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of Ras family proteins. The binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promotes release of GDP from Ras family proteins, enabling GTP binding (Chardin et al., Science, 1993, 260(5112): 1338-43). When in the GTP-bound state, Ras family proteins are active and engage effector proteins including C-RAF and phosphoinositide 3-kinase (PI3K) to promote the RAF/mitogen or extracellular signal- regulated kinases (MEK/ERK) pathway, PI3K/AKT/mammalian target of rapamycin (mTOR) pathway and RaIGDS (Rai guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6). These pathways affect diverse cellular processes such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth (Young et al., Adv. Cancer Res., 2009, 102:1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).

Cancer-associated mutations in Ras family proteins suppress their intrinsic and GAP-induced GTPase activity leading to an increased population of GTP-bound/active mutant Ras family proteins (McCormick et a/., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et a/., Mol. Cancer Res., 2015, 13(9): 1325-35). This in turn leads to persistent activation of effector pathways (e.g. RAF/MEK/ERK, PI3K/AKT/mTOR, RaIGDS pathways) downstream of mutant Ras family proteins. KRAS mutations (e.g. amino acids G12, G13, Q61 , A146) are found in a variety of human cancers including lung cancer, colorectal cancer and pancreatic cancer (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Alterations (e.g. mutation, overexpression, gene amplification) in Ras family proteins/Ras genes have also been described as a resistance mechanism against cancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 Jul;92(7):709-22) and the EGFR tyrosine kinase inhibitor osimertinib/AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et a!., Cancer Res., 2015, 7 5(12):2489-500).

In a subset of tumor indications such as gastric cancer, gastroesophageal junction cancer and esophageal cancer prominent amplification of the wildtype (WT) KRAS proto-oncogene acts as a driver alteration and renders tumor models bearing this genotype addicted to KRAS in vitro and in vivo (Wong et al. Nat Med., 2018, 24(7):968-977). In contrast, non-amplified KRAS WT cell lines are KRAS independent, unless they carry secondary alterations in genes indirectly causing activation of KRAS (Meyers et al., Nat Genet., 2017, 49:1779-1784). Based on these data, a therapeutic window is expected for a KRAS targeting agent with a KRAS WT targeting activity.

Genetic alterations affecting e.g. codon 12 of KRAS substitute the glycine residue naturally occurring at this position for different amino acids such as aspartic acid (the G12D mutation or KRAS G12D), cysteine (the G12C mutation or KRAS G12C), valine (the G12V mutation or KRAS G12V) among others. Similarly, mutations within codons 13, 61 and 146 of KRAS are commonly found in the KRAS gene. Altogether KRAS mutations are detectable in 35 % of lung, 45% of colorectal, and up to 90% of pancreatic cancers (Herdeis et al., Curr Opin Struct Biol., 2021 , 71 :136-147).

In summary, binders/inhibitors of wildtype or mutated KRAS (e.g., G12D, G12V and G12C) are expected to deliver anti-cancer efficacy.

Thus, there is the need to develop new compounds efficacious in the treatment of cancers mediated by KRAS, especially KRAS mutated in position 12 or 13 and/or in wild-type amplified KRAS mediated cancer, which also possess desirable pharmacological properties, including but not limited to: metabolic stability, plasma protein binding, solubility and permeability. Detailed description of the invention

It has now been found that, surprisingly, compounds of formula (V) wherein have the meanings given hereinafter act as inhibitors of KRAS and are involved in controlling cell proliferation. Thus, the compounds according to the invention may be used for example for the treatment of diseases characterized by excessive or abnormal cell proliferation.

Surprisingly, the compounds described herein have been found to possess anti-tumour activity, being useful in inhibiting the uncontrolled cellular proliferation which arises from malignant diseases. It is believed that this anti-tumor activity is, inter alia, derived from inhibition of KRAS mutated in position 12 or 13, preferably G12D, G12V or G13D mutant KRAS, or inhibition of WT KRAS, especially KRAS WT amplified. Advantageously, the compounds can be selective for certain KRAS mutants, preferably KRAS G12D, or can be effective against a panel of KRAS mutants including KRAS wildtype amplified.

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

Thus, in a first aspect, the present invention relates to a compound of the formula (V)

R ^1a and R ^1b are both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl;

R ^2a and R ^2b are both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one of R ^1a or R ^1b and one of R ^2a or R ^2b together with the carbon atoms they are attached form a cyclopropane ring;

Z is -(CR ^6a R ^6b ) _n -; each R ^6a and R ^6b is independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; or R ^6a and R ^6b together with the carbon atom they are attached to form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2;

X is =C(R ¹⁵ )- or -N(R ¹⁵ )-;

R ¹⁴ and R ¹⁵ together with the atoms to which they are attached form a Cs-ycycloalkyl or a 5-7 membered heterocyclyl comprising oxygen or sulfur, wherein said Cs-ycycloalkyl and 5-7 membered heterocyclyl are optionally substituted by one or more identical or different R ^3a and/or R ^3b , which R ^3a and R ^3b are each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl and halogen;

W is -N= or -CH=;

V is -N= or -CH=;

U is -N= or -C(R ¹¹ )=;

R ¹¹ is selected from hydrogen, halogen and Ci.4alkoxy; ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; each R ⁴ , if present, is independently selected from the group consisting of Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, cyano-Ci-ealkyl, halogen, -OH, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, -CN, Cs-scycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1 , 2 and 3;

R ⁵ is halogen or a 3-11 membered heterocyclyl optionally substituted with one or more identical or different Ci-ealkyl, Ci-ealkoxy, -C(O)-O-Ci-ealkyl or a 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl or -OH; or R ⁵ is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R ¹² , each R ¹² is selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, -C(O)-O-Ci. ealkyl, halogen and 3-11 membered heterocyclyl; or a salt thereof.

In another aspect, the present invention relates to a compound of formula (V’): wherein

R ^1a and R ^1b are both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl;

R ^2a and R ^2b are both independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one of R ^1a or R ^1b and one of R ^2a or R ^2b together with the carbon atoms they are attached form a cyclopropane ring;

Z is -(CR ^6a R ^6b ) _n -; each R ^6a and R ^6b is independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, Cs-scycloalkyl and 3-5 membered heterocyclyl; or R ^6a or R ^6b together with the carbon atom they are attached to form a cyclopropane ring; n is selected from the group consisting 0, 1 and 2;

X is =C(R ¹⁵ )- or -N(R ¹⁵ )-;

R ¹⁴ is selected from the group consisting of Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci- ehaloalkoxy and Ci-ethioalkoxy; and R ¹⁴ and R ¹⁵ together with the atoms to which they are attached form a Cs-ycycloalkyl or a 5-7 membered heterocyclyl comprising oxygen or sulfur, wherein said Cs-ycycloalkyl and 5-7 membered heterocyclyl are optionally substituted by one or more identical or different R ^3a and/or R ^3b , which R ^3a and R ^3b are each independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl and halogen;

W is nitrogen (-N=) or -CH=;

V is nitrogen (-N=) or -CH=;

U is nitrogen (-N=) or -C(R ¹¹ )=; each R ¹¹ is selected from hydrogen, halogen and Ci.4alkoxy; ring A is a ring selected from the group consisting of pyrrol, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole and triazole; each R ⁴ , if present, is independently selected from the group consisting of Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, cyano-Ci-ealkyl, halogen, -OH, -NH2, -NH(Ci-4alkyl), -N(Ci-4alkyl)2, -CN, Cs-scycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting 0, 1 , 2 and 3;

R ⁵ is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different Ci-ealkyl, Ci-ealkoxy or a 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl; or R ⁵ is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R ¹² , each R ¹² is selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen and 3-11 membered heterocyclyl; or a salt thereof.

It is to be understood that the following embodiments and aspects can be applied to formula (V) and to formula (V’), unless stated otherwise.

In another aspect, the invention relates to compounds of formula (I) wherein R ^1a , R ^1b , R ^2a , R ^2b , Z, R ⁵ , A, p, U, V and W have the meanings given herein.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ^1a and R ^1b are both independently selected from the group consisting of hydrogen and Ci-4alkyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ^2a and R ^2b are both independently selected from the group consisting of hydrogen and halogen.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ^1a and R ^1b are both independently selected from the group consisting of hydrogen and methyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ^2a and R ^2b are both independently selected from the group consisting of hydrogen and fluorine.

In another aspect, the invention relates to the compound of the formula (V), (V’), or (I), or a salt thereof, wherein R ^1a , R ^1b , R ^2a and R ^2b are hydrogen.

In another aspect, the invention relates to the compound of the formula (V), (V’), or (I), or a salt thereof, wherein Z is -(CR ^6a R ^6b ) _n - and n is 0.

In another aspect, the invention relates to the compound of the formula (V), (V’), or (I), or a salt thereof, wherein Z is -(CR ^6a R ^6b ) _n -; n is 1 ; and each R ^6a and R ^6b is independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, -NH ₂ , -NH(Ci- ₄ alkyl), -N(Ci- ₄ alkyl) ₂ ,

Cs-scycloalkyl and 3-5 membered heterocyclyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein Z is -CH ₂ -.

In another aspect, the invention relates to the compound of the formula (V), (V’), or (I), or a salt thereof, wherein R ^1a , R ^1b , R ^2a and R ^2b are hydrogen and Z is -CH ₂ -.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein Z is -(CR ^6a R ^6b ) _n -; n is 2; and each R ^6a and R ^6b is independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, halogen, - NH ₂ , -NH(Ci-4alkyl), -N(Ci-4alkyl) ₂ , Cs-scycloalkyl and 3-5 membered heterocyclyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein X is =C(R ¹⁵ )-; R ¹⁴ is selected from the group consisting of C ₂ .4alkyl, C ₂ .4alkoxy and C ₂ .4th ioalkoxy; or R ¹⁴ and R ¹⁵ together with the atoms to which they are attached form a Cs- ycycloalkyl or a 5-7 membered heterocyclyl comprising oxygen or sulfur, wherein said Cs- ycycloalkyl and 5-7 membered heterocyclyl are optionally substituted by one or more identical or different R ^3a and/or R ^3b , which R ^3a and R ^3b are each independently selected from the group consisting of Ci-4alkyl, Ci.4haloalkyl and halogen.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein p is 0.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein p is 1.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein p is 1 and R ⁴ is Ci-ealkyL

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein p is 1 and R ⁴ is methyl.

In another aspect the present invention relates to a compound of the formula (la) or a salt thereof, wherein A, V, U, W and R ⁵ are defined herein.

In another aspect, the invention relates to a compound of formula (lb) or a salt thereof, wherein A, V, U, W and R ⁵ are defined herein.

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

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein ring A is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein ring A is selected from

In another aspect, the invention relates to the compound of the invention, or a salt thereof,

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein ring A is

In another aspect the invention relates to a compound of formula (Ic), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein.

In another aspect the invention relates to a compound of formula (Id), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein.

In another aspect the invention relates to a compound of formula (Ila), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein. In another aspect, the invention relates to a compound of formula (lib), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein.

In another aspect the invention relates to a compound of formula (IV), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein.

In another aspect the invention relates to a compound of formula (He), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein.

In aother aspect the invention relates to a compound of formula (lid), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein.

In aother aspect the invention relates to a compound of formula (He), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein and wherein R ^3a and R ^3b are both identical or different and selected from halogen or Ci-4alkyl.

In another aspect the invention relates to a compound of formula (III), or a salt thereof, wherein V, U, W and R ⁵ are as defined herein, and wherein R ⁴ is hydrogen or Ci-4alkyl.

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

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein W is nitrogen (-N=); V is nitrogen (-N=); U is =C(R ¹¹ )-; R ¹¹ is selected from hydrogen, halogen and Ci.4alkoxy.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein W is -CH=; V is nitrogen (-N=); U is =C(R ¹¹ )-; R ¹¹ is selected from hydrogen, halogen and Ci-4alkoxy.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein V is -CH=; W is nitrogen (-N=); U is =C(R ¹¹ )-; R ¹¹ is selected from hydrogen, halogen and Ci-4alkoxy. In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ¹¹ is selected from hydrogen, -F, -Cl and -O-CH3.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein V is nitrogen (-N=); W is -CH=; U is nitrogen (-N=).

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein W is nitrogen (-N=); V is -CH=; U is nitrogen (-N=).

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein W is -CH=; V is -CH=; U is nitrogen (-N=).

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein W is nitrogen (-N=); V is nitrogen (-N=); U is nitrogen (-N=).

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is a 3-11 membered heterocyclyl optionally substituted with one or more identical or different Ci-ealkyl, Ci-ealkoxy or a 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl; or R ⁵ is -O-Ci-ealkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more, identical or different R ¹² , each R ¹² is selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen and 3-11 membered heterocyclyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is chlorine.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is halogen or a 6-11 membered heterocyclyl optionally substituted with one or more identical or different Ci-ealkyl, Ci-ealkoxy, -C(O)-O-Ci-ealkyl or a 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl or -OH.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is a 6-11 membered heterocyclyl optionally substituted with one or more identical or different Ci-ealkyl, Ci-ealkoxy or a 5-6 membered heterocyclyl, wherein the Ci-ealkyl is optionally substituted with cyclopropyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of 6 membered nitrogen containing heterocyclyl, optionally substituted with one or more independently selected Ci-4alkyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of 7 membered heterocyclyl, optionally substituted with one or more independently selected Ci-4alkyl. In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is -O-Ci-ealkyl substituted with a 5-9 membered heterocyclyl, wherein the 5-9 membered heterocyclyl is optionally substituted with one or more, identical or different R ¹² , each R ¹² is selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, -C(O)-O-Ci. ealkyl, halogen and 5 membered heterocyclyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is -O-Ci-ealkyl substituted with a 5-9 membered heterocyclyl, wherein the 5-9 membered heterocyclyl is optionally substituted with one or more, identical or different R ¹² , each R ¹² is selected from the group consisting of Ci-ealkyl, Ci-ealkoxy, halogen and 5 membered heterocyclyl.

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is selected from the group consisting of

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein R ⁵ is

In another aspect, the invention relates to the compound of the invention, or a salt thereof, wherein W is nitrogen (-N=); V is -CH=; U is nitrogen (-N=); and R ⁵ is selected from the group consisting of 6 membered nitrogen containg heterocyclyl, optionally substituted with one or more independently selected Ci-4alkyl.

Preferred embodiments of the invention are example compounds la-1, lla-1, lb-1, lb-2, lb-3, llb-1, I lb-2, lb-4, I lb-3, llb-4, llb-5, llb-6, llb-7, llla-1, lllb-1, Id-1, Id-2, lld-1, le-1, le-2, lle-1, le-3, le-4, le-5, lf-1, llf-1, lf-2, lg-1, lg-2, lg-4, llg-1, lh-1, IVa-1 and any subset thereof.

It is to be understood that any two or more aspects and/or preferred embodiments of formula (V), (V’), (I), (la), (lb), (Ic), (Id), (Ila), (lib), (IV), (He), (lid), (He) and (HI) - or subformulas thereof- may be combined in any way leading to a chemically stable structure to obtain further aspects and/or preferred embodiments of formula (V), (V’), (I), (la), (lb), (Ic), (Id), (Ha), (Hb), (IV), (He), (Hd), (He) and (HI) - or subformulas thereof.

The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of a compound of the invention (including all its embodiments).

The present invention further relates to a hydrate of a compound of the invention (including all its embodiments).

The present invention further relates to a solvate of a compound of the invention (including all its embodiments).

Compounds of the invention, (including all its embodiments) which e.g. bear ester groups are potential prodrugs the ester being cleaved under physiological conditions and are also part of the invention. The present invention further relates to a pharmaceutically acceptable salt of a compound of the invention (including all its embodiments).

The present invention further relates to a pharmaceutically acceptable salt of a compound of the invention (including all its embodiments) with anorganic or organic acids or bases.

Pharmaceutical compositions

A further object of the invention is a pharmaceutical composition comprising a compound of the invention - or a pharmaceutically acceptable salt thereof - and one or more pharmaceutically acceptable excipient(s).

In one aspect, said pharmaceutical composition optionally comprises one or more other pharmacologically active substance(s). Said one or more other pharmacologically active substance(s) may be the pharmacologically active substances or combination partners as herein defined.

Suitable pharmaceutical compositions for administering the compound(s) according to the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, suspensions - particularly solutions, suspensions or other mixtures for injection (s.c., i.v., i.m.) and infusion (injectables) - elixirs, syrups, sachets, emulsions, inhalatives or dispersible powders. The content of the compounds of the invention should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.

Suitable tablets may be obtained, for example, by mixing the compounds of the invention with known pharmaceutically acceptable excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with excipients normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly, the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing one or more compound(s) of the invention or combinations with one or more other pharmaceutically active substance(s) may additionally contain excipients like a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain excipients like suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of excipients like isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetra acetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more compound(s) of the invention or combinations with one or more other pharmaceutically active substance(s) may for example be prepared by mixing the compounds/active substance(s) with inert excipients such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with excipients provided for this purpose such as neutral fats or polyethylene glycol or the derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The pharmaceutical compositions are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may of course contain, apart from the above-mentioned excipients, additional excipients such as sodium citrate, calcium carbonate and dicalcium phosphate together with various excipients such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions, the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

For parenteral use, solutions of the active substances with suitable liquid excipients may be used.

The dosage range of the compound(s) of the invention applicable per day is usually from 1 mg to 2000 mg, preferably from 250 to 1250 mg. However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, age, the route of administration, severity of the disease, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered (continuous or intermittent treatment with one or multiple doses per day). Thus, 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 administering large amounts, it may be advisable to divide them up into a number of smaller doses spread over the day. Thus, in a further aspect the invention relates to a pharmaceutical composition comprising at least one (preferably one) compound(s) of the invention - or a pharmaceutically acceptable salt thereof - and one or more pharmaceutically acceptable excipient(s).

The compounds of the invention - or the pharmaceutically acceptable salts thereof - and the pharmaceutical compositions comprising such compound and salts may also be coadministered with other pharmacologically active substances, e.g. with other anti-neoplastic compounds (e.g. chemotherapy), i.e. used in combination (see combination treatment further below).

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

The combinations may be administered at therapeutically effective single or divided daily doses. The active components of the combinations may be administered in such doses which are therapeutically effective in monotherapy, or in such doses which are lower than the doses used in monotherapy, but when combined result in a desired (joint) therapeutically effective amount.

However, when the combined use of the two or more active substances or principles leads to a synergistic effect, it may also be possible to reduce the amount of one, more or all of the substances or principles to be administered, while still achieving the desired therapeutic action. This may for example be useful for avoiding, limiting or reducing any unwanted sideeffects that are associated with the use of one or more of the substances or principles when they are used in their usual amounts, while still obtaining the desired pharmacological or therapeutic effect.

Thus, in a further aspect the invention also relates to a pharmaceutical composition comprising a compound of the invention - or a pharmaceutically acceptable salt thereof - and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).

In a further aspect the invention also relates to a pharmaceutical preparation comprising a compound of the invention - or a pharmaceutically acceptable salt thereof - and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).

Pharmaceutical compositions to be co-administered or used in combination can also be provided in the form of a kit.

Thus, in a further aspect the invention also relates to a kit comprising

• a first pharmaceutical composition or dosage form comprising a compound of the invention and, optionally, one or more pharmaceutically acceptable excipient(s), and

• a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipient(s).

In one aspect such kit comprises a third pharmaceutical composition or dosage form comprising still another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipient(s).

Medical Uses - Methods of Treatment

Indications - patient populations

The present invention is directed to compounds inhibiting 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 inhibiting KRAS wildtype, preferably amplified, KRAS mutated at residue 13, such as KRAS G13D, or KRAS mutated at residue 61 , such as KRAS Q61 H. In particular, compounds of the invention (including all embodiments thereof) are potentially useful in the treatment and/or prevention of diseases and/or conditions mediated by KRAS, preferably by KRAS mutated at residue 12, e.g. KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D, or by an amplification of KRAS wildtype, or by KRAS mutated at residue 13, e.g. KRAS G13D, or by KRAS mutated at residue 61 , such as KRAS Q61 H.

Thus, in a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use as a medicament.

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in a method of treatment of the human or animal body.

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in 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 G12D, or by an amplification of KRAS wildtype, or by KRAS mutated at residue 13, e.g. KRAS G13D.

In a further aspect the invention relates to the use of a compound of the invention - or a pharmaceutically 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 G12D, or by an amplification of KRAS wildtype, or by KRAS mutated at residue 13, e.g. KRAS G13D.

In a further aspect the invention relates to a method 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 G12D, or by an amplification of KRAS wildtype, or by KRAS mutated at residue 13, e.g. KRAS G13D comprising administering a therapeutically effective amount of a compound of the invention - or a pharmaceutically acceptable salt thereof - to a human being.

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in the treatment and/or prevention of cancer.

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in a method of treatment and/or prevention of cancer in the human or animal body.

In a further aspect the invention relates to the use of a compound of the invention - or a pharmaceutically acceptable salt thereof - in the manufacture of a medicament for the treatment and/or prevention of cancer.

In a further aspect the invention relates to a method for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention - or a pharmaceutically acceptable salt thereof - to a human being.

Preferably, the cancer as defined herein (above or below) comprises a KRAS mutation. In particular, KRAS mutations include e.g. mutations of the KRAS gene and of the KRAS protein, such as overexpressed KRAS, amplified KRAS or KRAS, KRAS mutated at residue 12, KRAS mutated at residue 13, KRAS mutated at residue 61 , KRAS mutated at residue 146, in particular KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G13C, KRAS G13D, KRAS G13V, KRAS Q61 H, KRAS Q61E, KRAS Q61 P, KRAS A146P, KRAS A146T, KRAS A146V. KRAS may present one or more of these mutations/alterations.

Preferably, the cancer as defined herein (above or below) comprises a BRAF mutation in addition or in alternative to the KRAS mutation. Said BRAF mutation is in particular a class III BRAF mutation, e.g. as defined in Z. Yao, Nature, 2017, 548, 234-238.

Preferably, the cancer as defined herein (above or below) comprises a mutation in a receptor tyrosine kinase (RTK), including EGFR, MET and ERBB2 mutations, in addition or in alternative to the KRAS mutation.

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in the treatment and/or prevention of cancer, wherein the cancer comprises a KRAS mutation, said KRAS mutation being preferably selected from the group consisting of: KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; or an amplification of KRAS wildtype, amplification of the KRAS gene or overexpression of KRAS.

In a further aspect the invention relates to the use of a compound of the invention - or a pharmaceutically acceptable salt thereof - in the manufacture of a medicament for the treatment and/or prevention of cancer, wherein the cancer comprises a KRAS mutation, said KRAS mutation being preferably selected from the group consisting of: KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D; or an amplification of KRAS wildtype, amplification of the KRAS gene or overexpression of KRAS.

In a further aspect the invention relates to a method for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound of the invention - or a pharmaceutically acceptable salt thereof - to a human being, 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 an amplification of KRAS wildtype, amplification of the KRAS gene or overexpression of KRAS.

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

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

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

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in the treatment and/or prevention of cancer, wherein the cancer comprises wildtype amplified KRAS. Another aspect is based on identifying a link between the KRAS status of a patient and potential susceptibility to treatment with a compound of the invention. A KRAS inhibitor, such as a compound of the invention, may then advantageously be used to treat patients with a disease dependent on KRAS who may be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients for treatment with a compound of the invention particularly cancer patients. The selection is based on whether the tumor cells to be treated possess wild-type, preferably amplified, or KRAS mutated at residue 12, preferably G12C, G12D or G12V gene, or KRAS mutated at residue 13, preferably G13D gene. The KRAS gene status could therefore be used as a biomarker to indicate that selecting treatment with a compound of the invention may be advantageous.

According to one aspect, there is provided a method for selecting a patient for treatment with a compound of the invention 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 for wild-type (glycine at position 12) or mutant (cysteine, aspartic acid, valine, alanine or aginine at position 12, aspartic acid at position 13, amplification and/or overexpression) KRAS protein; and

• selecting a patient for treatment with a compound of the invention based thereon. The method may include or exclude the actual patient sample isolation step.

According to another aspect, there is provided a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring a KRAS mutation or an amplification of KRAS wildtype.

According to another aspect, there is provided a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring a G12C mutant, G12D mutant, G12V mutant, G12A mutant, G13D mutant or G12R mutant KRAS gene or an amplification of KRAS wildtype.

According to another aspect, there is provided a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring a G12C mutant, G12D mutant, G12V mutant or G13D mutant KRAS gene or an amplification of KRAS wildtype.

According to another aspect, there is provided a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring a G12D mutant KRAS gene. According to another aspect, there is provided a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring a G12V mutant KRAS gene.

According to another aspect, there is provided a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring a G13D mutant KRAS gene.

According to another aspect, there is provided a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in treating a cancer with tumor cells harbouring wildtype amplified KRAS or overexpressed KRAS.

According to another aspect, there is provided a method of treating a cancer with tumor cells harbouring a G12C mutant, G12D mutant, G12V mutant, G12A mutant or G12R mutant KRAS gene or an amplification of KRAS wildtype gene comprising administering an effective amount of a compound of the invention - or a pharmaceutically acceptable salt thereof - to a human being.

According to another aspect, there is provided a method of treating a cancer with tumor cells harbouring a G12C mutant, G12D mutant, G12V mutant, G12A mutant, G13D mutant or G12R mutant KRAS gene or an amplification of KRAS wildtype gene comprising administering an effective amount of a compound of the invention - or a pharmaceutically acceptable salt thereof.

Determining whether a tumor or cancer comprises a G12C KRAS mutation can be undertaken by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS, protein, or by assessing the characteristics of a putative KRAS mutant protein. The sequence of wild-type human KRAS is known in the art. Methods for detecting a mutation in a KRAS nucleotide sequence are known by those of skill 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 analyses. In some embodiments, samples are evaluated for G12C KRAS mutations by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS G12C mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS G12C mutation is identified using a direct sequencing method of specific regions (e.g. exon 2 and/or exon 3) in the KRAS gene. This technique will identify all possible mutations in the region sequenced. Methods for detecting a mutation in a KRAS protein are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g. an antibody) specific for the mutant protein, protein electrophoresis, Western blotting and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises a G12C KRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. In some embodiments the sample is a liquid biopsy and the test is done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood.

Analogously it can be determined whether a tumor or cancer comprises a KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D and KRAS G12R mutation or is a KRAS wildtype, preferably amplified.

Preferably, the disease/condition/cancer/tumors/cancer cells to be treated/prevented with a compound of the invention - or a pharmaceutically acceptable salt thereof - according to the methods and uses as herein (above and below) defined and disclosed is selected from the group consisting of: pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, oesophageal cancer, gastroesophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas.

Preferably, the disease/condition/cancer/tumors/cancer cells to be treated/prevented with a compound of the invention - or a pharmaceutically acceptable salt thereof - according to the methods and uses as herein (above and below) defined and disclosed 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.

In another aspect, the disease/condition/cancer/tumors/cancer cells to be treated/prevented with a compound of the invention - or a pharmaceutically acceptable salt thereof - according to the methods and uses as herein (above and below) defined and disclosed 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, cholangiocarcinoma and colorectal cancer (preferably colorectal adenocarcinoma). Preferably, said pancreatic cancer, lung cancer, cholangiocarcinoma, colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) or colorectal adenocarcinoma comprises a KRAS mutation, in particular a KRAS G12D or KRAS G12V mutation. Preferably (in alternative 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.

In another aspect, the disease/condition/cancer/tumors/cancer cells to be treated/prevented with a compound of the invention - or a pharmaceutically acceptable salt thereof - according to the methods and uses as herein (above and below) defined and disclosed is gastric cancer, ovarian cancer or esophageal cancer, said gastric cancer or esophageal cancer being preferably selected from the group consisting of: gastric adenocarcinoma (GAC), esophageal adenocarcinoma (EAC) and gastroesophageal junction cancer (GEJC). Preferably, said gastric cancer, ovarian cancer, esophageal cancer, gastric adenocarcinoma (GAC), esophageal adenocarcinoma (EAC) or gastroesophageal junction cancer (GEJC) comprises a KRAS mutation or wildtype amplified KRAS.

Particularly preferred, the cancer to be treated/prevented with a compound of the invention- or a pharmaceutically acceptable salt thereof - according to the methods and uses as herein (above and below) defined and disclosed is selected from the group consisting of:

• lung adenocarcinoma (preferably non-small cell lung cancer (NSCLC)) harbouring a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation), at position 13 (preferably G13D) or an amplification of KRAS wildtype;

• colorectal adenocarcinoma harbouring a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation), at position 13 (preferably G13D) or an amplification of KRAS wildtype;

• pancreatic adenocarcinoma (preferably pancreatic ductal adenocarcinoma (PDAC)) harbouring a RAS mutation at position 12 (preferably a KRAS and preferably a G12C, G12D, G12V, G12A, G12R mutation), at position 13 (preferably G13D) or an amplification of KRAS wildtype.

Preferably, “cancer” as used herein (above or below) includes drug-resistant cancer and cancer that has failed one, two or more lines of mono- or combination therapy with one or more anti-cancer agents. In particular, “cancer” (and any embodiment thereof) refers to any cancer (especially the cancer species defined hereinabove and hereinbelow) that is resistant to treatment with a KRAS G12C inhibitor. Different resistance mechanisms have already been reported. For example, the following articles describe resistance in patients following treatment with a KRAS G12C inhibitor: (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-ll pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov 2021 ;11 :1913-22.

In another aspect the disease/condition/cancer/tumors/cancer cells to be treated/prevented with a compound of the invention - or a pharmaceutically acceptable salt thereof - according to the methods and uses as herein (above and below) defined and disclosed is a RASopathy, preferably selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML) (also referred to as LEOPARD syndrome), Capillary Malformation-Arteriovenous Malformation Syndrome (CM- AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome (also known as NF1 -like Syndrome) and Hereditary gingival fibromatosis.

Additionally, the following cancers, tumors and other proliferative diseases may be treated with compounds of the invention - or a pharmaceutically acceptable salt thereof - without being restricted thereto. Preferably, the methods of treatment, methods, uses, compounds for use and pharmaceutical compositions for use as disclosed herein (above and below) are applied in treatments of diseases/conditions/cancers/tumors which (/.e. the respective cells) harbour a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation) or an amplification of KRAS wildtype alternatively they have been identified to harbour a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation) as herein described and/or referred or an amplification of KRAS wildtype: cancers/tumors/carcinomas of the head and neck: e.g. tumors/carcinomas/cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); cancers/tumors/carcinomas of the lung: e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer); neoplasms of the mediastinum: e.g. neurogenic tumors (including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma); cancers/tumors/carcinomas of the gastrointestinal (Gl) tract: e.g. tumors/carcinomas/cancers of the esophagus, stomach (gastric cancer), gastroesophageal junction cancer pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinary system (including kidney, e.g. renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor; ureter; urinary bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g. distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis) gastric cancer; cancers/tumors/carcinomas of the testis: e.g. seminomas, non-seminomas, gynecologic cancers/tumors/carcinomas: e.g. tumors/carcinomas/cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus); cancers/tumors/carcinomas of the breast: e.g. mammary carcinoma (infiltrating ductal, colloid, lobular invasive, tubular, adenocystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast; cancers/tumors/carcinomas of the endocrine system: e.g. tumors/carcinomas/cancers of the endocrine glands, thyroid gland (thyroid carcinomas/tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma/tumor), adrenal cortex (adrenal cortical carcinoma/tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors; sarcomas of the soft tissues: e.g. fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; sarcomas of the bone: e.g. myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma; mesothelioma: e.g. pleural mesothelioma, peritoneal mesothelioma; cancers of the skin: e.g. basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer; neoplasms of the central nervous system and brain: e.g. astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g. acoustic), spinal axis tumors; lymphomas and leukemias: e.g. B-cell non-Hodgkin lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin lymphomas (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 (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed-cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous/myeloid leukemia (AML), acute lymphatic/lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic/lymphatic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous/myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML); cancers of unknown primary site (CUP);

All cancers/tumors/carcinomas mentioned above which are characterized by their specific location/origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom.

All cancers/tumors/carcinomas mentioned above may be further differentiated by their histopathological classification:

Epithelial cancers, e.g. squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet-ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma;

Nonepithilial cancers, e.g. sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas;

The compounds of the invention may be used in therapeutic regimens in the context of first line, second line, or any further line treatments.

The compounds of the invention may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases/conditions/cancers/tumors, optionally also in combination with radiotherapy and/or surgery. The methods of treatment, methods, uses and compounds for use as disclosed herein (above and below) can be performed with any compound of the invention - or a pharmaceutically acceptable salt thereof - as disclosed or defined herein and with any pharmaceutical composition or kit comprising a compound of the invention - or a pharmaceutically acceptable salt thereof (each including all individual embodiments or generic subsets of compounds of the invention.

Combination treatment

The compounds of the invention - or the pharmaceutically acceptable salts thereof - and the pharmaceutical compositions comprising such compounds or salts may also be coadministered with other pharmacologically active substances, e.g. with other anti-neoplastic compounds {e.g. chemotherapy), or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. Preferably, the pharmacologically active substance(s) for co-administration is/are (an) anti- neoplastic compound(s).

Thus, in a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use as hereinbefore defined wherein said compound is administered before, after or together with one or more other pharmacologically active substance(s).

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use as hereinbefore defined, wherein said compound is administered in combination with one or more other pharmacologically active substance(s).

In a further aspect the invention relates to the use of a compound of the invention - or a pharmaceutically acceptable salt thereof - as hereinbefore defined wherein said compound is to be administered before, after or together with one or more other pharmacologically active substance(s).

In a further aspect the invention relates to a method e.g. a method for the treatment and/or prevention) as hereinbefore defined wherein the compound of the invention - or a pharmaceutically acceptable salt thereof - is administered before, after or together with a therapeutically effective amount of one or more other pharmacologically active substance(s). In a further aspect the invention relates to a method {e.g. a method for the treatment and/or prevention) as hereinbefore defined wherein the compound of the invention - or a pharmaceutically acceptable salt thereof - is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substance(s). In a further aspect the invention relates to a method for the treatment and/or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention - or a pharmaceutically acceptable salt thereof - and a therapeutically effective amount of one or more other pharmacologically active substance(s), wherein the compound of the invention - or a pharmaceutically acceptable salt thereof - is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the one or more other pharmacologically active substance(s).

In a further aspect the invention relates to a method for the treatment and/or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of a KRAS mutated at residue 12 or 13, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D and/or KRAS G12R inhibitors, preferably KRAS G12C, KRAS G12D or selective KRAS G12D inhibitors - or a pharmaceutically acceptable salt thereof - and a therapeutically effective amount of one or more other pharmacologically active substance(s), wherein the inhibitor - or a pharmaceutically acceptable salt thereof - is administered in combination with the one or more other pharmacologically active substance(s).

In a further aspect the invention relates to a method for the treatment and/or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of KRAS wildtype amplified or overexpressed - or a pharmaceutically acceptable salt thereof - and a therapeutically effective amount of one or more other pharmacologically active substance(s), wherein the inhibitor - or a pharmaceutically acceptable salt thereof - is administered in combination with the one or more other pharmacologically active substance(s).

In a further aspect the invention relates to a compound of the invention - or a pharmaceutically acceptable salt thereof - for use in the treatment and/or prevention of cancer, wherein the compound of the invention - or a pharmaceutically acceptable salt thereof - is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the one or more other pharmacologically active substance(s).

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

In a further aspect the invention relates to an inhibitor of KRAS wildtype amplified or overexpressed - or a pharmaceutically acceptable salt thereof - for use in the treatment and/or prevention of cancer, wherein the inhibitor - or a pharmaceutically acceptable salt thereof - is administered in combination with the one or more other pharmacologically active substance(s).

In a further aspect the invention relates to a kit comprising

• a first pharmaceutical composition or dosage form comprising a compound of the invention - or a pharmaceutically acceptable salt thereof - and, optionally, one or more pharmaceutically acceptable excipient(s), and

• a second pharmaceutical composition or dosage form comprising another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable excipient(s), for use in the treatment and/or prevention of cancer, wherein the first pharmaceutical composition is to be administered simultaneously, concurrently, sequentially, successively, alternately or separately with the second and/or additional pharmaceutical composition or dosage form.

In one aspect such kit for said use comprises a third pharmaceutical composition or dosage form comprising a third pharmaceutical composition or dosage form comprising still another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable excipient(s)

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

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

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

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

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

The pharmacologically active substance(s) to be used together/in combination with the compound of the invention - or a pharmaceutically acceptable salt thereof - (including all individual embodiments or generic subsets of compounds) or in the medical uses, uses, methods of treatment and/or prevention, pharmaceutical compositions as herein (above and below) defined can be selected from any one or more of the following (preferably there is one or two additional pharmacologically active substance used in all these embodiments):

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

2. an inhibitor of MEK and/or of mutants thereof a. e.g. trametinib, cobimetinib, binimetinib, selumetinib, refametinib; b. preferred is trametinib c. a MEK inhibitor as disclosed in WO 2013/136249; d. a MEK inhibitor as disclosed in WO 2013/136254

3. an inhibitor of SOS1 and/or of any mutants thereof (/.e. a compound that modulates/inhibits the GEF functionality of SOS1 , e.g. by binding to SOS1 and preventing protein-protein interaction between SOS1 and a (mutant) Ras protein, e.g. KRAS) a. e.g. BAY-293; b. a SOS1 inhibitor as disclosed in WO 2018/115380; c. a SOS1 inhibitor as disclosed in WO 2019/122129; d. a SOS1 inhibitor as disclosed in WO 2020/180768, WO 2020/180770, WO 2018/172250 and WO 2019/201848. 4. an inhibitor of YAP1, WWTR1, TEAD1, TEAD2, TEAD3 and Z or TEAD4 a. reversible inhibitors of TEAD transcription factors (e.g. disclosed in WO 2018/204532); b. irreversible inhibitors of TEAD transcription factors (e.g. disclosed in WO 2020/243423); c. protein-protein interaction inhibitors of the YAP/TAZ::TEAD interaction (e.g. disclosed in WO 2021/186324); d. inhibitors of TEAD palmitoylation.

5. an oncolytic virus

6. a RAS vaccine a. e.g. TG02 (Targovax).

7. a cell cycle inhibitor a. e.g. inhibitors of CDK4/6 and/or of any mutants therof i. e.g. palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600; ii. preferred are palbociclib and abemaciclib; iii. most preferred is abemaciclib. b. e.g. vinca alkaloids i. e.g. vinorelbine. c. e.g. inhibitors of Aurora kinase and/or of any mutants therof i. e.g. alisertib, barasertib.

8. an inhibitor of PTK2 (= FAK) and/or of any mutants thereof a. e.g. TAE226, Bl 853520.

9. an inhibitor of SHP2 and/or of any mutants thereof a. e.g. SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

10. an inhibitor of PI3 kinase (= PI3K) and/or of any mutants thereof a. e.g. inhibitors of PI3Ka and/or of any mutants therof i. e.g. alpelisib, serabelisib, GDC-0077, HH-CYH33, AMG 511 , buparlisib, dactolisib, pictilisib, taselisib.

11. an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of any mutants thereof a. e.g. ponatinib, infigratinib, nintedanib.

12. an inhibitor of AXL and/or of any mutants thereof

13. a taxane a. e.g. paclitaxel, nab-paclitaxel, docetaxel; b. preferred is paclitaxel.

14. a platinum-containing compound a. e.g. cisplatin, carboplatin, oxaliplatin b. preferred is oxaliplatin.

15. an antf-metabolite a. e.g. 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, combination of trifluridine and tipiracil (= TAS102); b. preferred is 5-fluorouracil.

16. an immunotherapeutic agent a. e.g. an immune checkpoint inhibitor i. e.g. an anti-CTLM mAb, ant/-PD1 mAb, ant/-PD-L1 mAb, ant/-PD-L2 mAb, ant/-LAG3 mAb, ant/-TIM3 mAb; ii. preferred is an ant/-PD1 mAb; iii. e.g. ipilimumab, nivolumab, pembrolizumab, tislelizumab atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), AMG-404, ezabenlimab; iv. preferred are nivolumab, pembrolizumab, ezabenlimab and PDR-001 (= spartalizumab); v. most preferred is ezabenlimab, pembrolizumab and nivolumab.

17. a topoisomerase inhibitor a. e.g. irinotecan, liposomal irinotecan (nal-IRI), topotecan, etoposide; b. most preferred is irinotecan and liposomal irinotecan (nal-IRI).

18. an inhibitor of A-Raf and/or B-Raf and/or C-Raf and/or of any mutants thereof a. e.g. 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.

19. an inhibitor of mTOR a. e.g. rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin 1 , dactolisib, GDC-0349, VS-5584, vistusertib, AZD8055.

20. an epigenetic regulator a. e.g. a BET inhibitor i. e.g. JQ-1, GSK 525762, OTX-015, CPI-0610, TEN-010, OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601 , CC-90010, AZD5153, I-BET151 , Bl 894999;

21. an inhibitor of IGF1/2 and/or of IGF1-R and/or of any mutants thereof a. e.g. xentuzumab (antibody 60833 in WO 2010/066868), MEDI-573 (= dusigitumab), linsitinib.

22. an inhibitor of a Src family kinase and/or of any mutants thereof a. e.g. an inhibitor of a kinase of the SrcA subfamily and/or of any mutants thereof, i.e. an inhibitor of Src, Yes, Fyn, Fgr and/or of any mutants thereof; b. e.g. an inhibitor of a kinase of the SrcB subfamily and/or of any mutants thereof, i.e. an inhibitor of Lek, Hck, Blk, Lyn and/or of any mutants thereof; c. e.g. an inhibitor of a kinase of the Frk subfamily and/or of any mutants thereof, i.e. an inhibitor of Frk and/or of any mutants thereof; d. e.g. dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391 , SU 6656, WH-4-023.

23. an apoptosis regulator a. e.g. an MDM2 inhibitor, e.g. an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 and/or of any mutants thereof; i. e.g. HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115; ii. preferred are HDM-201, RG-7388 and AMG-232; iii. an MDM2 inhibitor as disclosed in WO 2015/155332; iv. an MDM2 inhibitor as disclosed in WO 2016/001376; v. an MDM2 inhibitor as disclosed in WO 2016/026937; vi. an MDM2 inhibitor as disclosed in WO 2017/060431; b. e.g. a PARP inhibitor; c. e.g. an MCL-1 inhibitor; i. e.g. AZD-5991 , AMG-176, AMG-397, S64315, S63845, A-1210477;

24. an inhibitor of c-MET and/or of any mutants thereof a. e.g. savolitinib, cabozantinib, foretinib; b. MET antibodies, e.g. emibetuzumab, amivantamab;

25. an inhibitor of ERK and/or of any mutants thereof a. e.g. ulixertinib, LTT462;

26. an inhibitor of farnesyl transferase and/or of any mutants thereof a. e.g. tipifarnib;

In a further embodiment of the (combined) use and method (e.g. method for the treatment and/or prevention) as hereinbefore described one other pharmacologically active substance is to be administered before, after or together with the compound of the invention - or a pharmaceutically acceptable salt thereof - wherein said one other pharmacologically active substance is a SOS1 inhibitor; or a MEK inhibitor; or • trametinib, or

• an anti-PD-1 antibody; or

• ezabenlimab; or

• cetuximab; or

• afatinib; or

• standard of care (SoC) in a given indication; or

• a PI3 kinase inhibitor; or

• an inhibitor of TEAD palmitoylation; or

• a YAP/TAZ: :TEAD inhibitor.

In a further embodiment of the (combined) use and method (e.g. method for the treatment and/or prevention) as hereinbefore described one other pharmacologically active substance is to be administered in combination with the compound of the invention - or a pharmaceutically acceptable salt thereof - wherein said one other pharmacologically active substance is

• a SOS1 inhibitor; or

• a MEK inhibitor; or

• trametinib; or

• an anti-PD-1 antibody; or

• ezabenlimab; or

• cetuximab; or

• afatinib; or

• standard of care (SoC) in a given indication; or

• a PI3 kinase inhibitor; or

• an inhibitor of TEAD palmitoylation; or

• a YAP/TAZ: :TEAD inhibitor.

In a further aspect of the (combined) use and method (e.g. method for the treatment and/or prevention) as hereinbefore described two other pharmacologically active substances are to be administered before, after or together with the compound of the invention - or a pharmaceutically acceptable salt thereof - wherein said two other pharmacologically active substances are a MEK inhibitor and a SOS1 inhibitor; or trametinib and a SOS1 inhibitor; or an anti-PD-1 antibody (preferably ezabenlimab) and an ant/- LAG-3 antibody; or • an ant/-PD-1 antibody (preferably ezabenlimab) and a SOS1 inhibitor; or

• a MEK inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and/or ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof; or

• a SOS1 inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and/or ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof; or

• a MEK inhibitor and afatinib; or

• a MEK inhibitor and cetuximab; or

• trametinib and afatinib; or

• trametinib and cetuximab; or

• a SOS1 inhibitor and afatinib; or

• a SOS1 inhibitor and cetuximab; or

• a SOS1 inhibitor and an inhibitor of TEAD palmitoylation; or

• a SOS1 inhibitor and a YAP/TAZ::TEAD inhibitor.

In a further aspect of the (combined) use and method (e.g. method for the treatment and/or prevention) as hereinbefore described two other pharmacologically active substances are to be administered in combination with the compound of the invention - or a pharmaceutically acceptable salt thereof - wherein said two other pharmacologically active substances are

• a MEK inhibitor and a SOS1 inhibitor; or

• trametinib and a SOS1 inhibitor; or

• an anti-PD-1 antibody (preferably ezabenlimab) and an ant/- LAG-3 antibody; or

• an anti-PD-1 antibody (preferably ezabenlimab) and a SOS1 inhibitor; or

• a MEK inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and/or ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof; or

• a SOS1 inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and/or ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof; or

• a MEK inhibitor and afatinib; or

• a MEK inhibitor and cetuximab; or

• trametinib and afatinib; or

• trametinib and cetuximab; or

• a SOS1 inhibitor and afatinib; or

• a SOS1 inhibitor and cetuximab; or

• a SOS1 inhibitor and an inhibitor of TEAD palmitoylation; or

• a SOS1 inhibitor and a YAP/TAZ::TEAD inhibitor.

Additional pharmacologically active substance(s) which can also be used together/in combination with the compound of the invention - or a pharmaceutically acceptable salt thereof - (including all individual embodiments or generic subsets of compounds of the invention or in the medical uses, uses, methods of treatment and/or prevention, pharmaceutical compositions, kits as herein (above and below) defined include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors and/or of their corresponding receptors (growth factors such as for example platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER, e.g. HER2, HER3, HER4) and hepatocyte growth factor (HGF) and/or their corresponding receptors), inhibitors are for example (ant/-)growth factor antibodies, (ant/-)growth factor receptor antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5- Fll), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (e.g. anthracyclins such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g. tasquinimod), tubuline inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g. PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1/2 inhibitors, PI3K inhibitors, PI3Ka inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors), protein protein interaction inhibitors (e.g. IAP inhibitors/SMAC mimetics, Mcl-1 , MDM2/MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF- 1 R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g. venetoclax), Bcl-2/Bcl- xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g. everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1/2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g. carfilzomib), immunotherapeutic agents such as immune checkpoint inhibitors (e.g. CTLA4, PD1 , PD-L1 , PD-L2, LAG3, and TIM3 binding molecules/immunoglobulins, such as e.g. ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g. anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), t-cell engagers (e.g. bi-specific T-cell engagers (BiTEs®) like e.g. CD3 x BCMA, CD3 x CD33, CD3 x CD19), PSMA x CD3), tumor vaccines, immunomodulator, e.g. STING agonist, and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.

It is to be understood that the combinations, compositions, kits, methods, uses, pharmaceutical compositions or compounds for use according to this invention may envisage the simultaneous, concurrent, sequential, successive, alternate or separate administration of the active ingredients or components. It will be appreciated that the compound of the invention - or a pharmaceutically acceptable salt thereof - and the one or more other pharmacologically active substance(s) can be administered formulated either dependently or independently, such as e.g. the compound of the invention - or a pharmaceutically acceptable salt thereof - and the one or more other pharmacologically active substance(s) may be administered either as part of the same pharmaceutical composition/dosage form or, preferably, in separate pharmaceutical compositions/dosage forms.

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

The administration of the compound of formula the invention - or a pharmaceutically acceptable salt thereof - and the one or more other pharmacologically active substance(s) may take place by co-administering the active components or ingredients, such as e.g. by administering them simultaneously or concurrently in one single or in two or more separate formulations or dosage forms. Alternatively, the administration of the compound of the invention - or a pharmaceutically acceptable salt thereof - and the one or more other pharmacologically active substance(s) may take place by administering the active components or ingredients sequentially or in alternation, such as e.g. in two or more separate formulations or dosage forms.

For example, simultaneous administration includes administration at substantially the same time. This form of administration may also be referred to as “concomitant” administration. Concurrent administration includes administering the active agents within the same general time period, for example on the same day(s) but not necessarily at the same time. Alternate administration includes administration of one agent during a time period, for example over the course of a few days or a week, followed by administration of the other agent(s) during a subsequent period of time, for example over the course of a few days or a week, and then repeating the pattern for one or more cycles. Sequential or successive administration includes administration of one agent during a first time period (for example over the course of a few days or a week) using one or more doses, followed by administration of the other agent(s) during a second and/or additional time period (for example over the course of a few days or a week) using one or more doses. An overlapping schedule may also be employed, which includes administration of the active agents on different days over the treatment period, not necessarily according to a regular sequence. Variations on these general guidelines may also be employed, e.g. according to the agents used and the condition of the subject.

Definitions

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to:

The use of the prefix C _x.y , wherein x and y each represent a positive integer (x < y), indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x carbon atoms. The indication of the number of members in groups that contain one or more heteroatom(s) (e.g. heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total number of atoms of all the ring members or the total of all the ring and carbon chain members.

The indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure (e.g. cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all the carbon ring and carbon chain members. Obviously, a ring structure has at least three members.

In general, for groups comprising two or more subgroups (e.g. heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the last named subgroup is the radical attachment point, for example, the substituent aryl-Ci -ealkyl means an aryl group which is bound to a Ci- ealkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.

In groups like HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself.

The expression “compound of the invention” and grammatical variants thereof comprises compounds of formula (V), (V’), (I), (la), (lb), (Ic), (Id), (Ila), (lib), (IV), (He), (lid), (He) and/or (HI), including all salts, aspects and preferred embodiments thereof as herein defined. Any reference to a compound of the invention or to a compound of formula (V), (V’), (I), (la), (lb), (Ic), (Id), (Ha), (Hb), (IV), (He), (Hd), (He) and/or (HI) is intended to include a reference to the respective (sub)aspects and embodiments.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.

The term ”Ci- ₅ alkyl“ includes for example H ₃ C-, H3C-CH2-, H3C-CH2-CH2-, H ₃ C-CH(CH3)-, H3C-CH2-CH2-CH2-, H ₃ C-CH ₂ -CH(CH3)-, H ₃ C-CH(CH3)-CH ₂ -, H ₃ C-C(CH3) ₂ -, H3C-CH2-CH2- CH2-CH2-, H ₃ C-CH2-CH ₂ -CH(CH3)-, H ₃ C-CH2-CH(CH3)-CH ₂ -, H ₃ C-CH(CH3)-CH2-CH ₂ -, H ₃ C- CH ₂ -C(CH ₃ )2-, H ₃ C-C(CH3)2-CH ₂ -, H ₃ C-CH(CH3)-CH(CH3)- and H ₃ C-CH2-CH(CH ₂ CH3)-.

Further examples of alkyl are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1 -propyl (n-propyl; n- Pr; -CH2CH2CH3), 2-propyl (/-Pr; /so-propyl; -CH(CH3)2), 1 -butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1 -propyl (/so-butyl; /-Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (fert-butyl; t-Bu; -C(CH3)3), 1 -pentyl (n-pentyl; - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH ₂ CH ₂ CH3), 3-pentyl (-CH(CH ₂ CH ₃ )2), 3-methyl-1- butyl (/so-pentyl; -CH ₂ CH ₂ CH(CH3)2), 2-methyl-2-butyl (-C(CH ₃ )2CH ₂ CH3), 3-methyl-2-butyl (- CH(CH3)CH(CH3)2), 2, 2-dimethyl-1 -propyl (neo-pentyl; -CH2C(CH3)3), 2-methyl-1 -butyl (- CH ₂ CH(CH3)CH ₂ CH3), 1 -hexyl (n-hexyl; -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH3), 2-hexyl (- CH(CH3)CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH3)(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (- C(CH3)2CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH ₂ CH ₃ ), 4-methyl-2-pentyl (- CH(CH3)CH ₂ CH(CH ₃ )2), 3-methyl-3-pentyl (-C(CH3)(CH ₂ CH ₃ )2), 2-methyl-3-pentyl (-CH(CH ₂ CH3)CH(CH ₃ )2), 2,3-dimethyl-2-butyl (-C(CH3) ₂ CH(CH3) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH ₃ )3), 2,3-dimethyl-1-butyl (-CH ₂ CH(CH3)CH(CH3)CH ₃ ), 2,2-dimethyl-1-butyl (-CH ₂ C(CH3)2CH ₂ CH ₃ ), 3,3-dimethyl-1-butyl (-CH ₂ CH ₂ C(CH ₃ )3), 2-methyl-1 -pentyl (-CH ₂ CH(CH3)CH ₂ CH ₂ CH ₃ ), 3-methyl-1 -pentyl (-CH ₂ CH ₂ CH(CH3)CH ₂ CH ₃ ), 1 -heptyl (n-heptyl), 2-methyl-1 -hexyl, 3-methyl-1 -hexyl, 2, 2-dimethyl-1 -pentyl, 2, 3-dimethyl-1 -pentyl, 2, 4-dimethyl-1 -pentyl, 3, 3-dimethyl-1 -pentyl, 2,2,3-trimethyl-1 -butyl, 3-ethyl-1 -pentyl, 1 -octyl (n-octyl), 1 -nonyl (n-nonyl); 1 -decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.

The above definition for alkyl also applies if alkyl is a part of another (combined) group such as for example C _x-y alkylamino or C _x-y alkyloxy, the latter is abbreviated as C _x.y alkoxy.

C _x.y tth ioalky I oxy or C _x.y thioalkoxy means that at least one atom of the C _x.y alkyl group is substituted with a sulfur atom.

The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example -CH3 and -CH ₂ -, -CH ₂ CH ₃ and -CH ₂ CH ₂ - or >CHCH ₃ etc.

The term “Ci.4alkylene” includes for example -(CH ₂ )-, -(CH ₂ -CH ₂ )-, -(CH(CH3))-, -(CH ₂ -CH ₂ -CH ₂ )-, -(C(CH ₃ ) ₂ )-, -(CH(CH ₂ CH ₃ ))-, -(CH(CH ₃ )-CH ₂ )-, -(CH ₂ -CH(CH ₃ ))-, -(CH ₂ -CH ₂ -CH ₂ -CH ₂ )-, -(CH ₂ -CH ₂ -CH(CH ₃ ))-, -(CH(CH ₃ )-CH ₂ -CH ₂ )-, -(CH ₂ -CH(CH ₃ )-CH ₂ )-, -(CH ₂ -C(CH ₃ )2)-, -(C(CH ₃ )2-CH ₂ )-, -(CH(CH ₃ )-CH(CH ₃ ))-, -(CH ₂ -CH(CH ₂ CH ₃ ))-, -(CH(CH ₂ CH ₃ )-CH ₂ )-, -(CH(CH ₂ CH ₂ CH ₃ ))-, -(CH(CH(CH ₃ )) ₂ )- and -C(CH3)(CH ₂ CH ₃ )-.

Other examples of alkylene are methylene, ethylene, propylene, 1 -methylethylene, butylene, 1 -methylpropylene, 1 ,1 -dimethylethylene, 1 ,2-dimethylethylene, pentylene, 1 , 1 -dimethylpropylene, 2,2-dimethylpropylene, 1 ,2-dimethylpropylene,

1 ,3-dimethylpropylene, hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1 -methylethylene and butylene includes 1 -methylpropylene, 2-methylpropylene, 1 ,1 -dimethylethylene and 1 ,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part of another (combined) group such as for example in HO-C _x-y alkyleneamino or H2N-C _x-y alkyleneoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1- enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2- enyl, 1-methyl-prop-1-enyl, 1 -methylidenepropyl, pent-1 -enyl, pent-2-enyl, pent-3-enyl, pent- 4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2- methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1 , 3-dienyl, hexa-1 , 4-dienyl, penta- 1 ,4-dienyl, penta-1 , 3-dienyl, buta-1 , 3-dienyl, 2,3-dimethylbuta-1 ,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1 -enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part of another (combined) group such as for example in C _x.y alkenylamino or C _x.y alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed. 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 etc.

By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1 -methylethenylene and butenylene includes 1- methylpropenylene, 2-methylpropenylene, 1 ,1 -dimethylethenylene and

1 .2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is a part of another (combined) group as for example in HO-C _x-y alkenyleneamino or H2N-C _x-y alkenyleneoxy.

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.

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 etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1 -ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl,1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part of another (combined) group, as for example in C _x.y alkynylamino or C _x.y alkynyloxy.

Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed.

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 etc.

By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1 ,1-dimethylethynylene and 1 ,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is part of another (combined) group, as for example in HO-C _x-y alkynyleneamino or H2N-C _x-y alkynyleneoxy.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F,

-CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF ₂ , -CCI=CH ₂ , -CBr=CH ₂ , -C=C-CF ₃ , -CHFCH2CH3, -CHFCH2CF3 etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkylene (haloalkenylene, haloalkynylene). Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl (haloalkenyl, haloalkynyl), is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl).

Corresponding groups are for example -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH ₂ F etc.

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

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

Cycloalkvl is made up of the subgroups monocyclic cycloalkyl, bicyclic cycloalkyl and spiro-cycloalkyl. The ring systems are saturated and formed by linked carbon atoms. In bicyclic cycloalkyl two rings are joined together so that they have at least two carbon atoms in common. In spiro-cycloalkyl one carbon atom (spiroatom) belongs to two rings together.

If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl

(pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in C _x.y cycloalkylamino, C _x.y cycloalkyloxy or C _x.y cycloalkylalkyl.

If the free valency of a cycloalkyl is saturated, then an alicycle is obtained.

The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example: cyclohexyl and (cyclohexylene).

The above definition for cycloalkylene also applies if cycloalkylene is part of another (combined) group as for example in HO-C _x-y cycloalkyleneamino or H2N-Cx- _y cycloalkyleneoxy.

Cycloalkenyl is made up of the subgroups monocyclic cycloalkenyl, bicyclic cycloalkenyl and spiro-cycloalkenyl. However, the systems are unsaturated, i.e. there is at least one C- C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained.

If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

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

The above definition for cycloalkenyl also applies when cycloalkenyl is part of another (combined) group as for example in C _x-y cycloalkenylamino, C _x.y cycloalkenyloxy or Cx ycycloalkenylalkyl.

If the free valency of a cycloalkenyl is saturated, then an unsaturated alicycle is obtained. The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkenyl.

Corresponding groups are for example: cyclopentenyl and

The above definition for cycloalkenylene also applies if cycloalkenylene is part of another (combined) group as for example in HO-C _x-y cycloalkenyleneamino or H2N-Cx- _y cycloalkenyleneoxy.

Aryl denotes mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle. Preferably, it denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a fivemembered ring), wherein the second ring may also be aromatic or, however, may also be partially saturated.

If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

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

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

If the free valency of an aryl is saturated, then an aromatic group is obtained.

The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are for example: phenyl (o, m, p-phenylene), naphthyl and

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

Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups -CH2- independently of one another in the hydrocarbon rings by the groups -O-, -S- or -NH- or by replacing one or more of the groups =CH- by the group =N-, wherein a total of not more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between two sulphur atoms or between an oxygen and a sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be present in all the possible oxidation stages (sulphur sulfoxide -SO-, sulphone -SO2-; nitrogen N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is part of an aromatic system. A direct result of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl and spiro-heterocyclyl, which may be present in saturated or unsaturated form. By unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterocyclyl two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterocyclyl one carbon atom (spiroatom) belongs to two rings together.

If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Substituents on heterocyclyl do not count for the number of members of a heterocyclyl.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1 ,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1 ,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1 ,4]- oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, di hydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2/7-pyrrolyl, 4/7-pyranyl, 1 ,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3- aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza- bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza- bicyclo[3.2.2]nonyl, 1 ,4-dioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza- spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza- spiro[5.5]undecyl, 2.8-diaza-spiro[4,5]decyl etc.

Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferred monocyclic heterocyclyl is 4 to 7 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

Preferred monocyclic heterocyclyls are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azetidinyl. Preferred bicyclic heterocyclyl is 6 to 10 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

Preferred tricyclic heterocyclyl is 9 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

Preferred spiro-heterocyclyl is 7 to 11 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

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

If the free valency of a heterocyclyl is saturated, then a heterocycle is obtained.

The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners.

Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl.

Corresponding groups are for example: piperidinyl

2,3-dihydro-1 /7-pyrrolyl etc. The above definition of heterocyclylene also applies if heterocyclylene is part of another (combined) group as for example in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy. Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system.

If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molecule via every suitable position of the ring system, both carbon and nitrogen. Substituents on heteroaryl do not count for the number of members of a heteroaryl.

Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-/V-oxide, pyrrolyl-/V-oxide, pyrimidinyl-ZV-oxide, pyridazinyl-/V-oxide, pyrazinyl-/V-oxide, imidazolyl-ZV-oxide, isoxazolyl-/V-oxide, oxazolyl-/V- oxide, thiazolyl-/V-oxide, oxadiazolyl-/V-oxide, thiadiazolyl-/V-oxide, triazolyl-ZV-oxide, tetrazolyl-/V-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-/V-oxide, indolyl-/V-oxide, isoquinolyl-/V-oxide, quinazolinyl-/V-oxide, quinoxalinyl-/V-oxide, phthalazinyl-/V-oxide, indolizinyl- Z-oxide, indazolyl-/V-oxide, benzothiazolyl-/V-oxide, benzimidazolyl-ZV-oxide etc. Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferably, heteroaryls are 5-6 membered monocyclic or 9-10 membered bicyclic, each with 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

The above definition of heteroaryl also applies if heteroaryl is part of another (combined) group as for example in heteroarylamino, heteroaryloxy or heteroarylalkyl. If the free valency of a heteroaryl is saturated, a heteroaromatic group is obtained.

The term heteroarylene is also derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example:

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

By substituted is meant that a hydrogen atom which is bound directly to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (/.e. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2 or the like, may only be substituents on carbon atoms, whereas the bivalent substituents =0 and =NR may also be a substituent on sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring systems and requires replacement of two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group -CH2- or sulphur atoms (=0 group or =NR group only, one or two =0 groups possible or, e.g., one =0 group and one =NR group, each group replacing a free electron pair) of a ring system.

Stereochemistry/solvates/hydrates: Unless specifically indicated, throughout the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, EIZ isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates and hydrates of the free compound or solvates and hydrates of a salt of the compound.

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

Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases, or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt, or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group, or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

Salts: The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

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

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

Further pharmaceutically acceptable salts can be formed with cations from ammonia, L- arginine, calcium, 2,2’-iminobisethanol, L-lysine, magnesium, /V-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.

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

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts), also comprise a part of the invention.

In a representation such as for example the letter A has the function of a ring designation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings.

For bivalent groups in which it is crucial to determine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets where necessary for clarification purposes, as in the following representations:

If such a clarification is missing then the bivalent group can bind in both directions, /.e., e.g., - C(=O)NH- also includes -NHC(=O)- (and vice versa).

Groups or substituents are frequently selected from among a number of alternative groups/substituents with a corresponding group designation (e.g. R ^a , R ^b etc). If such a group is used repeatedly to define a compound according to the invention in different parts of the molecule, it is pointed out that the various uses are to be regarded as totally independent of one another.

By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient.

List of abbreviations

Examples

Features and advantages of the present invention will become apparent from the following detailed examples which illustrate the principles of the invention by way of example without restricting its scope:

Preparation of the compounds according to the invention

General

Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).

If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive.

Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM or in Synthos 3000 or Monowave 3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.

Chromatography

The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck. The preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is carried out on Agilent or Gilson systems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10 pm, 50 x 150 mm or SunFire™ Prep C18 OBD™ 5 pm, 30 x 50 mm or XBridge™ Prep C18, OBD™ 10 pm, 50 x 150 mm or XBridge™ Prep CI 8, OBD™ 5 pm, 30 x 150 mm or XBridge™ Prep C18, OBD™ 5 pm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 pm, 30 x 50 mm).

Different gradients of H2O/acetonitrile are used to elute the compounds, while for Agilent systems 5 % acidic modifier (20 mL HCOOH to 1 L H2O/acetonitrile (1/1)) is added to the water (acidic conditions). For Gilson systems the water is added 0.1 % HCOOH.

For the chromatography under basic conditions for Agilent systems H2O/acetonitrile gradients are used as well, while the water is made alkaline by addition of 5 % basic modifier (50 g NH4HCO3 + 50 mL NH3 (25 % in H2O) to 1 L with H2O). For Gilson systems the water is made alkaline as follows: 5mL NH4HCO3 solution (158 g in 1 L H2O) and 2 mL NH3 (28 % in H2O) are replenished to 1 L with H2O.

The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a JASCO SFC-system with the following colums: Chiralcel OJ (250 x 20 mm, 5 pm), Chiralpak AD (250 x 20 mm, 5 pm), Chiralpak AS (250 x 20 mm, 5 pm), Chiralpak IC (250 x 20 mm, 5 pm), Chiralpak IA (250 x 20 mm, 5 pm), Chiralcel OJ (250 x 20 mm, 5 pm), Chiralcel OD (250 x 20 mm, 5 pm), Phenomenex Lux C2 (250 x 20 mm, 5 pm).

The analytical HPLC (reaction control) of intermediate and final compounds is carried out using columns made by Waters (names: XBridge™ C18, 2.5 pm, 2.1 x 20 mm or XBridge™ C18, 2.5 pm, 2.1 x 30 mm or Aquity UPLC BEH C18, 1.7 pm, 2.1 x 50mm) and YMC (names: Triart C18, 3.0 pm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 pm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case.

HPLC-mass spectroscopy/UV-spectrometry

The retention times/MS-ESI ⁺ for characterizing the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time tRet. = 0.00.

Method A

HPLC Agilent 1100 system

MS 1200Series LC/MSD(API-ES+/-3000V, Quadrupol, G6140)

MSD signal settings Scan pos/neg 120 - 900m/z

Detection signal 315 nm (bandwidth 170nm, reference off) Spectrum range 230 - 400 nm

Peak width <0.01 min

Column Waters, Xbridge C18, 2.5 pm, 2.1x20 mm column

Column temperature 60°C

Solvent A: 20mM NH4HCO3/ NH ₃ in H ₂ O pH 9

B: ACN HPLC grade

Flow 1.00 mL/min

Gradient 0.00 - 1.50 min 10 % to 95 % B

1.50 - 2.00 min 95 % B

2.00 - 2.10 min 95 % to 10 % B

Method B

HPLC Agilent 1260 system

MS 1200 Series LC/MSD (MM-ES+APCI +/- 3000 V, Quadrupol, G6130)

Detection UV: 254 nm (bandwidth 8, reference off)

UV: 230 nm (bandwidth 8, reference off)

UV spectrum range: 190 - 400 nm; step: 4 nm

MS: positive and negative mode

Mass range 100 - 800 m/z

Column Waters; Part. No. 186003389; XBridge BEH C18, 2,5 pm, 30 x 2.1 mm

Column temperature 45 °C

Solvent A: 5 mM NH ₄ HCO ₃ /19 mM NH ₃ in H ₂ O; B: ACN (HPLC grade)

Flow 1.40 mL/min

Gradient 0.00 - 1.00 min: 5 % B to 100 % B

1.00 - 1.37 min: 100 % B

1.37 - 1.40 min: 100 % B to 5 % B

Method C

HPLC Agilent 1260 Series

MS Agilent LC/MSD Quadrupole

Detection MS: positive and negative mode

Mass range 100 - 750 m/z

Column Waters X-Bridge BEH C18, 2.5 pm, 2.1 x 30 mm XP Column temperature 45 °C

Solvent A: 20 mM NH ₄ HCO ₃ /30 mM NH ₃ in H ₂ O; B: ACN (HPLC grade)

Flow 1.40 mL/min

Gradient 0.00 - 1.00 min: 15% B to 95% B

1.00 - 1.30 min: 95 % B

Method D

HPLC Agilent 1100/1200 system

MS 1200 Series LC/MSD (MM-ES + APCI +/- 3000 V, Quadrupol,

G6130B)

MSD signal settings Scan pos 150 - 750

Detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off)

Spectrum range: 190 - 400 nm; slit: 4 nm

Peak width > 0.0031 min (0.063 s response time, 80Hz)

Column Waters, Part.No. 186003389, XBridge BEH C18, 2.5 pm, 2.1 x 30 mm) column

Column temperature 45 °C

Solvent A: 5 mM NH ₄ HCO ₃ /18 mM NH ₃ in H2O (pH = 9.2)

B: ACN (HPLC grade)

Flow 1.4 mL/min

Gradient 0.0 - 1.0 min 15 % to 95 % B

1.0 - 1.1 min 95 % B

Stop time: 1.3 min

Method E

HPLC Agilent 1100/1200 system

MS 1200 Series LC/MSD (MM-ES + APCI +/- 3000 V, Quadrupol,

G6130B)

MSD signal settings Scan pos/neg 150 - 750

Detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off)

Spectrum range: 190 - 400 nm; slit: 4 nm

Peak width > 0.0031 min (0.063 s response time, 80Hz)

Column Waters, Part.No. 186003389, XBridge BEH C18, 2.5 pm, 2.1 x 30 mm) column

Column temperature 45 °C

Solvent A: 5 mM NH ₄ HCO ₃ /18 mM NH ₃ in H2O (pH = 9.2) B: ACN (HPLC grade)

Flow 1.4 mL/min

Gradient 0.0 - 1.0 min 15 % to 95 % B

1.0 - 1.1 min 95 % B

Stop time: 1.3 min

Method F

HPLC Agilent 1100/1200 system

MS 1200 Series LC/MSD (API-ES +/- 3000/3500 V, Quadrupol,

G6140A)

MSD signal settings Scan pos/neg 150 - 750

Detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 10, reference off)

Spectrum range: 190 - 400 nm; slit: 4 nm

Peak width > 0.0031 min (0.063 s response time, 80Hz)

Column YMC; Part. No. TA12S03-0302WT; Triart C18, 3 pm, 12 nm; 30 x 2.0 mm column

Column temperature 45 °C

Solvent A: H2O + 0, 11 % formic acid

B: ACN + 0,1% formic acid (HPLC grade)

Flow 1.4 mL/min

Gradient 0.0 - 1.0 min 15 % to 95 % B

1.0 - 1.1 min 95 % B

Stop time: 1.23 min

Method G

UPLC-MS Waters Acquity-UPLC-SQ Detector-2

MSD signal settings Scan pos & Neg 100 - 1500,

Source Voltage: Capillary Vol(kV)- 3.50, Cone(V): 50

Source Temp: Desolvation Temp(°C): 350

Source Gas Flow: Desolvation (L/Hr): 750, Cone(L/Hr): 50

Detection signal Diode Array

Spectrum Range: 200 - 400 nm; Resolution: 1.2nm

Sampling rate 10 point/sec

Column AQUITY UPLC BEH C18 1.7pm, 2.1X50mm

Column temperature 35 °C

Solvent A: 0.07% formic acid in ACN B: 0.07% formic acid in water

Flow 0.6 mL/min

Gradient 0.0 - 0.30 min 97% B

0.30 - 2.20 min 97 % to 2 % B

2.20 - 3.30 min 2 % B

3.30 - 4.50 min 2 % to 97 % B

4.50 - 4.51 min 97 % B

Method H

UPLC-MS Waters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2

MSD signal settings Scan pos & Neg 100 - 1500,

Source Voltage: Capillary Vol(kV)- 3.50, Cone(V): 50

Source Temp: Desolvation Temp(°C): 350

Source Gas Flow: Desolvation (L/Hr): 750, Cone(L/Hr): 50

Detection signal Diode Array

Spectrum Range: 200 - 400 nm; Resolution: 1.2nm

Sampling rate 10 point/sec

Column AQUITY UPLC BEH C18 1.7pm, 2.1X50mm

Column temperature 35 °C

Solvent A: 0.07% formic acid in ACN

B: 0.07% formic acid in water

Flow 0.6 mL/min

Gradient 0.0 - 0.40 min 97% B

0.40 - 2.50 min 97 % to 2 % B

2.50 - 3.40 min 2 % B

3.40 - 3.50 min 2 % to 97 % B

3.50 - 4.0 min 97 % B

Method I

LC-MS Waters Arc-HPLC-SQ Detector-2

MSD signal settings ESI Scan pos & neg

Capillary Voltage 3.50 Kv cone voltage 30V Desolvation gas

750L/hr Desolvation Temp 350°c

Column X-Bridge C18, 4.6x 75mm, 3.5p

Column temperature 35 °C Solvent A: 10mM Ammonium Acetate in water

B: ACN

Flow 1.0 mL/min

Gradient 0.0 - 0.75 min 5% B

0.75 - 1.50 min 5 % to 40 % B

1.50 - 5.0 min 40 % to 98 % B

5.0 - 7.0 min 98 % B

Method J

LC-MS Waters Acquity-UPLC-SQ Detector-2

MSD signal settings ESI Scan pos & neg

Capillary Voltage 3.50 Kv cone voltage 50V Desolvation gas

750L/h Desolvation Temp 350°C

Column Waters Acquity-UPLC-SQ Detector-2

Column temperature 35 °C

Solvent A: 0.05% TFA in ACN

B: 0.05% TFA in water

Flow 0.6 mL/min

Gradient 0.0 - 0.3 min 97% B

0.3 - 2.2 min 97 % to 2 % B

2.2 - 3.3 min 2 % B

Method K

LC-MS Waters Arc-HPLC-SQ Detector-2

MSD signal settings ESI Scan pos & neg

Capillary Voltage 3.50 Kv cone voltage 30V Desolvation gas

750L/hr Desolvation Temp 350°C

Column X-Bridge C18, 4.6x 50mm, 3.5p

Column temperature 35 °C

Solvent A: 10mM Ammonium Acetate in water

B: ACN

Flow 2.0 mL/min

Gradient 0.0 - 0.2 min 10% B

0.2 - 2.50 min 10 % to 75 % B 2.50 - 3.0 min 75 % to 100 % B

3.0 - 4.8 min 100 % B

Method L

HPLC Agilent 1260 Series

MS Agilent LC/MSD Quadrupole

Detection MS: positive and negative mode

Mass range 550 - 1200 m/z

Column Waters X-Bridge BEH C18, 2.5 pm, 2.1 x 30 mm XP

Column temperature 45 °C

Solvent A: 20 mM NH ₄ HCQ ₃ /30 mM NH ₃ in H ₂ O; B: ACN (HPLC grade)

Flow 1.40 mL/min

Gradient 0.00 - 1.50 min: 50% B to 95% B

1.50 - 2.00 min: 95 % B

Method M

HPLC Agilent 1260 Series

MS Agilent LC/MSD Quadrupole

Detection MS: positive and negative mode

Mass range 550 - 1200 m/z

Column Waters X-Bridge BEH C18, 2.5 pm, 2.1 x 30 mm XP

Column temperature 45 °C

Solvent A: 20 mM NH ₄ HCQ ₃ /30 mM NH ₃ in H ₂ O; B: ACN (HPLC grade)

Flow 1.40 mL/min

Gradient 0.00 - 1.00 min: 50% B to 95% B

1.00 - 1.30 min: 95 % B

Method N

HPLC Agilent 1260 Series

MS Agilent LC/MSD Quadrupole

Detection MS: positive and negative mode

Mass range 100 - 750 m/z

Column YMC-Triart C18, 3pm, 12nm, 2.0x30mm

Column temperature: 45 °C

Solvent A: H ₂ Q+0,11% formic acid; B: ACN (HPLC grade)+0,1 % formic acid

Flow: 1.40 mL/min

Gradient: 0.00 - 1.00 min: 15% B to 95% B

1.00- 1.30 min: 95 % B

Method O

HPLC Waters - Alliance 2996

Detection signal PDA Detector

Spectrum Range: 200 - 400 nm; Resolution: 1.2nm

Sampling rate 1 point/sec

ELSD Parameters Gas Pressure:50 PSI, Drift tube Temp: 50°C, Gain:500

Column Atlantis T3 (4.6 x 250mm) 5.0pm

Column temperature Ambient

Solvent A O mM ammonium acetate in water

B: ACN

Flow 0.7 mL/min

Gradient 0.0 - 1.20 min 2% B

1.2 - 10.0 min 2% to 98 % B

10.0 - 12.0 min 98% B

12.0 - 14.0 min 97% to 2 % B

14.0 - 16.0 min 2 % B

Method P

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(°C): 350

Source Gas Flow: Desolvation (L/Hr): 650

Detection signal Diode Array

Spectrum Range: 200 - 400 nm; Resolution: 1.2nm

Sampling rate 10 point/sec

ELSD Parameters: GAS:2.0 SLM, Nebulizer Temp:40°C, Evaporative Temp:45°C

Column AQUITY UPLC BEH C18 1.7pm, 2.1X50mm

Column temperature 50 °C

Solvent A: 0.05% formic acid in water B: 0.05% formic acid in ACN

Flow 0.6 mL/min

Gradient 0.0 - 2.20 min 3% to 98% B

2.20 - 3.20 min 98% B

3.20 - 3.50 min 98% to 3% B

3.50 - 4.20 min 2% B

Method Q

HPLC-MS Waters Arc-HPLC with 2998PDA Detector and SQ Detector-2

MSD signal settings Scan Pos & Neg 100 - 1500,

Source Votage: Capillary Vol(kV)- 3.50, Cone(V): 30

Source Temp: Desolvation Temp(°C): 350

Source Gas Flow: Desolvation (L/h): 750

Detection signal PDA Detector

Spectrum Range: 200 - 400 nm; Resolution: 1.2nm

Sampling rate 10 point/sec

Column X-Bridge C18, 4.6x 50mm, 3.5pm

Column temperature 35 °C

Solvent A O mM ammonium acetate in water

B: ACN

Flow 1.0 mL/min

Gradient 0.0 - 0.75 min 5% B

0.75 - 1.50 min 5 % to 40 % B

1.50 - 5.0 min 40 % to 98 % B

5.0 - 7.0 min 98 % B

7.0 - 9.0 min 98 % to 5% B

9.0 - 10.01 min 5% B

Method R

HPLC Agilent 1200 system

Column Chiralpak IE, 5.0 pm, 2.1x150 mm column

Column temperature 40°C

Solvent EtOH/Heptane 1:1 + 0.1% diethylamine (isocratic)

Flow 0.60 mL/min GCMS

Method U

GC Agilent Technologies-7890B GC System with 7693

Auto Sampler and 5977A MSD

Injection Temperature 230°C

Column Flow 2.0 mL/min

Solvent delay 1.5 min

Split Ratio 10:01

Column Oven Temperature Program 100°C/1 min, 20°C/min/310 5min

Total run time 16 min

Interface Temperature 150°C

Ion Source Temperature 230°C

Gas He

Column & Column dimension ZB-5MS (30m X 0.32mm; 1 pm)

MSD Scan Range 50-900

Method V

GC Agilent Technologies-7890B GC System with 7693

Auto Sampler and 5977A MSD

Injection Temperature 230°C

Column Flow 2.0 mL/min

Solvent delay 1.5 min

Split Ratio 10:01

Column Oven Temperature Program 40°C/2 min, 15°C /min/200°/1 min,

25°C/min/310 0min,

Total run time 18min

Interface Temperature 150°C

Ion Source Temperature 230°C

Gas He

Column & Column dimension ZB-5MS (30m X 0.32mm; 1 pm)

MSD Scan Range 50-900

Method l/V

GC Agilent Technologies-7890B GC System with 7693

Auto Sampler and 5977A MSD

Injection Temperature 230°C Column Flow 2.0 mL/min

Solvent delay 1.5 min

Split Ratio 10:01

Column Oven Temperature Program 60°C/3 min, 20°C/min/31072min

Total run time 18 min

Interface Temperature 150°C

Ion Source Temperature 230°C

Gas He

Column & Column dimension ZB-5MS (30m X 0.32mm; 1 pm)

Method SFC-1

Make Waters UPC ² -MS

Soft Empowers

MS QDa

Column CHIRALCEL OX-3(4.6*150MM) 3pm

A-Solvent CO2

B-solvent ACN

Total Flow 3g/min

% of Co-Solvent 15

ABPR 1500psi

Colum temp 30°C

PDA range 200nm to 400nm

Resolution 1.2nm

MS Parameters

QDa MS scan range 100Da to 1000Da

Cone voltage

Positive scan 20V

Negative Scan 15V

The compounds according to the invention and intermediates are prepared by the methods of synthesis described hereinafter in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis. If a chemical structure in the following is depicted without exact configuration of a stereo center, e.g. of an asymmetrically substituted carbon atom, then both configurations shall be deemed to be included and disclosed in such a representation. The representation of a stereo center in racemic form shall always deem to include and disclose both enantiomers (if no other defined stereo center(s) exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined, stereo centers exist).

Synthesis of spiroketone intermediates A

Experimental procedure for the synthesis of A-2a

A-1a A-2a

To a suspension of 5-chloropentanenitrile (22.9 g, 195 mmol, 1.00 equiv.) in EtOH (136 mL) is added acetyl chloride (111 mL, 1.56 mol, 8.00 equiv.) dropwise at 0 °C. The reaction mixture is allowed to warm to rt and stirred for 12 h. The mixture is concentrated under reduced pressure and washed with Et20 and the crude product A-2a is used as the HCI salt directly in the next step without further purification (HPLC method: A; t _re t = 1 03 min; [M+H] ⁺ = 164).

Experimental procedure for the synthesis of A-3a

Crude A-2a (HCI salt) (28.0 g, 140 mmol, 1.00 equiv.) and ethylene glycol (7.38 g, 119 mmol, 0.90 equiv.) are dissolved in DCM (300 mL) and stirred at rt for 6 d. The resulting suspension is concentrated under reduced pressure, diluted with Et20 (200 mL) and filtered. The filtrate is concentrated under reduced pressure, taken up in DCM (200 mL) and treated with a KOH solution (2 M in water, 150 mL). The mixture is stirred at rt overnight keeping the phases intact. The phases are separated, the water phase is extracted with DCM (2x) and the combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude orthoester A-3a is used for the next step without further purification. (HPLC method: A; t _ret = 1.37 min; [M+H] ⁺ = 163). Experimental procedure for the synthesis of A-5a

To the stirred solution of tetrahydro-thiopyran-4-one (20.0 g, 0.172 mol, 1.0 equiv.) in n-hexane (240 mL) a solution of sodium iodide (31.0 g, 0.207 mol. 1.2 equiv.) in ACN (160 mL) is added under nitrogen atmosphere. Triethylamine (28.8 mL, 0.207 mol, 1.2 equiv.) is then added dropwise and cooled to 0°C. Chloro-trimethyl-silane (21.7 mL, 0.189 mol, 1.1 equiv.) is then added dropwise and the mixture is stirred for 3 d at rt until TLC shows complete conversion.

The reaction mixture is filtered through Celite and washed with hexane (200 mL). From the two layers formed, the hexane layer is taken, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by NP chromatography to provide A-5a.

The following intermediates A-5 (Table 1) are available in an analogous manner using different ketones A4. The crude product A-5 is purified by chromatography if necessary.

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

The following intermediates A-6 (Table 2) are available in an analogous manner from A-3a and suitable intermediates A-5. The crude product is purified by chromatography if necessary.

Table 2

Experimental procedure for the synthesis of A-8a

A-6a (14.9 g, 57.1 mmol, 1.0 equiv.) and sodium iodide (26.0 g, 171 mmol, 3.0 equiv.) are dissolved in acetone (120 mL) and stirred under reflux for 16 h. The reaction mixture is concentrated under reduced pressure, diluted with DCM and washed with a saturated sodium thiosulfate solution. The organic phase is separated, dried over MgSC , filtered and concentrated under reduced pressure. The crude product A-7a is used for the next step without further purification.

A-7a (30 g, 85.0 mmol, 1.0 equiv.) is dissolved in THF. The mixture is treated with potassium tert.-butoxide (28.7 g, 256 mmol, 3.0 equiv.) at 0°C and stirred at rt overnight. The reaction mixture is quenched by addition of water (2 mL), diluted by addition of Et20 and a saturated sodium hydrogencarbonate solution. The organic phase is separated, dried over MgSC , filtered and concentrated under reduced pressure. The crude product is purified by NP chromatography to give (racemic) compound A-8a (The reaction sequence A-1a A-8a is based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., Eur. J. Org. Chem. 2004, 79:3962-3967).

The desired enantiomer A-8b can then be obtained after chiral separation via SFC using the following conditions: Column: Lux;Cellulose-4 (250mmX30mmX5pm), 90% CO2, 10% ACN, Flow: 90g/min, Temp: 30°C, desired enantiomer A-8b (SFC-method: SFC-1 , t _re t=2.99min) as peak 2 after the undesired enantiomer has eluted.

The following intermediates A-8 (Table 3) are available in an analogous manner via intermediates A-7 using different ketones A-6. The crude product is purified by chromatography if necessary.

Table 3

Experimental procedure for the synthesis of A-10a

A-9a A-10a

To a stirred solution of 4-bromo-3,6-dihydro-2H-pyran (10.0 g, 0.061 mol, 1.0 equiv.) in THF (150mL) under argon, n-Butyllithium solution (2.5 M in hexanes, 49.1 mL, 0.123 mol, 2.0 equiv.) is slowly added at -78 °C over a period of 10 min. The mixture is stirred at -78 °C for 0.5 h. cyclopentanone (5.16 g, 0.061 mol, 1.0 equiv.) in dry THF (40 mL) is then added and the mixture is stirred at -78 °C for 0.5 h. The mixture is allowed to warm to rt. Water (100 mL) is added to quench the reaction and the aqueous layer is extracted with DCM. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue is then purified by flash chromatography on neutral alumina to yield A-10a.

Experimental procedure for the synthesis of A-11a

A-10a A-11a To a stirred solution of A-10a (5.00 g, 0.030 mol, 1.0 equiv.) in benzene (100 mL) under Ar, vanadyl acetylacetonate (0.788 g, 0.003 mol, 0.1 equiv.) is slowly added at 0 °C followed by dropwise addition of t-BuOOH (10.7 g, 0.036 mol, 1.2 equiv.). Benzene (100 mL) is added and the mixture is stirred at 0 °C for 2 h. The mixture is allowed to warm up to rt. Aq. saturated NaHCCh (2x100 ml) solution is added followed by extraction with EtOAc and the organic layers are dried, filtered, and concentrated. The crude product is purified via NP chromatography to yield A-11a.

To a stirred solution of A-11a (4.00 g, 0.022 mol, 1.0 equiv.) in dry DCM (400 mL) under argon at -78 °C, a solution of BFs.OEt2 (2.68 mL, 0.022 mol, 1.0 equiv.) diluted with DCM (20 mL) is added dropwise, then mixture is stirred at -78 °C for 3 h until TLC shows complete conversion. The mixture is then concentrated and the crude mixture is purified via NP chromatography to provide A-12a (HPLC method: H; t _re t = 1.21 min; [M+H] ⁺ = 185).

A-12a A-13a

To a stirred solution of A-12a (3.10 g, 0.017 mol, 1.0 equiv.) in benzene (62 mL) at rt, p-TsOH (960 mg, 0.005 mol, 0.3equiv.) and ethane-1 ,2-diol (9.49 mL, 0.17 mol, 10.0 equiv.) are added and the mixture is stirred for 10 min at RT, then the reaction is heated to 80-90°C with use of dean stark setup and stirred for 20 h until TLC shows complete conversion. The reaction mixture is cooled to rt, quenched with aq. 5% NaHCCh (60mL), and extracted with EtOAc. The organic layer is separated, dried, concentrated under reduced pressure, and the crude mixture is purified via NP chromatography to provide A-13a (HPLC method: H; t _re t = 1 .47 min; [M+H] ⁺ = 229). Experimental procedure for the synthesis of A-14a

A-13a A-14a

To a stirred solution of A-13a (1.35 g, 0.006 mol, 1.0 equiv.) in dry DCM (54 mL) at 0 °C, Dess- Martin periodinane (2.76 g, 0.007 mol, 1.1 equiv.) is added and the mixture is stirred rt for 1 h until TLC shows complete conversion. The reaction mixture is quenched with 5% NaHCCh (20mL) and washed with water, the organic layer is dried, concentrated under reduced pressure, and the crude mixture is purified via NP chromatography to provide A-14a (HPLC method: C; t _re t = 0.426 min; [M+H] ⁺ = 227).

Synthesis of alcohol-and amine-intermediates B

Experimental procedure for the synthesis of B-2 (method I)

B-1a (4.92 g, 19.1 mmol, 1.00 equiv.), N,N-Carbonyldiimidazole (5.14 g, 28.6 mmol, 1.50 equiv.) and mol. sieves (3A, 500 mg) is dissolved in DCM (29.5 mL) and stirred for 40 min at rt. After complete activation, N,O-dimethylhydroxylamine hydrochloride (2.79 g, 28.6 mmol, 1.50 equiv.) is added and the reaction is stirred again for 2 h at rt. After reaction completion is observed, water (100 mL) and DCM (150 mL) are added and the phases are separated, the water phase is extracted with DCM (2x). The combined organic phases are washed with brine and concentrated under reduced pressure. The residue is purified by NP chromatography to give the product B-2a.

The following intermediates B-2 (Table 4) are available in an analogous manner using different acids. The crude product is purified by chromatography if necessary. Table 4

Experimental procedure for the synthesis of B-2d (method II)

B-1d B-2d To a stirred solution of (S)-2-methyl-pyrrolidine-1 ,2-dicarboxylic acid 1 -tert-butyl ester (10.0 g, 43.6 mmol, 1.0 equiv.) in DCM (100 mL) is added DIPEA (47.7 mL, 261.7 mmol, 6.0 equiv.) and N,O-dimethyl hydroxylamine hydrochloride (10.2 g, 104 mmol, 2.4 equiv.) at 0°C. then T3P (109. mL, 1.6 mol/L, 174 mmol, 4.0 equiv.) is added at the same temperature dropwise. The resulting mixture is stirred for 2 d at reflux temperature. After complete conversion, the reaction mixture is diluted with water and extracted with DCM. The organic layer is dried and concentrated under reduced pressure. The crude compound is purified by NP chromatography to yield B-2d (HPLC method: G; t _ret = 2.07 min; [M+H] ⁺ = 273). Experimental procedure for the synthesis of B-3a

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

The following intermediates B-3 (Table 5) are available in an analogous manner from the corresponding starting materials B-2. The crude product is purified by chromatography if necessary.

Table 5 Experimental procedure for the synthesis of B-4 (method I)

B-3a B-4a

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

The following intermediates B-4 (Table 6) are available in an analogous manner from the corresponding starting materials B-3. The crude product is purified by chromatography if necessary. Table 6 Experimental procedure for the synthesis of B-4 (method II)

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

The following intermediates B-4 (Table 7) are available in an analogous manner from the corresponding starting materials B-3. The crude product is purified by chromatography if necessary.

Table 7

Experimental procedure for the synthesis of B-5a

B-4a B-5a B-4a (306 mg, 12.5 mmol, 1.00 equiv.) is dissolved in THF, (30.6 mL) under argon atmosphere. Lithium aluminium hydride (1 M in THF, 24.9 mL, 25.0 mmol, 2.00 equiv.) is added slowly. Reaction is stirred at 60 °C for 1 h. After complete conversion, the reaction is cooled to rt, Rochelle salt solution and KOH is added and stirred for 1 h. The existing suspension is extracted with DCM (3x), the combined organic phases are concentrated under reduced pressure to yield B-5a.

The following intermediates B-5 (Table 8) are available in an analogous manner from the corresponding starting materials B-4. The crude product is purified by chromatography if necessary.

Table 8 for the

B-6a B-7a B-8a

1 ,7-Dichloro-heptan-4-one (6.00 g, 32.8 mmol, 1.0 equiv.) and 2-amino-2-methyl-propionitrile (8.27 g, 98.3 mmol, 3.0equiv.) are added to ammonia (7 M in MeOH, 46.8 mL, 328 mmol, 10.0 equiv.) at 0°C and the mixture is allowed to reach rt and stirred for 24 h. After complete conversion, the reaction mixture is concentrated under reduced pressure, and the crude product is purified via NP chromatography yielding B-8a (HPLC method: H; t _re t = 0.23min; [M+H] ⁺ = 137). Experimental procedure for the synthesis of B-9a

B-8a B-9a

To a stirred solution of B-8a (300 mg, 2.21 mmol, 1.0 equiv.) in dry THF (5.0 mL), at -78°C, methyllithium (1.6 M in diethyl ether, 4.13 mL, 6.61 mmol, 3.0 equiv.) is added and stirred for 2 h at -78°C. After complete conversion, the reaction mixture is quenched with aq. saturated NH4CI solution and extracted with EtOAc. The organic layer is dried, filtered and concentrated under reduced pressure. The crude product is purified via NP chromatography yielding B-9a (HPLC method: H; t _ret = 0.28min; [M+H] ⁺ = 154).

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

Experimental procedure for the synthesis of B-10a

B-9a B-10a

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

Experimental procedure for the synthesis of B-12a

HCI N-(tert-butoxycarbonyl)-L-prolinal (3.60 g, 18.1 mmol, 1.0 equiv.) is dissolved in DCM (150 mL), and N-Benzylhydroxylamine hydrochloride (2.88 g, 18.1 mmol, 1.0 equiv.) and MgSO4 (2.17 g, 18.1 mmol, 1.0 equiv.) is added. The mixture is cooled to 0°C, and triethylamine (2.52 mL, 18.1 mmol, 1.0 equiv.) is added dropwise. The mixture is stirred for 18 h at rt. When complete, the reaction mixture is concentrated under reduced pressure and purified by NP chromatography yielding B-12a (HPLC method: C; t _re t = 0.49min; [M+H] ⁺ = 305).

Experimental procedure for the synthesis of B-13a

B-12a B-13a

B-12a (4.94 g, 16.2 mmol, 1.0 equiv.) is dissolved in dry THF (80 mL) and cooled to -60°C. Then Methylmagnesium bromide (3 M, 11.0 mL, 32.5 mml, 2.0 equiv.) is added dropwise. The reaction mixture is stirred for 5 h at -60°C. After complete conversion of starting material is observed the mixture is quenched with saturated NH4CI solution and extracted with DCM/Water. The combined organic phases are concentrated under reduced pressure and purified by NP chromatography yielding B-13a (HPLC method: C; t _re t = 0.84min; [M+H] ⁺ = 321).

Experimental procedure for the synthesis of B-14a

B-13a B-14a

To a stirred solution of B-13a (11.5 g, 35.9 mmol, 1.0 equiv.) in methanol (230 mL) and DCM (230 mL), at rt is added palladium hydroxide (20% on carbon, 4.20 g) and the mixture is stirred under hydrogen atmosphere for 7-8 h. After complete conversion, the reaction mixture is filtered through a Celite pad and the filtrate is concentrated under reduced pressure. The crude compound is purified by NP chromatography yielding B-14a (HPLC method: G; t _re t = 1.43min; [M+H] ⁺ = 215).

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

Experimental procedure for the synthesis of B-16a

B-15a B-16a

To a stirred solution of B-15a (1.10 g, 2.75 mmol, 1.00 equiv.) in DCM (8 ml) at rt is added HCI solution (4 M in dioxane, 2.75 ml, 11.0 mmol, 4.00 equiv.) is added. After 16 h, the reaction mixture is concentrated under reduced pressure to yield B-16a, which is directly used in the next step without purification.

Experimental procedure for the synthesis of B-17a

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

Experimental procedure for the synthesis of B-18a

B-17a B-18a

To a stirred solution of B-17a (3.0 g, 8.39 mmol, 1.0 equiv.) in DCM (83 mL), at 0°C triphenyl phosphine (3.30 g, 12.6 mmol 1.50 equiv.) and diisopropylazodicarboxylate (2.44 mL, 12.6 mmol, 1.50 equiv.) are added. The reaction mixture is stirred at rt for 4-5 h. After complete conversion, the reaction mixture is diluted with DCM (150 mL), washed with water and brine and dried, filtered, and concentrated. The crude compound is purified by NP chromatography yielding B-18a (HPLC method: G; t _re t = 1.47min; [M+H] ⁺ = 340).

Experimental procedure for the synthesis of B-19a

To a stirred solution of B-18a (900 mg, 2.65 mmol, 1.0 equiv.) in ACN (13.5 mL) at rt potassium hydroxide (0.45 g, 7.95 mmol, 3.0 equiv.) is added and stirred for 10 min. Thiophenol (0.73 g, 6.63 mmol, 2.50 equiv.) is then added and the reaction mixture is heated at 65°C for 2 h. After complete conversion, the reaction mixture is cooled to rt and solid is removed by filtration. The filtrate is concentrated, and the residue is triturated with n-pentane. The remaining solid is discarded and the n-pentane fractions are concentrated to obtain crude compound. The crude compound is dissolved in DCM (4.5 mL) and HCI (4 M in dioxane, 0.36 mL, 10.7 mmol, 4.0 equiv.) is added at 0°C and the reaction mixture is stirred at rt for 1-2 h. The reaction mixture is concentrated under reduced pressure, then the crude compound is triturated with diethyl ether and dried, to obtain desired product B-19a (HPLC method: O; t _re t = 2.31 min; [M+H] ⁺ = 155).

Experimental procedure for the synthesis of B-21a

(1 R,2R)-1 ,2-bis(2-hydroxyphenyl)ethylenediamine (408 mg, 1.59 mmol, 1.0 equiv.) is dissolved in toluene (5 mL), then acetaldehyde (232 pL, 4.11 mmol, 2.59 equiv.) is added and the mixture is stirred under nitrogen atmosphere for 18 h at r and further 20 h at 115°C. After full conversion, the reaction mixture is concentrated under reduced pressure and purified by RP chromatography yielding B-21a (HPLC method: A; t _re t = 1.46 min; [M+H] ⁺ = 297).

Experimental procedure for the synthesis of B-23a

B-21a B-22a B-23a

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

Experimental procedure for the synthesis of B-24a

B-23a B-24a

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

Experimental procedure for the synthesis of B-25a

B-24a B-25a

B-24a (122 mg, 0.22 mmol, 1 .0 equiv.) is dissolved in acetic acid (4 mL) and hydrobromic acid (33%, 130 pL, 0.74 mmol, 3.32 equiv.) is added. The reaction mixture is stirred under a nitrogen atmosphere at 115 °C overnight. After complete conversion, the reaction mixture is extracted with toluene/water. The water phase is freeze dried to obtain pure compound B-25a (HPLC method: C; t _ret = 0.08min; [M+H] ⁺ = 129). Synthesis of pyrimidine derivatives C

Experimental procedure for the synthesis of C-2a

C-1a C-2a

To a stirred solution of 2,4-dichloro-1 ,3,5-triazine (9.00 g, 60 mmol, 1.0 equiv.) in ACN (100 mL), (S)-3-methyl-1 ,4-diazepane-1 -carboxylic acid tert, butyl ester (10.9 g, 0.51 mmol, 0.85 equiv.) and DI PEA (11.6 g, 90 mmol, 1.5 equiv.) are added at 0°C and the mixture is allowed to reach rt and stirred for 2 h. After complete conversion, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic phases are washed with water, dried, filtered, concentrated under reduced pressure, and the crude product is purified by NP chromatography yielding C-2a (HPLC method: G; t _re t = 2.23min; [M+H] ⁺ = 328).

Experimental procedure for the synthesis of C-4a

C-3a C-4a

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

Experimental procedure for the synthesis of D-2a

D-1a D-2a

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

The following intermediates D-2 (Table 9) are available in an analogous manner from the corresponding aryl-chlorides and a suitable alcohol or amine as the nucleophile. The crude product is purified by chromatography if necessary.

Table 9 Experimental procedure for the synthesis of D-3a

D-3a

D-2a (5.00 g, 18.1 mmol, 1.0 equiv.) is dissolved in THF (100 mL) and NaOH (1 M in water, 27.1 mL, 27.1 mmol, 1.50 equiv.) is added. The resulting mixture is stirred at rt for 1 h. After complete conversion, the solvent is removed under under reduced pressure and the crude product is purified by RP chromatography yielding D-3a.

The following intermediates D-3 (Table 10) are available in an analogous manner. The crude product is purified by chromatography if necessary.

Table 10

Experimental procedure for the synthesis of D-4a

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

Synthesis of diketones E

Experimental procedure for the synthesis of E-1a

A-8b (5.08 g, 28.3 mmol, 1.01 equiv.) and magnesium bromide diethyl etherate (8.01 g, 30.7 mmol, 1.6 equiv.) are dissolved in dry DCM (50 mL) and stirred for 5 min at rt. DIPEA (7.5 mL, 0.04 mol, 1.53 equiv.) is added and after 5 min D-1a (6.62 g, 28.1 mmol, 1 equiv.) is added. The reaction is stirred for 16 h at rt. After complete conversion of starting material is observed, 1 M HCI is added and the mixture stirred for 30 min. The mixture is extracted with DCM/ water, and the organic phase is concentrated under reduced pressure and purified by RP chromatography, yielding E-1a.

The following intermediates E-1 (Table 11) are available in an analogous manner. The crude products are purified by chromatography if necessary.

Table 11

Experimental procedure for the synthesis of E-2

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

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

Table 12

Experimental procedure for the conversion of D-3 to E-4 (method I)

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

Experimental procedure for the conversion of D-3 to E-4 (method II) - a - a D-3a (333 mg, 1.33 mmol, 1.0 equiv.) and 1 ,1'-carbonyldiimidazole (236 mg, 1.46 mmol, 1.1 equiv.) under argon are dissolved in dry THF (3 mL) and stirred 1h at rt. After complete activation of the acid, a solution of A-8a (297 mg, 1.33 mmol, 1.0 equiv.) and LiHMDS (1 M in THF, 3.97 mL, 3.98 mmol, 3.0 equiv.) is added to the reaction mixture. The resulting mixture is stirred for 3 d at rt. After full conversion, the reaction mixture is diluted with an aq. saturated

NaHCOs solution and extracted with DCM. The organic phase is combined, dried, filtered and concentrated under reduced pressure to give the crude product. The crude product is dissolved in ACN and water, filtered, and purified by basic RP chromatography to give the desired product E-4b. The following intermediates E-4 (Table 13) are available in an analogous manner from the corresponding acids D and ketones A. The crude product is purified by chromatography if necessary.

Table 13

Experimental procedure for the synthesis of E-5a

E-1b (184 mg, 0.50 mmol, 1.0 equiv.) is dissolved in dry DMSO (500 pL), (1S)-1-[(2S)-1- methylpyrrolidin-2-yl]ethanol (96.8 mg, 0.67 mmol, 1.43 equiv.) and DIPEA (176 pL, 1.01 mmol, 2.0 equiv.) is added and stirred for 18 h at 70°C. After complete conversion, the reaction mixture is filtered and purified by RP chromatography yielding E-5a (HPLC method: C; t _re t = 0.74/0.80min; [M+H] ⁺ = 458).

Synthesis of azole-intermediates F r the is of F-2a

E-1a (1.02 g, 2.78 mmol, 1.0 equiv.) is dissolved in pyridine (86 mL) and hydroxylamine hydrochloride (238 mg, 3.43 mmol, 1.23 equiv.) is added. The reaction is stirred overnight at rt. After complete conversion the mixture is acidified with 1 M HCI and extracted with DCM. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography, yielding F-1a.

F-1a (335 mg, 0.88 mmol, 1.0 equiv.) is dissolved in THF (4.0 mL) and aq. HCI (4 M, 4.0 ml, 16.0 mmol, 18.1 equiv.) and stirred for 2 d at rt. After complete conversion, the mixture is concentrated under reduced pressure. The precipitate is collected by filtration and dried under reduced pressure yielding F-2a (HPLC method: A; t _re t = 1.33/1.13min; [M+H] ⁺ = 318).

Experimental procedure for the synthesis of F-4a

E-1a (2.25 g, 6.15 mmol, 1.0 equiv.) is dissolved in dioxane (10 mL) and hydroxylamine solution (50% in water, 390 pL, 6.36 mmol, 1.03 equiv.) is added. The reaction is stirred overnight under a nitrogen atmosphere. After complete conversion, the reaction mixture is concentrated under reduced pressure. Crude compound is dissolved in EtOAc and DCM, filtered and purified by NP chromatography yielding F-3a. F-3a (453 mg, 1.19 mmol, 1.0 equiv.) is dissolved in dry DCM (5 mL) and DIPEA (483 pL, 2.77 mmol, 2.32 equiv.) and methanesulfonyl chloride (95 pL, 1.22 mmol, 1.02 equiv.) is added. The resulting solution is stirred at rt until complete conversion is observed. The reaction is evaporated and extracted with DCM and water. The organic solvent is evaporated and the resulting residue is purified by NP chromatography, yielding F-4a (HPLC method: A; t _ret = 1.60min; [M+H] ⁺ = 362).

Experimental procedure for the synthesis of F-6

E-4e (333 mg, 0.48 mmol, 1 equiv.) is dissolved in dioxane (3.0 mL) and hydroxylamine (50% in water, 32.0 pL, 0.52 mmol, 1.10 equiv.) and formic acid (17.9 pL 0.48 mmol, 1.0 equiv.) is added. The reaction is stirred for 18h at rt. After complete conversion, the reaction mixture is extracted with DCM/ NaHCCh, the combined organic phases are concentrated under reduced pressure yielding crude F-5a.

F-5a (273 mg, 0.47 mmol, 1.0 equiv.) is dissolved in dioxane (4.0 mL) and HCI (4M in dioxane, 474 pL, 1.90 mmol, 4.0 equiv.) is added. The reaction stirred 1 h at 80°C. Then water (2 mL) is added and stirred again at 80°C for 1h. After complete conversion, the reaction mixture is extracted with DCM I aq. saturated NaHCCh solution. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding F-6a.

The following intermediates F-6 (Table 14) are available in an analogous manner. The crude product is purified by chromatography if necessary.

Table 14

Experimental procedure for the synthesis of F-8a

E-4d (100 mg, 0.18 mmol, 1.0 equiv.) is dissolved in dioxane (0.5 mL), hydroxylamine (50% in water, 12.4 pL, 0.20 mmol, 1.10 equiv.) and formic acid (6.93 pL 0.18 mmol, 1.0 equiv.) is added. The reaction is stirred for 18 h at rt. After complete conversion if starting material is observed the reaction is extracted with DCM/ aq. saturated NaHCCh, the combined organic phases are concentrated under reduced pressure yielding crude F-7a.

F-7a (127 mg, 227 pmol, 1.0 equiv.) is dissolved in trifluoracetic acid (0.8 mL). The reaction stirred 18 h at 80°C. After complete conversion the mixture is extracted with DCM I aq. saturated NaHCCh. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding F-8a (HPLC method: A; t _re t = 1.19min; [M+H] ⁺ = 398).

Experimental procedure for the synthesis of F-11a and F-12a E-2b (361 mg, 0.79 mmol, 1.0 equiv.) and hydroxylamine hydrochloride (224 mg, 3.22 mmol, 4.08 equiv.) are dissolved in ethanol (2.5 ml) and stirred at rt overnight. After complete conversion, the solvent is evaporated. The reaction is basified with saturated aq. NaHCCh solution and extracted with EtOAc. The solvent of the combined organic layers is evaporated. The residue is purified via RP chromatography to give F-9a and F-10a.

The regiosiomers are dissolved in acetic anhydride (500 pL) and stirred for 3 d at 80°C. Water (125 pL) is then added and the mixture is stirred overnight at 80°C. After complete conversion the mixture is cooled down to rt and extracted with EtOAc and aq. saturated NaHCOs. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding F-11a and F-12a (Table 15).

Table 15

Experimental procedure for the synthesis of F-14a

E-4c (5.26 g, 8.76 mmol, 1.0 equiv.) and hydroxylamine hydrochloride (1.44 g, 20.7 mmol, 2.36 equiv.) are dissolved in pyridine (25 mL). The reaction is stirred for 4 h at 80°C. After complete conversion, water and DCM are added and the organic layer is separated, washed with aq. 1 M HCI, dried, filtered and concentrated. The crude product is purified via NP chromatography yielding F-13a.

F-13a (1.73 mg, 3.09 mmol, 1.0 equiv.) is dissolved in THF (26 mL) and aq. HCI (4 M, 19.3 mL, 77.3 mmol, 25 equiv.) is added. The mixture is stirred for 3 h at 60°C. After complete conversion, the mixture is extracted with DCM I saturated aq. NaHCCh. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding F-14a (HPLC method: A; t _ret = 1.28min; [M+H] ⁺ = 396).

Experimental procedure for the synthesis of F-16a

E-4a (2.50 g, 4.62 mmol, 1.0 equiv.) is dissolved in dioxane (25 mL) and hydroxylamine (50% in water, 3.66 g, 55.4 mmol, 12.0 equiv.) is added. The reaction is stirred for 16 h at 50°C. After complete conversion, the reaction mixture is concentrated under reduced pressure, water and DCM are added and the organic layer is separated, dried, filtered and concentrated. The crude product is purified via NP chromatography yielding F-15a which is dissolved in acetic acid (15 mL) and stirred for 16 h at rt. After complete conversion the reaction mixture is cooled to 0°C, saturated aq. NaHCCh solution and EtOAc is added and the organic layer is separated, dried, filtered, and concentrated. The crude product is purified via NP chromatography yielding F-16a (HPLC method: H; t _re t = 2.75min; [M+H] ⁺ = 539).

Experimental procedure for the synthesis of F-18a

F-17a F-18a E-2a (3.0 g, 5.52 mmol, 1 equiv.) is dissolved in dioxane (2 mL) and hydroxylamine solution (50% in water, 0.72 mL, 22.1 mmol, 4 equiv.) is added. The reaction is stirred overnight under nitrogen at 80°C. After complete conversion, the reaction mixture is concentrated under reduced pressure. Crude compound poured into cold water and extracted with DCM. The combined organic layers are washed with brine and dried and concentrated under reduced pressure yielding crude F-17a.

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

Experimental procedure for the synthesis of F-20

E-4g (941 mg, 1.63 mmol, I .O equiv.) is dissolved in dioxane (5.0 mL), hydroxylamine solution (50% in water 110 pL, 1.79 mmol, 1.1 equiv.) and formic acid (61.4 pL 1.63 mmol, 1.2 equiv.) are added. The reaction is stirred for 18 h at rt. After complete conversion, the reaction is extracted with DCM I aq. saturated NaHCCh solution, the combined organic phases are concentrated under reduced pressure yielding crude F-19a.

F-19a (965 mg, 1.63 mmol, 1.0 equiv.) is dissolved in dioxane (2.0 mL) and HCI (4 M in dioxane, 1.63 pL, 6.50 mmol, 4.0 equiv.) is added. The reaction is stirred 1 h at 80°C. Then water (2 mL) is added and stirring continued at 80°C for 1 h. After complete conversion, the reaction mixture is extracted with DCM I aq. saturated NaHCCh solution. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding F-20a.

The following intermediates F-20 (Table 16) are available in an analogous manner. The crude products are purified by chromatography if necessary. Table 16

Experimental procedure for the synthesis of F-23a To E-4b (119 mg, 0.26 mmol, 1.0 equiv.) hydrazine (1.0M in THF, 273 pL, 0.27 mmol, 1.05 equiv.) is added and the reaction is stirred for 14 h at rt, then for 8 h at 55°C. After complete conversion, acetic acid (1.0 mL) and water (1.0 mL) is added and the mixture is stirred again for 18 h at 40°C, then for 20 h at 75°C. After complete deprotection is observed, the reaction is basified with aq. saturated NaHCCh solution and extracted with DCM. The combined organic layers are concentrated under reduced pressure and purified by RP chromatography yielding F-23a (HPLC method: C; t _ret = 0-59min; [M+H] ⁺ = 410).

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

Experimental procedure for the synthesis of F-25a

F-4a (67.0 mg, 0.17 mmol, 1.0 equiv.) is dissolved in dry DMSO (600 pL), B-25a (99.7 mg, 0.34 mmol, 2.0 equiv.) and DIPEA (70 pL, 0.40 mmol, 2.38 equiv.) are added. The reaction is stirred for 19 h at 90°C. After complete conversion of starting material is observed, water and ACN are added and mixture is filtered and purified by RP chromatography yielding F-25a (HPLC method: C; t _ret = 0.86min; [M+H] ⁺ = 454).

Experimental procedure for the synthesis of F-27a

F-4a F-27a

F-4a (2.20 g, 6.09 mmol, 1.0 equiv.) is dissolved in THF (8 mL) and aq. HCI (2 M, 2.30 mL, 4.60 mmol, 0.76 equiv.) is added and stirred for 18 h at 70°C. After complete conversion, the reaction mixture is cooled to rt, the precipitated is collected by filtration, dissolved in DCM and washed with aq. saturated NaHCCh. The organic phase is concentrated under reduced pressure yielding F-27a (HPLC method: A; t _re t = 1.35min; [M+H] ⁺ = 318). Experimental procedure for the synthesis of F-28

F-18a F-28a

F-18a (300 mg, 0.52 mmol, I .Oequiv.) is dissolved in THF (2.0 mL), aq. HCI (4 M, 2.0 mL, 8.0 mmol, 15.31 equiv.) is added and the reaction is stirred for 18 h at 50°C. After complete conversion, the reaction mixture is concentrated under reduced pressure and purified by RP chromatography, yielding F-28a.

The following ketones F-28 (Table 17) are available in an analogous manner from the corresponding ketals. The crude product is purified by chromatography if necessary.

Table 17 Experimental procedure for the synthesis of F-29a

Sodium hydride (60% in mineral oil, 37.9 mg, 0.95 mmol, 3.5 equiv.) is dissolved in dry THF (1 mL) and F-24a (142 mg, 0.27 mmol, 1 equiv.) is added and the mixture stirred for 1 h under reflux, lodomethane (134 mg, 0.95 mmol, 3.5 equiv.) is added and stirred again for 1 h under reflux. After complete conversion, the reaction mixture is cooled to rt and extracted with DCM I water. The combined organic phases are dried, filtered, and concentrated under reduced pressure yielding F-29a (HPLC method: A; t _re t = 1.68min; [M+H] ⁺ = 539). Experimental procedure for the synthesis of F-30a

F-29a (176 mg, 0.26 mmol, 1.0 equiv.) is dissolved in dioxane (2.0 mL), HCI (4M in dioxane, 327pL, 1 .31 mmol, 5.0 equiv.) is added and stirred over the weekend at rt. After complete, the reaction mixture is basified with DI PEA, concentrated under reduced pressure and purified by RP chromatography yielding F-30a (HPLC method: A; t _re t = 1.12min; [M+H] ⁺ = 395). Synthesis of aminocyanothiophenes G, I, II, and III

Experimental procedure for the synthesis of la-1 and lla-2

To a solution of F-27a (804 mg, 2.53 mmol, 1.0 equiv.) and mol. sieves (3A) in anhydrous isopropanol (16 mL) under an argon atmosphere are added malononitrile (341 mg, 5.06 mmol, 2.0 equiv.), sulfur (162 mg, 5.06 mmol, 2.0 equiv.) and B-Alanine (451 mg, 5.06 mmol, 2 equiv.). The reaction mixture is stirred at 90°C overnight. After complete conversion, the reaction mixture is cooled to rt, filtered, and extracted with DCM and aq. saturated NaHCCh. The organic phases are combined and concentrated under reduced pressure. The residue is dissolved in in ACN and water and purified by basic RP chromatography yielding la-1.

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

Table 18 Experimental procedure for the conversion of ketones F to I (method I) To a solution of F-11a (115 mg, 0.28 mmol, 1.0 equiv.) and mol. sieves (3A) in anhydrous ethanol (235 pL) under an argon atmosphere are added malononitrile (64.8 mg, 0.98 mmol, 3.5 equiv.), sulfur (35.9 mg, 1.12 mmol, 4.0 equiv.) and L-Proline (96.8 mg, 0.84 mmol, 3 equiv.). The reaction mixture is stirred at 80°C overnight. After complete conversion, the reaction mixture is cooled to rt, filtered and extracted with DCM and aq. saturated NaHCCh.

The organic phases are combined and concentrated under reduced pressure. The residue is dissolved in in ACN and water and purified by RP chromatography to give the desired product lb-1.

The following compounds I and II (Table 19) are available in an analogous manner from the corresponding ketones F. The crude product is purified by chromatography if necessary.

Table 19

Experimental procedure for the conversion of ketones F to II (method II) To a solution of F-20b (532 mg, 1.30 mmol, 1.0 equiv.) and mol. sieves (3A) in anhydrous methanol (8 mL) under an argon atmosphere, are added malononitrile (136 mg, 1.95 mmol, 1.5 equiv.), sulfur (62.5 mg, 1.95 mmol, 1.5 equiv.) and B-Alanine (146 mg, 1.56 mmol, 1.2 equiv.). The reaction mixture is stirred at 80°C overnight. After complete conversion, the reaction mixture is cooled to rt, filtered and extracted with DCM and aq. saturated NaHCCh.

The organic phases are combined and concentrated under reduced pressure. The residue is dissolved in in ACN and water and purified by RP chromatography to give the desired product llb-1.

The following compounds I and II (Table 20) are available in an analogous manner from the corresponding ketones F. The crude products are purified by chromatography if necessary.

Table 20

Experimental procedure for the conversion of ketones F to I and II (method III) To a solution of F-28a (70.0 mg, 0.18 mmol, 1.0 equiv.) and mol. sieves (3A) in anhydrous ethanol (2 mL) under an argon atmosphere are added malononitrile (61.38 mg, 0.88 mmol, 5.0 equiv.), sulfur (17.0 mg, 0.53 mmol, 3 equiv.) and B-Alanine (49.7 mg, 0.53 mmol, 3 equiv.). The reaction mixture is stirred at 80°C overnight. After complete conversion, the reaction mixture is cooled to rt, filtered, and extracted with DCM and aq. saturated NaHCCh. The organic phases are combined and concentrated under reduced pressure. The residue is dissolved in in ACN and water and purified by RP chromatography to give the desired product lb-4 The following compounds I and II (Table 21) are available in an analogous manner from the corresponding ketones F. The crude product is purified by chromatography if necessary. Traces of the alternative isoxazole regioisomer of llb-5 are removed via SFC (Column: AmyC (30mm x 250mm, 5pm), Column Temperature: 40°C, BPR: 100 bar, eluent: 30:70 EtOH (0.2% v/v DEA) : CO2, llb-5 collected as peak2 after the alternative isomer). Table 21

To a solution of F-23a (72.0 mg, 0.18 mmol, 1.0 equiv.) and mol. sieves (3A) in anhydrous ethanol (2.5mL) under an argon atmosphere, are added malononitrile (64.8 mg, 0.98 mmol, 3.5 equiv.), sulfur (35.9 mg, 1.12 mmol, 4 equiv.) and L-Proline (82.6 mg, 703 pmol, 4.0 equiv.). The reaction mixture is stirred at 90°C overnight. After complete conversion, the mixture is cooled to rt, filtered, and extracted with DCM and aq. saturated NaHCCh. The organic phases are combined and concentrated under reduced pressure. The residue is purified by RP chromatography to give the desired product llla-1 (HPLC method: A; t _ret = 1.28min; [M+H] ⁺ = 490).

Experimental procedure for the synthesis of lllb-1 To a solution of F-30a (58.0 mg, 0.15 mmol, 1.0 equiv.) and mol. sieves (3A) in anhydrous ethanol (1 mL) under an argon atmosphere, are added malononitrile (69.4 mg, 1.03 mmol, 7.0 equiv.), sulfur (23.6 mg, 0.74 mmol, 5.0 equiv.) and B-Alanine (65.9 mg, 0.74 mmol, 5.0 equiv.). The reaction mixture is stirred at 80°C overnight. After complete conversion, the mixture is cooled to rt, filtered, and extracted with DCM and aq. saturated NaHCCh. The organic phases are combined and concentrated under reduced pressure. The residue is purified by RP chromatography to give the desired product lllb-1 (HPLC method: A; t _ret = 1.20min; [M+H] ⁺ = 475).

Experimental procedure for the synthesis of G-1a la-1 G-1a la-1 (500 mg, 1.26 mmol, 1.0 equiv.) and N,N-dimethylformamide dimethyl acetal (255.5 pL, 1.88 mmol, 1.50 equiv.) are dissolved in dry DMF (1.5 mL) and stirred for 1h at rt. After complete conversion of starting material is observed, the mixture is concentrated under reduced pressure and purified by RP chromatography yielding G-1a.

The following intermediates G-1 and G-2 (Table 22) are available in an analogous manner from the corresponding compounds la and Ila. The crude products are purified by chromatography if necessary.

Table 22 Experimental procedure for the synthesis of Id-1 la-1 (50.0 mg, 0.13 mmol, 1.0 equiv.), B-19a (66.8 mg, 0.25 mmol, 2.0 equiv.), and DIPEA (43.8 pL, 0.25 mmol, 2.0 equiv.) is dissolved in dry ACN (1mL) and stirred over 2 d at 90°C. After complete conversion, the mixture is concentrated under reduced pressure. The residue is dissolved in ACN/water, filtered, and purified by RP chromatography yielding Id-1.

The following compounds I (Table 23) are available in an analogous manner using the suitable amine. The crude products are purified by chromatography if necessary.

Table 23

Experimental procedure for the synthesis of lld-1 lla-1 (150 mg, 0.377 mmol, 1.0 equiv.), (3S)-3-methyl-1-piperazinecarboxylic acid tert-butyl ester (238 mg, 1.13 mmol, 3.0 equiv.), and dry DIPEA (197 pL, 1.13 mmol, 3.0 equiv.) are dissolved in dry ACN (3 mL) and stirred for 12 h at 90°C. After complete conversion the mixture is filtered and concentrated under reduced pressure. The crude product is purified by RP chromatography yielding lld-1 (HPLC method: A; t _re t = 1.64min; [M+H] ⁺ = 562).

Experimental procedure for the synthesis of G-3a

The reaction is carried out in the glovebox under nitrogen atmosphere.

G-1a (180 mg, 0.38 mmol, 1.0 equiv.), B-10a (156 mg, 0.60 mmol, 1.60 equiv.), sodium tert- butoxide (54.4 mg, 0.57 mmol, 1.50 equiv.) and [BrettPhos pd(crotyl)]OTf (32.0 mg, 0.04 mmol, 0.1 equiv.) is dissolved in degassed dioxane (3.0 mL) and stirred for 16 h at 60°C. After complete conversion, the reaction mixture is extracted with EtOAc I water, the combined organic phases are dried, filtered, and concentrated under reduced pressure. The residue is purified by RP chromatography yielding G-3a.

The following compounds G-3 and G-4 (Table 24) are available in an analogous manner using the suitable alcohol B and chloride G-1 and G-2 respectively. The crude products are purified by chromatography if necessary.

Table 24

Experimental procedure for the synthesis of G-5a

G-3b (525 mg, 0.82 mmol, 1.0 equiv.) is dissolved in DCM (8.0 mL) and trifluoroacetic acid (1 mL) is added. The mixture is stirred for 3 h at rt. After complete conversion, the reaction mixture is concentrated under reduced pressure yielding G-5a (HPLC method: C; t _re t = 0.75min; [M+ H] ⁺ = 544).

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

Experimental procedure for the conversion of intermediates G to le or He (method I)

G-3d

G-3d (120 mg, 0.21 mmol, 1 .0 equiv.) is dissolved in ACN/water (1 :1 , 20 mL) and aq. sodium hydroxide (2 M, 20.0 mL, 40 mmol, 190 equiv.) is added. The reaction is stirred 2 h at 80°C. After completed conversion, the mixture is extracted with DCM. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding le-1 .

The following compounds le (Table 25) are available in an analogous manner. The crude products are purified by chromatography if necessary.

Table 25 Experimental procedure for the conversion of intermediates G to le or He (method II)

G-4a (26.0 mg, 0.05 mmol, 1.0 equiv.) is dissolved in ethanol (600 pL) aq. sodium hydroxide (2 M, 465 pL, 0.93 mmol, 20 equiv.) is added and stirred for 3 d at rt. After complete conversion, water and ACN are added and the product is purified by RP chromatography yielding lle-1.

The following compounds le and He (Table 26) are available in an analogous manner. The crude products are purified by chromatography if necessary.

Table 26 Experimental procedure for the conversion of intermediates G to le or He (method III)

G-3a (12.0 mg, 21.0 pmol, 1.0 equiv.) is dissolved in ethanol (0.5 mL) and aq. HCI cone (37.2%, 12.1 pL, 147 pL, 7.0 equiv.) is added and stirred for 2 h at 90°C. After complete conversion the mixture is concentrated under reduced pressure and purified by RP chromatography yielding le-5 (HPLC method: A; t _re t = 1.40min; [M+H] ⁺ = 517).

Experimental procedure for the synthesis of lf-1 Id-2 (2.33 g, 4.05 mmol, 1.0 equiv.) is dissolved in DCM (20 mL), HCI in dioxane (12.1 mL, 48.6 mmol, 12.1 equiv.) is added and the reaction is stirred for 2 h at rt. After complete conversion, the reaction is concentrated under reduced pressure, suspended in water, basified with DI PEA and extracted with DCM. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding lf-1 . The following compounds If and Ilf (Table 27) are available in an analogous manner from Id and lid. The crude product is purified by chromatography if necessary.

Table 27

Experimental procedure for the synthesis of lf-2 le-4 (28.0 mg, 0.05 mmol, 1.0 equiv.) is dissolved in DCM (1.5 mL) and trifluoroacetic acid (0.06 mL, 0.76 mmol, 16 equiv.) is added. The reaction is stirred at rt overnight. After complete conversion, the mixture is concentrated under reduced pressure. The residue is dissolved in methanol, loaded onto an SCX-2 column, and the product is eluted with NH3 (4M in methanol) yielding lf-2 (HPLC method: C; t _re t = 0.69min; [M+H] ⁺ = 489). Experimental procedure for the synthesis of lg-1 lf-1 (20.0 mg, 0.04 mmol, 1.0 equiv.) is dissolved in dry DCM (1 mL), cyclopropanecarboxaldehyd (2.95 mg, 0.04 mmol, 1.0 equiv.) is added followed by the addition of sodium triacetoxyborohydride (36.7 mg, 0.17 mmol, 4.0 equiv.). The solution is stirred for 1 h at rt. After complete conversion, the reaction mixture is quenched by the addition of water. The aqueous phase is extracted with DCM (3x). The combined organic phases are filtered and concentrated under reduced pressure. The residue is dissolved in DMF and purified by RP chromatography to give the desired product lg-1. The following compounds Ig (Table 28) are available in an analogous manner. The crude product is purified by chromatography if necessary.

Table 28 Experimental procedure for the synthesis of lg-4

(2R)-1 ,1-dimethhoxypropan-2-ol (30.3 mg, 0.25 mmol, 1.45 equiv.) is dissolved in aq. HCI (2 M, 130 pL, 0.26 mmol, 1.5 equiv.) and stirred overnight at rt. Methanol (1 mL) and sodium acetate (22.8 mg, 0.28 mmol, 1.6 equiv.) are then added. lf-1 (82.5 mg, 0.17 mmol, 1.0 equiv.) is dissolved in methanol (1.5 mL) and sodium cyanoborohydride (28.7 mg, 0.43 mmol, 2.50 equiv.) is added. The aldehyde solution is added portion wise. After complete conversion, the reaction mixture is extracted with DCM I water, the combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding lg-4 (HPLC method: A; t _re t = 1.46min; [M+H] ⁺ = 534). llb-5 (100 mg, 0.21 mmol, 1.0 equiv.) is dissolved in DCM (5 mL), tetrahydro-4H-pyran-4-one (1.05 g, 10.5 mmol, 50 equiv.) is added and stirred for 15 min. Sodium triacetoxyborohydride (178 mg, 0.84 mmol, 4.0 equiv.) is then added and the reaction is stirred for 2 h at rt. After complete conversion, the reaction mixture is concentrated under reduced pressure and purified by RP chromatography. Traces of the undesired isoxazole regioisomer are removed via SFC (Column: AmyC (20mm x 250mm, 5pm), Column Temperature: 40°C, BPR: 125 bar, Isocratic Conditions: 30:70 EtOH:CO2 (0.2% v/v DEA), llg-1 collected as peak 2 after the alternative isomer) yielding llg-1 (HPLC method: A; t _re t = 1.49min; [M+H] ⁺ = 560).

Experimental procedure for the synthesis of lh-1 lf-2 (22.0 mg, 0.05 mmol, 1.0 equiv.) is dissolved in dry THF (1 mL), sodium hydride (60% in mineral oil, 3.60 mg, 0.09 mmol, 2.0 equiv.) is added and stirred for 5 min at rt. lodomethane (12.8 mg, 0.09 mmol, 2.0 equiv.) is then added and stirred for 3 h at rt. After complete conversion, the reaction mixture is filtered and purified by RP chromatography yielding lh-1 (HPLC method: A; t _ret = 1.46min; [M+H] ⁺ = 503). Synthesis of aminocyanothiophenes H and IV

Experimental procedure for the synthesis of H-2a

H-1a H-2a

To a stirred solution of 2-oxo-cylohexanecarboxylic acid ethyl ester (10.0 g, 58.8 mmol, 1.0 equiv.) in ethanol (50 mL), sulfur (1.88 g, 58.8 mmol, 1.0 equiv.), morpholine (5.12 g, 58.8 mmol, 1.0 equiv.) and malononitrile (3.88 g, 58.8 mmol, 1.0 equiv.) are added. Then the reaction mixture is stirred at 55°C for 1 h. After complete conversion, the reaction mixture is concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The combined organic phases are concentrated under reduced pressure and purified by NP chromatography yielding H-2a (HPLC method: C; t _re t = 0.54min; [M+H] ⁺ = 251).

Experimental procedure for the synthesis of H-3a

H-2a (45.0 g, 180 mmol, 1.0 equiv.) is dissolved in ethanol (300 mL) and sodium hydroxide (43.2 g, 1.08 mol, 6.0 equiv.) dissolved in water (120 mL) is added. The resulting solution is heated to 60°C and stirred for 1 h. After complete conversion, the mixture is cooled to rt and neutralized with 10% HCI and extracted with EtOAc. The combined organic phases are washed with water and brine, then dried and concentrated under reduced pressure yielding H-3a (HPLC method: N; t _ret = 0.36min; [M-H]’ = 221).

Experimental procedure for the synthesis of H-4a

H-3a H-4a H-3a (1.00 g, 4.27 mmol, 1.0 equiv.) is dissolved in dry DMSO, (dimethoxymethyl)dimethylamine (3.0 mL, 22.5 mmol, 5.26 equiv.) is added slowly and stirred for 2 h at 90°C. After complete conversion the mixture is extracted with DCM I water. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography, yielding H-4a (HPLC method: C; t _re t = 0.60min; [M+H] ⁺ = 292).

Experimental procedure for the synthesis of H-5a

H-4a (711 mg, 2.44 mmol, 1.0 equiv.) is dissolved in dry THF (3.95 mL) and degassed with argon. LiHMDS (1 M in THF, 2.56 mL, 2.56 mmol, 1 .05 equiv.) is added slowly and the mixture is stirred for 5 min at rt. Then 5-bromopent-1-yne (359 mg, 2.44 mmol, 1.0 equiv.) is added and the mixture is stirred for20h at rt. After complete conversion, water is added to the reaction and concentrated under reduced pressure, then the mixture is extracted with DCM. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography, yielding H-5a (HPLC method: C; t _re t = 0.72min; [M+H] ⁺ = 358).

Experimental procedure for the synthesis of H-6a

H-5a (824 mg, 2.31 mmol, 1.0 equiv.) and Cs2CO3 (1502 mg, 11.5 mmol, 5.0 equiv.) is dissolved in NMP (8.20 mL), then thiophenol (1.18 mL 11.5 mmol, 5.0 equiv.) is added. The mixture is stirred for 7 h at 80°C. Acetic acid (1mL) is added and the mixture is extracted with DCM/water. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography, yielding H-6a (HPLC method: C; t _re t = 0.40min; [M+H] ⁺ = 344).

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

Experimental procedure for the synthesis of H-8a

C-4a (131 mg, 0.52 mmol, 1.24 equiv.) is dissolved in DMF (1.8 mL) and H-7a (168 mg, 0.42 mmol, 1.0 equiv.) is added. Then bis(propan-2-yl) amine (1.60 mL) and [1 ,1- Bis(dipehnylphosphino)ferrocene]dichloropalladium (II) (21.6 mg, 0.03 mmol, 0.07 equiv.) and copper(l)iodide (8.0 mg, 0.04 mmol, 0.10 equiv.) are added. The mixture is stirred at 80°C for 20 h. After complete conversion, the reaction mixture is extracted with DCM/water. The combined organic phases are concentrated under reduced pressure and purified by RP chromatography yielding H-8a (HPLC method: A; t _re t = 1.39min; [M+H] ⁺ = 520). Experimental procedure for the synthesis of H-9a

H-8a (75.5 mg, 0.15 mmol, 1.0 equiv.) is dissolved in methanol (3.7 mL) and degassed with argon, lmidazole-1-sulfonyl azide tetrafluoroborate (46.3 mg, 0.18 mmol, 1.22 equiv.) and copper(ll)sulfate (464 pg, 2.91 pmol, 0.02 equiv.) is added. The mixture is heated to 60°C. After complete conversion, the reaction mixture is concentrated under reduced pressure and purified by RP chromatography yielding H-9a (HPLC method: C; t _re t = 0.70min; [M+H] ⁺ = 546).

Experimental procedure for the synthesis of IVa-1

H-9a IVa-1

H-9a (30.5 mg, 0.06 mmol, 1.0 equiv.) is dissolved in ethanol (2 mL) and aq. HCI (2 M, 279 6 pL, 0.56 mmol, 10 equiv.) is added. The reaction is stirred 16 h at 60°C. After complete conversion, the reaction mixture is concentrated under reduced pressure, and purified by RP chromatography yielding IVa-1 (HPLC method: A; t _re t = 1.21min; [M+H] ⁺ = 491).

The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples.

KRAS::SOS1 AlphaScreen Binding Assay

This assay can be used to examine the potency with which compounds according to the invention binding to (mutated) KRAS inhibit the protein-protein interaction between SOS1 and (mutated) KRAS e.g., KRAS WT, KRAS G12C, KRAS G12D, KRAS G12V or KRAS G13D. This inhibits the GEF functionality of SOS1 and locks the corresponding (mutated) KRAS protein in its inactive, GDP-bound state. Low IC50 values in this assay setting are indicative of strong inhibition of protein-protein interaction between SOS1 and KRAS:

Description of the Assay:

These assays measure the inhibitory effect of compounds on KRAS mutant protein-protein interactions using the Alpha Screen technology by Perkin Elmer.

The following (mutant) enzyme forms of KRAS and interacting proteins are used in these assays at the given concentrations:

KRAS (G12D) 1-169, N-terminal 6His-tag, C-terminal avi-tag (Xtal BioStructures, Inc.); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 5 nM;

KRAS (G12C) 1-169, N-terminal 6His-tag for purification, cleaved off, C-terminal avi-tag, biotinylated, mutations: C51S, C80L, C118S (in house); final assay concentration 7.5 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 5 nM;

KRAS (G12V) 1-169, N-terminal 6His-tag, for purification, cleaved off, C-terminal avi-tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loaded (in house); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 10 nM;

KRAS (G13D) 1-169, N-terminal 6His-tag for purification, cleaved off, C-terminal avi-tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loaded (in house); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 10 nM;

KRAS (WT) 1-169, N-terminal 6His-tag for purification, cleaved off, C-terminal avi-tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loaded (in house); final assay concentration 10nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 10 nM.

Test compounds dissolved in DMSO are dispensed onto assay plates (Proxiplate 384 PLUS, white, PerkinElmer; 6008289) using an Access Labcyte Workstation with the Labcyte Echo 55x. For the chosen highest assay concentration of 100 pM, 150 nL of compound solution are transferred from a 10 mM DMSO compound stock solution. A series of eleven fivefold dilutions per compound are transferred to the assay plate, compound dilutions are tested in duplicates. DMSO are added as backfill to a total volume of 150 nL.

The assays run on a fully automated robotic system in a darkened room below 100 Lux. To 150 nl of compound dilution 10 pl of a mix including KRAS mutant protein, SOS1 (final assay concentrations see above) and GDP nucleotide (Sigma G7127; final assay concentration 10pM) in assay buffer (1 x PBS, 0.1% BSA, 0.05% Tween 20) are added into columns 1-24.

After 30 minutes incubation time 5 l of Alpha Screen bead mix in assay buffer are added into columns 1-23. Bead mix consists of AlphaLISA Glutathione Acceptor Beads (PerkinElmer, Cat No AL109) and AlphaScreen Streptavidin Donor Beads (PerkinElmer Cat No 6760002) in assay buffer at a final assay concentration of 10 pg/ml each.

Plates are kept at room temperature in a darkened incubator. After an additional 60 minutes incubation time the signal is measured in a PerkinElmer Envision HTS Multilabel Reader using the AlphaScreen specs from PerkinElmer.

Each plate contains up to 16 wells of a negative control depending on the dilution procedure (platewise or serial) (DMSO instead of test compound; with KRAS mutant::SOS1 GDP mix and bead mix; column 23) and 16 wells of a positive control (DMSO instead of test compound; with KRAS mutant::SOS1 GDP mix w/o bead mix; column 24).

As internal control known inhibitors of KRAS mutant: :SOS1 interaction can be measured on each compound plate. IC50 values are calculated and analyzed with Boehringer Ingelheim’s MEGALAB IC50 application using a 4 parametric logistic model.

Tables of example compounds disclosed herein contain IC50 values determined using the above assays (see Table 29).

Table 29

Ba/F3 cell model generation and proliferation assay

Ba/F3 cells are ordered from DSMZ (ACC300, Lot17) and grown in RPMI-1640 (ATCC 30- 2001) + 10 % FCS + 10 ng/mL IL-3 at 37 °C in 5 % CO2 atmosphere. Plasmids containing KRASG12 mutants (i.e. G12D, G12C, G12V) are obtained from GeneScript. To generate KRASG12-dependent Ba/F3 models, Ba/F3 cells are transduced with retroviruses containing vectors that harbor KRASG12 isoforms. Platinum-E cells (Cell Biolabs) are used for retrovirus packaging. Retrovirus is added to Ba/F3 cells. To ensure infection, 4 pg/mL polybrene is added and cells are spinfected. Infection efficiency is confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10 % to 20 % are further cultivated and puromycin selection with 1 pg/mL is initiated. As a control, parental Ba/F3 cells are used to show selection status. Selection is considered successful when parental Ba/F3 cells cultures died. To evaluate the transforming potential of KRASG12 mutations, the growth medium is no longer supplemented with IL-3. Ba/F3 cells harboring the empty vector are used as a control. Approximately ten days before conducting the experiments, puromycin is left out. For proliferation assays, Ba/F3 cells are seeded into 384-well plates at 1.5 x 10 ³ cells 160 pL in growth media (RPMI-1640 + 10 % FCS). Compounds are added using an Access Labcyte Workstation with a Labcyte Echo 550 or 555 accoustic dispenser. All treatments are performed in technical duplicates. Treated cells are incubated for 72 h at 37 °C with 5 % CO2. AlamarBlue™(ThermoFisher), a viability stain, is added and fluorescence measured in the PerkinElmer Envision HTS Multilabel Reader. The raw data are imported into and analyzed with the Boehringer Ingelheim proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

IC50 values of representative compounds according to the invention measured with this assay are presented in table 30. Table 30

Additional proliferation assays with mutant cancer cell lines

• NCI-H358 CTG proliferation assay (120 h) (NSCLC, G 12C) NCI-H358 cells (ATCC No. CRL-5807) are dispensed into white bottom opaque 96 well plates (Perkin Elmer cat no. 5680) at a density of 2000 cells per well in 100 pL RPMI-1640 ATCC- Formulation (Gibco # A10491) + 10 % FCS (fetal calf serum) (assay 1) or into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 200 cells per well in 60 pl RPMI-1640 ATCC-Formulation (Gibco # A10491) + 10 % FCS (fetal calf serum) (assay 2). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the HP Digital Dispenser D300 (Tecan) (assay 1) or the ECHO acoustic liquid handler system (Beckman Coulter) (assay 2), normalizing for added DMSO and including DMSO controls. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

• NCI-H2122 CTG proliferation assay (120 h) (NSCLC, G 12C)

The CTG assay is designed to measure quantitatively the proliferation of NCI-H2122 cells (ATCC CRL-5985), using the CellTiter Glow Assay Kit (Promega G7571). Cells are grown in RPMI medium (ATCC) supplemented with Fetal Calf Serum (Life Technologies, Gibco BRL, Cat. No. 10270-106). On “day 0” 200 NCI-H2122 cells are seeded in 60 pL RPMI ATCC+10 % FCS+ Penstrep in a black 384-well plate, flat and clear bottom (Greiner, PNr. 781091). Cells are then incubated in the plates at 37 °C in a CO2 incubator overnight. On day 1 , compounds (10 mM stock in DMSO) are added with the ECHO acoustic liquid handler system (Beckman Coulter), including DMSO controls. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

• AsPC-1 CTG proliferation assay (120 h) (pancreatic cancer, G12D)

The CTG assay is designed to measure quantitatively the proliferation of AsPC-1 cells (ATCC CRL-5985), using the CellTiter Glow Assay Kit (Promega G7571). Cells are grown in RPMI medium (ATCC) supplemented with Fetal Calf Serum (Life Technologies, Gibco BRL, Cat. No. 10270-106). On “day 0” 2000 AsPC-1 cells are seeded in 60 pL RPMI ATCC+10 % FCS+ Penstrep in a 384-well plate, flat and clear bottom (Greiner, PNr. 781091). Cells are then incubated in the plates at 37 °C in a CO2 incubator overnight. On day 1 , compounds (10 mM stock in DMSO) are added with the ECHO acoustic liquid handler system (Beckman Coulter), including DMSO controls. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

• GP2D proliferation assay ( 120 h) (colorectal cancer, G 12D)

GP2D cells (ATCC No. CRL-5807) are dispensed into white 384-well plates, flat and white bottom (Perkin Elmer, 6007680) at a density of 500 cells per well in 40 pl DMEM (Sigma, D6429) + 1x GlutaMAX (Gibco, 35050038) + 10 % FCS (fetal calf serum). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the HP Digital Dispenser D300 (Tecan), including DMSO controls and normalizing for added DMSO. For the TO time point measurement, untreated cells are analyzed at the time of compound addition. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four- parameter model.

• SAS CTG proliferation assay (120 h) (HNSCC, wt amplified)

SAS cells (JCRB0260) are dispensed into 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 300 cells per well in 60 pL DMEM:F12 (Gibco 31330-038) + 10% Fetal Calf Serum (HyClone, PNr.: SH30084.03) and incubated at 37 °C in a CO2 incubator overnight. The next day, compounds (10 mM stock in DMSO) are added with the ECHO acoustic liquid handler system (Beckman Coulter), including DMSO controls. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

• MKN1 CTG proliferation assay (120 h) (gastric cancer, wt amplified)

MKN1 cells (JCRB0252) are dispensed into white 384-well plates, flat and white bottom (Corning Costar, PNr.: 3570) at a density of 400 cells per well in 50 pL RPMI 1640 (PAN- Biotech, PNr.: P04-18047) + 10 % FCS (HyClone, PNr.: SH30084.03) (assay 1) or into black 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 200 cells per well in 60 pl RPMI-1640 (Gibco # A10491) + 10% FCS (HyClone, PNr.: SH30084.03) + PenStrep (Gibco, PNr.15140-122) (assay 2). Cells are incubated overnight at 37 °C in a humidified tissue culture incubator at 5 % CO2. Compounds (10 mM stock in DMSO) are added at logarithmic dose series using the HP Digital Dispenser D300 (Tecan) (assay 1 + 2) or the ECHO acoustic liquid handler system (Beckman Coulter) (assay 3), including DMSO controls and normalizing for added DMSO. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

• SK-CO-1 CTG proliferation assay (120 h) (CRC, G12V)

SK-CO-1 cells (ATCC HTB-39) are dispensed into 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 500 cells per well in 60 pL EMEM (Sigma M5650) + 10% Fetal Calf Serum (HyClone, PNr.: SH30084.03) and incubated at 37 °C in a CO2 incubator overnight. The next day, compounds (10 mM stock in DMSO) are added with the ECHO acoustic liquid handler system (Beckman Coulter), including DMSO controls. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

• LOVO CTG proliferation assay (120 h) (CRC, G 13D)

LOVO cells (ATCC CCL-229) are dispensed into 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 1000 cells per well in 60 pL DMEM (Sigma D6429) + 10% Fetal Calf Serum (HyClone, PNr.: SH30084.03) and incubated at 37 °C in a CO2 incubator overnight. The next day, compounds (10 mM stock in DMSO) are added with the ECHO acoustic liquid handler system (Beckman Coulter), including DMSO controls. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

• A375 CTG proliferation assay (120 h) (melanoma, wt, B-Raf mutant, negative control) A375 cells (ATCC CRL-1619) are dispensed into 384-well plates, flat and clear bottom (Greiner, PNr. 781091) at a density of 300 cells per well in 60 pL DMEM (Sigma D6429) + 10% Fetal Calf Serum (HyClone, PNr.: SH30084.03) and incubated at 37 °C in a CO2 incubator overnight. The next day, compounds (10 mM stock in DMSO) are added at logarithmic dose series using the HP Digital Dispenser D300 (Tecan), including DMSO controls. Plates are incubated for 120 h, and cell viability is measured using CellTiter-Glo luminescent cell viability reagent (Promega product code G7570). Viability (stated as percent of control) is defined as relative luminescence units RLU of each well divided by the RLU of cells in DMSO controls. IC50 values are determined from viability measurements by non-linear regression using a four-parameter model.

IC50 values of representative compounds according to the invention measured with these assays in the indicated cell lines are presented in table 31 and 32. Table 31

Table 32

ERK Phosphorylation Assay

ERK phosphorylation assays are used to examine the potency with which compounds inhibit the KRAS G12C-mediated signal transduction in a KRAS G12C mutant human cancer cell line in vitro. This demonstrates the molecular mode of action of compounds according to the invention by interfering with the RAS G12C protein signal transduction cascade. Low IC50 values in this assay setting are indicative of high potency of the compounds according to the invention. It is observed that compounds according to the invention demonstrate an inhibitory effect on ERK phosphorylation in a KRAS G12C mutant human cancer cell line, thus confirming the molecular mode of action of the compounds on RAS G12C protein signal transduction.

ERK phosphorylation assays are performed using the following human cell lines:

NCI-H358 (ATCC (ATCC CRL-5807): human lung cancer with a KRAS G12C mutation assay 1) and NCI-H358_Cas9_SOS2, i.e. the same cell line, in which SOS2 is knocked assay 2). Vectors containing the designed DNA sequences for the production of gRNA for SOS2 protein knock-out are obtained from Sigma-Aldrich. To generate the NCI-H358 SOS2 knock-out cell line, NCI-H358 cells expressing Cas9 endonuclease are transfected with XtremeGene9 reagent and the correspondent plasmids. Transfection efficiency is confirmed by measuring GFP-positive cells using a cell analyzer. GFP positive cells are collected and further expanded. These GFP-positive cell pools are single-cell diluted and SOS2 knock-out clones are identified via Western-blot and genomic DNA sequencing analysis.

Materials used for the assay: RPMI-1640 Medium (ATCC® 30-2001 ™)

Fetal Bovine Serum (FBS) from HyClone (SH30071.03)

Non-essential amino acids from Thermo Fischer Scientific (11140035) Pyruvate from Thermo Fischer Scientific (11360039)

Glutamax from Thermo Fischer Scientific (35050061)

384 plates from Greiner Bio-One (781182)

Proxiplate™ 384 from PerkinElmer Inc. (6008280)

AlphaLISA SureFire Ultra p-ERK1/2 (Thr202/Tyr204) Assay Kit (ALSU-PERK-A500)

EGF from Sigma (E4127)

Acceptor Mix: Protein A Acceptor Beads from PerkinElmer (6760137M)

Donor Mix: AlphaScreen Streptavidin-coated Donor Beads from PerkinElmer (6760002) Trametinib

Staurosporine from Sigma Aldrich (S6942)

Assay setup:

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

Analogously the described assay (pERK reduction; SureFire) can be performed on additional cell lines, carrying various KRAS mutations or KRAS wildtype, allowing the measurement and determination of the activity of compounds on various additional KRAS allels in a cellular background. Metabolic (microsomal) stability assay

The metabolic degradation of the test compound is assayed at 37 °C with pooled liver microsomes (mouse (MLM), rat (RLM) or human (HLM)). The final incubation volume of 48 pL per time point contains TRIS buffer (pH 7.5; 0.1 M), magnesium chloride (6.5 mM), microsomal protein (0.5 mg/mL for mouse/rat, 1 mg/mL for human specimens) and the test compound at a final concentration of 1 pM. Following a short preincubation period at 37 °C, the reactions are initiated by addition of 12 pL beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 10 mM) and terminated by transfering an aliquot into solvent after different time points (0, 5, 15, 30, 60 min). Additionally, the NADPH-independent degradation is monitored in incubations without NADPH, terminated at the last time point by addition of acetonitrile. The quenched incubations are pelleted by centrifugation (4,000 rpm, 15 min). An aliquot of the supernatant is assayed by LC-MS/MS to quantify the concentration of parent compound in the individual samples.

In vitro intrinsic clearance (CL _in t. in vitro) is calculated from the time course of the disappearance of the test drug during the microsomal incubation. Each plot is fitted to the first-order elimination rate constant as C(t) = Co*exp(- e*t), where C(t) and Co are the concentration of unchanged test drug at incubation time t and that at preincubation and ke is the disappearance rate constant of the unchanged drug. Subsequently, CLmt, in vitro (pL min ^-1 ■ amount protein) values are converted to predicted CLmt./n vivo (mL min ^-1 kg ^-1 ) from incubation parameters according to the equation CLmt, in vivo = CLmt, in vitro x (incubation volume (ml) I amount protein (mg)) x (amount protein (mg) I g liver tissue) x (liver weight I body wt.). For better across species comparison the predicted clearance is expressed as percent of the liver blood flow [% QH] (mL min ^-1 kg ^-1 ) in the individual species. In general, high stability (corresponding to low % QH) of the compounds across species is desired.

Table 33 shows metabolic stability data obtained with the disclosed assay in HLM for a selection of compounds according to the invention.

Table 33:

Plasma protein binding assay (PPB) Binding of test compounds to plasma was determined using equilibrium dialysis (ED) and quantitative mass spectrometry interfaced with liquid chromatography (LC-MS). In brief, ED was performed with dialysis devices consisting of two chambers separated by a semipermeable membrane with a molecular weight cut-off of 5-10 kg/mol. One chamber was filled with 10 % FCS in PBS containing 1-10 pmol/L test compound and the other chamber was filled with phosphate-buffer saline (PBS) with or without dextran. The dialysis chamber was incubated for 3-5 hours at 37°C. After incubation, protein was precipitated from aliquots of each chamber and the concentration of test compound in the supernatant of the plasmacontaining compartment (c _se rum) and of the buffer-containing compartment (Cbuffer) was determined by LC-MS. The fraction of unbound test compound (not bound to plasma) (f _u ) was calculated according to the following equation: 100

Table 34 shows metabolic stability data obtained with the disclosed assay for a selection of compounds according to the invention.

Table 34:

Mechanism based inhibition of CYP3A4 assay (MB! 3A4):

The time dependent inhibition towards CYP3A4 is assayed in human liver microsomes (0.02 mg/mL) with midazolam (15 pM) as a substrate. The test compounds and water control (wells w/o test compound) are preincubated in presence of NADPH (1 mM) with human liver microsomes (0.2 mg/mL) at a concentration of 25 uM for 0 min and 30 min. After preincubation, the incubate is diluted 1 :10 and the substrate midazolam is added for the main incubation (15 min). The main incubation is quenched with acetonitrile and the formation of hydroxymidazolam is quantified via LC/MS-MS. The formation of hydroxy-midazolam from the 30 min preincubation relative to the formation from the 0 min preincubation is used as a readout. Values of less than 100 % mean that the substrate midazolam is metabolized to a lower extent upon 30 min preincubation compared to 0 min preincubation. In general low effects upon 30 min preincubation are desired (corresponding to values close to 100 %/ not different to the values determined with water control).

Table 35 shows data obtained with the disclosed assay for a selection of compounds according to the invention.

Table 35:

Solubility measurement (DMSO solution precipitation method)

A 10 mM DMSO stock solution of a test compound is used to determine its aqueous solubility. The DMSO solution is diluted with an aqueous medium (Mcllvaine buffer with pH=4.5 or 6.8) to a final concentration of 250 pM. After 24 h of shaking at ambient temperature a potentially formed precipitate is removed by filtration. The concentration of the test compound in the filtrate is determined by LC-LIV methods by calibrating the signal to the signal of a reference solution with complete dissolution of the test compound in acetonitrile/water (1 :1) with known concentration.

Table 35 shows data obtained with the disclosed assay for a selection of compounds according to the invention.

Table 36:

Caco-2 assay

The assay provides information on the potential of a compound to pass the cell membrane, on the extent of oral absorption as well as on whether the compound is actively transported by uptake and/or efflux transporters. Permeability measurements across polarized, confluent Caco-2 cell monolayers grown on permeable filter supports (Corning, catalog #3391) are used. 10 pM test compound solution in assay buffer (128.13 mM NaCI, 5.36 mM KCI, 1 mM MgSC , 1.8 mM CaCI ₂ , 4.17 mM NaHCO ₃ , 1.19 mM Na ₂ HPO ₄ , 0.41 mM NaH ₂ PO ₄ , 15 mM 2-[4-(2- hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), 20 mM glucose, pH 7.4) was added to the donor compartment of the cell chamber containing a monolayer of Caco-2 cells in between the donor and the receiver compartment. The receiver and donor compartments contain 0.25 % bovine serum albumine (BSA) in assay buffer. Passive diffusion and/or active transport of compounds across the monolayer is measured in both apical to basolateral (a-b) and basolateral to apical (b-a) direction, a-b permeability (PappAB) represents drug absorption from the intestine into the blood and b-a permeability (PappBA) drug secretion from the blood back into the intestine via both passive permeability as well as active transport mechanisms mediated by efflux and uptake transporters that are expressed on the Caco-2 cells. After a pre-incubation of 25-30 min at 37 °C, at predefined time points (0, 30, 60 and 90 min), samples were taken from the receiver and donor compartment, respectively. Concentrations of test compounds in samples were measured by HPLC/MS/MS, samples from the donor compartment were diluted 1 :50 (v:v) with assay buffer, samples from receiver compartment were measured without dilution.

Apparent permeabilities in a-b (PappAB) and b-a (PappBA) directions are calculated according to the formula:

Vrec [mL] : buffer volume in receiver compartment

Cdon [pmol/mL] : concentration of test compound in donor compartment at t = 0 ACrec: difference between concentrations of test compound in receiver compartment at start and end of incubation time

At: Incubation time

Vrec ■ ACrec I At [pmol/min]: Amount of compound transferred to receiver compartment per time

A [cm ² ]: filter surface

Caco-2 efflux ratios (ER) are calculated as the ratio of PappBA I PappAB.

Table 37 shows data obtained with the disclosed assay for a selection of compounds according to the invention.

Table 37:

The formulation examples which follow illustrate the present invention without restricting its scope:

Examples of pharmaceutical formulations

A) Tablets per tablet active substance according to the invention 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

>

500 mg

The finely ground active substance, lactose and some 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 the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet active substance according to the invention 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodiumcarboxymethyl starch 23 mg magnesium stearate 2 mg

>

400 mg

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

C) Tablets per tablet active substance according to the invention 25 mg lactose 50 mg microcrystalline cellulose 24 mg magnesium stearate 1 mg

100 mg

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

D) Ampoule solution active substance according to the invention 50 mg sodium chloride 50 mg water for inj. 5 mL

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