2-METHYL-AZA-QUINAZOLINES - BAYER AG (2024)

2-METHYL-AZA-QUINAZOLINES

The present invention covers 2-methyl-aza-quinazoline compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

BACKGROUND

The present invention covers 2-methyl-aza-quinazoline compounds of general formula (I) which inhibit the Ras-Sosl interaction.

US 2011/0054173 A1 discloses certain 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and 1- or 2-(4-(heteroaryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and their use as agrochemicals and animal health products.

In the 2-position substituted quinazoline compounds are described e.g. in EP 0326328, EP 0326329, W093/007124, W02003/087098 and US 5,236,925. These compounds are either not described as pharmaceutically active compounds or, if they are described as pharmacologically active compounds, they are described as compounds having affinity to the Epidermal Growth Factor Receptor (EGFR).

In the majority (45-100%) of patients receiving EGFR inhibitors skin toxicity is a class-specific side effect that is typically manifested as a papulopustular rash. The skin toxicity is related to the inhibition of EGFR in the skin, which is crucial for the normal development and physiology of the epidermis.

Flowever, the state of the art does not describe: the 2-methyl substituted quinazoline compounds of general formula (I) of the present invention as described and defined herein, i.e. compounds having a quinazoline core bearing a methyl group on the carbon atom 2 which effectively and selectively inhibit the Ras-Sosl interaction without significantly targeting the EGFR receptor.

Ras proteins play an important role in human cancer. Mutations in Ras proteins can be found in 20- 30% of all human tumors and are recognized as tumorigenic drivers especially in lung, colorectal and pancreatic cancers (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al. 2011 Nature Reviews Cancer). Three human Ras genes are known that encode four different Ras proteins of 21 kDa size: Fl-Ras, N-Ras, and two splice variants of K-Ras, namely K-Ras 4A and K-Ras- 4B. All Ras isoforms are highly conserved within the GTP-binding domain and differ mainly in the hypervariable C-terminal region. The C-termini of the different Ras-isoforms are posttranslationally modified by lipidation (farnesylation, palmitoylation) to facilitate membrane anchorage. The localization of Ras-proteins at the cytoplasmic membrane provides vicinity to transmembrane growth receptors and has been shown to be essential for transmitting growth signals from extracellular growth factor binding to intracellular downstream pathways. A variety of upstream signals may activate Ras proteins depending on the cellular context, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), nerve growth factor receptor (NGFR) and others. Activated Ras can signal through various downstream pathways, e.g. the Raf-MEK-ERK or the PI3K-PDK1-Akt pathways.

On the molecular level, Ras proteins function as molecular switches. By binding GTP and GDP they exist in an active (GTP-bound) and inactive (GDP-bound) state in the cell. Active GTP-loaded Ras recruits other proteins by binding of their cognate Ras-binding domains (RBDs) resulting in activation of the effector protein followed by downstream signalling events of diverse functions, e.g. cytoskeletal rearrangements or transcriptional activation. The activity status of Ras is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs function as activators of Ras by promoting the nucleotide exchange from GDP to GTP. GAPs deactivate Ras-GTP by catalyzing the hydrolysis of the bound GTP to GDP. In a cancer cell, point mutations, typically within the GTP-binding region at codon 12, eliminate the ability of RAS to efficiently hydrolyse bound GTP, even in the presence of a GAP. Therefore, cancer cells comprise increased levels of active mutated Ras-GTP, which is thought to be a key factor for driving cancer cell proliferation.

Three main families of RAS-specific GEFs have been identified so far (reviewed in Vigil 2010 Nature Reviews Cancer; Rojas et al 2011, Genes & Cancer 2(3) 298-305). There are two son of sevenless proteins (SOS1 and SOS2), 4 different isoforms of Ras guanine nucleotide releasing proteins (Ras- GRP1-4) and two Ras guanine nucleotide releasing factors (Ras-GRFl and 2). The SOS proteins are ubiquitously expressed and are recruited to sites of activated growth factors. Ras-GRFs are expressed mainly in the nervous system, where they are involved in Calcium-dependent activation of Ras. In contrast, Ras GRP proteins are expressed in hematopoietic cells and act in concert with non-receptor tyrosine kinases. In the context of cancer, mainly SOS proteins have been found to be involved.

Targeting Ras for cancer therapy has been a dream since the 1990s (Downward 2002 Nature Reviews Cancer, Krens et al. 2010 Drug Discovery Today). Due to the compact nature, the high affinity towards GDP and GTP in combination with high intracellular GTP concentrations, the Ras protein itself has always been considered to be undruggable, i.e. the chance to identify small chemical molecules that would bind to and inhibit active Ras was rated extremely low. Alternative approaches have been undertaken to reduce Ras signaling, e.g. by addressing more promising drug targets such as enzymes involved in the posttranslational modification of Ras proteins, especially farnesyltransferase and geranylgeranyltransferase (Berndt 2011 Nature Reviews Cancer). Inhibitors of farnesyltransferase (FTIs) were identified and developed with promising antitumor effects in preclinical models. Unexpectedly, in clinical trials these inhibitors have been of limited efficacy. Targeting upstream and downstream kinases involved in Ras signaling pathways has been more successful. Several drugs are and have been in clinical trials that inhibit different kinases, e.g. EGFR, Raf, MEK, Akt, PI3K (Takashima & Falter 2013 Expert Opin. Ther. Targets). Marketed cancer drugs are available that inhibit Raf, EGFR or MEK.

Nevertheless, there is still a large unmet need for the treatment of Ras-dependent tumors that are resistant against current therapies. Many research groups have been active to identify small molecules that target Ras directly (Ras small molecules have been reviewed in: Cox et al. 2014 Nature Reviews Drug Discovery, Spiegel et al. 2014 Nature Chemical Biology, Cromm 2015 Angewandte Chemie, Marin-Ramos et al Seminars in Cancer Biology). One group of inhibitors comprises small molecules that inhibit the interaction of Ras with its effectors Raf or PI3K. Another group of compounds acts as covalent inhibitors of a specific cysteine mutant form of K-Ras (glycine to cysteine point mutation G12C). The specific targeting of the Ras-G12C mutant might have the benefit of reduced side effects, as the wildtype Ras proteins should not be affected. Furthermore, several reports show small molecules and peptides that interrupt the GEF assisted activation of Ras (Hillig et al 2019 PNAS; Gray et al 2019 Angewandte Chemie). There seem to be several different binding sites possible that result in this mode of action. Inhibitors may bind to Ras or to the GEF in an allosteric or orthosteric fashion. All these approaches of direct Ras-targeting are in preclinical research stage. Stabilized peptides have been shown to be active in the nanomolar range. (Leshchiner et al. 2015 PNAS). Their usefulness as drugs in a clinical setting has to be awaited.

The Epidermal Growth Factor Receptor (EGFR) is a tyrosine kinase (TK) receptor that is activated upon binding to the Epidermal Growth Factor and other growth factor ligands, triggering several downstream pathways, including RAS/MAPK, PI3K/Akt and STAT that regulate different cellular processes, including DNA synthesis and proliferation (Russo A, Oncotarget.4254, 2015). The family of HER (ErbB) receptor tyrosine kinases consists of four members, ie, epidermal growth factor receptors [EGFR (FIERI or ErbBl), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4)]. Overexpression, mutation, or aberrant activity of these receptors has been implicated in various types of cancer (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147).

First-generation inhibitors ErlotinibandGefitinibare smallmolecule inhibitorsof theEGFR/HER‐1 (humanepidermalgrowth factor receptor) tyrosine kinase. Erlotinib and Gefitinibwere developed as reversible and highly specificsmall‐moleculetyrosinekinase inhibitorsthatcompetitivelyblockthebindingofadenosine triphosphate to its binding site in the tyrosine kinase domain of EGFR, thereby inhibiting autophosphorylationandblockingdownstreamsignaling(CataldoVD,NEnglJMed,2011,364,947). Second‐generationinhibitors Afatinibisanoraltyrosinekinaseinhibitor(TKI)approvedforthefirst‐linetreatmentofpatientswith NSCLCwhosetumorsaredrivenbyactivatingmutationsofgenescodingforepidermalgrowthfactor receptor (EGFR). Afatinib is also an inhibitor of a specific EGFR mutation (T790M) that causes resistance to first‐generation EGFR‐targeted TKIs in about half of patients receiving those drugs. (EngleJA,AmJHealthSystPharm2014,71(22),1933). Neratinib,apan‐HER inhibitor, irreversible tyrosinekinase inhibitorbindsand inhibits the tyrosine kinaseactivityofepidermalgrowthfactorreceptors,EGFR(orHER1),HER2andHER4,whichleadsto reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been showntobeeffectiveagainstHER2‐overexpressingormutanttumorsinvitroandinvivo.Neratinibis currently being investigated in various clinical trials in breast cancers and other solid tumors, includingthosewithHER2mutation(FeldingerK,BreastCancer(DoveMedPress),2015,7,147). Dacomitinib is an irreversible inhibitor of EGFR, HER2, and HER4. In preclinical cell lines and xenograftstudies,dacomitinibdemonstratedactivitiesagainstbothactivatingEGFRmutationsand EGFRT790M(LiaoBC,CurrOpinOncol.2015,27(2),94). Third‐generationinhibitors Thethird‐generationEGFR‐TKIsweredesignedtoinhibitEGFRT790Mwhilesparingwild‐typeEGFR. AZD9291 (AstraZeneca,Macclesfield,UK), amono‐anilino‐pyrimidine compound, is an irreversible mutant selectiveEGFR‐TKI.Thisdrug is structurallydifferent from the firstand second‐generation EGFR‐TKIs. In preclinical studies, it potently inhibited phosphorylation of EGFR in cell lines with activating EGFRmutations (EGFRdel19 and EGFR L858R) and EGFR T790M.AZD9291 also caused profound and sustained tumor regression in tumor xenograft and transgenic mouse models harboring activating EGFR mutations and EGFR T790M. AZD9291 was less potent in inhibiting phosphorylationofwild‐typeEGFRcelllines(LiaoBC,CurrOpinOncol.2015,27(2),94). Rociletinib(CO‐1686)(ClovisOncology,Boulder,Colo),a2,4‐disubstitutedpyrimidinemolecule,isan irreversiblemutantselectiveEGFR‐TKI.Inpreclinicalstudies,CO‐1686ledtotumorregressionincell‐ lines, xenograftmodels, and transgenicmousemodels harboring activating EGFRmutations and EGFRT790M(WalterAO,CancerDiscov,2013,3(12),1404). HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, South Korea) is an orally administered, selective inhibitor foractivatingEGFRmutationsandEGFRT790M. Ithas lowactivityagainstwild‐ typeEGFR(SteuerCE,Cancer.2015,121(8),E1). Hilligetal2019PNASdescribecompoundslike asapotentSOS1 inhibitorandasatoolcompoundforfurther investigationofRAS‐SOS1biology in vitro. WO2018/172250(BayerPharmaAG)describes2‐methyl‐quinazolinelike asinhibitingRas‐Sosinteraction. WO2018/115380(BoehringerIngelheim)describesbenzylaminosubstitutedquinazolineslike asSOS1inhibitors. WO2019/122129(BoehringerIngelheim)describesbenzylaminosubstitutedpyridopyrimidinoeslike

asSOS1inhibitors. Ithasnowbeenfound,andthisconstitutesthebasisofthepresentinvention,thatthecompounds ofthepresentinventionhavesurprisingandadvantageousproperties. Inparticular,thecompoundsofthepresentinventionhavesurprisinglybeenfoundtoeffectivelyand selectivelyinhibittheRas‐Sos1interactionwithoutsignificantlytargetingtheEGFRreceptorandmay therefore be used for the treatment or prophylaxis of hyper‐proliferative disorders, in particular cancer. Furthermorethecompoundsofthepresentinventionshowgoodmetablicstabilityandpermeability. DESCRIPTIONOFTHEINVENTION Inaccordancewithafirstaspect,thepresentinventioncoverscompoundsofgeneralformula(I): wherein R¹ isselectedfrom ‐H,halogen,‐OH,‐CN,‐NO₂,C₁‐C₆‐alkylsulfanyl, ‐NR^aR^b,whereinR^aandR^bareindependentlyselectedfrom‐HorC₁‐C₆‐alkyl, C₁‐C₆‐alkyl,C₁‐C₆‐alkoxy,C₂‐C₆‐alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl, C₄‐C₈‐cycloalkenyl, 4‐ to 7‐membered heterocycloalkyl, 5‐ to 10 membered heterocycloalkenyl, heterospirocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl,phenyl,heteroaryl,C₁‐C₆‐haloalkyl,‐C(=O)OH, ‐C(=O)OR^c,whereinR^cstandsforC₁‐C₆‐alkyl,C₃‐C₆‐alkenyl,C₃‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl orC₄‐C₈‐cycloalkenyl, ‐N=S(=O)(R^d)R^e,whereinR^d andR^e are independently selected fromC₁‐C₆‐alkyl,C₂‐C₆‐ alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkylorC₄‐C₈‐cycloalkenyl, ‐NH‐C(O)‐C₁‐C₆‐alkyl, ‐NH‐C(O)‐NR^aR^b,whereinR^aandR^bareselectedindependentlyfromahydrogenatomor aC₁‐C₆‐alkyl, ‐NH‐(CH₂)_k‐NH‐C(O)‐C₁‐C₆‐alkyl,whereinkis1or2, ‐NH‐(CH₂)_l‐R^f, wherein l is 0, 1 or 2 and R^f stands for a 4‐ to 7‐membered heterocycloalkyl,heteroarylorC₁‐C₆‐alkylsulfonyl, whereby in all foregoing definitions the C₁‐C₆‐alkyl‐, C₁‐C₆‐alkoxy‐, the 4‐ to 7‐ memberedheterocycloalkylandtheheteroarylcanbeoptionallysubstituted,one ortwoorthreetimes,identicallyordifferently,withahalogenatom,hydroxy,oxo (=O),acyano,nitro,C₁‐C₆‐alkyl,C₂‐C₆‐alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl,4‐to 7‐memberedheterocycloalkyl,C₁‐C₆‐alkoxy,C₁‐C₆‐haloalkyl,C₁‐C₆‐haloalkoxy,C₁‐ C₆‐alkylsulfonyl, phenyl, benzyl, heteroaryl, ‐CH₂‐heteroaryl, C₃‐C₈‐cycloalkoxy. phenyloxy,heteroaryloxy, ‐NH‐C(O)‐C₁‐C₆‐alkylor–NR^aR^b,whereinR^aandR^bare independentlyselectedfromahydrogenatomorC₁‐C₆‐alkyl, ‐O‐(CH₂)_z‐phenyl, ‐O(CH₂)_z‐C₄‐C₇‐heterocycloalkyl, ‐O(CH₂)_z‐heteroaryl,wherein z is0,1 or2,andthephenyl,heterocycloalkylandheteroarylcanoptionallybesubstitutedwith agroupselectedfromhydroxy,heterocycloalkylorheterocaclyoalkenyl,whichbothcan besubstitutedwithamethyl‐and/oroxo‐group, whereinL₂astandsforC(O),L₂bstandsforabondorC₁‐C₆‐ alkylene,X2standsfor , andRx₂standsfor orinwhichafurtherR¹asdefinedabovecanbedirectlyattachedtoafirstR¹equaling C₁‐C₆‐alkyl,C₁‐C₆‐alkoxy,C₂‐C₆‐alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl,C₄‐C₈‐cycloalkenyl, 4‐ to 7‐membered heterocycloalkyl, 5‐ to 10 membered heterocycloalkenyl, heterospirocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl,C₁‐C₆‐haloalkyl, y is1,2or3; andeitherbothTandVstandfornitrogenorTstandsforcarbonandVfornitrogenorTfor nitrogenandVforcarbon; A isselectedfromthegroupconsistingofC_6‐10aryl,5‐10memberedheteroaryland9‐10 memberedbicyclicheterocyclyl; R² iseach independentlyselectedfromthegroupconsistingofC_1‐4alkyl,C_2‐4alkenyl,C_{2‐ 4}alkinyl, C_1‐4haloalkyl, hydroxy‐C_1‐4alkyl, hydroxy‐C_1‐4haloalkyl, C_3‐6cycloalkyl, 3‐6 membered heterocyclyl, hydroxy‐C_3‐6cycloalkyl, C_1‐4haloalkyl substitutedwith a 3‐6 membered heterocyclyl, 3‐6 membered heterocyclyl substituted with hydroxy, halogen,‐NH₂,‐SO₂‐C_1‐4alkylandthebivalentsubstituent=O,while=Omayonlybea substituentinanon‐aromaticring; x is1,2or3; oratautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureofsame. Inaccordancewithafurtherfirstaspect,thepresentinventioncoverscompoundsofgeneralformula (Ia): wherein R¹ isselectedfrom ‐H,halogen,‐OH,‐CN,‐NO₂,C₁‐C₆‐alkylsulfanyl, ‐NR^aR^b,whereinR^aandR^bareindependentlyselectedfrom‐HorC₁‐C₆‐alkyl, C₁‐C₆‐alkyl,C₁‐C₆‐alkoxy,C₂‐C₆‐alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl, C₄‐C₈‐cycloalkenyl, 4‐ to 7‐membered heterocycloalkyl, 5‐ to 10 membered heterocycloalkenyl,heterospirocycloalkyloptionally substitutedby anoxo‐group (=O), fused heterocycloalkyl optionally substituted by an oxo‐group (=O), bridged heterocycloalkyloptionallysubstitutedbyanoxo‐group(=O),phenyl,heteroaryl,C₁‐C₆‐ haloalkyl,‐C(=O)OH, ‐C(=O)OR^c,whereinR^cstandsforC₁‐C₆‐alkyl,C₃‐C₆‐alkenyl,C₃‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl orC₄‐C₈‐cycloalkenyl, ‐N=S(=O)(R^d)R^e,whereinR^d andR^e are independently selected fromC₁‐C₆‐alkyl,C₂‐C₆‐ alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkylorC₄‐C₈‐cycloalkenyl, ‐NH‐C(O)‐C₁‐C₆‐alkyl, ‐NH‐C(O)‐NR^aR^b,whereinR^aandR^bareselectedindependentlyfromahydrogenatomor aC₁‐C₆‐alkyl, ‐NH‐(CH₂)_k‐NH‐C(O)‐C₁‐C₆‐alkyl,whereinkis1or2, ‐NH‐(CH₂)_l‐R^f, wherein l is 0, 1 or 2 and R^f stands for a 4‐ to 7‐membered heterocycloalkyl,heteroarylorC₁‐C₆‐alkylsulfonyl, whereby in all foregoing definitions the C₁‐C₆‐alkyl‐, C₁‐C₆‐alkoxy‐, the 4‐ to 7‐ memberedheterocycloalkylandtheheteroarylcanbeoptionallysubstituted,one ortwoorthreetimes,identicallyordifferently,withahalogenatom,hydroxy,oxo (=O),acyano,nitro,C₁‐C₆‐alkyl,C₂‐C₆‐alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl,4‐to 7‐memberedheterocycloalkyl,C₁‐C₆‐alkoxy,C₁‐C₆‐haloalkyl,C₁‐C₆‐haloalkoxy,C₁‐ C₆‐alkylsulfonyl, phenyl, benzyl, heteroaryl, ‐CH₂‐heteroaryl, C₃‐C₈‐cycloalkoxy. phenyloxy,heteroaryloxy, ‐NH‐C(O)‐C₁‐C₆‐alkylor–NR^aR^b,whereinR^aandR^bare independentlyselectedfromahydrogenatomorC₁‐C₆‐alkyl, ‐O‐(CH₂)_z‐phenyl, ‐O(CH₂)_z‐C₄‐C₇‐heterocycloalkyl, ‐O(CH₂)_z‐heteroaryl,wherein z is0,1 or2,andthephenyl,heterocycloalkylandheteroarylcanoptionallybesubstitutedwith agroupselectedfromhydroxy,heterocycloalkylorheterocaclyoalkenyl,whichbothcan besubstitutedwithamethyl‐and/oroxo‐group, whereinL₂astandsforC(O),L₂bstandsforabondorC₁‐C₆‐ alkylene,X2standsfor andRx₂standsfor orinwhichafurtherR¹asdefinedabovecanbedirectlyattachedtoafirstR¹equaling C₁‐C₆‐alkyl,C₁‐C₆‐alkoxy,C₂‐C₆‐alkenyl,C₂‐C₆‐alkynyl,C₃‐C₈‐cycloalkyl,C₄‐C₈‐cycloalkenyl, 4‐ to 7‐membered heterocycloalkyl, 5‐ to 10 membered heterocycloalkenyl, heterospirocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl,C₁‐C₆‐haloalkyl, y is1,2or3; andeitherbothTandVstandfornitrogenorTstandsforcarbonandVfornitrogenorTfor nitrogenandVforcarbon; A isselectedfromthegroupconsistingofC_6‐10aryl,5‐10memberedheteroaryland9‐10 memberedbicyclicheterocyclyl; R² iseach independentlyselectedfromthegroupconsistingofC_1‐4alkyl,C_2‐4alkenyl,C_{2‐ 4}alkinyl, C_1‐4haloalkyl, hydroxy‐C_1‐4alkyl, hydroxy‐C_1‐4haloalkyl, C_3‐6cycloalkyl, 3‐6 membered heterocyclyl, hydroxy‐C_3‐6cycloalkyl, C_1‐4haloalkyl substitutedwith a 3‐6 membered heterocyclyl, 3‐6 membered heterocyclyl substituted with hydroxy, halogen,‐NH₂,‐SO₂‐C_1‐4alkylandthebivalentsubstituent=O,while=Omayonlybea substituentinanon‐aromaticring; R⁶ isselectedfromthegroupconsistingof‐H,halogen,C₁‐₄alkyl,C_3‐7‐cycloalkyl,C_{4‐ 7}heterocycloalkyloptionallycomprising1or2nitrogen,1oxygenor1sulphuratom,‐ O‐C_1‐4alkyl,‐NH₂,‐NH(C_1‐4alykl)or‐NH(C_1‐4alkyl)₂, x is1,2or3; oratautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureofsame. AlternativelyR⁶offormula(Ia)isselectedfromthegroupconsistingof‐H,‐CH₃,‐CH(CH₃)₂,‐CH₂OH,‐ CF₃or‐CHF₂. DEFINITIONS When groups in the compounds according to the invention are substituted, it ispossible for said groups tobemono‐substitutedorpoly‐substitutedwith substituent(s),unlessotherwise specified. Within the scopeof thepresent invention, themeaningsofallgroupswhichoccur repeatedlyare independent from one another. It is possible that groups in the compounds according to the inventionaresubstitutedwithone,twoorthreeidenticalordifferentsubstituents,particularlywith onesubstituent. Asusedherein,anoxosubstituentrepresentsanoxygenatom,whichisboundtoacarbonatomor toasulfuratomviaadoublebond. Theterm“ringsubstituent”meansasubstituentattachedtoanaromaticornonaromaticringwhich replacesanavailablehydrogenatomonthering. Should a composite substituent be composed of more than one parts, e.g. (C₁‐C₄‐alkoxy)‐(C₁‐C₄‐alkyl)‐,itispossibleforthepositionofa*givenparttobeatanysuitableposition ofsaidcompositesubstituent, i.e.theC₁‐C₄‐alkoxypartcanbeattachedtoanycarbonatomofthe C₁‐C₄‐alkylpartofsaid(C₁‐C₄‐alkoxy)‐(C₁‐C₄‐alkyl)‐group.Ahyphenatthebeginningorattheendof suchacompositesubstituentindicatesthepointofattachmentofsaidcompositesubstituenttothe rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent,itispossibleforsaidsubstituenttobeboundatanysuitablepositionofsaidring,be it boundtoasuitablecarbonatomand/ortoasuitableheteroatom. Theterm“comprising”whenusedinthespecificationincludes“consistingof”. Ifwithinthepresenttextany item isreferredtoas“asmentionedherein”, itmeansthat itmaybe mentionedanywhereinthepresenttext. Thetermsasmentionedinthepresenttexthavethefollowingmeanings: Theterm“halogenatom”meansafluorine,chlorine,bromineoriodineatom,particularlyafluorine, chlorineorbromineatom. Theterm“C₁‐C₆‐alkyl”meansalinearorbranched,saturated,monovalenthydrocarbongrouphaving 1,2,3,4,5or6carbonatoms,e.g.amethyl,ethyl,propyl,isopropyl,butyl,sec‐butyl,isobutyl,tert‐ butyl,pentyl,isopentyl,2‐methylbutyl,1‐methylbutyl,1‐ethylpropyl,1,2‐dimethylpropyl,neo‐pentyl, 1,1‐dimethylpropyl, hexyl, 1‐methylpentyl, 2‐methylpentyl, 3‐methylpentyl, 4‐methylpentyl, 1‐ethylbutyl, 2‐ethylbutyl, 1,1‐dimethylbutyl, 2,2‐dimethylbutyl, 3,3‐dimethylbutyl, 2,3‐dimethylbutyl,1,2‐dimethylbutylor1,3‐dimethylbutylgroup,oran isomer thereof.Particularly, saidgrouphas1,2,3or4carbonatoms(“C₁‐C₄‐alkyl”),e.g.amethyl,ethyl,propyl,isopropyl,butyl, sec‐butylisobutyl,ortert‐butylgroup,moreparticularly1,2or3carbonatoms(“C₁‐C₃‐alkyl”),e.g.a methyl,ethyl,n‐propylorisopropylgroup. The term “C₁‐C₆‐hydroxyalkyl” means a linear or branched, saturated, monovalent hydrocarbon group inwhich the term“C₁‐C₆‐alkyl” isdefinedsupra,and inwhich1,2or3hydrogenatomsare replaced with a hydroxy group, e.g. a hydroxymethyl, 1‐hydroxyethyl, 2‐hydroxyethyl, 1,2‐dihydroxyethyl, 3‐hydroxypropyl, 2‐hydroxypropyl, 1‐hydroxypropyl, 1‐hydroxypropan‐2‐yl, 2‐hydroxypropan‐2‐yl, 2,3‐dihydroxypropyl, 1,3‐dihydroxypropan‐2‐yl, 3‐hydroxy‐2‐methyl‐propyl, 2‐hydroxy‐2‐methyl‐propyl,1‐hydroxy‐2‐methyl‐propylgroup. Theterm“C₁‐C₆‐alkylsulfanyl”meansa linearorbranched,saturated,monovalentgroupofformula (C₁‐C₆‐alkyl)‐S‐, in which the term “C₁‐C₆‐alkyl” is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl,propylsulfanyl,isopropylsulfanyl,butylsulfanyl,sec‐butylsulfanyl,isobutylsulfanyl,tert‐ butylsulfanyl,pentylsulfanyl,isopentylsulfanyl,hexylsulfanylgroup. Theterm“C₁‐C₆‐alkylsulfonyl”meansa linearorbranched,saturated,monovalentgroupofformula (C₁‐C₆‐alkyl)‐SO₂‐, in which the term “C₁‐C₆‐alkyl” is as defined supra, e.g. a methylsulfonyl, ethylsulfonyl,propylsulfonyl,isopropylsulfonyl,butylsulfonyl,sec‐butylsulfonyl,isobutylsulfonyl,tert‐ butylsulfonyl,pentylsulfonyl,isopentylsulfonyl,hexylsulfonylgroup. The term “C₁‐C₆‐alkoxy” means a linear or branched, saturated, monovalent group of formula (C₁‐C₆‐alkyl)‐O‐, in which the term “C₁‐C₆‐alkyl” is as defined supra, e.g. a methoxy, ethoxy, n‐propoxy, isopropoxy, n‐butoxy, sec‐butoxy, isobutoxy, tert‐butoxy, pentyloxy, isopentyloxy or n‐hexyloxygroup,oranisomerthereof. The term “C₂‐C₆‐alkenyl” means a linear or branched, monovalent hydrocarbon group, which containsoneor twodoublebonds,andwhichhas2,3,4,5or6carbonatoms,particularly2or3 carbon atoms (“C₂‐C₃‐alkenyl”), it being understood that in the case inwhich said alkenyl group containsmorethanonedoublebond,thenitispossibleforsaiddoublebondstobeisolatedfrom,or conjugated with, each other. Said alkenyl group is, for example, an ethenyl (or “vinyl”), prop‐2‐en‐1‐yl (or “allyl”), prop‐1‐en‐1‐yl, but‐3‐enyl, but‐2‐enyl, but‐1‐enyl, pent‐4‐enyl, pent‐3‐enyl, pent‐2‐enyl, pent‐1‐enyl, hex‐5‐enyl, hex‐4‐enyl, hex‐3‐enyl, hex‐2‐enyl, hex‐1‐enyl, prop‐1‐en‐2‐yl (or “isopropenyl”), 2‐methylprop‐2‐enyl, 1‐methylprop‐2‐enyl, 2‐methylprop‐1‐enyl, 1‐methylprop‐1‐enyl, 3‐methylbut‐3‐enyl, 2‐methylbut‐3‐enyl, 1‐methylbut‐3‐enyl, 3‐methylbut‐2‐enyl, 2‐methylbut‐2‐enyl, 1‐methylbut‐2‐enyl, 3‐methylbut‐1‐enyl, 2‐methylbut‐1‐enyl,1‐methylbut‐1‐enyl,1,1‐dimethylprop‐2‐enyl,1‐ethylprop‐1‐enyl,1‐propylvinyl, 1‐isopropylvinyl, 4‐methylpent‐4‐enyl, 3‐methylpent‐4‐enyl, 2‐methylpent‐4‐enyl, 1‐methylpent‐4‐enyl, 4‐methylpent‐3‐enyl, 3‐methylpent‐3‐enyl, 2‐methylpent‐3‐enyl, 1‐methylpent‐3‐enyl, 4‐methylpent‐2‐enyl, 3‐methylpent‐2‐enyl, 2‐methylpent‐2‐enyl, 1‐methylpent‐2‐enyl, 4‐methylpent‐1‐enyl, 3‐methylpent‐1‐enyl, 2‐methylpent‐1‐enyl, 1‐methylpent‐1‐enyl, 3‐ethylbut‐3‐enyl, 2‐ethylbut‐3‐enyl, 1‐ethylbut‐3‐enyl, 3‐ethylbut‐2‐enyl, 2‐ethylbut‐2‐enyl, 1‐ethylbut‐2‐enyl, 3‐ethylbut‐1‐enyl, 2‐ethylbut‐1‐enyl, 1‐ethylbut‐1‐enyl, 2‐propylprop‐2‐enyl, 1‐propylprop‐2‐enyl, 2‐isopropylprop‐2‐enyl, 1‐isopropylprop‐2‐enyl, 2‐propylprop‐1‐enyl, 1‐propylprop‐1‐enyl, 2‐isopropylprop‐1‐enyl, 1‐isopropylprop‐1‐enyl, 3,3‐dimethylprop‐1‐enyl, 1‐(1,1‐dimethylethyl)ethenyl, buta‐1,3‐dienyl, penta‐1,4‐dienyl or hexa‐1,5‐dienylgroup.Particularly,saidgroupisvinylorallyl. Theterm“C₂‐C₆‐alkynyl”meansalinearorbranched,monovalenthydrocarbongroupwhichcontains onetriplebond,andwhichcontains2,3,4,5or6carbonatoms,particularly2or3carbonatoms (“C₂‐C₃‐alkynyl”). Said C₂‐C₆‐alkynyl group is, for example, ethynyl, prop‐1‐ynyl, prop‐2‐ynyl (or “propargyl”), but‐1‐ynyl, but‐2‐ynyl, but‐3‐ynyl, pent‐1‐ynyl, pent‐2‐ynyl, pent‐3‐ynyl, pent‐4‐ynyl, hex‐1‐ynyl,hex‐2‐ynyl,hex‐3‐ynyl,hex‐4‐ynyl,hex‐5‐ynyl,1‐methylprop‐2‐ynyl,2‐methylbut‐3‐ynyl, 1‐methylbut‐3‐ynyl, 1‐methylbut‐2‐ynyl, 3‐methylbut‐1‐ynyl, 1‐ethylprop‐2‐ynyl, 3‐methylpent‐4‐ynyl, 2‐methylpent‐4‐ynyl, 1‐methylpent‐4‐ynyl, 2‐methylpent‐3‐ynyl, 1‐methylpent‐3‐ynyl, 4‐methylpent‐2‐ynyl, 1‐methylpent‐2‐ynyl, 4‐methylpent‐1‐ynyl, 3‐methylpent‐1‐ynyl, 2‐ethylbut‐3‐ynyl, 1‐ethylbut‐3‐ynyl, 1‐ethylbut‐2‐ynyl, 1‐propylprop‐2‐ynyl, 1‐isopropylprop‐2‐ynyl, 2,2‐dimethylbut‐3‐ynyl, 1,1‐dimethylbut‐3‐ynyl, 1,1‐dimethylbut‐2‐ynyl or 3,3‐dimethylbut‐1‐ynylgroup.Particularly,saidalkynylgroupisethynyl,prop‐1‐ynylorprop‐2‐ynyl. The term “C₃‐C₈‐cycloalkyl”means a saturated,monovalent,mono‐ or bicyclic hydrocarbon ring whichcontains3,4,5,6,7or8carbonatoms(“C₃‐C₈‐cycloalkyl”).SaidC₃‐C₈‐cycloalkylgroup isfor example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl. The term “C₄‐C₈‐cycloalkenyl” means a monovalent, mono‐ or bicyclic hydrocarbon ring which contains4,5,6,7or8carbonatomsandonedoublebond.Particularly,saidringcontains4,5or6 carbon atoms (“C₄‐C₆‐cycloalkenyl”). Said C₄‐C₈‐cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group,orabicyclichydrocarbonring,e.g.abicyclo[2.2.1]hept‐2‐enylorbicyclo[2.2.2]oct‐2‐enyl. The term “C₃‐C₈‐cycloalkoxy”means a saturated,monovalent,mono‐orbicyclic groupof formula (C₃‐C₈‐cycloalkyl)‐O‐, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “C₃‐C₈‐cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxyorcyclooctyloxygroup. Theterm"spirocycloalkyl"meansasaturated,monovalentbicyclichydrocarbongroup inwhichthe two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains5,6,7,8,9,10or11carbonatoms, itbeingpossible forsaidspirocycloalkylgroup tobe attachedtotherestofthemoleculeviaanyoneofthecarbonatomsexceptthespirocarbonatom. Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl,spiro[4.5]decyl,spiro[4.6]undecylorspiro[5.5]undecyl. Theterms“4‐to7‐memberedheterocycloalkyl”meansamonocyclic,saturatedheterocyclewith4, 5,6or7ringatomsintotal,whichcontainsoneortwoidenticalordifferentringheteroatomsfrom theseriesN,OandS, itbeingpossibleforsaidheterocycloalkylgrouptobeattachedtotherestof themoleculeviaanyoneofthecarbonatomsor,ifpresent,anitrogenatom. Said heterocycloalkyl group, without being limited thereto, can be a 4‐membered ring, such as azetidinyl,oxetanylorthietanyl,forexample;ora5‐memberedring,suchastetrahydrofuranyl,1,3‐ dioxolanyl,thiolanyl,pyrrolidinyl, imidazolidinyl,pyrazolidinyl,1,1‐dioxidothiolanyl,1,2‐oxazolidinyl, 1,3‐oxazolidinylor1,3‐thiazolidinyl,forexample;ora6‐memberedring,suchastetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl,morpholinyl,dithianyl,thiomorpholinyl,piperazinyl,1,3‐dioxanyl, 1,4‐dioxanylor1,2‐oxazinanyl,forexample,ora7‐memberedring,suchasazepanyl,1,4‐diazepanyl or1,4‐oxazepanyl,forexample. Particularly, “4‐ to 6‐membered heterocycloalkyl”means a 4‐ to 6‐membered heterocycloalkyl as defined supracontainingone ringnitrogenatomandoptionallyone further ringheteroatom from the series:N,O, S.More particularly, “5‐ or 6‐membered heterocycloalkyl”means amonocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionallyonefurtherringheteroatomfromtheseries:N,O. Theterm“4‐to7‐memeberedazacycloalkyl”meansamonocyclicsaturatedheterocyclywith4,5,6 or7ringatomsintotalwhichisattachedtotherestofthemoleculeviathenitrogenatomandwhich optionallycontainsonemoreheteroatomselectedfromnitrogenandoxygen. Said4‐ to7‐membered azacycloalkyl group,withoutbeing limited thereto, canbe a4‐membered ring,suchasazetidin‐1‐yl,forexample;ora5‐memberedring,suchaspyrrolidin‐1‐yl,imidazolidin‐1‐ yl, pyrazolidin‐1‐yl, 1,2‐oxazolidin‐2‐yl or 1,3‐oxazolidin‐3‐yl, for example; or a 6‐membered ring, such as piperidin‐1‐yl, morpholin‐4‐yl, piperazin‐1‐yl or 1,2‐oxazinan‐2‐yl, for example, or a 7‐memberedring,suchasazepan‐1‐yl,1,4‐diazepan‐1‐ylor1,4‐oxazepan‐4‐yl,forexample. Theterm“5‐to10‐memberedheterocycloalkenyl”meansamonocyclic,unsaturated,non‐aromatic heterocyclewith5,6,7,8,9or10ringatomsintotal,whichcontainsoneortwodoublebondsand oneortwoidenticalordifferentringheteroatomsfromtheseries:N,O,S;itbeingpossibleforsaid heterocycloalkenylgrouptobeattachedtotherestofthemoleculeviaanyoneofthecarbonatoms or,ifpresent,anitrogenatom. Said heterocycloalkenyl group is, for example, 4H‐pyranyl, 2H‐pyranyl, 2,5‐dihydro‐1H‐pyrrolyl, [1,3]dioxolyl, 4H‐[1,3,4]thiadiazinyl, 2,5‐dihydrofuranyl, 2,3‐dihydrofuranyl, 2,5‐dihydrothiophenyl, 2,3‐dihydrothiophenyl,4,5‐dihydrooxazolylor4H‐[1,4]thiazinyl. Theterm“heterospirocycloalkyl”meansabicyclic,saturatedheterocyclewith6,7,8,9,10or11ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl”containsone,twoorthree identicalordifferentringheteroatomsfromthe series:N,O,S;itbeingpossibleforsaidheterospirocycloalkylgrouptobeattachedtotherestofthe moleculeviaanyoneofthecarbonatoms,exceptthespirocarbonatom,or, ifpresent,anitrogen atom. Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl,thiazaspiro[4.3]octyl,azaspiro[5.5]undecyl,oroneofthefurtherhom*ologous scaffolds such as spiro[3.4]‐, spiro[4.4]‐, spiro[2.4]‐, spiro[2.5]‐, spiro[2.6]‐, spiro[3.5]‐, spiro[3.6]‐, spiro[4.5]‐andspiro[4.6]‐. Theterm“6‐to10‐memberedazaspirocycloalkyl”meansabicyclic,saturatedheterocyclewith6,7, 8,9or10ringatomsintotal,inwhichthetworingsshareonecommonringcarbonatomandwhich isboundtotherestofthemoleculeviathenitrogenatomandwhichazaspirocycloalkylmaycontain upto2furtherheteroatomsselectedfromnitrogenandoxygen. Said azaspirocycloalkyl is for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro[5.5]undecyl,diazaspiro[3.3]heptyl,triazaspiro[3.4]octyloroneofthefurtherhom*ologous scaffoldssuchasspiro[3.4]‐,spiro[4.4]‐,spiro[2.4]‐,spiro[2.5]‐,spiro[2.6]‐,spiro[3.5]‐,spiro[3.6]‐and spiro[4.5]‐,wherebytheseazaspirocycloalkylgroupsarealwaysboundviathenitrogenatomtothe restofthemolecule. Ofthesegroupspreferenceisgivento2‐oxa‐6‐azaspiro[3.3]hept‐6‐yland2,5,7‐triazaspiro[3.4]octan‐ 2‐yl. Theterm“fusedheterocycloalkyl”meansabicyclic,saturatedheterocyclewith6,7,8,9or10ring atomsintotal,inwhichthetworingssharetwoadjacentringatoms,which“fusedheterocycloalkyl” containsoneortwoidenticalordifferentringheteroatomsfromtheseries:N,O,S;itbeingpossible forsaidfusedheterocycloalkylgrouptobeattachedtotherestofthemoleculeviaanyoneofthe carbonatomsor,ifpresent,anitrogenatom. Said fused heterocycloalkyl group is, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thiazabicyclo[4.3.0]nonyl or azabicyclo[4.4.0]decyl. Theterm“bridgedheterocycloalkyl”meansabicyclic,saturatedheterocyclewith7,8,9or10ring atomsintotal,inwhichthetworingssharetwocommonringatomswhicharenotadjacent,which “bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series:N,O,S;itbeingpossibleforsaidbridgedheterocycloalkylgrouptobeattachedtotherestof themolecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogenatom. Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo‐ [2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi‐ cyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl,diazabicyclo[3.3.2]decyl,oxazabicyclo[3.3.2]decyl,thiazabicyclo[3.3.2]decylor azabicyclo[4.2.2]decyl. Theterm“heteroaryl”meansamonovalent,monocyclic,bicyclicortricyclicaromaticringhaving5,6, 8,9,10,11,12,13or14ringatoms(a“5‐to14‐memberedheteroaryl”group),particularly5,6,9or 10ringatoms,whichcontainsatleastoneringheteroatomandoptionallyone,twoorthreefurther ring heteroatoms from the series:N,O and/or S, andwhich is bound via a ring carbon atom or optionallyviaaringnitrogenatom(ifallowedbyvalency). Saidheteroarylgroupcanbea5‐memberedheteroarylgroup,suchas,forexample,thienyl,furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6‐membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl,pyrimidinyl,pyrazinylor triazinyl;ora tricyclicheteroarylgroup, suchas, forexample, carbazolyl,acridinylorphenazinyl;a8‐memberedheteroarylgroup,suchasforexample6,7‐dihydro‐ 5H‐pyrrolo[1,2‐a]imidazolylora9‐memberedheteroarylgroup,suchas,forexample,benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl,thienopyridinyl,1H‐pyrrolo[2,3‐b]pyridinylor purinyl; or a 10‐membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl,cinnolinyl,phthalazinyl,quinoxalinylorpteridinyl. In general, and unless otherwisem*ntioned, the heteroaryl or heteroarylene groups include all possibleisomericformsthereof,e.g.:tautomersandpositionalisomerswithrespecttothepointof linkage to the restof themolecule.Thus, for some illustrativenon‐restrictingexamples, the term pyridinyl includespyridin‐2‐yl,pyridin‐3‐yl andpyridin‐4‐yl;or the term thienyl includes thien‐2‐yl andthien‐3‐yl. A C4 to C12 carbocyclic, heterocyclic, optionally bicyclic, optionally aromatic or optionally heteroaromatic ring system,wherein inabicyclic,aromaticorheteroaromatic ring systemoneor two double bonds can be hydrogenated is selected from the group of the substituents phenyl, naphthyl, 1,2,3,4‐tetrahydronaphthyl, 1,3‐benzodioxolyl, quinolinyl, isoquinolinyl, 2,3‐dihydro‐1,4‐ benzodioxinyl, imidazo[1,2‐a]pyridinyl, furanyl, thienyl, pyridinyl, 2H‐1,4‐benzoxazinyl‐3(4H)‐one, 2,1,3‐benzothiadiazolyl,1‐benzofuranyl,1‐benzothienyl,1H‐indazolyl,1H‐indolyl,1H‐benzimidazolyl, 1,3‐benzothiazolyl, thieno[2,3‐b]pyridinyl, thieno[2,3‐c]pyridinyl, thieno[3,2‐c]pyridinyl, pyrimidinyl, 1H‐pyrazolyl, 6,7‐dihydro‐5H‐pyrrolo[1,2‐a]imidazolyl, 1,2‐oxazolyl, 1H‐imidazolyl, 1,3,4‐oxadiazolyl, 1H‐tetrazolyl,1H‐pyrrolyl,1H‐pyrrolo[2,3‐b]pyridinylor3,4‐dihydro‐2H‐1,4‐benzoxazinyl. Particularly, the heteroaryl group is a quinolinyl, isoquinolinyl, imidazo[1,2‐a]pyridinyl, furanyl, thienyl, pyridinyl, 2,1,3‐benzothiadiazolyl, 1‐benzofuranyl, 1‐benzothiophenyl, 1H‐indazolyl, 1H‐ indolyl, 1H‐benzimidazolyl, 1,3‐benzothiazolyl, thieno[2,3‐b]pyridinyl, thieno[2,3‐c]pyridinyl, thieno[3,2‐c]pyridinyl, pyrimidinyl, 1H‐pyrazolyl, 6,7‐dihydro‐5H‐pyrrolo[1,2‐a]imidazolyl, 1,2‐ oxazolyl, 1H‐imidazolyl, 1,3,4‐oxadiazolyl, 1H‐tetrazolyl, 1H‐pyrrolyl, 1H‐pyrrolo[2,3‐b]pyridinyl or 3,4‐dihydro‐2H‐1,4‐benzoxazinylgroup. IncompositesubstituentssuchasC₁‐C₆‐haloalkyl,C₁‐C₄‐haloalkyl,C₁‐C₆‐haloalkoxy,‐(CH₂)‐heteroaryl, heteroaryloxy, ‐O‐(CH₂)_x‐heteroaryl, ‐O‐(CH₂)_z‐heteroaryl, O‐(CH₂)‐4‐ to 7‐membered heterocycloalkyl,bicyclicheteroaryl,C₁‐C₆‐hydroxyalkyl, ‐O‐(CH₂)_x‐C₃‐C₈‐cycloalkyl,O‐(CH₂)_x‐phenyl, ‐ O‐(CH₂)_x‐heterocyclyl and C₃‐C₈‐cycloalkyloxy the definition of the residue to which the further substituentisattachedisthesameasgivenfortheresidueswhichdonotbearafurthersubstituent, e.g.inC₁‐C₆‐haloalkyltheC₁‐C₆‐alkylhasthesamemeaningsasgivenfortheC₁‐C₆‐alkylearlier. The term“C₁‐C₆”,asused in thepresent text,e.g. in thecontextof thedefinitionof“C₁‐C₆‐alkyl”, “C₁‐C₆‐haloalkyl”, “C₁‐C₆‐hydroxyalkyl”, “C₁‐C₆‐alkoxy” or “C₁‐C₆‐haloalkoxy”means an alkyl group havingafinitenumberofcarbonatomsof1to6,i.e.1,2,3,4,5or6carbonatoms. Further, as used herein, the term “C₃‐C₈”, as used in the present text, e.g. in the context of the definitionof“C₃‐C₈‐cycloalkyl”,meansacycloalkylgrouphavingafinitenumberofcarbonatomsof3 to8,i.e.3,4,5,6,7or8carbonatoms. Whenarangeofvaluesisgiven,saidrangeencompasseseachvalueandsub‐rangewithinsaidrange. Forexample: "C₁‐C₆"encompassesC₁,C₂,C₃,C₄,C₅,C₆,C₁‐C₆,C₁‐C₅,C₁‐C₄,C₁‐C₃,C₁‐C₂,C₂‐C₆,C₂‐C₅,C₂‐C₄,C₂‐C₃, C₃‐C₆,C₃‐C₅,C₃‐C₄,C₄‐C₆,C₄‐C₅,andC₅‐C₆; "C₂‐C₆"encompassesC₂,C₃,C₄,C₅,C₆,C₂‐C₆,C₂‐C₅,C₂‐C₄,C₂‐C₃,C₃‐C₆,C₃‐C₅,C₃‐C₄,C₄‐C₆,C₄‐C₅,and C₅‐C₆; "C₃‐C₁₀"encompassesC₃,C₄,C₅,C₆,C₇,C₈,C₉,C₁₀,C₃‐C₁₀,C₃‐C₉,C₃‐C₈,C₃‐C₇,C₃‐C₆,C₃‐C₅,C₃‐C₄,C₄‐C₁₀, C₄‐C₉,C₄‐C₈,C₄‐C₇,C₄‐C₆,C₄‐C₅,C₅‐C₁₀,C₅‐C₉,C₅‐C₈,C₅‐C₇,C₅‐C₆,C₆‐C₁₀,C₆‐C₉,C₆‐C₈,C₆‐C₇,C₇‐C₁₀,C₇‐C₉, C₇‐C₈,C₈‐C₁₀,C₈‐C₉andC₉‐C₁₀; "C₃‐C₈"encompassesC₃,C₄,C₅,C₆,C₇,C₈,C₃‐C₈,C₃‐C₇,C₃‐C₆,C₃‐C₅,C₃‐C₄,C₄‐C₈,C₄‐C₇,C₄‐C₆,C₄‐C₅, C₅‐C₈,C₅‐C₇,C₅‐C₆,C₆‐C₈,C₆‐C₇andC₇‐C₈; "C₃‐C₆"encompassesC₃,C₄,C₅,C₆,C₃‐C₆,C₃‐C₅,C₃‐C₄,C₄‐C₆,C₄‐C₅,andC₅‐C₆; "C₄‐C₈"encompassesC₄,C₅,C₆,C₇,C₈,C₄‐C₈,C₄‐C₇,C₄‐C₆,C₄‐C₅,C₅‐C₈,C₅‐C₇,C₅‐C₆,C₆‐C₈,C₆‐C₇and C₇‐C₈; "C₄‐C₇"encompassesC₄,C₅,C₆,C₇,C₄‐C₇,C₄‐C₆,C₄‐C₅,C₅‐C₇,C₅‐C₆andC₆‐C₇; "C₄‐C₆"encompassesC₄,C₅,C₆,C₄‐C₆,C₄‐C₅andC₅‐C₆; "C₅‐C₁₀"encompassesC₅,C₆,C₇,C₈,C₉,C₁₀,C₅‐C₁₀,C₅‐C₉,C₅‐C₈,C₅‐C₇,C₅‐C₆,C₆‐C₁₀,C₆‐C₉,C₆‐C₈,C₆‐C₇, C₇‐C₁₀,C₇‐C₉,C₇‐C₈,C₈‐C₁₀,C₈‐C₉andC₉‐C₁₀; "C₆‐C₁₀"encompassesC₆,C₇,C₈,C₉,C₁₀,C₆‐C₁₀,C₆‐C₉,C₆‐C₈,C₆‐C₇,C₇‐C₁₀,C₇‐C₉,C₇‐C₈,C₈‐C₁₀,C₈‐C₉and C₉‐C₁₀. Asusedherein,theterm“leavinggroup”meansanatomoragroupofatomsthat isdisplaced ina chemicalreactionasstablespeciestakingwithitthebondingelectrons.Inparticular,suchaleaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4‐methylphenyl)sulfonyl]oxy, [(4‐bromophenyl)sulfonyl]oxy, [(4‐nitrophenyl)sulfonyl]oxy, [(2‐nitrophenyl)sulfonyl]oxy, [(4‐isopropylphenyl)sulfonyl]oxy, [(2,4,6‐triisopropylphenyl)sulfonyl]oxy, [(2,4,6‐trimethylphenyl)sulfonyl]oxy, [(4‐tert‐butyl‐ phenyl)sulfonyl]oxyand[(4‐methoxyphenyl)sulfonyl]oxy. It ispossible for the compoundsofgeneral formula (I) toexistas isotopicvariants.The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularlydeuterium‐containingcompoundsofgeneralformula(I). The term “Isotopic variant”of a compoundor a reagent isdefined as a compound exhibiting an unnaturalproportionofoneormoreoftheisotopesthatconstitutesuchacompound. The term “Isotopic variantof the compoundof general formula (I)” isdefined as a compoundof generalformula(I)exhibitinganunnaturalproportionofoneormoreoftheisotopesthatconstitute suchacompound. Theexpression“unnaturalproportion”meansaproportionofsuch isotopewhich ishigherthan its naturalabundance.Thenaturalabundancesofisotopestobeappliedinthiscontextaredescribedin “IsotopicCompositionsoftheElements1997”,PureAppl.Chem.,70(1),217‐235,1998. Examplesof such isotopes include stable and radioactive isotopesof hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹Iand ¹³¹I, respectively. With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium‐ containing compounds of general formula (I)”). Isotopic variants of the compounds of general formula(I)inwhichoneormoreradioactiveisotopes,suchas³Hor¹⁴C,areincorporatedareuseful e.g.indrugand/orsubstratetissuedistributionstudies.Theseisotopesareparticularlypreferredfor theeaseoftheirincorporationanddetectability.Positronemittingisotopessuchas¹⁸For¹¹Cmaybe incorporated intoacompoundofgeneral formula (I).These isotopicvariantsof thecompoundsof general formula (I) are useful for in vivo imaging applications. Deuterium‐containing and ¹³C‐ containing compounds of general formula (I) can be used inmass spectrometry analyses in the contextofpreclinicalorclinicalstudies. Isotopic variantsof the compoundsof general formula (I) can generallybe preparedbymethods knowntoapersonskilledintheart,suchasthosedescribedintheschemesand/orexamplesherein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium‐ containing reagent.Dependingon thedesired sitesofdeuteration, in somecasesdeuterium from D₂O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.Deuteriumgas isalsoauseful reagent for incorporatingdeuterium intomolecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporationofdeuterium.Metalcatalysts(i.e.Pd,Pt,andRh)inthepresenceofdeuteriumgascan beusedtodirectlyexchangedeuteriumforhydrogeninfunctionalgroupscontaininghydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies suchas forexampleC/D/N Isotopes,Quebec,Canada;Cambridge Isotope Laboratories Inc.,Andover,MA,USA;andCombiPhosCatalysts,Inc.,Princeton,NJ,USA. The term “deuterium‐containing compound of general formula (I)” is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and inwhich the abundanceofdeuterium at eachdeuteratedpositionof the compoundofgeneralformula(I)ishigherthanthenaturalabundanceofdeuterium,whichisabout 0.015%.Particularly, inadeuterium‐containingcompoundofgeneral formula (I) theabundanceof deuteriumateachdeuteratedpositionofthecompoundofgeneralformula(I) ishigherthan10%, 20%,30%,40%,50%,60%,70%or80%,preferablyhigherthan90%,95%,96%or97%,evenmore preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuteratedposition(s). Theselective incorporationofoneormoredeuteriumatom(s) intoacompoundofgeneralformula (I)mayalterthephysicochemicalproperties(suchasforexampleacidity[C.L.Perrin,etal.,J.Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641 ], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or themetabolic profile of the molecule andmay result in changes in the ratio of parent compound tometabolites or in the amounts ofmetabolites formed. Such changesmay result in certain therapeutic advantages and hence may be preferred in some circ*mstances. Reduced rates of metabolism and metabolic switching,wheretheratioofmetabolitesischanged,havebeenreported(A.E.Mutlibetal.,Toxicol. Appl.Pharmacol.,2000,169,102).Thesechanges in theexposure toparentdrugandmetabolites canhaveimportantconsequenceswithrespecttothepharmacodynamics,tolerabilityandefficacyof a deuterium‐containing compound of general formula (I). In some cases deuterium substitution reducesoreliminatestheformationofanundesiredortoxicmetaboliteandenhancestheformation ofadesiredmetabolite (e.g.Nevirapine:A.M. Sharmaetal.,Chem.Res.Toxicol.,2013,26,410; Efavirenz:A.E.Mutlibetal.,Toxicol.Appl.Pharmacol.,2000,169,102). Inother cases themajor effectofdeuterationistoreducetherateofsystemicclearance.Asaresult,thebiologicalhalf‐lifeof the compound is increased. The potential clinical benefitswould include the ability tomaintain similarsystemicexposurewithdecreasedpeaklevelsandincreasedtroughlevels.Thiscouldresultin lowersideeffectsandenhancedefficacy,dependingontheparticularcompound’spharmaco*kinetic/ pharmacodynamic relationship.ML‐337 (C. J.Wenthuretal., J.Med.Chem.,2013,56,5208)and Odanacatib(K.Kassahunetal.,WO2012/112363)areexamplesforthisdeuteriumeffect.Stillother caseshavebeenreportedinwhichreducedratesofmetabolismresultinanincreaseinexposureof thedrugwithoutchangingtherateofsystemicclearance(e.g.Rofecoxib:F.Schneideretal.,Arzneim. Forsch. /Drug.Res., 2006, 56, 295; Telaprevir: F.Maltais et al., J.Med. Chem., 2009, 52, 7993). Deuterateddrugsshowingthiseffectmayhavereduceddosingrequirements(e.g.lowernumberof dosesorlowerdosagetoachievethedesiredeffect)and/ormayproducelowermetaboliteloads. Acompoundofgeneral formula (I)mayhavemultiplepotentialsitesofattack formetabolism.To optimize the above‐described effects on physicochemical properties and metabolic profile, deuterium‐containing compounds of general formula (I) having a certain pattern of one ormore deuterium‐hydrogenexchange(s)canbeselected.Particularly,thedeuteriumatom(s)ofdeuterium‐ containingcompound(s)ofgeneralformula(I)is/areattachedtoacarbonatomand/oris/arelocated atthosepositionsofthecompoundofgeneralformula(I),whicharesitesofattackformetabolizing enzymessuchase.g.cytochromeP₄₅₀. In another embodiment the present invention concerns a deuterium‐containing compound of generalformula(I),inwhichone,twoorthreeofthehydrogenatom(s)ineitheroneorbothofthe methylgroupsshowningeneralformula(I)is/arereplacedwithadeuteriumatom. AlsothehydrogenatomonthecarbonatombetweenthenitrogenatomandthegroupA1canbe replacedwithadeuteriumatomeitherasthesinglereplacementofahydrogenbyadeuteriumorin additiontothebeforementionedreplacementsineitheroneorbothofthemethylgroupsshownin generalformula(I). Wherethepluralformofthewordcompounds,salts,polymorphs,hydrates,solvatesandthelike,is usedherein,thisistakentomeanalsoasinglecompound,salt,polymorph,isomer,hydrate,solvate orthelike. By"stablecompound'or"stablestructure"ismeantacompoundthatissufficientlyrobusttosurvive isolation toausefuldegreeofpurity froma reactionmixture,and formulation intoanefficacious therapeuticagent. Thecompoundsof thepresent inventioncontainat leastoneoroptionallyevenmoreasymmetric centres,dependingupon the locationandnatureof thevarioussubstituentsdesired. It ispossible thatoneormoreasymmetriccarbonatomsarepresent in the (R)or (S)configuration,whichcan resultinracemicmixturesinthecaseofasingleasymmetriccentre,andindiastereomericmixtures inthecaseofmultipleasymmetriccentres.Incertaininstances,itispossiblethatasymmetryalsobe presentduetorestrictedrotationaboutagivenbond,forexample,thecentralbondadjoiningtwo substitutedaromaticringsofthespecifiedcompounds. Preferredisomersarethosewhichproducethemoredesirablebiologicalactivity.Separated,pureor partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compoundsofthepresentinventionarealsoincludedwithinthescopeofthepresentinvention.The purificationandtheseparationofsuchmaterialscanbeaccomplishedbystandardtechniquesknown intheart. Theopticalisomerscanbeobtainedbyresolutionoftheracemicmixturesaccordingtoconventional processes,forexample,bytheformationofdiastereoisomericsaltsusinganopticallyactiveacidor base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomericsalts.Adifferentprocessforseparationofoptical isomers involvestheuseofchiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columnsusingachiralphasearecommerciallyavailable,suchasthosemanufacturedbyDaicel,e.g., ChiracelOD andChiracelOJ, forexample,amongmanyothers,whichareall routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compoundsofthepresent inventioncan likewisebeobtainedbychiralsynthesesutilizingoptically activestartingmaterials. InordertodistinguishdifferenttypesofisomersfromeachotherreferenceismadetoIUPACRules SectionE(PureApplChem45,11‐30,1976). Thepresentinventionincludesallpossiblestereoisomersofthecompoundsofthepresentinvention assinglestereoisomers,orasanymixtureofsaidstereoisomers,e.g.(R)‐or(S)‐isomers,inanyratio. Isolationofasinglestereoisomer,e.g.asingleenantiomerorasinglediastereomer,ofacompound of the present invention is achieved by any suitable state of the art method, such as chromatography,especiallychiralchromatography,forexample. Further,itispossibleforthecompoundsofthepresentinventiontoexistastautomers.Forexample, anycompoundof thepresent inventionwhichcontainsan imidazopyridinemoietyasaheteroaryl groupforexamplecanexistasa1Htautomer,ora3Htautomer,orevenamixtureinanyamountof thetwotautomers,namely: Thepresentinventionincludesallpossibletautomersofthecompoundsofthepresentinventionas singletautomers,orasanymixtureofsaidtautomers,inanyratio. Further,thecompoundsofthepresentinventioncanexistasN‐oxides,whicharedefinedinthatat least one nitrogen of the compounds of the present invention is oxidised. The present invention includesallsuchpossibleN‐oxides. Thepresent inventionalsocoversusefulformsofthecompoundsofthepresent invention,suchas metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/orco‐precipitates. The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compoundsofthepresentinventioncontainpolarsolvents,inparticularwater,methanolorethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amountofpolarsolvents,inparticularwater,toexistinastoichiometricornon‐stoichiometricratio. Inthecaseofstoichiometricsolvates,e.g.ahydrate,hemi‐,(semi‐),mono‐,sesqui‐,di‐,tri‐,tetra‐, penta‐etc.solvatesorhydrates, respectively,arepossible.Thepresent invention includesallsuch hydratesorsolvates. Further,itispossibleforthecompoundsofthepresentinventiontoexistinfreeform,e.g.asafree base,orasafreeacid,orasazwitterion,ortoexist intheformofasalt.Saidsaltmaybeanysalt, eitheranorganicor inorganicadditionsalt,particularlyanypharmaceuticallyacceptableorganicor inorganicaddition salt,which is customarilyused inpharmacy,orwhich isused, forexample, for isolatingorpurifyingthecompoundsofthepresentinvention. Theterm“pharmaceuticallyacceptablesalt"referstoan inorganicororganicacidadditionsaltofa compoundof thepresent invention.Forexample,seeS.M.Berge,etal.“PharmaceuticalSalts,” J. Pharm.Sci.1977,66,1‐19. Asuitablepharmaceuticallyacceptablesaltofthecompoundsofthepresent inventionmaybe,for example,anacid‐additionsaltofacompoundofthepresentinventionbearinganitrogenatom,ina chain or in a ring, for example,which is sufficiently basic, such as an acid‐addition saltwith an inorganicacid,or“mineralacid”, suchashydrochloric,hydrobromic,hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, orwith an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2‐(4‐hydroxybenzoyl)‐benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3‐hydroxy‐2‐naphthoic, nicotinic, pamoic, pectinic, 3‐phenylpropionic, pivalic, 2‐ hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para‐toluenesulfonic, methanesulfonic, 2‐naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonicacid, citric, tartaric, stearic, lactic,oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D‐gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric,aspartic,sulfosalicylic,orthiocyanicacid,forexample. Further,anothersuitablypharmaceuticallyacceptablesaltofacompoundofthepresent invention whichissufficientlyacidic,isanalkalimetalsalt,forexampleasodiumorpotassiumsalt,analkaline earthmetalsalt,forexampleacalcium,magnesiumorstrontiumsalt,oranaluminiumorazincsalt, oranammoniumsaltderivedfromammoniaorfromanorganicprimary,secondaryortertiaryamine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine,N‐methylmorpholine, arginine, lysine, 1,2‐ethylenediamine,N‐methylpiperidine,N‐ methyl‐glucamine, N,N‐dimethyl‐glucamine, N‐ethyl‐glucamine, 1,6‐hexanediamine, glucosamine, sarcosine,serinol,2‐amino‐1,3‐propanediol,3‐amino‐1,2‐propanediol,4‐amino‐1,2,3‐butanetriol,or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n‐propyl)ammonium, tetra(n‐butyl)ammonium, N‐benzyl‐N,N,N‐trimethylammonium,cholineorbenzalkonium. Thoseskilledintheartwillfurtherrecognisethatitispossibleforacidadditionsaltsoftheclaimed compoundstobepreparedbyreactionofthecompoundswiththeappropriateinorganicororganic acidviaanyofanumberofknownmethods.Alternatively,alkaliandalkalineearthmetal saltsof acidiccompoundsofthepresent inventionarepreparedbyreactingthecompoundsofthepresent inventionwiththeappropriatebaseviaavarietyofknownmethods. Thepresentinventionincludesallpossiblesaltsofthecompoundsofthepresentinventionassingle salts,orasanymixtureofsaidsalts,inanyratio. Inthepresenttext,inparticularintheExperimentalSection,forthesynthesisofintermediatesand of examples of the present invention,when a compound ismentioned as a salt formwith the correspondingbaseoracid, theexactstoichiometriccompositionofsaidsalt form,asobtainedby therespectivepreparationand/orpurificationprocess,is,inmostcases,unknown. Unlessspecifiedotherwise,suffixestochemicalnamesorstructuralformulaerelatingtosalts,such as"hydrochloride","trifluoroacetate","sodiumsalt",or"xHCl","xCF₃COOH","xNa⁺",forexample, meanasaltform,thestoichiometryofwhichsaltformnotbeingspecified. Thisappliesanalogously tocases inwhichsynthesis intermediatesorexamplecompoundsorsalts thereofhavebeenobtained,bythepreparationand/orpurificationprocessesdescribed,assolvates, suchashydrates,with(ifdefined)unknownstoichiometriccomposition. As used herein, the term “in vivo hydrolysable ester”means an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceuticallyacceptableesterwhichishydrolysedinthehumanoranimalbodytoproducethe parentacidoralcohol.Suitablepharmaceuticallyacceptableestersforcarboxy includeforexample alkyl,cycloalkylandoptionallysubstitutedphenylalkyl,inparticularbenzylesters,C₁‐C₆alkoxymethyl esters,e.g.methoxymethyl,C₁‐C₆alkanoyloxymethylesters,e.g.pivaloyloxymethyl,phthalidylesters, C₃‐C₈ cycloalkoxy‐carbonyloxy‐C₁‐C₆alkylesters,e.g.1‐cyclohexylcarbonyloxyethyl ;1,3‐dioxolen‐2‐ onylmethyl esters, e.g. 5‐methyl‐1,3‐dioxolen‐2‐onylmethyl ; and C₁‐C₆‐alkoxycarbonyloxyethyl esters,e.g.1‐methoxycarbonyloxyethyl,itbeingpossibleforsaidesterstobeformedatanycarboxy groupinthecompoundsofthepresentinvention. An invivohydrolysableesterofacompoundof thepresent inventioncontainingahydroxygroup includes inorganic esters such as phosphate esters and [alpha]‐acyloxyalkyl ethers and related compoundswhichasa resultof the in vivohydrolysisof theesterbreakdown togive theparent hydroxy group. Examples of [alpha]‐acyloxyalkyl ethers include acetoxymethoxy and 2,2‐ dimethylpropionyloxymethoxy.Aselectionof invivohydrolysableesterforminggroupsforhydroxy includealkanoyl,benzoyl,phenylacetylandsubstitutedbenzoylandphenylacetyl,alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN‐(dialkylaminoethyl)‐N‐alkylcarbamoyl (to give carbamates),dialkylaminoacetylandcarboxyacetyl.Thepresentinventioncoversallsuchesters. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compoundsofthepresent invention,eitherassinglepolymorph,orasamixtureofmorethanone polymorph,inanyratio. Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs”heredesignates compoundswhich themselves canbebiologically activeor inactive,butare converted (forexamplemetabolicallyorhydrolytically) into compounds accordingtotheinventionduringtheirresidencetimeinthebody. Inaccordancewithotherembodiments,thepresentinventioncoversthefollowingcompounds. A) AcompoundofformulaIorIa,wherein R¹ isselectedfrom ‐H,‐Br,‐OH,‐NO₂,‐CH₃, ,‐O‐CH₃,‐O‐CH₂‐CH₃,‐O‐CH(CH₃)₂, ‐O‐(CH₂)₃CH₃,‐O‐(CH₂)₂CH(CH₃)₂, ‐O‐CH₂‐phenyl,‐O‐(CH₂)₂‐O‐CH₃,‐O‐(CH₂)₂‐S(O)₂‐CH₃,‐CH₂‐OH,‐C(CH₃)₂‐OH, ‐C(O)OH,‐C(O)OCH₃,‐NH₂,‐NH(CH₃),‐N(CH₃)₂, ‐NH‐(CH₂)₂‐NH‐C(O)‐CH₃,‐NH‐(CH₂)₂‐morpholino,‐NH‐C(O)‐CH₃, ‐NH‐C(O)‐NH‐CH₃,‐NH‐C(O)‐N(CH₃)₂,‐NH‐S(O)₂‐CH₃,‐N=S(O)(CH₃)₂, y is1or2; A isselectedfromthegroupconsistingofC_6‐10aryl,5‐10memberedheteroaryland9‐10 memberedbicyclicheterocyclyl; R² iseach independentlyselectedfromthegroupconsistingofC_1‐4alkyl,C_2‐4alkenyl,C_{2‐ 4}alkinyl, C_1‐4haloalkyl, hydroxy‐C_1‐4alkyl, hydroxy‐C_1‐4haloalkyl, C_3‐6cycloalkyl, 3‐6 membered heterocyclyl, hydroxy‐C_3‐6cycloalkyl, C_1‐4haloalkyl substitutedwith a 3‐6 membered heterocyclyl, 3‐6 membered heterocyclyl substituted with hydroxy, halogen,‐NH₂,‐SO₂‐C_1‐4alkylandthebivalentsubstituent=O,while=Omayonlybea substituentinanon‐aromaticring x is1,2or3; oratautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureofsame. B) AcompoundasdefinedinA(above),wherein A isselectedfromthegroupconsistingofC_6‐10‐aryl,5‐10memberedheteroaryland9‐10 memberedbicyclicheterocyclyl; R2 iseachindependentlyselectedfromthegroupconsistingofC_1‐4‐alkyl,C_2‐4‐alkenyl,C_2‐4‐ alkinyl, C_1‐4‐haloalkyl, hydroxy‐C_1‐4‐alkyl, hydroxy‐C_1‐4‐haloalkyl, C_3‐6‐cycloalkyl, 3‐6 membered heterocyclyl, hydroxy‐C_3‐6‐cycloalkyl, C_1‐4‐haloalkyl substitutedwith a 3‐6 membered heterocyclyl, 3‐6 membered heterocyclyl substituted with hydroxy, halogen,‐NH₂,‐SO₂‐C_1‐4‐alkylandthebivalentsubstituent=O,while=Omayonlybea substituentinanon‐aromaticring x is1,2or3 oratautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureofsame. C) AcompoundasdefinedinAorB(above),wherein A isselectedfromthegroupconsistingofC_6‐10aryl,5‐10memberedheteroaryland9‐10 memberedbicyclicheterocyclyl; x is1or2 R² iseachindependentlyselectedfromthegroupconsistingofC_1‐4‐alkyl,C_2‐4‐alkinyl,C_1‐4‐ haloalkyl,hydroxy‐C_1‐4‐haloalkyl,C_1‐4‐haloalkylsubstitutedwitha3‐6membered heterocyclyl,halogen,andthebivalentsubstituent=O,while=Omayonlybea substituentinanon‐aromaticring oratautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureofsame. D) AcompoundasdefinedinA,BorC(above),wherein andwherein R³ isselectedfromthegroupconsistingofC_1‐4‐alkyl,C_1‐4‐haloalkyl,hydroxy‐C_1‐4‐alkyl, hydroxy‐C_1‐4‐haloalkyl,C_1‐4‐haloalkylsubstitutedwitha3‐6memberedheterocyclyl, C_3‐6‐cycloalkyl,hydroxy‐C_3‐6‐cycloalkyl,3‐6memberedheterocyclyl,3‐6membered hydroxy‐heterocyclyl,halogenand‐SO₂‐C_1‐4‐alkyl; R⁴ isselectedfromthegroupconsistingofhydrogenand‐NH₂, R⁵ isselectedfromthegroupconsistingofhydrogen,C_1‐4‐alkylandhalogen; or R³andR⁵togetherwiththecarbonatomstheyareattachedforma5‐6membered nonaromaticcarbocycle,a5‐6memberednon‐aromaticheterocycleora5‐6 memberedheteroaryl,whereinthe5‐6memberednon‐aromaticcarbocycle,5‐6 memberednonaromaticheterocycleand5‐6memberedheteroarylarealloptionally substitutedbyoneormorehalogenorbyanoxogroup oratautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureofsame. E) AcompoundasdefinedinA,B,CorD(above),wherein R³ isselectedfromthegroupconsistingofC_1‐4‐haloalkyl,hydroxy‐C_1‐4‐haloalkylandC_1‐4‐ haloalkylsubstitutedwitha3‐6memberedheterocyclyl; R⁴ ishydrogen; R⁵ isselectedfromthegroupconsistingofhydrogen,C_1‐4‐alkylandfluorine; or R³andR⁵togetherwiththecarbonatomstheyareattachedforma5‐6membered nonaromaticcarbocycle,a5‐6memberednon‐aromaticheterocycleora5‐6 memberedheteroaryl,whereinthe5‐6memberednon‐aromaticcarbocycle,5‐6 memberednonaromaticheterocycleand5‐6memberedheteroarylarealloptionally substitutedbyoneormorefluorineorbyanoxogroup oratautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureofsame. F) AcompoundasdefinedinA,B,C,DorE(above),wherein isselectedfrom orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixture ofsame. G) ThecompoundasdefinedinA,B,C,D,EorF(above),whereinVisnitrogenandTiscarbonor astereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. H) ThecompoundasdefinedinA,B,C,D,E,ForG(above),whereiny=1andR¹isselectedfrom orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixture ofsame. I) ThecompoundasdefinedinA,B,C,D,E,F,GorH(above),whereinVisnitrogen,Tiscarbon,y =1, R¹isselectedfrom and isselectedfrom orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixture ofsame. J) ThecompoundasdefinedinA,B,C,D,E,F,G,HorI(above),whichisselectedfromthegroup consistingof: N‐[(3R)‐1‐[2‐methyl‐4‐[[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[2‐methyl‐4‐[[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐fluoro‐2,8‐dimethylpyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2,8‐dimethylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixture ofsame. K) ASOS1inhibitorcompoundasdescribedhereinorasdefinedinA,B,C,D,E,F,G,H,IorJ (above)foruseinthetreatmentand/orpreventionofcancer,whereinsaidSOS1inhibitor compoundisadministeredincombinationwithatleastoneotherpharmacologicallyactive substanceandwhereineachofsaidotherpharmacologicallyactivesubstance(s)isselected fromthegroupconsistingof:aninhibitorofHRas,NRasorKRASandmutantsthereof,in particularaninhibitorofKRAS‐G12C;aninhibitorofMAPkinases,inparticularMEK1,MEK2, ERK1,ERK2,ERK5and/orofaninhibitorofPI3‐kinasesandmutantsthereof;aninhibitorof TropomyosinReceptorkinasesand/orofmutantsthereof;aninhibitorofSHP2andmutants thereof;inhibitorofEGFRand/orofmutantsthereof;aninhibitorofFGFR1and/orFGFR2 and/orFGFR3and/orofmutantsthereof;aninhibitorofALKand/orofmutantsthereof;an inhibitorofc‐METand/orofmutantsthereof;aninhibitorofBCR‐ABLand/orofmutants thereof;aninhibitorofErbB2(Her2)and/orofmutantsthereof;aninhibitorofAXLand/orof mutantsthereof;aninhibitorofA‐Rafand/orB‐Rafand/orC‐Rafand/orofmutantsthereof;an inhibitorofmTORandmutantsthereof;aninhibitorofIGF1/2and/orofIGF1‐R;aninhibitorof farnesyltransferase. Inaccordancewithfurtherembodiments,thepresentinventioncoversthefollowingcompounds. AcompoundofformulaIorIaasdefinedinA,B,C,D,E,F,G,HorI(above),wherein R¹ isselectedfrom

R¹canalsobeselectedfrom

AcompoundofformulaIorIaasdefinedinA,B,C,D,E,F,G,HorI(above),wherein R¹ isselectedfrom AcompoundofformulaIasdefinedinA,B,C,D,E,F,G,HorI(above),wherein AcompoundofformulaIorIaasdefinedinA,B,C,D,E,F,G,HorI(above),wherein AcompoundofformulaIorIaasdefinedinA,B,C,D,E,F,G,HorI(above),wherein AcompoundofformulaIorIaasdefinedinA,B,C,D,E,F,G,HorI(above),wherein AcompoundofformulaIorIaasdefinedinA,B,C,D,E,F,G,HorI(above),wherein AcompoundofformulaIorIaasdefinedinA,B,C,D,E,F,G,HorI(above),wherein Inaparticularfurtherembodimentofthefirstaspect,thepresentinventioncoverscombinationsof twoormoreoftheabovementionedembodimentsundertheheading“furtherembodimentsofthe firstaspectofthepresentinvention”. Further embodiments of this invention can be presented by the following alternative claim set possibility: 1.Acompoundofgeneralformula(1) wherein R^1a isselectedfromthegroupconsistingof 5‐6memberedheteroaryl,9‐10memberedbicyclicheteroarylorphenyl,alloptionally oneormoretimessubstitutedby ‐H,‐OH,‐CN,‐NO₂,‐NH₂,halogen,‐COOH,‐COO‐CH₃,‐SF₅,(1E)‐2‐ethoxyethenyl, [(tert‐butoxy)carbonyl]amino,1H‐pyrazol‐1‐yl,2‐(methylamino)ethoxy,oxolan‐3‐ yloxy,(1‐methylpyrrolidin‐3‐yl)oxy,C_1‐6‐alkyloptionallysubstitutedoneormore timeswith‐Fand/or‐OHand/or‐O‐C_1‐6‐alkylor‐S‐C_1‐6‐alkyl,bothoptionally substitutedoneormoretimeswith‐F; R^2a isselectedfromthegroupconsistingof−F,−Cl,−OCH₃,−COOCH₃,−S(=O)₂‐CH₃,−O‐CH₂‐ CH₂R⁹,−C(=O)‐NHR^3a,2,5‐dihydrofuran‐3‐yl,4,5‐dihydrofuran‐2‐yl,oxolan‐3‐yl,oxetan‐ 3‐yloxy,cyclopentylamino,5,6‐dihydro‐2H‐pyran‐3‐yl,oxan‐3‐yl,3,6‐dihydro‐2H‐pyran‐ 4‐yl,1‐methyl‐1H‐pyrazol‐4‐yl,oxan‐4‐yl,[(oxetan‐2‐yl)methyl]amino,−N(R^3a)‐CH(R^3a)‐ CH₂‐R¹²,1‐methylpiperidin‐4‐yl,1‐methyl‐1,2,3,6‐tetrahydropyridin‐4‐yl,1‐oxa‐6‐ azaspiro[3.3]heptan‐6‐yl,[(oxolan‐2‐yl)methyl]amino,2‐oxa‐6‐azaspiro[3.3]heptan‐6‐yl, (1‐methylpyrrolidin‐3‐yl)oxy,(5‐oxopyrrolidin‐3‐yl)amino,3‐(difluoromethyl)azetidin‐1‐ yl,2‐oxa‐6‐azaspiro[3.4]octan‐6‐yl,3‐oxo‐1,4‐diazepan‐1‐yl,−R²²‐COOC(CH₃)₃,4‐cyano‐4‐ methylpiperidin‐1‐yl,2‐oxa‐6‐azaspiro[3.5]nonan‐6‐yl,2‐oxa‐7‐azaspiro[3.5]nonan‐7‐yl, 5‐oxo‐2,6‐diazaspiro[3.4]octan‐2‐yl,7‐oxo‐2,6‐diazaspiro[3.4]octan‐2‐yl,8‐oxo‐2,7‐ diazaspiro[4.4]nonan‐2‐yl,4‐methyl‐2,3‐dioxo‐1,4‐diazepan‐1‐yl, ; R^3a isselectedfromthegroupconsistingof−Hand−CH₃; R^4a isselectedfromthegroupconsistingof−Hand−F; R^5a isselectedfromthegroupconsistingof−H,−F,−Cl,−Br,−CN,−NO₂,−OH,−CH₂OH, −COOH,‐COO‐CH₃,−CH₃,−CF₃,−CHF₂,−CF₂−CH₃,−CF₂−CH₂OH,−CF₂−C(CH₃)₂OH,−O‐CH₃, −O‐CH₂‐CHF₂,−O‐CF₃,‐O‐CHF₂,−S‐CF₃,−SF₅,(1E)‐2‐ethoxyethenyl,and[(tert‐ butoxy)carbonyl]amino; R^6a isselectedfromthegroupconsistingof−H,−F,−Cl,−CH₃,−CHF₂,−O‐CH₃,−O‐CHF₂,1H‐ pyrazol‐1‐yl,2‐(methylamino)ethoxy,oxolan‐3‐yloxy,and(1‐methylpyrrolidin‐3‐yl)oxy; R⁷ isselectedfromthegroupconsistingof−H,−NH₂,−F,and−Br; R⁸ isselectedfromthegroupconsistingof−H,−CH₃,and−F; R⁹ isselectedfromthegroupconsistingof−H,−CH₂‐CH₃,and–NH‐CH₃; R¹⁰ isselectedfromthegroupconsistingof R¹¹ isselectedfromthegroupconsistingof‐CH₂‐CH₂‐CH₂‐,‐CH₂‐O‐CH₂‐,‐CH₂‐CH₂‐O‐, −N(CH₃)‐CH₂‐CH₂−,‐CH₂‐NH‐CH₂‐and‐CH₂‐N(R³¹)‐CH₂‐; R¹² isselectedfromthegroupconsistingof‐H,‐OCH₃,and‐N(CH₃)₂; R¹³ isselectedfromthegroupconsistingof R¹⁴ isselectedfromthegroupconsistingof−CH₂‐C(R^4a)₂‐CH₂‐,‐CH₂‐CH₂‐C(=O)‐and‐CH₂‐O‐ C(=O)‐; R¹⁵ isselectedfromthegroupconsistingof−H,−OH,−F,−OCH₃,−N(CH₃)₂,−C(=O)‐NH₂,‐ COOH,pyrrolidin‐1‐yl,‐NH‐SO₂‐R³⁴,‐N(R^3a)‐CO‐R³⁵,andmorpholin‐4‐yl; R¹⁶ isselectedfromthegroupconsistingof−H,−CH₃,−F,and−CH₂‐CH₂OH; R¹⁷ isselectedfromthegroupconsistingof−Hand−N(CH₃)₂; R¹⁸ isselectedfromthegroupconsistingof−Hand–CH=CH₂; R¹⁹ isselectedfromthegroupconsistingof=CH₂and=O; R²⁰ isselectedfromthegroupconsistingof−Hand−CN; R²¹ isselectedfromthegroupconsistingof−H,−CH₃,and–C(=O)‐CH₃; R²² isselectedfromthegroupconsistingof R²³ isselectedfromthegroupconsistingof−H,−CH₃,and−COOH; R²⁴ isselectedfromthegroupconsistingof−CH₃and–C(=O)‐O‐C(CH₃)₃; R²⁵ isselectedfromthegroupconsistingof−NH−and R²⁶ isselectedfromthegroupconsistingof−Hand−OH; R²⁷ isselectedfromthegroupconsistingof−H,−CH₃,−CH₂‐CH₃,−CN,−CH₂OH,cyclopropyl, −CH₂‐CN,−N(CH₃)₂,−C(CH₃)₂OH,−NH‐C(=O)‐CH₃,−S(=O)₂CH₃,−CH₂‐CH₂‐OR³⁶,−CH₂‐ CF₂R^4a,−C(=O)‐N(R^3a)₂,oxetane‐3‐carbonyl,−C(=O)‐C(R³⁸)(R³⁹)R^4a,and R²⁸ isselectedfromthegroupconsistingof−H,−CH₃,−OH,−N(CH₃)₂,−S(=O)₂NH₂,and– C(=O)‐NHR^3a; R²⁹ isselectedfromthegroupconsistingof−H,−CH₃,and−CH₂OH; R³¹ isselectedfromthegroupconsistingof−CH₃and–C(=O)‐CH₃; R³² isselectedfromthegroupconsistingof−Hand−CF₃; R³³ isselectedfromthegroupconsistingof−H,−CN,and−CF₃; R³⁴ isselectedfromthegroupconsistingof−CH₃andcyclopropyl; R³⁵ isselectedfromthegroupconsistingof−CH₃,−OCH₃,cyclopropyl,−CH₂‐OCH₃,−CHF₂, oxetan‐3‐yl,and1‐methylazetidin‐3‐yl; R³⁶ isselectedfromthegroupconsistingof−H,−CH₃,and R³⁷ isselectedfromthegroupconsistingof−H,−F,and−CN; R³⁸ isselectedfromthegroupconsistingof−H,−CH₃,−CH₂‐NH₂,−CH₂‐NH‐CH₃,and−CH₂‐ CH₂‐CH₂‐CH₂‐CH₂‐CH₂‐CH₂‐C(=O)‐OR^3a;and R³⁹ isselectedfromthegroupconsistingof−H,−NH₂,−F,−NH‐CH₃,−OCH₃,and−N(CH₃)₂. orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 2.Thecompoundaccordingtoclaim1ofgeneralformula(I)inwhich: R^1a isselectedfromthegroupconsistingof 5‐chloro‐1,3‐thiazol‐2‐yl, 6‐aminopyridin‐2‐yl, 5‐bromopyridin‐3‐yl, 3‐(trifluoromethyl)‐1,2,4‐oxadiazol‐5‐yl, 3‐fluoro‐1‐benzofuran‐7‐yl, R^4a isselectedfromthegroupconsistingof−Hand−F; R^5a isselectedfromthegroupconsistingof−H,−F,−Cl,−Br,−CN,−NO₂,−OH,−CH₂OH, −COOH,‐COO‐CH₃,−CH₃,−CF₃,−CHF₂,−CF₂−CH₃,−CF₂−CH₂OH,−CF₂−C(CH₃)₂OH,−O‐CH₃, −O‐CH₂‐CHF₂,−O‐CF₃,‐O‐CHF₂,−S‐CF₃,−SF₅,(1E)‐2‐ethoxyethenyl,and[(tert‐ butoxy)carbonyl]amino; R^6a isselectedfromthegroupconsistingof−H,−F,−Cl,−CH₃,−CHF₂,−O‐CH₃,−O‐CHF₂,1H‐ pyrazol‐1‐yl,2‐(methylamino)ethoxy,oxolan‐3‐yloxy,and(1‐methylpyrrolidin‐3‐yl)oxy; R⁷ isselectedfromthegroupconsistingof−H,−NH₂,−F,and−Br;and R⁸ isselectedfromthegroupconsistingof−H,−CH₃,and−F; orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 3.Thecompoundaccordingtoclaim2ofgeneralformula(I)inwhich: R^1a is R^5a isselectedfromthegroupconsistingof−CF₃,−CHF₂,−CF₂−CH₃,−CF₂−CH₂OH,and −CF₂−C(CH₃)₂OH;and R^6a isselectedfromthegroupconsistingof−H,−F,and−CH₃; orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 4.Thecompoundaccordingtoclaim1ofgeneralformula(1a) orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 5.Thecompoundaccordingtoclaim1ofgeneralformula(1b) orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 6.Thecompoundaccordingtoclaim4ofgeneralformula(1a)inwhich: R^1a is R^2a isselectedfromthegroupconsistingof−F,−Cl,−OCH₃,−COOCH₃,−S(=O)₂‐CH₃,−O‐CH₂‐ CH₂R⁹,−C(=O)‐NHR^3a,2,5‐dihydrofuran‐3‐yl,4,5‐dihydrofuran‐2‐yl,oxolan‐3‐yl,oxetan‐ 3‐yloxy,cyclopentylamino,5,6‐dihydro‐2H‐pyran‐3‐yl,oxan‐3‐yl,3,6‐dihydro‐2H‐pyran‐ 4‐yl,1‐methyl‐1H‐pyrazol‐4‐yl,oxan‐4‐yl,[(oxetan‐2‐yl)methyl]amino,−N(R^3a)‐CH(R^3a)‐ CH₂‐R¹²,1‐methylpiperidin‐4‐yl,1‐methyl‐1,2,3,6‐tetrahydropyridin‐4‐yl,1‐oxa‐6‐ azaspiro[3.3]heptan‐6‐yl,[(oxolan‐2‐yl)methyl]amino,2‐oxa‐6‐azaspiro[3.3]heptan‐6‐yl, (1‐methylpyrrolidin‐3‐yl)oxy,(5‐oxopyrrolidin‐3‐yl)amino,3‐(difluoromethyl)azetidin‐1‐ yl,2‐oxa‐6‐azaspiro[3.4]octan‐6‐yl,3‐oxo‐1,4‐diazepan‐1‐yl,−R²²‐COOC(CH₃)₃,4‐cyano‐4‐ methylpiperidin‐1‐yl,2‐oxa‐6‐azaspiro[3.5]nonan‐6‐yl,2‐oxa‐7‐azaspiro[3.5]nonan‐7‐yl, 5‐oxo‐2,6‐diazaspiro[3.4]octan‐2‐yl,7‐oxo‐2,6‐diazaspiro[3.4]octan‐2‐yl,8‐oxo‐2,7‐ diazaspiro[4.4]nonan‐2‐yl,4‐methyl‐2,3‐dioxo‐1,4‐diazepan‐1‐yl, ,and R^3a isselectedfromthegroupconsistingof−Hand–CH₃; R^4a isselectedfromthegroupconsistingof−Hand−F; R^5a isselectedfromthegroupconsistingof−CF₃,−CHF₂,−CF₂−CH₃,−CF₂−CH₂OH,and −CF₂−C(CH₃)₂OH;and R^6a isselectedfromthegroupconsistingof−H,−F,and−CH₃; R⁹ isselectedfromthegroupconsistingof−H,−CH₂‐CH₃,and–NH‐CH₃; R¹⁰ isselectedfromthegroupconsistingof 1¹ R isselectedfromthegroupconsistingof‐CH₂‐CH₂‐CH₂‐,‐CH₂‐O‐CH₂‐,‐CH₂‐CH₂‐O‐, −N(CH₃)‐CH₂‐CH₂−,‐CH₂‐NH‐CH₂‐and‐CH₂‐N(R³¹)‐CH₂‐; R¹² isselectedfromthegroupconsistingof‐H,‐OCH₃,and‐N(CH₃)₂; R¹³ isselectedfromthegroupconsistingof R¹⁴ isselectedfromthegroupconsistingof−CH₂‐C(R^4a)₂‐CH₂‐,‐CH₂‐CH₂‐C(=O)‐and‐CH₂‐O‐ C(=O)‐; R¹⁵ isselectedfromthegroupconsistingof−H,−OH,−F,−OCH₃,−N(CH₃)₂,−C(=O)‐NH₂,‐ COOH,pyrrolidin‐1‐yl,‐NH‐SO₂‐R³⁴,‐N(R^3a)‐CO‐R³⁵,andmorpholin‐4‐yl; R¹⁶ isselectedfromthegroupconsistingof−H,−CH₃,−F,and−CH₂‐CH₂OH; R¹⁷ isselectedfromthegroupconsistingof−Hand−N(CH₃)₂; R¹⁸ isselectedfromthegroupconsistingof−Hand–CH=CH₂; R¹⁹ isselectedfromthegroupconsistingof=CH₂and=O; R²⁰ isselectedfromthegroupconsistingof−Hand−CN; R²¹ isselectedfromthegroupconsistingof−H,−CH₃,and–C(=O)‐CH₃;

R²² isselectedfromthegroupconsistingof , , , , , ,and ; R²³ isselectedfromthegroupconsistingof−H,−CH₃,and−COOH; R²⁴ isselectedfromthegroupconsistingof−CH₃and–C(=O)‐O‐C(CH₃)₃; R²⁵ isselectedfromthegroupconsistingof−NH−and ; R²⁶ isselectedfromthegroupconsistingof−Hand−OH; R²⁷ isselectedfromthegroupconsistingof−H,−CH₃,−CH₂‐CH₃,−CN,−CH₂OH,cyclopropyl, −CH₂‐CN,−N(CH₃)₂,−C(CH₃)₂OH,−NH‐C(=O)‐CH₃,−S(=O)₂CH₃,−CH₂‐CH₂‐OR³⁶,−CH₂‐ CF₂R^4a,−C(=O)‐N(R^3a)₂,oxetane‐3‐carbonyl,−C(=O)‐C(R³⁸)(R³⁹)R^4a,and ; R²⁸ isselectedfromthegroupconsistingof−H,−CH₃,−OH,−N(CH₃)₂,−S(=O)₂NH₂,and– C(=O)‐NHR^3a; R²⁹ isselectedfromthegroupconsistingof−H,−CH₃,and−CH₂OH; R³¹ isselectedfromthegroupconsistingof−CH₃and–C(=O)‐CH₃; R³² isselectedfromthegroupconsistingof−Hand−CF₃; R³³ isselectedfromthegroupconsistingof−H,−CN,and−CF₃; R³⁴ isselectedfromthegroupconsistingof−CH₃andcyclopropyl; R³⁵ isselectedfromthegroupconsistingof−CH₃,−OCH₃,cyclopropyl,−CH₂‐OCH₃,−CHF₂, oxetan‐3‐yl,and1‐methylazetidin‐3‐yl; R³⁶ isselectedfromthegroupconsistingof−H,−CH₃,and ; R³⁷ isselectedfromthegroupconsistingof−H,−F,and−CN; R³⁸ isselectedfromthegroupconsistingof−H,−CH₃,−CH₂‐NH₂,−CH₂‐NH‐CH₃,and−CH₂‐ CH₂‐CH₂‐CH₂‐CH₂‐CH₂‐CH₂‐C(=O)‐OR^3a;and R³⁹ isselectedfromthegroupconsistingof−H,−NH₂,−F,−NH‐CH₃,−OCH₃,and−N(CH₃)₂. orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 7.Thecompoundaccordingtoclaim5ofgeneralformula(1b)inwhich: R^1a is ; R^2a isselectedfromthegroupconsistingof−F,−Cl,−OCH₃,−COOCH₃,−S(=O)₂‐CH₃,−O‐CH₂‐ CH₂R⁹,−C(=O)‐NHR^3a,2,5‐dihydrofuran‐3‐yl,4,5‐dihydrofuran‐2‐yl,oxolan‐3‐yl,oxetan‐ 3‐yloxy,cyclopentylamino,5,6‐dihydro‐2H‐pyran‐3‐yl,oxan‐3‐yl,3,6‐dihydro‐2H‐pyran‐ 4‐yl,1‐methyl‐1H‐pyrazol‐4‐yl,oxan‐4‐yl,[(oxetan‐2‐yl)methyl]amino,−N(R^3a)‐CH(R^3a)‐ CH₂‐R¹²,1‐methylpiperidin‐4‐yl,1‐methyl‐1,2,3,6‐tetrahydropyridin‐4‐yl,1‐oxa‐6‐ azaspiro[3.3]heptan‐6‐yl,[(oxolan‐2‐yl)methyl]amino,2‐oxa‐6‐azaspiro[3.3]heptan‐6‐yl, (1‐methylpyrrolidin‐3‐yl)oxy,(5‐oxopyrrolidin‐3‐yl)amino,3‐(difluoromethyl)azetidin‐1‐ yl,2‐oxa‐6‐azaspiro[3.4]octan‐6‐yl,3‐oxo‐1,4‐diazepan‐1‐yl,−R²²‐COOC(CH₃)₃,4‐cyano‐4‐ methylpiperidin‐1‐yl,2‐oxa‐6‐azaspiro[3.5]nonan‐6‐yl,2‐oxa‐7‐azaspiro[3.5]nonan‐7‐yl, 5‐oxo‐2,6‐diazaspiro[3.4]octan‐2‐yl,7‐oxo‐2,6‐diazaspiro[3.4]octan‐2‐yl,8‐oxo‐2,7‐ diazaspiro[4.4]nonan‐2‐yl,4‐methyl‐2,3‐dioxo‐1,4‐diazepan‐1‐yl,

, , , , ,and ; R^3a isselectedfromthegroupconsistingof−Hand–CH₃; R^4a isselectedfromthegroupconsistingof−Hand−F; R^5a isselectedfromthegroupconsistingof−CF₃,−CHF₂,−CF₂−CH₃,−CF₂−CH₂OH,and −CF₂−C(CH₃)₂OH;and R^6a isselectedfromthegroupconsistingof−H,−F,and−CH₃; R⁹ isselectedfromthegroupconsistingof−H,−CH₂‐CH₃,and–NH‐CH₃; R¹⁰ isselectedfromthegroupconsistingof and ; R¹¹ isselectedfromthegroupconsistingof‐CH₂‐CH₂‐CH₂‐,‐CH₂‐O‐CH₂‐,‐CH₂‐CH₂‐O‐, −N(CH₃)‐CH₂‐CH₂−,‐CH₂‐NH‐CH₂‐and‐CH₂‐N(R³¹)‐CH₂‐; R¹² isselectedfromthegroupconsistingof‐H,‐OCH₃,and‐N(CH₃)₂; R¹³ isselectedfromthegroupconsistingof , , , ,and ; R¹⁴ isselectedfromthegroupconsistingof−CH₂‐C(R^4a)₂‐CH₂‐,‐CH₂‐CH₂‐C(=O)‐and‐CH₂‐O‐ C(=O)‐; R¹⁵ isselectedfromthegroupconsistingof−H,−OH,−F,−OCH₃,−N(CH₃)₂,−C(=O)‐NH₂,‐ COOH,pyrrolidin‐1‐yl,‐NH‐SO₂‐R³⁴,‐N(R^3a)‐CO‐R³⁵,andmorpholin‐4‐yl; R¹⁶ isselectedfromthegroupconsistingof−H,−CH₃,−F,and−CH₂‐CH₂OH; R¹⁷ isselectedfromthegroupconsistingof−Hand−N(CH₃)₂; R¹⁸ isselectedfromthegroupconsistingof−Hand–CH=CH₂; R¹⁹ isselectedfromthegroupconsistingof=CH₂and=O; R²⁰ isselectedfromthegroupconsistingof−Hand−CN; R²¹ isselectedfromthegroupconsistingof−H,−CH₃,and–C(=O)‐CH₃;

R²² isselectedfromthegroupconsistingof , , , , , ,and ; R²³ isselectedfromthegroupconsistingof−H,−CH₃,and−COOH; R²⁴ isselectedfromthegroupconsistingof−CH₃and–C(=O)‐O‐C(CH₃)₃; R²⁵ isselectedfromthegroupconsistingof−NH−and ; R²⁶ isselectedfromthegroupconsistingof−Hand−OH; R²⁷ isselectedfromthegroupconsistingof−H,−CH₃,−CH₂‐CH₃,−CN,−CH₂OH,cyclopropyl, −CH₂‐CN,−N(CH₃)₂,−C(CH₃)₂OH,−NH‐C(=O)‐CH₃,−S(=O)₂CH₃,−CH₂‐CH₂‐OR³⁶,−CH₂‐ CF₂R^4a,−C(=O)‐N(R^3a)₂,oxetane‐3‐carbonyl,−C(=O)‐C(R³⁸)(R³⁹)R^4a,and ; R²⁸ isselectedfromthegroupconsistingof−H,−CH₃,−OH,−N(CH₃)₂,−S(=O)₂NH₂,and– C(=O)‐NHR^3a; R²⁹ isselectedfromthegroupconsistingof−H,−CH₃,and−CH₂OH; R³¹ isselectedfromthegroupconsistingof−CH₃and–C(=O)‐CH₃; R³² isselectedfromthegroupconsistingof−Hand−CF₃; R³³ isselectedfromthegroupconsistingof−H,−CN,and−CF₃; R³⁴ isselectedfromthegroupconsistingof−CH₃andcyclopropyl; R³⁵ isselectedfromthegroupconsistingof−CH₃,−OCH₃,cyclopropyl,−CH₂‐OCH₃,−CHF₂, oxetan‐3‐yl,and1‐methylazetidin‐3‐yl; R³⁶ isselectedfromthegroupconsistingof−H,−CH₃,and ; R³⁷ isselectedfromthegroupconsistingof−H,−F,and−CN;

R³⁸ isselectedfromthegroupconsistingof−H,−CH₃,−CH₂‐NH₂,−CH₂‐NH‐CH₃,and−CH₂‐ CH₂‐CH₂‐CH₂‐CH₂‐CH₂‐CH₂‐C(=O)‐OR^3a;and R³⁹ isselectedfromthegroupconsistingof−H,−NH₂,−F,−NH‐CH₃,−OCH₃,and−N(CH₃)₂. orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 8.Acompoundaccordingtoclaim1,whichisselectedfromthegroupconsistingof: N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐ 4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐ 4‐amine N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]‐2‐methyl‐6‐pyrrolidin‐1‐yl‐pyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}‐6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐ 4‐amine N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]‐2‐methyl‐6‐pyrrolidin‐1‐yl‐pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐fluoro‐2‐methyl‐N‐[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐[(3R)‐1‐[2‐methyl‐4‐[[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[2‐methyl‐4‐[[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]‐6‐fluoro‐2‐methyl‐pyrido[3,4‐d]pyrimidin‐4‐ amine N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide

N‐[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]‐6‐fluoro‐2‐methyl‐pyrido[3,4‐d]pyrimidin‐4‐ amine N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐fluoro‐2,8‐dimethylpyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2,8‐dimethylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐ 2,8‐dimethylpyrido[3,4‐d]pyrimidin‐4‐amine 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2,8‐dimethylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2,8‐dimethyl‐6‐(4‐methylpiperazin‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine 2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2,8‐dimethylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one N‐{(3S)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3S)‐1‐[2‐methyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide 6‐ethoxy‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 1‐(3‐{(1R)‐1‐[(6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐yl)amino]ethyl}‐2‐fluorophenyl)‐1,1‐ difluoro‐2‐methylpropan‐2‐ol 6‐ethoxy‐N‐{(1R)‐1‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]ethyl}‐2‐methylpyrido[3,4‐d]pyrimidin‐ 4‐amine N‐{(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluorophenyl]ethyl}‐6‐ethoxy‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}‐6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐ 4‐amine 6‐ethoxy‐2‐methyl‐N‐{(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}‐6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine

N‐{(1R)‐1‐[3‐amino‐5‐(trifluoromethyl)phenyl]ethyl}‐6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐ 4‐amine 6‐methoxy‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐ amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐methoxy‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]ethyl}‐6‐methoxy‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}‐6‐methoxy‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine 6‐methoxy‐2‐methyl‐N‐{(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluorophenyl]ethyl}‐6‐methoxy‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine 2,2‐difluoro‐2‐(2‐fluoro‐3‐{(1R)‐1‐[(6‐methoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl)amino]ethyl}phenyl)ethan‐1‐ol 1,1‐difluoro‐1‐(2‐fluoro‐3‐{(1R)‐1‐[(6‐methoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl)amino]ethyl}phenyl)‐2‐methylpropan‐2‐ol N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(1,1‐difluoro‐2‐hydroxyethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(1,1‐difluoro‐2‐hydroxy‐2‐methylpropyl)‐2‐fluorophenyl]ethyl}amino)‐ 2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[2‐methyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl}acetamide N‐[(3R)‐1‐(2‐methyl‐4‐{[(1R)‐1‐(2‐methylphenyl)ethyl]amino}pyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(2‐methyl‐4‐{[(1R)‐1‐(3‐methylphenyl)ethyl]amino}pyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(2‐methyl‐4‐{[(1R)‐1‐(4‐methylphenyl)ethyl]amino}pyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide

N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2‐fluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐fluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(4‐fluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2‐methoxyphenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐methoxyphenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2‐chlorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐chlorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐{(3R)‐1‐[4‐({(1RS)‐1‐[2‐(difluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[4‐({(1RS)‐1‐[2‐(difluoromethoxy)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethoxy)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[2‐methyl‐4‐({(1R)‐1‐[3‐(trifluoromethoxy)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐bromophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(2‐methyl‐4‐{[(1R)‐1‐{3‐[(trifluoromethyl)sulfanyl]phenyl}ethyl]amino}pyrido[3,4‐ d]pyrimidin‐6‐yl)pyrrolidin‐3‐yl]acetamide N‐{(3R)‐1‐[2‐methyl‐4‐({(1R)‐1‐[3‐(pentafluoro‐lambda⁶‐ sulfanyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide methyl3‐[(1R)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]benzoate N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐cyanophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(2‐methyl‐4‐{[(1R)‐1‐(3‐nitrophenyl)ethyl]amino}pyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide

tert‐butyl{3‐[(1RS)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]phenyl}carbamate N‐[(3R)‐1‐(4‐{[(1R)‐1‐(4‐fluoro‐3‐methylphenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2,3‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3,4‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2,4‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1RS)‐1‐(3,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1RS)‐1‐(2,6‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1RS)‐1‐(2,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(5‐bromo‐2‐methylphenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐bromo‐5‐fluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐bromo‐4‐fluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐bromo‐2‐fluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(5‐bromo‐2‐fluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(5‐bromo‐2‐methoxyphenyl)ethyl]amino}‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐fluoro‐1‐benzofuran‐7‐yl)ethyl]amino}‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl)pyrrolidin‐3‐yl]acetamide. N‐[(3R)‐1‐(4‐{[(1S)‐1‐(3‐fluoro‐1‐benzofuran‐7‐yl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl)pyrrolidin‐3‐yl]acetamide N‐{(3R)‐1‐[2‐methyl‐4‐({(1RS)‐1‐[2‐(1H‐pyrazol‐1‐yl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide

N‐{(3R)‐1‐[4‐({(1RS)‐1‐[3‐(difluoromethyl)‐1‐methyl‐1H‐pyrazol‐4‐yl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3R)‐1‐[2‐methyl‐4‐({(1RS)‐1‐[1‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐4‐ yl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐[(3R)‐1‐(4‐{[(1RS)‐1‐(5‐chloro‐1,3‐thiazol‐2‐yl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl)pyrrolidin‐3‐yl]acetamide N‐{(3R)‐1‐[2‐methyl‐4‐({(1RS)‐1‐[3‐(trifluoromethyl)‐1,2,4‐oxadiazol‐5‐ yl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(5‐bromopyridin‐3‐yl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(6‐aminopyridin‐2‐yl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐amino‐5‐(trifluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐[(3R)‐1‐(4‐{[1‐(3‐aminophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)pyrrolidin‐ 3‐yl]acetamide(mixtureofstereoisomers) tert‐butyl{3‐[(1S)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]phenyl}carbamate tert‐butyl{3‐[(1R)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]phenyl}carbamate N‐[(3R)‐1‐(4‐{[(1S)‐1‐(3‐aminophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐aminophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1S)‐1‐(3,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1S)‐1‐(2,6‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2,6‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide

N‐[(3R)‐1‐(4‐{[(1S)‐1‐(2,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide 3‐[(1R)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]benzoicacid N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(hydroxymethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]pyrrolidin‐3‐yl}acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐hydroxyphenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(2,2‐difluoroethoxy)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐[(3R)‐1‐(4‐{[(1R)‐1‐{3‐[(E)‐2‐ethoxyethenyl]phenyl}ethyl]amino}‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl)pyrrolidin‐3‐yl]acetamide N‐{(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}‐2‐methyl‐6‐(4‐methylpiperazin‐1‐yl)pyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}‐2‐methyl‐6‐(4‐methylpiperazin‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl}‐2‐methyl‐6‐(4‐methylpiperazin‐1‐yl)pyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(4‐methylpiperazin‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]ethyl}‐2‐methyl‐6‐(4‐methylpiperazin‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine 2,2‐difluoro‐2‐{2‐fluoro‐3‐[(1R)‐1‐{[2‐methyl‐6‐(4‐methylpiperazin‐1‐yl)pyrido[3,4‐d]pyrimidin‐ 4‐yl]amino}ethyl]phenyl}ethan‐1‐ol 1,1‐difluoro‐1‐{2‐fluoro‐3‐[(1R)‐1‐{[2‐methyl‐6‐(4‐methylpiperazin‐1‐yl)pyrido[3,4‐d]pyrimidin‐ 4‐yl]amino}ethyl]phenyl}‐2‐methylpropan‐2‐ol N‐{(1R)‐1‐[3‐amino‐5‐(trifluoromethyl)phenyl]ethyl}‐2‐methyl‐6‐(4‐methylpiperazin‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}‐6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl}‐6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluorophenyl]ethyl}‐6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐ yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine

6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐N‐{(1R)‐1‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]ethyl}‐ 2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}‐6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐ 2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine 2‐{3‐[(1R)‐1‐({6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]‐2‐fluorophenyl}‐2,2‐difluoroethan‐1‐ol 1‐{3‐[(1R)‐1‐({6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]‐2‐fluorophenyl}‐1,1‐difluoro‐2‐methylpropan‐2‐ol 2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐2,6‐ diazaspiro[3.4]octan‐7‐one 2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one 2‐[4‐({(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐ 2,6‐diazaspiro[3.4]octan‐7‐one 2‐[4‐({(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one 2‐[4‐({(1R)‐1‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one 2‐[4‐({(1R)‐1‐[3‐(1,1‐difluoro‐2‐hydroxyethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one 2‐[4‐({(1R)‐1‐[3‐amino‐5‐(trifluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]piperazin‐1‐yl}ethan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]piperazin‐1‐yl}ethan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(1,1‐difluoro‐2‐hydroxy‐2‐methylpropyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one

1‐{4‐[4‐({(1R)‐1‐[3‐amino‐5‐(trifluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶‐ethyl‐2‐methylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁶‐cyclopropyl‐N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐N⁶‐(propan‐2‐yl)pyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶‐ethyl‐N⁶,2‐dimethylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶,2‐dimethyl‐N⁶‐(prop‐2‐en‐1‐ yl)pyrido[3,4‐d]pyrimidine‐4,6‐diamine N⁶‐cyclopropyl‐N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶,2‐dimethylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁶‐cyclobutyl‐N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶,2‐dimethyl‐N⁶‐(propan‐2‐yl)pyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶‐(2‐methoxyethyl)‐2‐methylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(piperidin‐1‐yl)pyrido[3,4‐ d]pyrimidin‐4‐amine N⁶‐cyclopentyl‐N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(piperazin‐1‐yl)pyrido[3,4‐ d]pyrimidin‐4‐amine (3S)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐ol (3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐ol N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(morpholin‐4‐yl)pyrido[3,4‐ d]pyrimidin‐4‐amine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐N⁶‐{[(2RS)‐oxetan‐2‐ yl]methyl}pyrido[3,4‐d]pyrimidine‐4,6‐diamine

N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐N⁶‐[(3R)‐oxolan‐3‐yl]pyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶‐(2‐methoxyethyl)‐N⁶,2‐ dimethylpyrido[3,4‐d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐N⁶,N⁶‐di(prop‐2‐en‐1‐ yl)pyrido[3,4‐d]pyrimidine‐4,6‐diamine 6‐[2‐azabicyclo[2.2.1]heptan‐2‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(1‐oxa‐6‐azaspiro[3.3]heptan‐ 6‐yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(2‐oxa‐6‐azaspiro[3.3]heptan‐ 6‐yl)pyrido[3,4‐d]pyrimidin‐4‐amine N⁶‐cyclohexyl‐N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine 4‐{[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]amino}pyrrolidin‐2‐one(mixtureofstereoisomers) 4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]piperazin‐2‐one 6‐(1,4‐diazepan‐1‐yl)‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(4‐methylpiperazin‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3R)‐3‐methylmorpholin‐4‐ yl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3S)‐3‐methylmorpholin‐4‐ yl]pyrido[3,4‐d]pyrimidin‐4‐amine (3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidin‐3‐ol (3S)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidin‐3‐ol N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐N⁶‐(oxan‐4‐yl)pyrido[3,4‐ d]pyrimidine‐4,6‐diamine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐N⁶‐{[(2R)‐oxolan‐2‐ yl]methyl}pyrido[3,4‐d]pyrimidine‐4,6‐diamine

N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(3S)‐3‐methoxypyrrolidin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶‐[2‐(dimethylamino)ethyl]‐N⁶,2‐ dimethylpyrido[3,4‐d]pyrimidine‐4,6‐diamine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(thiomorpholin‐4‐yl)pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐[3‐(difluoromethyl)azetidin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(3,3‐difluoropyrrolidin‐1‐yl)‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(2,6‐dihydropyrrolo[3,4‐c]pyrazol‐5(4H)‐ yl)‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]piperidine‐4‐carbonitrile N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[hexahydrocyclopenta[c]pyrrol‐2(1H)‐yl]‐ 2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[hexahydropyrrolo[3,4‐c]pyrrol‐2(1H)‐ yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3aR,6aS)‐tetrahydro‐1H‐ furo[3,4‐c]pyrrol‐5(3H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(3aRS,6aRS)‐hexahydro‐5H‐furo[2,3‐ c]pyrrol‐5‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(2‐oxa‐6‐azaspiro[3.4]octan‐6‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine N⁶‐cyclohexyl‐N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶,2‐dimethylpyrido[3,4‐ d]pyrimidine‐4,6‐diamine 4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐1,4‐diazepan‐2‐one (3S)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidine‐3‐carboxamide (6R)‐4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐6‐methylpiperazin‐2‐one (6S)‐4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐6‐methylpiperazin‐2‐one

N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(3,3‐dimethylpiperazin‐1‐yl)‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(4‐methyl‐1,4‐diazepan‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(4‐ethylpiperazin‐1‐yl)‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(3S)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐ 2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐ 2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine {1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidin‐4‐yl}methanol N⁴‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐N⁶,2‐dimethyl‐N⁶‐(oxan‐4‐yl)pyrido[3,4‐ d]pyrimidine‐4,6‐diamine 4‐{[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]amino}cyclohexan‐1‐ol(mixtureofstereoisomers) (1RS,4SR,5RS)‐2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐2‐azabicyclo[2.2.1]heptane‐5‐carbonitrile(mixtureof stereoisomers) N²‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐N,N,N²‐trimethylglycinamide N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(6,7‐dihydropyrazolo[1,5‐a]pyrazin‐ 5(4H)‐yl)‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(5,6‐dihydroimidazo[1,5‐a]pyrazin‐7(8H)‐ yl)‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐ yl)‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(1‐methyl‐4,6‐ dihydropyrrolo[3,4‐c]pyrazol‐5(1H)‐yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐(5,6‐dihydro[1,2,4]triazolo[1,5‐a]pyrazin‐ 7(8H)‐yl)‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐4‐methylpiperidine‐4‐carbonitrile {4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}acetonitrile

2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐2,6‐diazaspiro[3.4]octan‐5‐one 2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3aS,6aS)‐1‐ methylhexahydropyrrolo[3,4‐b]pyrrol‐5(1H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3aRS,6aSR)‐5‐ methylhexahydropyrrolo[3,4‐c]pyrrol‐2(1H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine(mixtureof stereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3aR,6aR)‐1‐ methylhexahydropyrrolo[3,4‐b]pyrrol‐5(1H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(8aS)‐hexahydropyrrolo[1,2‐a]pyrazin‐ 2(1H)‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(8aR)‐hexahydropyrrolo[1,2‐a]pyrazin‐ 2(1H)‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(6‐methyl‐2,6‐ diazaspiro[3.4]octan‐2‐yl)pyrido[3,4‐d]pyrimidin‐4‐amine 6‐(4‐cyclopropylpiperazin‐1‐yl)‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(2‐oxa‐6‐azaspiro[3.5]nonan‐6‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(2‐oxa‐7‐azaspiro[3.5]nonan‐7‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine (3RS)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐3‐methylpyrrolidine‐3‐carboxamide 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]piperidine‐4‐carboxamide 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one (3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidine‐3‐carboxamide (3S)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidine‐3‐carboxamide N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(cis)‐3,4,5‐trimethylpiperazin‐ 1‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers)

N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3R,5R)‐3,4,5‐ trimethylpiperazin‐1‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(3S,5S)‐3,4,5‐ trimethylpiperazin‐1‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[3‐(dimethylamino)piperidin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[4‐(dimethylamino)piperidin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐3‐methylpyrrolidine‐3‐carboxylicacid(mixtureofstereoisomers) 4‐{[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]amino}‐1‐methylcyclohexan‐1‐ol(mixtureofstereoisomers) 2‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐ol 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐3‐(2‐hydroxyethyl)pyrrolidin‐3‐ol(mixtureofstereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(3‐methyl‐5,6‐ dihydro[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐yl)pyrido[3,4‐d]pyrimidin‐4‐amine 2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]hexahydropyrrolo[1,2‐a]pyrazin‐6(2H)‐one(mixtureofstereoisomers) (5RS)‐7‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,7‐diazaspiro[4.4]nonan‐3‐one(mixtureofstereoisomers) 6‐[[1,3'‐bipyrrolidin]‐1'‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) 7‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]hexahydro‐3H‐[1,3]oxazolo[3,4‐a]pyrazin‐3‐one(mixtureofstereoisomers) 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐4‐methyl‐1,4‐diazepane‐2,3‐dione 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐1,4‐diazepan‐1‐yl}ethan‐1‐one N‐{(3RS)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}‐N‐methylacetamide(mixtureofstereoisomers) N‐{1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidin‐4‐yl}acetamide

(3RS)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐N‐methylpiperidine‐3‐carboxamide(mixtureofstereoisomers) 2‐{1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidin‐4‐yl}propan‐2‐ol (2R)‐4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐6‐oxopiperazine‐2‐carboxylicacid N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[4‐(2‐methoxyethyl)piperazin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine 5‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐4,5,6,7‐tetrahydropyrazolo[1,5‐a]pyrazine‐2‐carbonitrile 6‐[4‐(2,2‐difluoroethyl)piperazin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine 1‐[5‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]hexahydropyrrolo[3,4‐c]pyrrol‐2(1H)‐yl]ethan‐1‐one(mixtureof stereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[3‐(piperidin‐1‐yl)pyrrolidin‐1‐ yl]pyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[3‐(morpholin‐4‐yl)pyrrolidin‐ 1‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) 6‐[7,7‐difluorohexahydropyrrolo[1,2‐a]pyrazin‐2(1H)‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐ fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine(mixtureofstereoisomers) (3RS)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidine‐3‐sulfonamide N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[4‐(2,2,2‐ trifluoroethyl)piperazin‐1‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine tert‐butyl{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}carbamate tert‐butyl{3‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐3‐azabicyclo[3.1.0]hexan‐1‐yl}carbamate(mixtureofstereoisomers) tert‐butyl{1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐4‐fluoropyrrolidin‐3‐yl}carbamate(mixtureofstereoisomers) tert‐butyl6‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octane‐2‐carboxylate tert‐butyl2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,7‐diazaspiro[3.5]nonane‐7‐carboxylate

tert‐butyl7‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,7‐diazaspiro[3.5]nonane‐2‐carboxylate N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐(6‐methyl‐2,6‐ diazaspiro[3.4]octan‐2‐yl)pyrido[3,4‐d]pyrimidin‐4‐amine tert‐butyl2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octane‐6‐carboxylate methyl4‐(2‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethoxy)benzoate 4‐(2‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethoxy)benzoicacid 6‐(methanesulfonyl)‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐[(3R)‐3‐aminopyrrolidin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐aminehydrochloridesalt N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}cyclopropanecarboxamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}‐2,2‐difluoroacetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}‐2‐methoxyacetamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}oxetane‐3‐carboxamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}‐1‐methylazetidine‐3‐carboxamide methyl{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}carbamate N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}methanesulfonamide N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}cyclopropanesulfonamide cyclopropyl{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}methanone 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐2‐methoxyethan‐1‐one

1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐2,2‐difluoroethan‐1‐one {4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}(oxetan‐3‐yl)methanone 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐2‐(dimethylamino)ethan‐1‐one {4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}(1‐fluorocyclopropyl)methanone 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐2,2‐difluoropropan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazine‐1‐carbonyl}cyclopropane‐1‐carbonitrile methyl10‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐10‐oxodecanoate 10‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐10‐oxodecanoicacid 4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]‐N,N‐dimethylpiperazine‐1‐carboxamide N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[4‐(methanesulfonyl)piperazin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine 2‐amino‐1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐2‐(methylamino)ethan‐1‐one 3‐amino‐1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}propan‐1‐one 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}‐3‐(methylamino)propan‐1‐one 6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2‐methyl‐N‐{(1R)‐1‐[3‐ (trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 2‐[2‐methyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐yl]‐ 2,6‐diazaspiro[3.4]octan‐7‐one 1‐{4‐[2‐methyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐ yl]piperazin‐1‐yl}ethan‐1‐one

2‐methyl‐6‐(4‐methylpiperazin‐1‐yl)‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐fluoro‐2‐methyl‐N‐{(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐ 4‐amine 2‐methyl‐6‐(4‐methylpiperazin‐1‐yl)‐N‐{(1R)‐1‐[2‐methyl‐3‐ (trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 2‐[2‐methyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one 6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2‐methyl‐N‐{(1R)‐1‐[2‐methyl‐3‐ (trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 1‐{4‐[2‐methyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one 2‐methyl‐N‐{(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}‐6‐(1‐oxa‐6‐azaspiro[3.3]heptan‐ 6‐yl)pyrido[3,4‐d]pyrimidin‐4‐amine 6‐fluoro‐2,8‐dimethyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐ amine 1‐{4‐[2,8‐dimethyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐ yl]piperazin‐1‐yl}ethan‐1‐one 2,8‐dimethyl‐6‐(4‐methylpiperazin‐1‐yl)‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2,8‐dimethyl‐N‐{(1R)‐1‐[3‐ (trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 2‐[2,8‐dimethyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐yl]‐ 2,6‐diazaspiro[3.4]octan‐7‐one 6‐fluoro‐2,8‐dimethyl‐N‐{(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 1‐{4‐[2,8‐dimethyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one 2‐[2,8‐dimethyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]‐2,6‐diazaspiro[3.4]octan‐7‐one 2,8‐dimethyl‐6‐(4‐methylpiperazin‐1‐yl)‐N‐{(1R)‐1‐[2‐methyl‐3‐ (trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2,8‐dimethyl‐N‐{(1R)‐1‐[2‐methyl‐3‐ (trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine

N‐{(3R)‐1‐[2,8‐dimethyl‐4‐({(1R)‐1‐[2‐methyl‐3‐ (trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide N‐{(3S)‐1‐[2,8‐dimethyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide 6‐chloro‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 2‐methyl‐6‐(1‐methyl‐1H‐pyrazol‐4‐yl)‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐(4,5‐dihydrofuran‐2‐yl)‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐(2,5‐dihydrofuran‐3‐yl)‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐(3,6‐dihydro‐2H‐pyran‐4‐yl)‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 6‐(5,6‐dihydro‐2H‐pyran‐3‐yl)‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine 2‐methyl‐6‐(1‐methyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐{(1R)‐1‐[3‐ (trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine 2‐methyl‐6‐[(3RS)‐oxolan‐3‐yl]‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amineamine(mixtureofstereoisomers) 2‐methyl‐6‐(oxan‐4‐yl)‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐ amine 2‐methyl‐6‐[(3RS)‐oxan‐3‐yl]‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine(mixtureofstereoisomers) 2‐methyl‐6‐(1‐methylpiperidin‐4‐yl)‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐ d]pyrimidin‐4‐amine methyl2‐methyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidine‐6‐ carboxylate 2‐methyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidine‐6‐ carboxamide N,2‐dimethyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidine‐6‐ carboxamide 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperidine‐4‐carbonitrile N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(2S)‐2,4‐dimethylpiperazin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine

{1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐4‐methylpiperazin‐2‐yl}methanol(mixtureofstereoisomers) N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[2‐(trifluoromethyl)‐5,6‐ dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[2‐(trifluoromethyl)‐5,6‐ dihydro[1,2,4]triazolo[1,5‐a]pyrazin‐7(8H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine 6‐(cyclobutyloxy)‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine 6‐butoxy‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐d]pyrimidin‐ 4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[2‐ (methylamino)ethoxy]pyrido[3,4‐d]pyrimidin‐4‐amine N‐[(1R)‐1‐{3‐(difluoromethyl)‐2‐[2‐(methylamino)ethoxy]phenyl}ethyl]‐2‐methyl‐6‐[2‐ (methylamino)ethoxy]pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[(oxetan‐3‐yl)oxy]pyrido[3,4‐ d]pyrimidin‐4‐amine tert‐butyl3‐{[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]oxy}azetidine‐1‐carboxylate N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐{[(3R)‐oxolan‐3‐ yl]oxy}pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐{[(3R)‐oxolan‐3‐yl]oxy}phenyl]ethyl}‐2‐methyl‐6‐{[(3R)‐oxolan‐ 3‐yl]oxy}pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐{[(3S)‐oxolan‐3‐ yl]oxy}pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐{[(3S)‐oxolan‐3‐yl]oxy}phenyl]ethyl}‐2‐methyl‐6‐{[(3S)‐oxolan‐ 3‐yl]oxy}pyrido[3,4‐d]pyrimidin‐4‐amine N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐{[(3S)‐1‐methylpyrrolidin‐3‐yl]oxy}phenyl]ethyl}‐2‐methyl‐6‐ {[(3S)‐1‐methylpyrrolidin‐3‐yl]oxy}pyrido[3,4‐d]pyrimidin‐4‐amine 6‐[(azetidin‐3‐yl)oxy]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐aminehydrochloride tert‐butyl{(3‐trans)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐4‐fluoropyrrolidin‐3‐yl}carbamate(mixtureof stereoisomers) 6‐[(trans)‐3‐amino‐4‐fluoropyrrolidin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐ 2‐methylpyrido[3,4‐d]pyrimidin‐4‐aminehydrochloride(mixtureofstereoisomers)

tert‐butyl{(cis)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐4‐fluoropyrrolidin‐3‐yl}carbamate(mixtureof stereoisomers) 6‐[(cis)‐3‐amino‐4‐fluoropyrrolidin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐aminehydrochloride(mixtureofstereoisomers) orastereoisomer,atautomer,anN‐oxide,ahydrate,asolvate,orasaltthereof,oramixtureof same. 9.Acompoundofgeneralformula(1)accordingtoanyoneofclaims1to8foruseinthetreatment orprophylaxisofadisease. 10.Apharmaceuticalcompositioncomprisingacompoundofgeneral formula (1)accordingtoany oneofclaims1to8andoneormorepharmaceuticallyacceptableexcipients. 11.Apharmaceuticalcombinationcomprising: ^ one or more first active ingredients, in particular compounds of general formula (1) accordingtoanyoneofclaims1to8,and ^ one ormore further active ingredients, in particular anti‐hyperproliferative and/or anti‐ canceragents. 12.Useofacompoundofgeneralformula(1)accordingtoanyoneofclaims1to8forthetreatment orprophylaxisofadisease. 13. Use of a compound of general formula (1) according to any one of claims 1 to 8 for the preparationofamedicamentforthetreatmentorprophylaxisofadisease. 14.Useaccordingtoclaim9,12or13,whereinthedisease isahyperproliferativedisorder,suchas cancer,forexample. 15.UseofSOS1Inhibitorsforthetreatmentorprophylaxisofadisease,especiallyforthetreatment orprophylaxisofcancer. Thepresentinventioncoversanysub‐combinationwithinanyembodimentoraspectofthepresent inventionofcompoundsofgeneralformula(I),supra. Thepresentinventioncoversanysub‐combinationwithinanyembodimentoraspectofthepresent invention of intermediate compounds of general formula (II).The present invention covers the compoundsofgeneralformula(I)whicharedisclosedintheExampleSectionofthistext,infra. SYNTHESISOFCOMPOUNDS(OVERVIEW) Thecompoundsofthepresentinventioncanbepreparedasdescribedinthefollowingsection.The schemesandtheproceduresdescribedbelowillustrategeneralsyntheticroutestothecompounds

ofgeneralformula(I)oftheinventionandarenotintendedtobelimiting.Itiscleartotheperson skilledintheartthattheorderoftransformationsasexemplifiedintheschemescanbemodifiedin variousways.Theorderoftransformationsexemplifiedintheschemesisthereforenotintendedto belimiting.Inaddition,interconversionofanyofthesubstituentscanbeachievedbeforeand/or aftertheexemplifiedtransformations.Thesemodificationscanbesuchastheintroductionof protectinggroups,cleavageofprotectinggroups,exchange,reductionoroxidationoffunctional groups,halogenation,metallation,substitutionorotherreactionsknowntothepersonskilledinthe art.Thesetransformationsincludethosewhichintroduceafunctionalitywhichallowsforfurther interconversionofsubstituents.Appropriateprotectinggroupsandtheirintroductionandcleavage arewell‐knowntothepersonskilledintheart(seeforexampleP.G.M.WutsandT.W.Greenein "ProtectiveGroupsinOrganicSynthesis",4'"edition,Wiley2006).Specificexamplesaredescribedin thesubsequentparagraphs.Further,itispossiblethattwoormoresuccessivestepsmaybe performedwithoutwork‐upbeingperformedbetweensaidsteps,e.g.a"one‐pot"reaction,asis well‐knowntothepersonskilledintheart. Thesynthesesofthecompoundsofthepresentinventionarepreferablycarriedoutaccordingtothe generalsyntheticsequence,showninschemes1‐7.

Scheme1:Routeforthepreparationofcompoundsofgeneralformula8,whereinT,V,R¹andxhave themeaningasgivenforgeneralformula(I),supraandRisalkyl,Halischloro,bromooriodoandLG hasthemeaningasaleavinggroup,preferablychloro,bromoorasulfonategroupasdepictedin scheme1.Specificexamplesaredescribedinthesubsequentparagraphs. Step1 ^7(Scheme1) Azaquinazolineformation Inthefirststep(scheme1)aminoacidesterderivative1(whichiscommerciallyavailableor describedintheliterature)canbeconvertedtothecorrespondingazaquinazoline7inanalogyto literatureprocedures.Typicallyacetonitrileandhydrochloricacidinorganicsolventsuchasfor example1,4‐dioxaneatelevatedtemperaturesisused.ForexampleseeACSMedicinalChemistry Letters,2013,vol.4,#9p.846–851;JournalofMedicinalChemistry,2009,vol.52,#8p.2341‐ 2351orWO2015/54572andreferencestherein.

Step2 ^7(Scheme1) Azaquinazolineformation Alternativelyhalogensubstitutedbenzoicacidderivativeofgeneralformula2(whichiscommercially availableordescribedintheliterature)canbeconvertedtothecorrespondingazaquinazoline7in analogytoliteratureprocedures.Typicallyderivative2isreactedwithacetamidine,coppermetal,a basesuchasforexamplepotassiumcarbonateinanorganicsolventsuchasforexampleDMFat elevatedtemperature.ForexampleseeWO2005/51410,US2008/107623andreferencestherein. Step3 ^7(Scheme1) Azaquinalzolineformation Alternativelyaminosubstitutedbenzoicacidderivativeofgeneralformula3(whichiscommercially availableordescribedintheliterature)canbeconvertedtothecorrespondingazaquinazoline7in analogytoliteratureprocedures.Typicallyderivative3isreactedwithacetylchlorideoracetic anhydride,anammoniasourcesuchasforexampleammoniaorammoniumacetate,abasesuchas forexampletriethylamineorpyridinewithorwithoutDMAPinanorganicsolventsuchasfor exampleDMF,toluene,1,4‐dioxane/wateratelevatedtemperature.ForexampleseeBioorganic andMedicinalChemistryLetters,2011,vol.21,#4p.1270–1274;BioorganicandMedicinal ChemistryLetters,2010,vol.20,#7p.2330–2334;WO2008/117079orWO2006/74187and referencestherein. Step4 ^7(Scheme1) Azaquinazolineformation Alternativelybenzoxazinonederivativeofgeneralformula4(whichiscommerciallyavailableorcan bepreparedinanalogytoliteratureprocedures)canbeconvertedtothecorresponding azaquinazoline7inanalogytoliteratureprocedures.Typicallyderivative4isreactedwith ammoniumacetateinasolventatelevatedtemperature.ForexampleseeBioorganicandMedicinal ChemistryLetters,2011,vol.21,#4p.1270–1274orUS6350750andreferencestherein. Step5 ^7(Scheme1) Azaquinazolineformation Alternativelybenzoicacidamidederivativeofgeneralformula5(whichiscommerciallyavailableor describedintheliterature)canbeconvertedtothecorrespondingazaquinazoline7inanalogyto literatureprocedures.Typicallyderivative5isreactedwithabasesuchasforexamplesodium hydroxideinasolventsuchasforexamplewateratelevatedtemperature.Forexamplesee

BioorganicandMedicinalChemistryLetters,2008,vol.18,#16p.4573–4577andreferences therein. Step6 ^7(Scheme1) Azaquinazolineformation Alternativelyaminobenzoicacidamidederivativeofgeneralformula6(whichiscommercially availableordescribedintheliterature)canbeconvertedtothecorrespondingazaquinazoline7in analogytoliteratureprocedures.Typicallyderivative6isreactedwithaceticacidatelevated temperature.ForexampleseeBioorganicandMedicinalChemistryLetters,2008,vol.18,#3p.1037 –1041andreferencestherein. Step7 ^8(Scheme1) Conversionofhydroxylgroupintoleavinggroup Inthenextstep(scheme1)hydroxyazaquinazolinederivative7canbeconvertedtothe correspondingazaquinazoline8inanalogytoliteratureprocedures. ForW=chlorotypicallytrichlorophosphateorthionylchloride,withorwithoutN,N‐dimethylaniline orN,N‐diisopropylethylaminewithorwithoutanorganicsolventsuchasforexampletolueneat elevatedtemperaturesisused.ForexamplesseeBioorganicandMedicinalChemistryLetters,2011, 1270;JournalofMedicinalChemistry,2009,2341;ACSMedicinalChemistryLetters,2013,846; BioorganicandMedicinalChemistryLetters,2010,2330;US6350750orWO2015/54572and referencestherein. ForW=bromotypicallyphosphorusoxytribromide,withorwithoutN,N‐dimethylanilineorN,N‐ diisopropylethylaminewithorwithoutanorganicsolventsuchasforexampletolueneatelevated temperaturesisused.ForexamplesseeUS2012/53174;WO2012/30912orWO2012/66122and referencestherein. ForW=2,4,6‐triisopropylsulfonatetypically2,4,6‐triisopropylbenzenesulfonylchloride,abasesuch asforexampletriethylamineand/orDMAPinanorganicsolventsuchasforexample dichloromethaneisused.ForexamplesseeWO2010/99379US2012/53176andreferencestherein. ForW=tosylatetypically4‐methylbenzene‐1‐sulfonylchloride,abasesuchasforexample triethylamineorpotassiumcarbonateand/orDMAPinanorganicsolventsuchasforexample dichloromethaneoracetonitrileisused.ForexamplesseeOrganicLetters,2011,4374orBioorganic andMedicinalChemistryLetters,2013,2663andreferencestherein. ForW=trifluoromethanesulfonatetypicallyN,N‐bis(trifluoromethylsulfonyl)anilineor trifluoromethanesulfonicanhydride,abasesuchasforexampletriethylamineor1,8‐ diazabicyclo[5.4.0]undec‐7‐eneand/orDMAPinanorganicsolventsuchasforexample dichloromethaneisused.ForexamplesseeJournaloftheAmericanChemicalSociety,2015,13433or WO2014/100501andreferencestherein. Scheme 1. Synthesis route for the preparation of compounds of general formula (I), which are compounds of general formula (I), in which R2, A and x has the meaning as given for general formula (I), supra. Step 9 ^ 10 (Scheme 1) Acetyl formation In the first step (scheme 1) the bromo derivative 9 (which is commercially available or described in the literature) could be converted to the corresponding acetyl 10 in analogy to the numerous literature procedures. For example the reaction can be performed using different chemistries known to those skilled in the art, for example, Grignard chemistry using magnesium in an organic solvent as for example THF; or palladium catalyzed chemistry or Stille chemistry. For such transformations see the teachings of (Grignard: Fillon et al., Tetahedron 2003, 59, 8199; Leazer et al., Org. Synth.2005, 82, 115; Palladium: WO2005/5382; Stille: WO2019/122129 and the references therein. Step 10 ^ 11 (Scheme 1) Sulfinimine formation In the first step (scheme 1) aldehyde derivative 10 (which is commercially available or described in the literature) could be converted to the corresponding sulfinimine 11 in analogy

to the numerous literature procedures. For example the reaction could be performed at ambient temperature using Titanium(IV)ethoxide or Titanium(IV) isopropoxide in an organic solvent as for example THF. For a review about sulfinimine chemistry see for example Chem. Rev.2010, 110, 3600–3740; Chem. Soc. Rev.2009, 38, 1162–1186; Tetrahedron 2004, 60, 8003 or WO2019/122129 and the references therein. Step 11 ^ 12 (Scheme 1) Formation of sulfinamide In the next step (scheme 1) sulfinimine 11 can be converted to the corresponding sulfinamide 12 in analogy to the numerous literature procedures. For example the reaction can be performed using a reducing agent, for example, sodium borohydride or borane-THF, in a protic organic solvent as for example ethanol or methanol or tetrahydrofuran. Such transformations are known to those skilled in the art, see the teachings of Pan et al., Tetrahedron Asym., 2011, 22, 329; WO2019/122129; Li et al., Chem. Med. Chem., 2018, 13, 1363; Ghosh et al., Eur. J. Med. Chem., 2018, 160, 171. Alternatively, the reaction can be performed using a reducing agent, for example, diisopropylaluminium hydride, in an aprotic solvent, for example, toluene. Such transformations are known to those skilled in the art, see the teachings of WO2017/6282; Lee et al., Synlett., 2019, 30, 401. Step 12 ^ 13 (Scheme 1) Formation of amine In the next step (scheme 2) sulfinamide 12 can be converted to the corresponding amine 13 in analogy to the numerous literature procedures. For example the reaction can be performed using acetylchloride in a protic organic solvent as for example methanol. For a review about sulfinimine and sulfonamide chemistry see for example Chem. Rev.2010, 110, 3600–3740; Chem. Soc. Rev.2009, 38, 1162–1186; Tetrahedron 2004, 60, 8003 or WO2013030138 and the references therein.

Scheme 2 Synthesis route for the preparation of compounds of general formula (I), which are compounds of general formula (I), in which R2, A and x has the meaning as given for general formula (I), supra. Step 10 ^ 14 (Scheme 2) Formation of alcohol In the first step (scheme 2) ketone derivative 10 (which is commercially available or described in the literature) could be converted to the corresponding chiral alcohol 14 in analogy to the numerous literature procedures. For example the enanioselective reduction could be performed using catalytic hydrogenation, with hydrogen gas under pressure with a catalyst, for example a BINAP-derived catalyst, e.g. (R)- or (S)-RUCY-Xyl-BINAP (see WO2019/122129 page 140 or WO2013/185103 page 81). Step 14 ^ 15 (Scheme 2) Formation of azide In the next step (scheme 2) alcohol 14 can be converted to the corresponding azide 15 in analogy to the numerous literature procedures. For example the reaction can be performed using diphenylphosphonic azide and a base, for example, DBU, in an aprotic organic solvent as for example, toluene (see the teachings of WO2019/122129 page 144). For a review about azide chemistry see for example Chem. Rev.1988, 88, 297. Step 15 ^ 13 (Scheme 2) Formation of amine In the next step (scheme 2) azide 15 can be converted to the corresponding amine 13 in analogy to the numerous literature procedures. For example the reaction can be performed using the Staudinger reduction conditions, with a phosphine, for example, triphenyl phosphine, in water with various different organic solvents, for example methanol, ethanol or THF. Alternatively, the azide reduction can be carried out using catalytic hydrogenation methods, using a metal catalyst, for example, palladium on charcoal, under a pressurized atmosphere of hydrogen (see WO2019/122129 page 144). For a review about azide chemistry see for example Chem. Rev.1988, 88, 297. Scheme 3. Synthesis route for the preparation of compounds of general formula (I), which are compounds of general formula (I), in which R2, A and x has the meaning as given for general formula (I), supra. To those skilled in the art it is possible to carry out the chemical reactions described in Schemes 1 and 2, where the stereoisomers can be separated using various methods known to those skilled in the art, such as, for example, separation using chiral HPLC purification. The separation of these stereoisomers can be carried out on compounds of general formula 13. Scheme4:Routeforthepreparationofcompoundsofgeneralformula16(acompoundofgeneral formulaI),whereinT,V,R¹,R²,x,yandAhavethemeaningasgivenforgeneralformula(I),supra andLGhasthemeaningasaleavinggroup,preferablychloro,bromoorasulfonategroupas depictedinscheme4.Specificexamplesaredescribedinthesubsequentparagraphs. Step12+8 ^17(Scheme4)

Aminecoupling Inthefirststep(scheme4)aminederivativerac‐13andazaquinazolinederivative8areconvertedto amine16inanalogytoliteratureprocedures.Typicallythereactionisperformedinanorganic solventsuchasforexampleTHF,DMF,acetonitriledichloromethaneorisopropylalcoholwithor withoutabasesuchasforexampletriethylamine,N‐ethyl‐N,N‐diisopropylamine,potassium carbonateorpotassiumtert‐butylate. ForLG=chloroseeforexampletheliteraturereferencesWO2008/86462;WO2008/86462or EuropeanJournalofMedicinalChemistry,2015,462andreferencestherein. ForLG=bromoseeforexampletheliteraturereferencesUS2009/247519orJournalofOrganic Chemistry,2009,8460andreferencestherein. ForLG=tosylateseeforexampletheliteraturereferencesSyntheticCommunications,2012,1715; Synthesis2015,2055orBioorganicandMedicinalChemistryLetters,2013,2663andreferences therein. ForLG=triflateseeforexampletheliteraturereferencesBioorganicandMedicinalChemistry Letters,2013,3325andreferencestherein. ForLG=2,4,6‐triisopropylbenzenesulfonateseeforexampletheliteraturereferenceWO2010/99379 andreferencestherein. Inaccordancewithafurtheraspect,thepresentinventioncoversintermediatecompoundswhichare usefulinthepreparationofcompoundsofthepresentinventionofgeneralformula(I),particularlyin themethodsdescribedherein. The present invention covers the intermediate compounds which are disclosed in the Example Sectionofthistext,infra. Thepresentinventioncoversanysub‐combinationwithinanyembodimentoraspectofthepresent inventionofintermediatecompounds. Inaccordancewithanotheraspect,thepresentinventioncoversmethodsofpreparingcompounds ofthepresentinvention,saidmethodscomprisingthestepasdescribedbelowand/orthe ExperimentalSection. ThepreparationofcompoundsofgeneralformulaIcanbeperformedinaproticoraproticsolvent, preferablyindioxan,tetrahydrofuran,N,N‐dimethylformamide,dimethylsulfoxid,methanol,ethanol or2‐propanol.

PreferredbaseswhichcanbeusedforthepreparationofcompoundsofthegeneralformulaIare N,N‐diisopropylethylaminortriethylamin. Said compound of general formula I can then optionally be converted into solvates, salts and/or solvatesofsuchsaltsusingthecorresponding(i)solventsand/or(ii)basesoracids. Thepresent inventioncoversmethodsofpreparingcompoundsofthepresent inventionofgeneral formula(I),saidmethodscomprisingthestepsasdescribedintheExperimentalSectionherein. The compounds of general formula (I) of the present invention can be converted to any salt, preferablypharmaceuticallyacceptablesalts,asdescribedherein,byanymethodwhichisknownto thepersonskilled intheart.Similarly,anysaltofacompoundofgeneralformula(I)ofthepresent inventioncanbeconverted intothefreecompound,byanymethodwhich isknowntotheperson skilledintheart. One of the most fundamental characteristics of cancer cells is their ability to sustain chronic proliferationwhereasinnormaltissuestheentryintoandprogressionthroughthecelldivisioncycle is tightly controlled to ensure a homeostasis of cell number andmaintenance of normal tissue function.Lossofproliferationcontrolisemphasizedasoneofthesixhallmarksofcancer[HanahanD andWeinberg15RA,Cell100,57,2000;HanahanDandWeinbergRA,Cell144,646,2011]. Compoundsofgeneralformula(I)ofthepresentinventiondemonstrateavaluablepharmacological spectrumofactionwhichcouldnothavebeenpredicted.Compoundsofthepresentinventionhave surprisinglybeenfoundtoeffectivelyinhibittheRas‐Sos1interactionanditispossiblethereforethat saidcompoundsbeusedforthetreatmentorprophylaxisofdiseases,preferablyhyperproliferative disordersinhumansandanimals. Compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferationand/orcelldivision,and/orproduceapoptosis.Thismethodcomprisesadministeringto amammal inneedthereof, includingahuman,anamountofacompoundofgeneralformula(I)of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate,solvateoresterthereof,whichiseffectivetotreatthedisorder. Hyperproliferativedisordersinclude,butarenotlimitedto,forexample:psoriasis,keloids,andother hyperplasiasaffectingtheskin,benignprostatehyperplasia(BPH),solidtumours,suchascancersof thebreast,respiratorytract,brain,reproductiveorgans,digestivetract,urinarytract,eye,liver,skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas,sarcomas,andleukaemias. Examplesofbreastcancersinclude,butarenotlimitedto,invasiveductalcarcinoma,invasivelobular carcinoma,ductalcarcinomainsitu,andlobularcarcinomainsitu.

Examplesofcancersoftherespiratorytractinclude,butarenotlimitedto,small‐cellandnon‐small‐ celllungcarcinoma,aswellasbronchialadenomaandpleuropulmonaryblastoma. Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellarand cerebralastrocytoma,medulloblastoma,ependymoma,aswellasneuroectodermal andpinealtumour. Tumours of themale reproductive organs include, but are not limited to, prostate and testicular cancer. Tumoursof the female reproductiveorgans include,butarenot limited to,endometrial, cervical, ovarian,vagin*l,andvulvarcancer,aswellassarcomaoftheuterus. Tumoursofthedigestive tract include,butarenot limitedto,anal,colon,colorectal,oesophageal, gallbladder,gastric,pancreatic,rectal,small‐intestine,andsalivaryglandcancers. Tumoursof theurinary tract include,but arenot limited to,bladder,penile, kidney, renalpelvis, ureter,urethralandhumanpapillaryrenalcancers. Eyecancersinclude,butarenotlimitedto,intraocularmelanomaandretinoblastoma. Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma),andmixedhepatocellularcholangiocarcinoma. Skincancers include,butarenot limitedto,squamouscellcarcinoma,Kaposi’ssarcoma,malignant melanoma,Merkelcellskincancer,andnon‐melanomaskincancer. Head‐and‐neckcancers include,butarenot limitedto, laryngeal,hypopharyngeal,nasopharyngeal, oropharyngealcancer,lipandoralcavitycancerandsquamouscell. Lymphomas include, but are not limited to, AIDS‐related lymphoma, non‐Hodgkin’s lymphoma, cutaneous T‐cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervoussystem. Sarcomasinclude,butarenotlimitedto,sarcomaofthesofttissue,osteosarcoma,malignantfibrous histiocytoma,lymphosarcoma,andrhabdomyosarcoma. Leukemias include,butarenot limited to,acutemyeloid leukemia,acute lymphoblastic leukemia, chroniclymphocyticleukemia,chronicmyelogenousleukemia,andhairycellleukemia. The present invention also providesmethods of treating angiogenic disorders including diseases associatedwithexcessiveand/orabnormalangiogenesis.

Inappropriateandectopicexpressionofangiogenesiscanbedeleterioustoanorganism.Anumber ofpathologicalconditionsareassociatedwiththegrowthofextraneousbloodvessels.Theseinclude, for example,diabetic retinopathy, ischemic retinal‐veinocclusion, and retinopathyofprematurity [Aielloetal.,NewEngl.J.Med.,1994,331,1480;Peeretal.,Lab.Invest.,1995,72,638],age‐related maculardegeneration(AMD)[Lopezetal.,Invest.Opththalmol.Vis.Sci.,1996,37,855],neovascular glaucoma,psoriasis,retrolental fibroplasias,angiofibroma, inflammation,rheumatoidarthritis (RA), restenosis,in‐stentrestenosis,vasculargraftrestenosis,etc.Inaddition,the increasedbloodsupply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement andmetastasis.Moreover, the growthofnewblood and lymph vessels in a tumour providesanescaperouteforrenegadecells,encouragingmetastasisandtheconsequencespreadof thecancer.Thus,compoundsofgeneralformula(I)ofthepresentinventioncanbeutilizedtotreat and/orpreventanyoftheaforementionedangiogenesisdisorders,forexamplebyinhibitingand/or reducingbloodvessel formation;by inhibiting,blocking, reducing,decreasing,etc.endothelial cell proliferation,orother types involved inangiogenesis,aswellascausingcelldeathorapoptosisof suchcelltypes. Thesedisordershavebeenwell characterized inhumans,but also existwith a similar etiology in othermammals,andcanbe treatedbyadministeringpharmaceuticalcompositionsof thepresent invention. Theterm“treating”or“treatment”asstatedthroughoutthisdocument isusedconventionally,for example themanagementorcareofasubject for thepurposeofcombating,alleviating,reducing, relieving,improvingtheconditionofadiseaseordisorder,suchasacarcinoma. The compoundsof thepresent invention canbeused inparticular in therapyandprevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswithorwithoutpre‐treatmentofthetumourgrowth. Generally, the use of chemotherapeutic agents and/or anti‐cancer agents in combinationwith a compoundorpharmaceuticalcompositionofthepresentinventionwillserveto: 1. yieldbetterefficacy in reducing thegrowthofa tumouroreveneliminate the tumouras comparedtoadministrationofeitheragentalone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide forachemotherapeutic treatment that iswell tolerated in thepatientwith fewer deleteriouspharmacologicalcomplicationsthanobservedwithsingleagentchemotherapies andcertainothercombinedtherapies,

4. provide for treating abroader spectrumofdifferent cancer types inmammals, especially humans, 5. provideforahigherresponserateamongtreatedpatients, 6. provide for a longer survival time among treated patients compared to standard chemotherapytreatments, 7. providealongertimefortumourprogression,and/or 8. yield efficacy and tolerability results at least as good as those of the agents used alone, comparedtoknowninstanceswhereothercanceragentcombinationsproduceantagonistic effects. In addition, the compounds of general formula (I) of the present invention can also be used in combinationwithradiotherapyand/orsurgicalintervention. In a further embodiment of the present invention, the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compoundof thepresent inventionprior to radiation treatmentof the cell renders the cellmore susceptibletoDNAdamageandcelldeaththanthecellwouldbe intheabsenceofanytreatment with a compound of the present invention. In one aspect, the cell is treatedwith at least one compoundofgeneralformula(I)ofthepresentinvention. Thus,thepresentinventionalsoprovidesamethodofkillingacell,whereinacellisadministeredone ormorecompoundsofthepresentinventionincombinationwithconventionalradiationtherapy. Thepresent invention alsoprovides amethodof rendering a cellmore susceptible to celldeath, wherein the cell is treated with one ormore compounds of general formula (I) of the present inventionpriortothetreatmentofthecelltocauseorinducecelldeath.Inoneaspect,afterthecell is treatedwithoneormorecompoundsofgeneral formula (I)of thepresent invention, thecell is treatedwithat leastonecompound,orat leastonemethod,oracombinationthereof, inorderto causeDNAdamageforthepurposeofinhibitingthefunctionofthenormalcellorkillingthecell. Inotherembodimentsofthepresent invention,acell iskilledbytreatingthecellwithat leastone DNAdamagingagent,i.e.aftertreatingacellwithoneormorecompoundsofgeneralformula(I)of thepresent invention to sensitize the cell to celldeath, the cell is treatedwithat leastoneDNA damagingagenttokillthecell.DNAdamagingagentsusefulinthepresentinventioninclude,butare not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X‐rays, ultraviolet radiation),carcinogenicagents,andmutagenicagents.

Inotherembodiments,acelliskilledbytreatingthecellwithatleastonemethodtocauseorinduce DNAdamage.Suchmethods include,butarenot limited to,activationofacellsignallingpathway thatresultsinDNAdamagewhenthepathwayisactivated,inhibitingofacellsignallingpathwaythat results inDNAdamagewhenthepathway is inhibited,and inducingabiochemicalchange inacell, whereinthechangeresultsinDNAdamage.Bywayofanon‐limitingexample,aDNArepairpathway inacellcanbeinhibited,therebypreventingtherepairofDNAdamageandresultinginanabnormal accumulationofDNAdamageinacell. In one aspect of the invention, a compound of general formula (I) of the present invention is administeredtoacellpriortotheradiationorotherinductionofDNAdamageinthecell.Inanother aspectoftheinvention,acompoundofgeneralformula(I)ofthepresentinventionisadministered to a cell concomitantlywith the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of general formula (I) of the present invention is administeredtoacell immediatelyafterradiationorotherinductionofDNAdamageinthecellhas begun. Inanotheraspect,thecellisinvitro.Inanotherembodiment,thecellisinvivo. Itispossibleforthecompoundsaccordingtotheinventiontohavesystemicand/orlocalactivity.For this purpose, they can be administered in a suitablemanner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vagin*l, dermal, transdermal, conjunctival,oticrouteorasanimplantorstent. For theseadministration routes, it ispossible for thecompoundsaccording to the invention tobe administeredinsuitableadministrationforms. For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modifiedmanner,suchas,forexample,tablets(uncoatedorcoatedtablets,forexamplewithenteric or controlled release coatings that dissolve with a delay or are insoluble), orally‐disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar‐coatedtablets,granules,pellets,powders,emulsions,suspensions,aerosolsorsolutions. It is possibleto incorporatethecompoundsaccordingtothe invention incrystallineand/oramorphised and/ordissolvedformintosaiddosageforms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal, intralumbalor intratumoral)orwith inclusionof absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or

intraperitoneal).Administrationformswhicharesuitableforparenteraladministrationare,interalia, preparationsforinjectionandinfusionintheformofsolutions,suspensions,emulsions,lyophylisates orsterilepowders. Exampleswhicharesuitableforotheradministrationroutesarepharmaceuticalformsforinhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops,eyeointments,eyebaths,ocular inserts,eardrops,earsprays,earpowders,ear‐rinses,ear tampons; vagin*l capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions,emulsions,ointments,creams,transdermaltherapeuticsystems(suchas,forexample, patches),milk,pastes,foams,dustingpowders,implantsorstents. Thecompoundsaccordingtotheinventioncanbeincorporatedintothestatedadministrationforms. Thiscanbeeffectedinamannerknownpersebymixingwithpharmaceuticallysuitableexcipients. Pharmaceuticallysuitableexcipientsinclude,interalia, ^ fillers and carriers (for example cellulose,microcrystalline cellulose (such as, for example, Avicel^®),lactose,mannitol,starch,calciumphosphate(suchas,forexample,Di‐Cafos^®)), ^ ointmentbases(forexamplepetroleumjelly,paraffins,triglycerides,waxes,woolwax,wool waxalcohols,lanolin,hydrophilicointment,polyethyleneglycols), ^ basesforsuppositories(forexamplepolyethyleneglycols,cacaobutter,hardfat), ^ solvents(forexamplewater,ethanol,isopropanol,glycerol,propyleneglycol,mediumchain‐ lengthtriglyceridesfattyoils,liquidpolyethyleneglycols,paraffins), ^ surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette^®), sorbitan fatty acid esters(suchas,forexample,Span^®),polyoxyethylenesorbitanfattyacidesters(suchas,for example,Tween^®),polyoxyethylenefattyacidglycerides(suchas,forexample,Cremophor^®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters,poloxamers(suchas,forexample,Pluronic^®), ^ buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), ^ isotonicityagents(forexampleglucose,sodiumchloride), ^ adsorbents(forexamplehighly‐dispersesilicas),

^ viscosity‐increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl‐ cellulose, carboxymethylcellulose‐sodium, starch, carbomers,polyacrylicacids (suchas, for example,Carbopol^®);alginates,gelatine), ^ disintegrants (for examplemodified starch, carboxymethylcellulose‐sodium, sodium starch glycolate (such as, for example, Explotab^®), cross‐ linked polyvinylpyrrolidone, croscarmellose‐sodium(suchas,forexample,AcDiSol^®)), ^ flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate,stearicacid,talc,highly‐dispersesilicas(suchas,forexample,Aerosil^®)), ^ coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon^®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl‐ methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylatessuchas,forexample,Eudragit^®)), ^ capsulematerials(forexamplegelatine,hydroxypropylmethylcellulose), ^ synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit^®), polyvinylpyrrolidones (such as, for example,Kollidon^®),polyvinylalcohols,polyvinylacetates,polyethyleneoxides,polyethylene glycolsandtheircopolymersandblockcopolymers), ^ plasticizers(forexamplepolyethyleneglycols,propyleneglycol,glycerol,triacetine,triacetyl citrate,dibutylphthalate), ^ penetrationenhancers, ^ stabilisers(forexampleantioxidantssuchas,forexample,ascorbicacid,ascorbylpalmitate, sodiumascorbate,butylhydroxyanisole,butylhydroxytoluene,propylgallate), ^ preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidineacetate,sodiumbenzoate), ^ colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), ^ flavourings,sweeteners,flavour‐and/orodour‐maskingagents.

Thepresentinventionfurthermorerelatestoapharmaceuticalcompositionwhichcompriseatleast one compound according to the invention, conventionally together with one or more pharmaceuticallysuitableexcipient(s),andtotheiruseaccordingtothepresentinvention. Inaccordancewithanotheraspect, thepresent invention coverspharmaceutical combinations, in particularmedicaments, comprising at least one compound of general formula (I) of the present inventionandatleastoneormorefurtheractiveingredients,inparticularforthetreatmentand/or prophylaxisofahyper‐proliferativedisorder,inparticularcancer. Particularly,thepresentinventioncoversapharmaceuticalcombination,whichcomprises: ^ one or more first active ingredients, in particular compounds of general formula (I) as definedsupra,and ^ one ormore further active ingredients, in particular those used for treatment of hyper‐ proliferativedisorder,inparticularcancer. The term“combination” in thepresent invention isusedasknown topersonsskilled in theart, it beingpossibleforsaidcombinationtobeafixedcombination,anon‐fixedcombinationorakit‐of‐ parts. A“fixedcombination” inthepresent invention isusedasknowntopersonsskilled intheartand is defined as a combination wherein, for example, a first active ingredient, such as one ormore compounds of general formula (I) of the present invention, and a further active ingredient are presenttogetherinoneunitdosageorinonesingleentity.Oneexampleofa“fixedcombination”isa pharmaceutical compositionwherein a first active ingredient and a further active ingredient are presentinadmixtureforsimultaneousadministration,suchasinaformulation.Anotherexampleofa “fixedcombination” isapharmaceuticalcombinationwhereinafirstactive ingredientandafurther activeingredientarepresentinoneunitwithoutbeinginadmixture. Anon‐fixedcombinationor“kit‐of‐parts”inthepresentinventionisusedasknowntopersonsskilled in the art and is defined as a combinationwherein a first active ingredient and a further active ingredientarepresentinmorethanoneunit.Oneexampleofanon‐fixedcombinationorkit‐of‐parts is a combinationwherein the first active ingredient and the further active ingredient arepresent separately. It is possible for the components of the non‐fixed combination or kit‐of‐parts to be administeredseparately,sequentially,simultaneously,concurrentlyorchronologicallystaggered. Thecompoundsofthepresentinventioncanbeadministeredasthesolepharmaceuticalagentorin combinationwith one ormore other pharmaceutically active ingredientswhere the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical

combinations.Forexample,thecompoundsofthepresent inventioncanbecombinedwithknown anti‐tumoragents(cancertherapeutics). Examplesofanti‐tumoragents(cancertherapeutics)include: 131I‐chTNT, abarelix, abiraterone, aclarubicin, ado‐trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin,arsenic trioxide,asparaginase,axitinib,azacitidine,basiliximab,belotecan,bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin,carboquone,carfilzomib,carmofur,carmustine,catumaxomab,celecoxib,celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide,cyproterone,cytarabine,dacarbazine,dactinomycin,daratumumab,darbepoetin alfa, darolutamide, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag,endostatin,enocitabine,enzalutamide,epirubicin,epitiostanol,epoetinalfa,epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM‐CSF, goserelin, granisetron, granulocyte colony stimulating factor, histaminedihydrochloride,histrelin,hydroxycarbamide, I‐125 seeds, lansoprazole, ibandronicacid, ibritumomabtiuxetan,ibrutinib,idarubicin,ifosfamide,imatinib,imiquimod,improsulfan,indisetron, incadronic acid, ingenolmebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane(123I),iomeprol,ipilimumab,irinotecan,Itraconazole,ixabepilone,ixazomib,lanreotide, lansoprazole, lapatinib, larotrectinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen,

methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine,miriplatin,mitobronitol,mitoguazone,mitolactol,mitomycin,mitotane,mitoxantrone, mogamulizumab,molgramostim,mopidamol,morphinehydrochloride,morphine sulfate,nabilone, nabiximols,nafarelin,naloxone+pentazocine,naltrexone,nartograstim,necitumumab,nedaplatin, nelarabine,neridronicacid,netupitant/palonosetron,nivolumabpentetreotide,nilotinib,nilutamide, nimorazole,nimotuzumab,nimustine,nintedanib,nitracrine,nivolumab,obinutuzumab,octreotide, ofatumumab,olaparib,omacetaxinemepesuccinate,omeprazole,ondansetron,oprelvekin,orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, pacl*taxel,palbociclib,palifermin,palladium‐103seed,palonosetron,pamidronicacid,panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG‐epoetin beta (methoxy PEG‐epoetin beta),pembrolizumab,pegfilgrastim,peginterferonalfa‐2b,pemetrexed,pentazocine,pentostatin, peplomycin,Perflubutane,perfosfamide,Pertuzumab,picibanil,pilocarpine,pirarubicin,pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide‐K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium‐223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium‐186 etidronate, rituximab, rogaratinib, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel‐T, sizofiran,sobuzoxane,sodiumglycididazole,sonidegib,sorafenib,stanozolol,streptozocin,sunitinib, talaporfin,talimogenelaherparepvec,tamibarotene,tamoxifen,tapentadol,tasonermin,teceleukin, technetium (99mTc) nofetumomabmerpentan, 99mTc‐HYNIC‐[Tyr3]‐octreotide, tegafur, tegafur + gimeracil+oteracil,temoporfin,temozolomide,temsirolimus,teniposide,testosterone,tetrofosmin, thalidomide,thiotepa,thymalfasin,thyrotropinalfa,tioguanine,tocilizumab,topotecan,toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumabemtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium‐90 glass microspheres,zinostatin,zinostatinstimalamer,zoledronicacid,zorubicin. FurtherexamplesofcombinationpartnersareATR inhibitors(e.g.BAY1895344),DHODH inhibitors (e.g.BAY2402234),SHP2 inhibitors(e.g.SHP099,RMC‐4550,TNO155)orH‐,N‐orK‐Ras inhibitors, including inhibitorsofmutants thereof, especially K‐RAS‐G12C inhibitors (e.g.ARS‐853,ARS‐1620, AMG‐510,MRTX849,MRTX1257)orfarnesyltransferaseinhibitors.

Inparticular,thepresentinventioncoversacombinationofacovalentinhibitorofKRAS‐G12Canda SOS1 inhibitor. Ithasbeen shown that covalentKRAS‐G12C inhibitors (e.g.ARS‐853orARS‐1620) specificallybind toKRAS‐G12C in theGDP‐bound state,butnot in theGTP‐bound state (Patricelli 2016CancerDiscovery;Janesetal.2018Cell),therebytrappingKRAS‐G12CinitsinactiveGDP‐bound state.Inaddition,ithasbeenshownthatcertainRASmutants,whichusuallyexistintheactive,GTP‐ boundstate,areundergoingaslowintrinsicGTPhydrolysis,inparticularG12CandG12Dmutantsof KRAS(Hunteretal.2015MolecularCancerResearch). Itcanbepostulatedthateventhosemutant RAS proteins require the activation by nucleotide exchange factors like SOS1 for full activity and tumorigenesis.TreatmentwithaSOS1 inhibitor isexpected toshift the intracellularequilibriumof KRASmutantstowardsthe inactiveGDP‐boundstate,which inturnfavoursbindingof inhibitorsof KRASwhichbindpreferentiallytotheGDP‐boundstateofRAS,asisthecaseforcovalentKRAS‐G12C inhibitors likeARS‐853andARS‐1620.Synergisticanti‐proliferativeactivity invitrohasbeenshown forthecombinationofBAY‐293withARS‐853(Hillig2019PNAS). Baseduponstandardlaboratorytechniquesknowntoevaluatecompoundsusefulforthetreatment ofhyper‐proliferativedisorders,by standard toxicity testsandby standardpharmacologicalassays for the determination of treatment of the conditions identified above in mammals, and by comparisonof these resultswith the resultsofknownactive ingredientsormedicaments thatare usedtotreattheseconditions,theeffectivedosageofthecompoundsofthepresentinventioncan readilybedeterminedfortreatmentofeachdesiredindication.Theamountoftheactiveingredient tobeadministered in the treatmentofoneof theseconditionscanvarywidelyaccording to such considerationsastheparticularcompoundanddosageunitemployed,themodeofadministration, theperiodof treatment, theageandsexof thepatient treated,and thenatureandextentof the conditiontreated. Thetotalamountoftheactive ingredienttobeadministeredwillgenerallyrangefromabout0.001 mg/kgtoabout200mg/kgbodyweightperday,andpreferablyfromabout0.01mg/kgtoabout20 mg/kgbodyweightperday.Clinicallyusefuldosingscheduleswillrangefromonetothreetimesa daydosingtoonceeveryfourweeksdosing.Inaddition,itispossiblefor"drugholidays",inwhicha patient isnotdosedwithadrugforacertainperiodoftime,tobebeneficialtotheoverallbalance betweenpharmacologicaleffectandtolerability.Itispossibleforaunitdosagetocontainfromabout 0.5mgtoabout1500mgofactiveingredient,andcanbeadministeredoneormoretimesperdayor lessthanonceaday.Theaveragedailydosageforadministrationbyinjection,includingintravenous, intramuscular,subcutaneousandparenteralinjections,anduseofinfusiontechniqueswillpreferably be from 0.01 to 200mg/kg of total body weight. The average daily rectal dosage regimen will preferablybefrom0.01to200mg/kgoftotalbodyweight.Theaveragedailyvagin*ldosageregimen

willpreferablybe from0.01 to200mg/kgof totalbodyweight.Theaveragedaily topicaldosage regimenwillpreferablybe from0.1 to200mgadministeredbetweenone to four timesdaily.The transdermalconcentrationwillpreferablybethatrequiredtomaintainadailydoseoffrom0.01to 200mg/kg.Theaveragedailyinhalationdosageregimenwillpreferablybefrom0.01to100mg/kgof totalbodyweight. Ofcoursethespecific initialandcontinuingdosageregimenforeachpatientwillvaryaccordingto thenatureandseverityoftheconditionasdeterminedbytheattendingdiagnostician,theactivityof the specific compound employed, the age and general condition of the patient, time of administration, routeofadministration, rateofexcretionof thedrug,drug combinations,and the like.Thedesiredmodeoftreatmentandnumberofdosesofacompoundofthepresentinventionor a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilledintheartusingconventionaltreatmenttests. EXPERIMENTALSECTION Thefollowingtableliststheabbreviationsusedinthisparagraph,andintheexamplessection. BuLi Butyllithium DCE Dichloroethane DCM Dichloromethane DMF Dimethylformamide DMSO Dimethylsulfoxide EA Ethylacetate FA Formicacid HPLC,LC highperformanceliquidchromatography h hour LiHMDS Lithiumbis(trimethylsilyl)amide KHMDS Potassiumbis(trimethylsilyl)amide KOtBu Potassiumtert‐butoxide min minute LDA Lithiumdiisopropylamid MS massspectroscopy

NMR nuclearmagneticresonance NaHMDS Sodiumbis(trimethylsilyl)amide PE Petrolether Rac Racemate R_f Retardiationfactor R_t Retentiontime RT Roomtemperature TFA Trifluoroaceticacid THF Tetrahydrofuran TLC thin‐layerchromatography ChemicalnamesweregeneratedusingACD/NameBatchVersion12.01orAutonom2000. Allreagents,forwhichthesynthesisisnotdescribedintheexperimentalpart,areeither commerciallyavailableorsynthesizedasdescribedinliteraturereferences. AnalyticalMethods LC‐MSMethod1: Column: AscentisExpressC182.7µm,30x2.1mm Fragment.potential: 50V Massrange: 80‐800m/z Solvent: A=H₂O+0.1%volHCOOH B=methanol+0.1%volHCOOH Gradient: 0‐1min5%B,1‐4min5‐100%B4‐5min100%B,5‐6min100‐5%B,6‐ 6.5min5%B Flow: 0.8mL/min Temperature: 30°C Injection: 1.0µL Detection: MM‐ES+APCI+DAD(254nm) Systemtimedelay: 0.2min LC‐MSMethod2:MSinstrumenttype:MicromassQuatroMicro;HPLCinstrumenttype:Agilent1100 Series;UVDAD;column:ChromolithFlashRP‐18E25‐2mm;mobilephaseA:0.0375%TFA inwater, mobilephaseB:0.01875%TFAinacetonitrile;gradient:0.0min100%A ^1.0min95%A ^3.0min 95%A ^3.5min5%A ^3.51min5%A ^4.0min95%A;flowrate:0.8mL/min;columntemp: 50°C;UVdetection:220nm&254nm. LC‐MS Method 3: System: WatersAcquityUPLC‐MS:BinarySolventManager,Sample Manager/Organizer,PDA,ELSD

Column: AcquityUPLCBEHC181.7µm,50x2.1mm Solvent: A=H₂O+H₂O+0.1%vol.HCOOC(99%) B=acetonitrile Gradient: 0‐1.6min1‐99%B,1.6‐2min99%B Flow: 0.8mL/min Temperature: 60°C Injection: 2.0µL Detection: DADscanrange210‐400nm+ELSD LC‐MSMethod4: System: ShimadzuLC‐MS:UFLC20‐ADandLCMS2020MSdetector Column: Shim‐packXR‐ODS2.2µm,3.0x50mm Solvent: A=H₂O+0.05%vol.HCOOC(99%) B=acetonitrile+0.05%vol.HCOOC(99%) LC‐MSMethod5: System: WatersAcquityUPLC‐MS:BinarySolventManager,Sample Manager/Organizer,PDA,ELSD Column: AcquityUPLCBEHC181.7µm,50x2.1mm Solvent: A=H₂O+0.2%vol.NH₃(32%) B=acetonitrile Gradient: 0‐1.6min1‐99%B,1.6‐2min99%B Flow: 0.8mL/min Temperature: 60°C Injection: 2.0µL Detection: DADscanrange210‐400nm+ELSD LC‐MSMethod6: System: InstrumentHPLC:WatersUPLCAcquity;InstrumentMS:WatersZQ Column: AcquityUPLCBEHC181.7µm,50x2.1mm Solvent: A=H₂O+0.1%vol.HCOOC(99%) B=acetonitrile Gradient: 0‐1.6min1‐99%B,1.6‐1.8min99%B,1.81‐2min1%B Flow: 0.8mL/min Temperature: 60°C Detection: PDAscanrange210‐400nm LC‐MSMethod7: System: Agilent1290UHPLC‐MSTof Column: BEHC18(Waters)1.7µm,50x2.1mm Solvent: A=H₂O+0.05%vol.HCOOC(99%) B=acetonitrile+0.05%vol.HCOOC(99%) Gradient: 0‐1.7min2‐90%B,1.7‐2min90%B,2‐2.5min90‐2%B Flow: 1.2mL/min Temperature: 60°C Detection: DADscanrange210‐400nm LC‐MSMethod8: System: WatersAcquityUPLC‐MS:BinarySolventManager,Sample Manager/Organizer,PDA,ELSD

Column: AcquityUPLCBEHC181.7µm,50x2.1mm Solvent: A=H₂O+0.1%vol.HCOOC(99%) B=acetonitrile Gradient: 0‐1.6min1‐99%B,1.6‐2min99%B Flow: 0.8mL/min Temperature: 60°C Injection: 2.0µL Detection: DADscanrange210‐400nm+ELSD LC‐MSMethod9: System: WatersAcquityUPLC‐MSSingleQuad Column: KinetexC18(Phenomenex)2.6µm,50x2.1mm Solvent: A=H₂O+0.05%vol.HCOOC(99%) B=acetonitrile+0.05%vol.HCOOC(99%) Gradient: 0‐0.2min2%B,0.2‐1.7min2‐90%B,1.7‐1.9min90%B,1.9‐2min 90‐2%B,2‐2.5min2%B Flow: 1.3mL/min Temperature: 60°C Detection: DADscanrange210‐400nm LC‐MSmethod10: System:WatersAcquityUPLC‐MSSingleQuad;Column:AcquityUPLCBEHC181.7µm,50x2.1mm; Solvent:A=H2O+0.2%vol.NH3(32%),B=acetonitrile;Gradient:0‐1.6min1‐99%B,1.6‐2min99% B;Flow:0.8mL/min;Temperature: 60°C;Detection:DADscanrange210‐400nm PreparativeHPLC a) Autopurifier:acidicconditions System: WatersAutopurificationsystem:Pump2545,SampleManager2767, CFO,DAD2996,ELSD2424,SQD Column: XBrigdeC185.0µm100x30mm Solvent: A=H₂O+0.1%vol.HCOOH(99%) B=acetonitrile Gradient: 0‐0.5min5%B25mL/min,0.51‐5.5min10‐100%B70mL/min,5.51‐6.5 min100%B70mL/min Temperature: RT Solution: max.250mg/max.2.5mLDMSOorDMF Injection: 1x2.5mL Detection: DADscanrange210–400nm,MSESI+,ESI‐,scanrange160‐1000m/z b) Autopurifier:basicconditions System: WatersAutopurificationsystem:Pump2545,SampleManager2767, CFO,DAD2996,ELSD2424,SQD Column: XBrigdeC185.0µm100x30mm Solvent: A=H₂O+0.2%vol.NH₃(32%) B=acetonitrile

Gradient: 0‐0.5min5%B25mL/min,0.51‐5.5min10‐100%B70mL/min,5.51‐6.5 min100%B70mL/min Temperature: RT Solution: max.250mg/max.2.5mLDMSOorDMF Injection: 1x2.5mL Detection: DADscanrange210–400nm,MSESI+,ESI‐,scanrange160‐1000m/z MethodX1: Instrument:LabomaticHD5000,Labocord‐5000;GilsonGX‐241,LabcolVario4000;Column:Chiralpak IE5µm250x20mm;EluentA:MTBE+0.1%vol.Diethylamine(99%);EluentB:Ethanol;Isocratic: 90%A+10%B;Flow30.0mL/min;UV254nm. MethodX2: Instrument:LabomaticHD5000,Labocord‐5000;GilsonGX‐241,LabcolVario4000;Column:Chiralpak IA5µm250x30mm;EluentA:MTBE+0.1%vol.Diethylamine(99%);EluentB:Ethanol;Isocratic: 85%A+15%B;Flow40.0mL/min;UV254nm. MethodX3: Instrument:LabomaticHD5000,Labocord‐5000;GilsonGX‐241,LabcolVario4000,Column:Chiralpak IA5.0µm250x30mm;Eluent:100%Acetonitrile;Flow50.0mL/min;UV280nm. MethodX4: Instrument:WatersAutopurificationsystem;Column:WatersXBrigdeC185.0µm100x30mm; EluentA:H₂O+0.2%vol.NH₃(32%),EluentB:Acetonitrile;Gradient:0.00–0.50min8%B(25‐ >70mL/min),0.51–5.50min8‐15%B(70mL/min),DADscan:210‐400nm. MethodX5: Instrument:LabomaticHD5000,Labocord‐5000;GilsonGX‐241,LabcolVario4000,Column:Chiralpak IF5.0µm250x30mm;EluentA:Hexane+0.1%vol.Diethylamine(99%);EluentB:Ethanol;Isocratic: 90%A+10%B;Flow50.0mL/min;UV280nm. MethodX6: Instrument:WatersAutopurificationsystem;Column:WatersXBrigdeC185.0µm100x30mm; EluentA:H₂O+0.2%vol.NH₃(32%),EluentB:Acetonitrile;Gradient:0.00–0.50min30%B(25‐ >70mL/min),0.51–5.50min30‐45%B(70mL/min),DADscan:210‐400nm. MethodX7: Instrument:LabomaticHD5000,Labocord‐5000;GilsonGX‐241,LabcolVario4000, Column:ChiralpakID5.0µm250x30mm;EluentA:Hexane+0.1%volDiethylamin(99%);EluentB:2‐ Propanol;Isocratic:85%A+15%B;Flow50.0mL/min;UV254nm.

Synthesisofintermediates13 Experimentalprocedure[A]forthesynthesisof13‐a(seeWO2019/122129,page141,line2–page 144,line1) Asolutionof12‐a(13.20g,45.00mmol;1.0equiv.)in1,4‐dioxane(100ml)iscooledto0°Cand treatedwith4NHCIin1,4‐dioxane(50.00ml,200.00mmol,4.4equiv.).Thereactionmixtureis stirredfor3h.Aftercompleteconversionofthestartingmaterial,thereactionmixtureis concentratedunderreducedpressure,theprecipitatefilteredandwashedwithdiethyletherto obtainthedesiredproduct13‐aasHCIsalt. Thecrudeproduct13ispurifiedbychromatographyifnecessaryandisolatedasHCIsalt. Experimentalprocedure[B]forthesynthesisofB‐5k(seeWO2019/122129,page144,line2–page 146,line1) Alcohol14(2.00g,9.61m mol,1.0equiv.)isdissolvedinanhydroustoluene(20mL). Diazabicycloundecene(1.73mL,11.5mmol,1.2equiv.)anddiphenylphosphonicazide(2.28mL,10.6 mmol,1.1equiv.)areaddedsubsequently.Thereactionmixtureisstirredat40°Cfor18huntil completeconversionof14isachieved.Thereactionmixtureiscooledtoroomtemperatureandthe organiclayeriswashedwithaqueousNa₂CO₃solution(2x10mL).AzideB‐7athusobtainedisnot isolatedbutdirectlyconvertedinthenextstep. Pd/C(200mg,10%w/w,10%Pd)isaddedtotheorganiclayer.Thereactionmixtureischargedwith aH₂atmosphere(10bar)andisstirredfor24huntilcompleteconversionof15isachieved.The reactionisfilteredandthevolatilesareremovedinvacuo.Theresidueisdissolvedinmethyltert‐ butylether(30mL)andtreatedwithHCIindioxane(4.8mL,4M).Thewhiteprecipitateisfilter, washedwithmethyltert‐butylether(20mL)andfurtherdriedinvacuotofurnishthedesired product13.Thecrudeproductispurifiedbychromatographyifnecessary. Table1:Intermediates13(benzylamines)availableinanalogousmannerstartingfromdifferent sulfonamides12(experimentalprocedure[A],table1,column2)oralcohols14viaazides15 (experimentalprocedure[B],table1,column3) Table1:

ThesynthesisofthedifferentnecessarysulfonamidesB‐4isdescribedinWO2019/122129atpage 136line2topage140line9. ThesynthesisofthedifferentnecessaryalcoholsB‐6isdescribedinWO2019/122129atpage140 line10topage141line1(incl.table14). Intermediate1 1‐bromo‐3‐(difluoromethyl)‐2‐fluorobenzene Toasolutionof3‐bromo‐2‐fluorobenzaldehyde(4.07g,20.1mmol)inDCM(35ml)at0°Cwasadded slowlydropwiseasolutionofN‐ethyl‐N‐(trifluoro‐lambda⁴‐sulfanyl)ethanamine(4.0ml,30mmol)in DCM (10ml).The reactionwasallowed towarmand stirredatRTovernight.The reactionmixture was added to ice‐water and extractedwithDCM. Theorganicswere combined,washedwith sat. NaCl(aq), filtered through an hydrophobic filter and concentrated under reduced pressure. The residuewaspurifiedbysilicachromatography(Hexane:EtOAc)andgavethetitledcompound(3.57g, 75%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:2.518(0.97),2.522(0.62),7.113(7.95),7.248(16.00),7.303 (4.71),7.323(9.95),7.343(5.61),7.383(7.82),7.642(3.92),7.659(6.89),7.678(3.45),7.911(3.70), 7.928(6.59),7.948(3.45). Intermediate2

1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐one Toasolutionof1‐bromo‐3‐(difluoromethyl)‐2‐fluorobenzene(3.07g,13.6mmol) inanhydrousTHF (10ml)at‐10°Cwasaddedisopropylmagnesiumchloride(2MinTHF,7.5ml,15mmol).Thereaction wasstirredat‐10°Cfor1handthentoaddedtoaceticanhydride(3.9ml,41mmol)cooledto‐15°C. The reactionwaswas towarm to0°C and stirred for15min. The reactionwasquenchedby the additionofwaterandstirredat60°Cfor15min.ThereactionmixturewasextractedwithDCM.The organics were combined, washed with sat. NaHCO3(aq), sat. NaCl(aq), filtered through an hydrophobicfilterandconcentratedunderreducedpressure.Thecrudeproduct(787mg,28%)was useddirectlywithoutanyfurtherpurification. Intermediate3 (R)‐N‐{1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethylidene}‐2‐methylpropane‐2‐sulfinamide To a solutionof1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐one (787mg,4.18mmol) and (R)‐2‐ methyl‐2‐propane‐2‐sulfinamide (760mg,6.27mmol)wasaddedTi(OEt)4 (2.86g,12.5mmol)and heatedat80°Covernight.ThereactionwasaddedtoamixtureofEtOAcandice‐waterandextracted withEtOAc.Theorganicswerecombined, filtered throughanhydrophobic filterandconcentrated underreducedpressure.Theresidue(1.31g,97%)wasuseddirectlyinthenextstep. Intermediate4 (R)‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpropane‐2‐sulfinamide To a solution of (R)‐N‐{1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethylidene}‐2‐methylpropane‐2‐ sulfinamide(1218mg,4.18mmol)inTHF(12ml)wascooledto0°CandNaBH4(158mg,4.18mmol) wasadded.ThereactionwasstirredatRTfor2h.ThereactionwasaddedtoamixtureofEtOAcand ice‐water,thenextractedwithEtOAc.Theorganicswerecombined,filteredthroughanhydrophobic

filterandconcentratedunderreducedpressure.Thetitledcompound(802mg,62%)wasobtained aftersilicachromatography(EtOAc:Hexane)alongwithitsdiastereoisomer(166mg,13%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.099(16.00),1.154(0.44),1.172(0.85),1.190(0.42),1.401 (2.11),1.418(2.10),1.987(1.59),5.870(0.54),5.889(0.52),7.074(0.41),7.209(0.86),7.345(1.03). Intermediate5 (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐amine,saltwithhydrogenchloride x^HCl To an ice‐cooled solution of (R)‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpropane‐2‐sulfinamide(1.00g,3.41mmol)indioxane(7.5ml)wasaddedHCl(4Mindioxane, 3.75ml). The reactionwas allowed towarm to RT and stirred for 3h. The reactionmixturewas concentrated under reduced pressure to approximately a volume of about 2ml. The solid was collected by filtered and was washed withMTBE and the titled compound (618mg, 76%) was obtained. ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.102 (7.29),1.532 (7.14),1.549 (7.00),2.518 (0.81),2.523 (0.57),3.072(2.53),3.565(5.88),4.636(0.46),4.653(1.59),4.670(1.66),4.681(0.63),4.686(0.58), 5.760(16.00),7.119(2.25),7.254(4.53),7.388(2.02),7.429(1.08),7.449(2.38),7.468(1.37),7.651 (1.03),7.669(1.76),7.687(0.86),7.888(0.87),7.906(1.16),7.925(0.54),8.584(0.43),8.709(1.89). Intermediate6 6‐Fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol A round‐bottom flask was charged with 5.00 g (32.0mmol, commercially available) 5‐Amino‐2‐ fluoro‐4‐pyridinecarboxylicacid,7.57g(80mmol,commerciallyavailable)acetamidinehydrochloride , and 6.56 g (80mmol) anhydrous sodium acetate. Themixturewas suspended in 50.0ml of 2‐ methoxyethanol,andthenthemixturewasstirredat130°Cfor16h.Thecourseofthereactionwas monitoredbyLC/MS.Completeconversionwasobserved.Theresultingmixturewaspouredintocold waterandstirredfor30min.Theprecipitatewasfilteredoffanddriedinvacuo.5.95g(98%d.Th.) ofthetitlecompoundwasobtainedinformofabeige‐colouredsolid. 1H‐NMR (400MHz,DMSO‐d6):^ [ppm]=13.14‐11.96 (brs,1H),8.66 (s,1H),7.59 (d,1H),2.37 (s, 3H).

Intermediate7 6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol Around‐bottomflaskwaschargedwithethanol(110ml)andcooledwithanicebath.Totheethanol wascarefullyaddedsodium(3.73g,163mmol)andstirredfor5min.6‐fluoro‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐ol(5.85g,32.7mmol)wasaddedandthemixturewasstirredat110°Cfor16h.The courseofthereactionwasmonitoredbyLC/MS,nearlycompleteconversionwasdetected.The solutionwascooledtoroomtemperatureandconcentratedinvacuo.Undercoolinginanice‐bath theresiduewasdilutedwith500mlofwater,thenacidifiedwith2Mhydrochloricacid(200mL)to pH=1andextractedwithdichloromethane(2x200ml)andamixtureof dichlormethane/isopropanol(4:1,5x200ml).Thecombinedorganiclayersweredriedoversodium sulfateandthenconcentratedinvacuo.Thetitlecompound(4.83g,77%)wasobtainedinformofa beige/brown‐colouredsolid. 1H‐NMR(400MHz,DMSO):^[ppm]=8.62(s,1H),7.17(s,1H),4.34(q,2H),1.34(t,3H). Intermediate8 6‐methoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol Amixtureof5‐amino‐2‐methoxypyridine‐4‐carboxylicacid(2.50g,14.9mmol),ethanimidamide hydrochloride(2.81g,29.7mmol)andanhydroussodiumacetate(2.44g,29.7mmol)in2‐ methoxyethanol(40ml)washeatedunderrefluxconditionsfor6h.Thesolutionwascooledtoroom temperatureandwater(50ml)wasadded.Theprecipitatewascollectedbyfiltration,washedwith wateranddriedinvacuotogivethetitledcompound(2.31g). 1H‐NMR(400MHz,DMSO):^[ppm]=2.27(brs,1H),8.60(d,1H),7.19(d,1H),3.79‐3.98(s,3H),2.32 (s,3H). Intermediate9 N‐[(3R)‐1‐(4‐hydroxy‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)pyrrolidin‐3‐yl]acetamide

Amixtureof6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol(10.0g,55.8mmol)andN‐[(3R)‐pyrrolidin‐ 3‐yl]acetamide(12.5g,97.7mmolinDMSO(40ml)wasaddedtriethylamine(23ml,170mmol)and heated at 90°C for 16h. The reactionmixturewas concentrated under reduced pressure and the residuepurifiedbysilicachromatography(DCM:EtOH)togivethetitledcompound(13.56g,80%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.035(2.29),1.052(4.89),1.070(2.52),1.807(16.00),1.898 (0.76),1.911(0.63),1.922(0.47),1.929(0.47),2.159(0.51),2.174(0.60),2.190(0.55),2.205(0.43), 2.258(0.80),2.284(13.66),2.522(1.32),2.539(4.91),2.669(0.43),3.288(0.67),3.297(0.72),3.314 (0.92),3.417(0.41),3.421(1.02),3.434(1.07),3.439(1.07),3.452(1.13),3.457(0.54),3.469(0.53), 3.484 (0.62),3.497 (0.71),3.504 (0.71),3.513 (0.72),3.531 (1.07),3.549 (0.56),3.556 (0.49),3.635 (0.82),3.650(0.97),3.662(0.83),3.677(0.77),4.345(1.31),4.358(1.96),4.370(0.96),5.758(0.45), 6.737(3.67),8.162(1.02),8.179(1.01),8.571(4.12),12.085(0.80). Intermediate10 N‐[(3S)‐1‐(4‐hydroxy‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)pyrrolidin‐3‐yl]acetamide Analogouslyto Intermediate9usingN‐[(3S)‐pyrrolidin‐3‐yl]acetamide(2.15g,16.7mmol)gavethe titledcompound(1.06g,63%)aftersilicachromatography(DCM:EtOH). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.035(2.38),1.052(5.02),1.069(2.64),1.807(16.00),1.898 (0.70),1.912(0.55),2.159(0.45),2.174(0.53),2.190(0.47),2.283(13.64),2.518(0.44),3.287(0.65), 3.297 (0.72),3.314 (1.02),3.337 (4.95),3.428 (0.67),3.445 (0.66),3.482 (0.55),3.495 (0.62),3.502 (0.60),3.513(0.66),3.547(0.49),3.555(0.44),3.634(0.76),3.649(0.89),3.660(0.77),3.676(0.70), 4.347 (0.64),4.361 (0.64),5.758 (1.76),6.732 (3.35),6.734 (3.31),8.161 (0.91),8.177 (0.89),8.567 (3.83),8.568(3.81). Intermediate11

2‐methyl‐6‐(4‐methylpiperazin‐1‐yl)pyrido[3,4‐d]pyrimidin‐4‐ol Analogously to Intermediate 9 using 1‐methylpiperazine (2.24 g, 22.3 mmol) gave the titled compound(1.69g,55%)aftersilicachromatography(DCM:EtOH). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.052(0.49),2.178(0.53),2.219(13.17),2.296(16.00),2.404 (2.87),2.417(3.99),2.430(3.10),2.518(1.22),2.523(0.83),3.509(2.77),3.522(3.47),3.535(2.74), 7.110(3.66),8.592(4.09),12.145(0.89). Intermediate12 6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol Analogously to Intermediate9using (3R)‐N,N‐dimethylpyrrolidin‐3‐amine (2.55g,22.3mmol)gave thetitledcompound(2.17g,68%)aftersilicachromatography(DCM:EtOH). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.824(0.41),2.206(16.00),2.279(9.34),2.288(0.61),3.131 (0.58),3.152(0.65),3.155(0.72),3.176(0.56),3.364(0.79),3.381(0.62),3.390(0.41),3.619(0.53), 3.694(0.40),3.712(0.48),3.719(0.46),6.751(2.42),6.753(2.36),8.555(2.60),8.557(2.56). Intermediate13 2‐(4‐hydroxy‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)‐2,6‐diazaspiro[3.4]octan‐7‐one AnalogouslytoIntermediate9using2,6‐diazaspiro[3.4]octan‐7‐oneoxalatesalt(4.83g,22.3mmol) gavethetitledcompound(1g,30%)aftersilicachromatography(DCM:EtOH). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.035(1.25),1.052(2.83),1.069(1.11),2.290(16.00),2.327 (0.45),2.518(2.47),2.523(1.44),2.539(8.49),2.669(0.48),3.165(6.18),3.336(0.51),3.411(0.68),

3.428(1.27),3.445(1.25),3.463(0.57),3.982(15.13),6.737(4.83),6.739(4.60),7.675(1.53),8.562 (4.66),8.565(4.55),12.151(0.73). Intermediate14 1‐[4‐(4‐hydroxy‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)piperazin‐1‐yl]ethan‐1‐one AnalogouslytoIntermediate9using1‐(piperazin‐1‐yl)ethan‐1‐one(2.38g,18.6mmol)gavethetitled compound(511g,16%)aftersilicachromatography(DCM:EtOH). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.052(0.58),2.050(16.00),2.301(14.44),2.518(1.23),2.523 (0.89),2.540(2.37),3.523(1.33),3.532(1.43),3.538(1.95),3.563(3.09),3.578(3.59),3.595(2.31), 7.146(3.41),7.148(3.39),8.615(3.86),12.174(0.84). Intermediate15 7‐chloro‐2‐methylpyrido[4,3‐d]pyrimidin‐4‐ol Toasolutionof5‐amino‐2‐chloropyridine‐4‐carboxylicacid(100g,579mmol)andethanimidamide hydrochloride(164g,1.74mol)in2‐methoxyethanol(1.2L)wasaddedsodiumacetate(143g,1.74 mol)at room temperature.The reactionmixturewas stirredat130 °C for48hours.The reaction mixtruewasconcentratedtoremoveabout400ml2‐methoxyethanolunderreducedpressure.The residuewaspoured intowater,brownsolidwasprecipitated.Theprecipitateswere filtered,dried underreducedpressurebyoilpumptogive7‐chloro‐2‐methylpyrido[4,3‐d]pyrimidin‐4‐olasabrown solid(77g,67%) ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:2.384(16.00),2.518(0.89),2.523(0.59),7.928(4.21),7.930 (4.17),8.817(3.76),8.819(3.55). Intermediate16 1‐(4‐hydroxy‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)piperidine‐4‐carbonitrile

Analogously to Intermediate9using1piperidine‐4‐carbonitrile (2.46g,22.3mmol)gave the titled compound(1.51g,48%)gavethetitlecompoundaftersilicachromatography(DCM:EtOH). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.052 (0.81),1.070 (0.41),1.722 (0.42),1.734 (0.75),1.744 (1.07),1.755(0.93),1.767(1.26),1.776(1.05),1.789(0.60),1.798(0.52),1.919(0.47),1.928(0.95), 1.936(1.02),1.944(0.99),1.952(0.87),1.961(0.74),1.968(0.75),1.976(0.71),2.296(16.00),2.518 (0.97),2.523(0.66),3.114(0.51),3.124(0.74),3.134(0.98),3.145(0.73),3.156(0.49),3.393(0.81), 3.401 (0.94),3.414 (0.91),3.426 (1.28),3.435 (1.20),3.448 (1.08),3.456 (0.95),3.820 (0.81),3.830 (1.04),3.836(0.99),3.846(0.90),3.854(0.81),3.863(0.86),3.870(0.91),3.879(0.70),5.758(0.61), 7.157(3.88),8.599(4.25),12.156(0.92). Intermediate17 6‐[(2S)‐2,4‐dimethylpiperazin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol AnalogouslytoIntermediate9using(3S)‐1,3‐dimethylpiperazine(153mg,1.34mmol)gavethetitled compound(30mg,16%)gavethetitlecompoundafterpreparativeHPLCpurification(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.120 (6.27),1.137 (6.28),1.751 (0.45),1.921 (0.49),1.941 (0.71),1.950(0.75),1.971(0.53),1.979(0.42),2.114(0.77),2.125(0.91),2.142(0.91),2.152(0.83), 2.201(11.69),2.291(16.00),2.304(0.42),2.518(3.07),2.523(2.26),2.702(1.07),2.729(0.99),2.843 (0.68),2.871(0.64),3.017(0.43),3.025(0.49),3.048(0.91),3.056(0.83),3.079(0.52),3.957(0.61), 3.989(0.57),4.535(0.56),7.036(3.56),8.595(3.91). Intermediate18 6‐[2‐(hydroxymethyl)‐4‐methylpiperazin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol(mixtureof stereoisomers)

AnalogouslytoIntermediate9using[4‐methylpiperazin‐2‐yl]methanol(218mg,1.67mmol)gavethe titled compound (40mg,17%)gave the title compoundafterpreparativeHPLCpurification (basic method). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.751 (0.99),1.909 (0.46),1.930 (0.67),1.938 (0.70),1.960 (1.09),1.969(1.06),1.988(0.85),1.998(0.74),2.066(0.78),2.118(0.78),2.200(10.96),2.287(16.00), 2.302 (0.49),2.306 (0.46),2.518 (3.49),2.523 (2.57),2.815 (0.67),2.843 (0.60),2.997 (0.46),3.019 (0.81),3.027(0.74),3.052(1.30),3.081(0.95),3.727(0.49),3.739(0.49),4.072(0.56),4.103(0.53), 4.285(0.53),4.627(0.42),4.770(0.60),7.072(3.49),8.563(4.23). Intermediate19 2‐methyl‐6‐[2‐(trifluoromethyl)‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐ ol Analogously to Intermediate 9 using 2‐(trifluoromethyl)‐5,6,7,8‐tetrahydroimidazo[1,2‐a]pyrazine (128mg,670µmol)gavethetitlecompound(40mg,34%)afterpreparativeHPLCpurification(basic method). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:2.315(16.00),2.327(1.22),2.332(0.79),2.518(4.14),2.523 (2.82),2.665(0.66),2.669(0.91),2.673(0.64),4.152(3.17),4.162(3.14),4.821(7.48),7.335(3.95), 7.805(2.85),7.808(2.91),8.673(4.41). Intermediate20 2‐methyl‐6‐[2‐(trifluoromethyl)‐5,6‐dihydro[1,2,4]triazolo[1,5‐a]pyrazin‐7(8H)‐yl]pyrido[3,4‐ d]pyrimidin‐4‐ol

Analogously to Intermediate 9 using 2‐(trifluoromethyl)‐5,6,7,8‐tetrahydro[1,2,4]triazolo[1,5‐ a]pyrazine (215mg, 1.12mmol) gave the title compound (25mg, 13%) after preparative HPLC purification(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.056(0.83),1.071(0.88),1.752(0.45),2.320(16.00),2.430 (0.80),2.518(7.83),2.523(5.50),2.540(1.66),2.665(0.77),2.669(1.03),2.673(0.77),4.260(1.23), 4.272 (2.59),4.286 (2.00),4.373 (1.76),4.386 (2.40),4.400 (1.13),4.997 (6.61),7.422 (3.99),7.424 (3.99),8.088(0.45),8.681(4.22),8.683(4.22). Example1 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ amine To a solution of 6‐ethoxy‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol (75.0 mg, 365 µmol) and 2,4,6‐ tri(propan‐2‐yl)benzene‐1‐sulfonylchloride(188mg,621µmol)wasaddedtriethylamine(180µl,1.3 mmol)followedbyDMAP(6.70mg,54.8µmol)andstirredatRTfor1h.Tothereactionwasadded (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐amine hydrochloride (99.0 mg, 439 µmol) and stirredatRTovernight.ThereactionwasdilutedwithwaterandDCMandextractedwithDCM.The organics were combined, washed with sat. NaCl(aq), filtered through an hydrophobic filter and concentratedunderreducedpressure.TheresiduewaspurifiedbypreparativeHPLC(basicmethod) andgavethetitledcompound(14mg,10%). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.349 (2.26),1.366 (5.02),1.384 (2.32),1.586 (2.95),1.604 (2.94),2.322(0.41),2.326(0.58),2.331(0.60),2.342(8.54),2.518(1.99),2.522(1.25),2.669(0.49), 4.337(0.68),4.355(2.20),4.372(2.13),4.389(0.63),5.742(0.52),5.758(16.00),5.777(0.45),7.098

(0.64),7.234(1.31),7.268(0.48),7.287(1.04),7.306(0.60),7.370(0.58),7.502(0.64),7.667(0.63), 7.745(2.20),8.567(0.72),8.585(0.69),8.698(2.49). Example2 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐amine Using themethoddescribed forExample1using6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol (200 mg, 1.12 mmol) and (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐amine hydrochloride (302 mg,1.34mmol)gavethetitledcompound(187mg,45%)afterpreparativeHPLC. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.604(5.88),1.621(5.85),2.392(16.00),2.518(1.16),2.522 (0.75),5.741(0.80),5.758(2.24),5.775(0.79),7.102(1.27),7.238(2.56),7.278(0.89),7.297(1.99), 7.316 (1.13),7.374 (1.16),7.497 (0.70),7.514 (1.18),7.532 (0.57),7.667 (0.64),7.685 (1.18),7.704 (0.58),8.152(2.56),8.735(3.89),8.796(1.23),8.814(1.20). Example3 Example3:N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐ pyrido[3,4‐d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide To a solution of Example 2 (40mg, 114µmol) inDMSO (1.5ml)was addedN‐[(3R)‐pyrrolidin‐3‐ yl]acetamide (58 mg, 457 µmol) and heated at 110°C overnight. The reaction was purified by preparativeHPLC(basicmethod)andgavethetitledcompound(41mg,74%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(1.65),1.603(4.46),1.620(4.45),1.826(16.00),1.932 (0.54),1.945(0.57),2.183(0.44),2.199(0.54),2.214(0.48),2.290(13.85),2.332(0.42),2.518(2.11), 2.523 (1.31),2.673 (0.42),3.302 (2.03),3.312 (2.35),3.328 (2.85),3.339 (2.94),3.504 (0.49),3.518 (0.51),3.525(0.60),3.530(0.68),3.538(0.58),3.544(0.72),3.550(0.65),3.563(0.51),3.601(0.46), 3.620 (0.93),3.638 (0.54),3.646 (0.65),3.665 (0.96),3.681 (0.95),3.693 (0.82),3.708 (0.73),4.395 (0.58),4.407(0.58),5.762(0.66),5.780(1.02),5.798(0.66),7.079(2.80),7.101(1.04),7.237(2.19),

7.276 (0.77),7.295 (1.67),7.314 (0.97),7.373 (0.90),7.483 (0.56),7.501 (0.96),7.518 (0.47),7.629 (0.52),7.647(0.96),7.665(0.47),8.155(4.92),8.196(1.14),8.212(1.13),8.395(1.08),8.414(1.04), 8.633(4.17). Example4 N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide UsingthemethoddescribedforExample3:Example2(40mg,114µmol)wastreatedwithN‐[(3S)‐ pyrrolidin‐3‐yl]acetamide(59mg,457µmol)andgavethetitledcompound(41mg,75%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(3.59),1.604(4.53),1.622(4.52),1.830(16.00),1.929 (0.56),1.943(0.58),1.960(0.42),2.180(0.46),2.197(0.55),2.212(0.49),2.288(14.00),2.518(1.56), 2.523 (0.97),3.548 (0.41),3.554 (0.59),3.561 (0.43),3.568 (0.67),3.574 (0.63),3.587 (0.86),3.606 (0.98),3.624(0.53),3.632(0.54),3.645(0.83),3.661(0.93),3.672(0.79),3.687(0.71),4.400(0.58), 4.413 (0.58),5.757 (0.70),5.775 (1.05),5.793 (0.67),7.074 (2.82),7.100 (1.06),7.237 (2.21),7.274 (0.78),7.293(1.70),7.312(0.99),7.372(0.91),7.483(0.57),7.499(0.98),7.517(0.48),7.626(0.52), 7.644 (0.96),7.661 (0.48),8.202 (1.23),8.208 (0.94),8.219 (1.21),8.396 (1.15),8.414 (1.11),8.633 (4.25). Example5 N‐[(1R)‐1‐[3‐(difluoromethyl)‐2‐fluoro‐phenyl]ethyl]‐2‐methyl‐6‐pyrrolidin‐1‐yl‐pyrido[3,4‐ d]pyrimidin‐4‐amine UsingthemethoddescribedforExample3:Example2(40mg,114µmol)wastreatedwithpyrrolidine (32mg,457µmol)andgavethetitledcompound(42mg,86%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(13.90),1.604(5.13),1.622(5.13),1.990(1.90),2.000 (2.33),2.007(5.52),2.014(2.31),2.023(1.97),2.285(16.00),2.518(1.84),2.522(1.19),3.448(0.59), 3.457 (1.23),3.473 (3.14),3.481 (3.09),3.497 (1.14),3.506 (0.55),5.762 (0.77),5.780 (1.18),5.798

(0.74),7.061(3.26),7.100(1.17),7.236(2.42),7.270(0.85),7.289(1.85),7.308(1.07),7.372(1.02), 7.481 (0.63),7.498 (1.06),7.516 (0.51),7.634 (0.58),7.652 (1.05),7.670 (0.52),8.362 (1.27),8.380 (1.22),8.621(4.54). Example6 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}‐6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ amine Using themethoddescribed forExample1using6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐oland (1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethan‐1‐aminehydrochloridegavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.542(5.50),1.560(5.58),2.401(16.00),2.518(1.42),2.523 (1.00),2.543(8.10),5.706(0.82),5.723(1.27),5.741(0.81),7.079(1.03),7.216(2.15),7.278(0.70), 7.297 (1.70),7.317 (1.11),7.353 (0.92),7.388 (1.66),7.407 (1.12),7.637 (1.34),7.656 (1.19),8.143 (2.44),8.145(2.48),8.711(4.26),8.828(1.24),8.846(1.20). Example7 N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 6 was treated with N‐[(3R)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.539(3.55),1.556(3.58),1.825(13.28),1.928(0.46),1.942 (0.48),2.195(0.47),2.210(0.41),2.303(11.17),2.323(0.45),2.327(0.57),2.518(2.39),2.523(1.71), 2.540(16.00),2.669(0.52),3.300(0.57),3.310(0.66),3.523(0.45),3.536(0.47),3.542(0.42),3.613 (0.72),3.631(0.40),3.638(0.50),3.658(0.77),3.674(0.76),3.685(0.64),3.700(0.57),4.391(0.49), 4.405 (0.48),5.720 (0.55),5.738 (0.84),5.756 (0.54),7.069 (2.40),7.075 (0.97),7.214 (1.47),7.277

(0.52),7.296(1.27),7.315(0.84),7.351(0.62),7.376(1.27),7.393(0.82),7.630(1.01),7.649(0.89), 8.192(0.97),8.208(0.96),8.434(0.95),8.453(0.91),8.610(3.38). Example8 N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 6 was treated with N‐[(3S)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.539(4.28),1.557(4.28),1.829(16.00),1.925(0.58),1.938 (0.59),1.956(0.41),2.175(0.46),2.191(0.55),2.206(0.49),2.303(13.86),2.323(0.54),2.327(0.69), 2.331 (0.49),2.518 (2.77),2.523 (1.97),2.541 (6.90),2.665 (0.47),2.669 (0.63),2.673 (0.44),3.308 (0.74),3.319(0.95),3.345(0.98),3.550(0.57),3.564(0.65),3.570(0.63),3.582(0.75),3.599(0.98), 3.616 (0.51),3.625 (0.50),3.638 (0.81),3.654 (0.91),3.665 (0.76),3.680 (0.67),4.400 (0.59),4.413 (0.57),5.716(0.66),5.734(1.01),5.751(0.65),7.063(2.77),7.076(0.90),7.214(1.77),7.275(0.64), 7.294 (1.53),7.313 (1.04),7.351 (0.73),7.375 (1.50),7.393 (0.97),7.627 (1.19),7.646 (1.06),8.199 (1.19),8.216(1.15),8.435(1.12),8.453(1.07),8.610(4.01). Example9 N‐[(1R)‐1‐[3‐(difluoromethyl)‐2‐methyl‐phenyl]ethyl]‐2‐methyl‐6‐pyrrolidin‐1‐yl‐pyrido[3,4‐ d]pyrimidin‐4‐amine Using themethoddescribed forExample3:Example6was treatedwithpyrrolidineandgave the titledcompound. ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.541 (5.03),1.558 (4.97),1.986 (1.89),1.996 (2.29),2.003 (5.67),2.010(2.30),2.019(1.99),2.299(16.00),2.322(0.61),2.326(0.81),2.332(0.59),2.518(3.54),

2.523 (2.38),2.539 (7.68),2.664 (0.57),2.669 (0.80),2.673 (0.58),3.441 (0.58),3.450 (1.11),3.466 (3.01),3.476(3.00),3.483(1.78),3.492(1.08),3.502(0.57),5.720(0.73),5.739(1.14),5.756(0.73), 7.051 (3.18),7.075 (0.97),7.212 (2.01),7.271 (0.67),7.290 (1.65),7.310 (1.10),7.350 (0.84),7.374 (1.62),7.392(1.06),7.640(1.28),7.660(1.14),8.396(1.23),8.414(1.19),8.599(4.28). Example10 6‐fluoro‐2‐methyl‐N‐[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]pyrido[3,4‐d]pyrimidin‐4‐amine Using themethoddescribed forExample1using6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐oland (1R)‐1‐[3‐(trifluoromethyl)phenyl]ethan‐1‐aminehydrochloridegavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.612(5.87),1.629(5.90),1.986(0.64),2.421(16.00),2.518 (1.36),2.523(0.91),5.603(0.79),5.620(1.18),5.639(0.77),7.550(0.50),7.569(1.59),7.588(1.81), 7.598 (2.01),7.617 (0.61),7.752 (1.37),7.770 (1.08),7.830 (2.25),8.098 (2.53),8.101 (2.53),8.731 (4.14),8.765(1.20),8.784(1.16). Example11 N‐[(3R)‐1‐[2‐methyl‐4‐[[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4‐d]pyrimidin‐6‐ yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 10 was treated with N‐[(3R)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.613(4.68),1.631(4.71),1.823(16.00),1.927(0.53),1.940 (0.56),2.179(0.44),2.195(0.52),2.210(0.46),2.321(14.30),2.332(0.69),2.518(1.70),2.523(1.16), 2.669 (0.57),3.294 (0.64),3.303 (0.69),3.519 (0.40),3.525 (0.50),3.532 (0.40),3.538 (0.55),3.545 (0.49),3.610(0.90),3.628(0.48),3.636(0.59),3.655(0.91),3.670(0.88),3.682(0.76),3.698(0.67), 4.390 (0.56),4.404 (0.55),5.623 (0.67),5.642 (0.98),5.659 (0.64),7.033 (2.77),7.569 (1.35),7.589

(2.87),7.732(1.17),7.750(0.87),7.797(1.99),8.191(1.11),8.208(1.09),8.377(1.14),8.397(1.10), 8.633(4.11). Example12 N‐[(3S)‐1‐[2‐methyl‐4‐[[(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4‐d]pyrimidin‐6‐ yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 10 was treated with N‐[(3S)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.615(4.44),1.633(4.45),1.824(16.00),1.924(0.53),1.938 (0.54),2.176(0.43),2.193(0.51),2.207(0.44),2.320(13.83),2.332(0.62),2.518(1.81),2.523(1.17), 2.540 (5.21),2.669 (0.52),3.304 (0.67),3.315 (0.78),3.546 (0.53),3.559 (0.59),3.565 (0.55),3.580 (0.68),3.599(0.90),3.618(0.48),3.625(0.51),3.636(0.76),3.651(0.87),3.662(0.73),3.678(0.64), 4.395 (0.54),4.409 (0.53),5.618 (0.63),5.636 (0.93),5.654 (0.61),7.027 (2.64),7.568 (1.28),7.587 (2.70),7.592(1.40),7.732(1.12),7.749(0.83),7.795(1.87),8.196(1.09),8.213(1.08),8.376(1.13), 8.395(1.07),8.634(3.91). Example13 N‐[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]‐6‐fluoro‐2‐methyl‐pyrido[3,4‐d]pyrimidin‐4‐amine Using themethoddescribed forExample1using6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐oland (1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethanaminehydrochloridegavethetitledcompound. ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.600 (5.73),1.618 (5.72),1.910 (4.85),1.957 (9.96),2.004 (4.33),2.435(16.00),2.518(2.83),2.523(1.94),2.673(0.48),5.596(0.56),5.614(0.85),5.632(0.55), 7.436 (3.99),7.442 (1.34),7.451 (1.86),7.471 (0.45),7.567 (1.06),7.579 (0.73),7.583 (0.95),7.672 (2.13),8.110(2.28),8.113(2.30),8.726(3.70),8.738(0.94),8.756(0.86).

Example14 N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐d]pyrimidin‐6‐ yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 13 was treated with N‐[(3R)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.600(4.60),1.618(4.63),1.822(16.00),1.906(4.45),1.924 (0.60),1.937(0.69),1.953(8.68),2.000(3.68),2.175(0.50),2.192(0.57),2.207(0.51),2.223(0.41), 2.323(1.11),2.333(14.89),2.518(4.14),2.523(2.81),2.665(0.69),2.669(0.96),2.673(0.68),3.291 (0.57),3.301(0.75),3.318(0.95),3.516(0.41),3.522(0.48),3.535(0.57),3.542(0.56),3.555(0.47), 3.606 (0.81),3.614 (0.47),3.624 (0.51),3.632 (0.68),3.649 (0.93),3.664 (0.81),3.676 (0.77),3.692 (0.60),4.391(0.60),4.403(0.59),5.619(0.60),5.637(0.87),5.656(0.57),7.042(2.54),7.407(0.45), 7.429 (2.75),7.447 (1.71),7.466 (0.59),7.547 (1.22),7.564 (0.99),7.651 (2.18),8.191 (1.10),8.208 (1.10),8.353(1.23),8.372(1.17),8.628(4.36). Example15 N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐d]pyrimidin‐6‐ yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 13 was treated with N‐[(3S)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.602(4.60),1.619(4.59),1.822(16.00),1.904(4.38),1.921 (0.62),1.935(0.66),1.952(8.60),1.998(3.64),2.173(0.54),2.190(0.59),2.206(0.51),2.333(14.50), 2.518 (3.18),2.523 (2.14),2.665 (0.53),2.669 (0.73),2.673 (0.52),3.301 (0.73),3.311 (0.72),3.535 (0.46),3.541(0.59),3.554(0.62),3.561(0.52),3.575(0.53),3.597(0.82),3.605(0.47),3.615(0.53),

3.623 (0.56),3.631 (0.81),3.647 (0.92),3.658 (0.70),3.674 (0.69),4.393 (0.61),4.405 (0.60),5.614 (0.59),5.632(0.88),5.651(0.60),7.038(2.54),7.406(0.46),7.428(2.78),7.446(1.74),7.466(0.59), 7.547 (1.21),7.564 (0.99),7.650 (2.20),8.195 (1.12),8.211 (1.10),8.352 (1.22),8.372 (1.17),8.628 (4.42). Example16 N‐[(1R)‐1‐[3‐(1,1‐difluoroethyl)phenyl]ethyl]‐6‐fluoro‐2‐methyl‐pyrido[3,4‐d]pyrimidin‐4‐amine Using themethoddescribed forExample1using6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐oland (1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluoro‐phenyl]ethanaminehydrochloridegavethetitledcompound. ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.600 (5.37),1.617 (5.29),1.981 (2.65),2.028 (5.15),2.076 (2.38),2.332(0.68),2.392(16.00),2.518(3.61),2.523(2.50),2.673(0.68),5.735(0.79),5.753(1.23), 5.770 (0.79),7.235 (0.82),7.254 (1.84),7.273 (1.08),7.429 (0.66),7.447 (1.11),7.463 (0.56),7.621 (0.59),7.637(1.05),7.655(0.52),8.150(2.33),8.153(2.33),8.735(3.90),8.792(1.14),8.810(1.11). Example17 N‐[(3R)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 16 was treated with N‐[(3R)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.597(4.59),1.615(4.59),1.827(16.00),1.932(0.59),1.945 (0.64),1.963(0.51),1.981(2.75),2.029(5.16),2.077(2.35),2.183(0.54),2.199(0.60),2.214(0.54), 2.232(0.43),2.289(13.51),2.518(4.05),2.523(2.72),3.301(0.73),3.312(0.87),3.526(0.44),3.532 (0.56),3.545(0.60),3.551(0.52),3.621(0.89),3.639(0.51),3.647(0.62),3.667(0.92),3.683(0.94),

3.694 (0.81),3.710 (0.71),4.395 (0.62),4.408 (0.60),5.755 (0.73),5.773 (1.11),5.791 (0.70),7.079 (2.91),7.231(0.83),7.250(1.80),7.269(1.05),7.413(0.67),7.431(1.08),7.447(0.51),7.583(0.59), 7.600(1.05),7.617(0.52),8.198(1.22),8.214(1.18),8.396(1.18),8.414(1.13),8.630(4.27). Example18 N‐[(3S)‐1‐[4‐[[(1R)‐1‐[3‐(1,1‐difluoroethyl)‐2‐fluoro‐phenyl]ethyl]amino]‐2‐methyl‐pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl]acetamide Using the method described for Example 3: Example 16 was treated with N‐[(3S)‐pyrrolidin‐3‐ yl]acetamideandgavethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.514(0.42),1.598(4.69),1.616(4.66),1.830(16.00),1.912 (0.41),1.930(0.64),1.944(0.67),1.960(0.65),1.981(2.81),2.007(0.47),2.029(5.36),2.076(2.45), 2.182(0.56),2.197(0.67),2.216(0.92),2.229(0.52),2.287(13.61),2.318(0.44),2.323(0.80),2.327 (1.08),2.331(0.78),2.518(3.87),2.523(2.53),2.665(0.67),2.669(0.95),2.673(0.64),3.315(1.05), 3.352 (0.80),3.556 (0.59),3.570 (0.69),3.576 (0.64),3.589 (0.87),3.606 (1.03),3.624 (0.54),3.632 (0.52),3.646(0.85),3.662(0.95),3.673(0.80),3.688(0.70),4.401(0.62),4.413(0.60),5.750(0.74), 5.767 (1.13),5.785 (0.70),7.074 (2.93),7.229 (0.85),7.248 (1.85),7.267 (1.11),7.412 (0.67),7.430 (1.09),7.447(0.52),7.580(0.62),7.596(1.06),7.614(0.52),8.203(1.26),8.220(1.21),8.396(1.21), 8.414(1.14),8.631(4.33). Example19 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐fluoro‐2,8‐dimethylpyrido[3,4‐d]pyrimidin‐4‐ amine

ToasolutionofExample2(250mg,714µmol) inDMSO(5ml)wasaddedDBU(213µl,3.6mmol) andnitromethane (193µl,1.43mmol)andstirred for4daysatRT.The reactionwasdilutedwith waterandthesolidcollectedbyfiltrationandwashedwithwater.Thesolidwasdriedtogivethetitle compound(261mg,95%). ¹H‐NMR (600MHz,DMSO‐d6)δ [ppm]:0.909 (0.44),1.111 (2.03),1.233 (0.43),1.601 (6.17),1.612 (5.96),2.386(0.69),2.388(0.89),2.391(0.77),2.395(0.65),2.403(16.00),2.519(1.95),2.522(1.82), 2.525(1.44),2.613(0.46),2.616(0.66),2.619(0.53),2.727(12.15),3.313(0.74),5.757(0.60),7.142 (1.06),7.232(2.12),7.276(0.96),7.289(2.03),7.302(1.12),7.323(0.94),7.496(0.63),7.508(1.10), 7.519 (0.57),7.658 (0.60),7.669 (1.12),7.681 (0.57),7.949 (2.43),8.088 (0.78),8.316 (4.63),8.693 (0.48). Example20 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2,8‐dimethylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide ToasolutionofExample19 (20.8mg,57µmol) inDMSO (0.5ml)wasaddedN‐[(3R)‐pyrrolidin‐3‐ yl]acetamide(14mg,114µmol)andTEA(32µl,228µmol).Thereactionwasheatedat110°Cfor16h. ThereactionwasallowedtocoolandthenpurifiedbypreparativeHPLC(basicmethod)togivethe titledcompound(9.5mg,35%). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.094 (3.50),1.170 (0.41),1.228 (1.01),1.591 (5.83),1.608 (6.19),1.820(16.00),1.903(1.21),1.913(0.98),1.927(0.99),1.944(0.74),2.164(0.77),2.179(0.98), 2.195(0.91),2.211(0.68),2.297(12.97),2.323(1.19),2.637(13.81),2.657(1.41),2.665(1.17),3.286 (1.41),3.297(1.92),3.478(0.48),3.503(0.95),3.517(1.03),3.536(0.66),3.589(0.59),3.606(1.24), 3.624 (0.90),3.631 (1.01),3.655 (1.28),3.670 (1.35),3.682 (1.17),3.698 (1.01),4.352 (0.62),4.366 (1.06),4.379(1.05),5.753(0.98),5.770(1.50),5.788(1.01),6.896(3.50),7.095(1.23),7.231(2.49), 7.264 (1.09),7.283 (2.32),7.302 (1.39),7.367 (1.13),7.473 (0.99),7.490 (1.63),7.507 (0.88),7.614 (0.92),7.632(1.64),7.649(0.87),8.084(0.50),8.172(1.75),8.188(1.72),8.275(1.03),8.292(1.07). Example21 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(3R)‐3‐(dimethylamino)pyrrolidin‐1‐yl]‐2,8‐ dimethylpyrido[3,4‐d]pyrimidin‐4‐amine

Using the method described for Example 20: Example 19 was treated with (3R)‐N,N‐ dimethylpyrrolidin‐3‐amine (58.0mg,508µmol)andgave the titledcompound (25mg,51%)after preparativeHPLC(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.602 (3.56),1.619 (3.58),1.854 (0.51),1.876 (0.42),2.182 (0.49),2.197(0.49),2.239(16.00),2.296(9.36),2.323(0.67),2.327(0.82),2.639(8.90),2.665(0.68), 2.669 (0.81),2.812 (0.40),2.830 (0.53),3.153 (0.62),3.178 (0.80),3.198 (0.59),3.383 (0.67),3.400 (0.64),3.645(0.43),3.666(0.70),3.742(0.56),3.759(0.67),3.766(0.64),3.784(0.48),5.757(0.56), 5.775 (0.86),5.793 (0.54),6.865 (2.29),7.100 (0.76),7.236 (1.58),7.262 (0.61),7.282 (1.35),7.301 (0.80),7.371(0.70),7.474(0.53),7.491(0.87),7.509(0.44),7.619(0.48),7.638(0.87),7.655(0.45), 8.217(0.95),8.235(0.94). Example22 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2,8‐dimethylpyrido[3,4‐d]pyrimidin‐ 6‐yl]piperazin‐1‐yl}ethan‐1‐one UsingthemethoddescribedforExample20:Example19wastreatedwith1‐(piperazin‐1‐yl)ethan‐1‐ one(65.1mg,508µmol)andgavethetitledcompound(20mg,40%)afterpreparativeHPLC(basic method). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.967 (0.44),1.107 (0.42),1.603 (5.55),1.621 (5.45),1.957 (0.40), 2.074 (16.00), 2.321 (15.94), 2.432 (0.46), 2.522 (4.88), 2.658 (14.29), 2.669 (1.88), 3.516 (1.82),3.606(9.65),5.749(0.91),5.766(1.31),5.784(0.82),7.101(1.29),7.238(2.64),7.272(0.97), 7.293 (4.58),7.310 (1.29),7.374 (1.12),7.485 (0.72),7.500 (1.25),7.517 (0.63),7.622 (0.70),7.641 (1.22),7.658(0.63),8.340(1.37),8.359(1.35). Example23

N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2,8‐dimethyl‐6‐(4‐methylpiperazin‐1‐ yl)pyrido[3,4‐d]pyrimidin‐4‐amine UsingthemethoddescribedforExample20:Example19wastreatedwith1‐methylpiperazine(110 µl,1.0mmol)andgavethetitledcompound(30mg,60%)afterpreparativeHPLC(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.860 (0.75),0.967 (2.61),1.109 (1.08),1.144 (1.52),1.209 (0.57),1.224(0.66),1.596(5.12),1.614(5.11),2.252(10.44),2.313(16.00),2.322(1.22),2.327(1.13), 2.332(0.78),2.459(2.46),2.471(3.88),2.518(3.87),2.523(2.45),2.642(13.95),2.660(0.42),2.665 (0.72),2.669(0.97),2.673(0.71),3.525(2.34),3.537(3.14),3.549(2.33),5.744(0.78),5.762(1.20), 5.780 (0.77),7.101 (1.16),7.237 (2.68),7.245 (3.17),7.269 (0.89),7.289 (1.92),7.307 (1.11),7.373 (1.02),7.480(0.65),7.497(1.10),7.514(0.54),7.620(0.59),7.637(1.08),7.655(0.53),8.313(1.29), 8.331(1.24). Example24 2‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2,8‐dimethylpyrido[3,4‐d]pyrimidin‐6‐ yl]‐2,6‐diazaspiro[3.4]octan‐7‐one UsingthemethoddescribedforExample20:Example19wastreatedwith2,6‐diazaspiro[3.4]octan‐ 7‐one(64.1mg,508µmol)andgavethetitledcompound(20mg,40%)afterpreparativeHPLC(basic method). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.109 (0.49),1.231 (0.52),1.348 (0.42),1.569 (0.44),1.587 (5.53),1.605(5.56),2.286(0.50),2.310(16.00),2.322(1.35),2.327(1.54),2.332(1.12),2.422(0.79), 2.428(0.51),2.432(0.74),2.449(0.49),2.518(5.90),2.523(3.76),2.542(8.45),2.632(13.73),2.660 (0.51),2.665(1.05),2.669(1.45),2.673(1.05),2.678(0.49),3.522(6.98),3.954(0.86),3.978(8.61), 4.003 (0.84),5.738 (0.91),5.756 (1.33),5.774 (0.83),6.966 (3.70),7.097 (1.28),7.233 (2.68),7.265

(0.95),7.285(2.08),7.303(1.25),7.369(1.15),7.478(0.74),7.495(1.24),7.513(0.64),7.617(0.69), 7.634(1.30),7.653(0.69),7.676(2.61),8.088(0.56),8.299(1.40),8.317(1.35). Example25 N‐{(3S)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]pyrrolidin‐3‐yl}acetamide Toasolutionofintermediate10(57.7mg,201µmol)andPyBOP(136mg,261µmol)inDMF(580µL) was added DBU (90 µl, 600 µmol) followed by (1R)‐1‐[3‐(difluoromethyl)phenyl]ethan‐1‐amine hydrochloride(50.0mg,241µmol).ThereactionwasstirredatRTfor16h.Thetitledcompoundwas isolated(50mg,54%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.601(4.90),1.619(4.90),1.823(16.00),1.922(0.60),1.935 (0.61),1.953(0.44),2.174(0.49),2.190(0.58),2.205(0.52),2.221(0.40),2.326(14.40),2.518(1.83), 2.522 (1.14),2.669 (0.42),3.303 (0.74),3.313 (0.85),3.542 (0.59),3.550 (0.43),3.556 (0.67),3.563 (0.62),3.577(0.71),3.597(1.00),3.615(0.54),3.623(0.59),3.632(0.84),3.648(0.99),3.658(0.81), 3.674 (0.72),4.394 (0.62),4.406 (0.61),5.623 (0.67),5.641 (1.01),5.659 (0.66),6.884 (1.24),7.024 (2.60),7.045(2.98),7.164(1.15),7.415(0.75),7.434(1.54),7.459(1.15),7.478(1.73),7.497(0.74), 7.597 (1.22),7.616 (0.96),7.637 (2.00),8.195 (1.21),8.211 (1.20),8.361 (1.23),8.381 (1.18),8.630 (4.29). Example26 N‐{(3S)‐1‐[2‐methyl‐4‐({(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}acetamide UsingthemethoddescribedforExample25:Intermediate10wastreatedwith(1R)‐1‐[2‐methyl‐3‐ (trifluoromethyl)phenyl]ethan‐1‐amine hydrochloride (50.0 mg, 209 µmol) and gave the titled compound(30mg,35%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.557(4.32),1.575(4.42),1.831(16.00),1.928(0.56),1.941 (0.56),1.960(0.41),2.178(0.45),2.194(0.54),2.209(0.49),2.226(0.40),2.281(13.18),2.518(3.92), 2.523 (2.45),2.539 (0.42),2.618 (5.45),3.313 (0.80),3.349 (1.00),3.554 (0.55),3.567 (0.64),3.574 (0.62),3.585(0.71),3.602(0.99),3.620(0.51),3.628(0.49),3.643(0.82),3.658(0.90),3.670(0.76), 3.685 (0.68),4.402 (0.56),4.414 (0.56),5.682 (0.65),5.699 (1.02),5.716 (0.66),7.062 (2.74),7.338 (0.63),7.357(1.37),7.377(0.80),7.527(1.47),7.546(1.20),7.737(1.29),7.756(1.17),8.202(1.19), 8.218(1.14),8.492(1.11),8.510(1.07),8.613(4.06). Table1:Examples27‐34 Using themethod described for Example 25: Intermediate 7was treatedwith the corresponding phenylethan‐1‐aminesortheirhydrochloridesaltsandgavethedesiredcompoundsafterpreparative HPLCpurification(basicmethod).

Table2:Examples35‐42 Using themethod described for Example 25: Intermediate 8was treatedwith the corresponding phenylethan‐1‐aminesortheirhydrochloridesaltsandgavethedesiredcompoundsafterpreparative HPLCpurification(basicmethod).

Table3:Examples43‐91 Using themethod described for Example 25: Intermediate 9was treatedwith the corresponding phenylethan‐1‐aminesortheirhydrochloridesaltsandgavethedesiredcompoundsafterpreparative HPLCpurification(basicmethod).

Example92 N‐[(3R)‐1‐(4‐{[1‐(3‐aminophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)pyrrolidin‐3‐ yl]acetamide(mixtureofstereoisomers) ToExample68(25.0mg,49.4µmol)wasadded4MHClindioxane(3.1ml)followedbyMeOH(3ml). The reactionwas stirred at RT for 3h and concentrated. The titled compound (9mg, 43%)was isolatedafterpreparativeHPLC(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.514(4.94),1.532(5.01),1.819(16.00),1.914(0.59),1.928 (0.64),1.944(0.49),2.167(0.57),2.184(0.74),2.199(0.62),2.215(0.48),2.327(0.77),2.344(15.22), 2.522 (2.32),2.665 (0.44),2.669 (0.61),2.673 (0.44),3.280 (0.42),3.290 (0.54),3.305 (0.88),3.528 (0.62),3.545(0.57),3.590(0.66),3.603(0.73),3.622(0.79),3.638(0.76),3.659(0.70),3.669(0.61), 3.685 (0.47),4.370 (0.45),4.384 (0.77),4.397 (0.73),4.410 (0.44),5.003 (3.73),5.512 (0.68),5.531 (0.99),5.548(0.68),6.392(1.18),6.396(1.20),6.412(1.25),6.415(1.32),6.563(1.45),6.583(1.90), 6.589 (2.20),6.594 (2.57),6.931 (1.52),6.950 (2.59),6.970 (1.28),7.070 (2.87),8.184 (1.30),8.201 (1.32),8.219(1.48),8.239(1.40),8.617(5.00). Example93 tert‐butyl{3‐[(1S)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]phenyl}carbamate Example68(116mg,230µmol)waspurifiedbychiralHPLCtogive: Example93(68mg,56%,e.e.>95%).Rt=8.51min Example94(37mg,33%,e.e.>95%).Rt=6.24mins Analytical Method: Instrument: Agilent: 1260, Aurora SFC‐Module; Column: Chiralpak IC 5µ 100x4.6mm;eluentA:CO2;eluentB:2‐propanol+0.4vol%diethylamine; isocratic:30%B;flow:4 ml/min;temperature:37.5°C;BPR:100bar;UV:280nm

PreparativeMethod:Instrument:Sepiatec:PrepSFC100;Column:ChiralpakIC5µ250x30mm;eluent A: CO2; eluent B: 2‐propanol + 0.4 vol % diethylamine; isocratic: 30%B; flow: 100 ml/min; temperature:40°C;BPR:150bar;UV:280nm. Example94 tert‐butyl{3‐[(1R)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]phenyl}carbamate Seeexample93fordetails. Example95 N‐[(3R)‐1‐(4‐{[(1S)‐1‐(3‐aminophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)pyrrolidin‐3‐ yl]acetamide Using themethoddescribed forExample92:Example93gave the titled compound (12mg,60%) afterpreparativeHPLC(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.593(4.29),1.610(4.27),1.822(16.00),1.949(0.54),1.963 (0.56),1.979(0.47),2.190(0.41),2.206(0.52),2.222(0.49),2.518(3.31),2.523(2.89),2.530(9.56), 3.316 (0.90),3.326 (1.04),3.344 (1.36),3.558 (0.52),3.572 (0.58),3.592 (0.67),3.611 (0.74),3.629 (0.46),3.637(0.44),3.655(0.79),3.670(0.79),3.681(0.67),3.697(0.59),4.380(0.60),4.392(0.59), 5.665 (0.56),5.684 (0.80),5.701 (0.55),6.468 (0.91),6.471 (0.93),6.487 (0.96),6.490 (1.01),6.590 (1.05),6.609(1.26),6.619(1.54),6.623(1.93),6.988(1.36),7.007(2.26),7.026(1.16),7.276(2.17), 8.209(1.18),8.225(1.15),8.726(4.11). Example96 N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐aminophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)pyrrolidin‐3‐ yl]acetamide

Using themethoddescribed forExample92:Example94gave the titled compound (12mg,60%) afterpreparativeHPLC(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.584(4.03),1.601(4.08),1.821(16.00),1.950(0.51),1.962 (0.55),1.980(0.44),2.204(0.49),2.219(0.44),2.323(0.51),2.327(0.73),2.332(0.52),2.518(3.95), 2.523 (2.49),2.665 (0.53),2.669 (0.76),2.673 (0.52),3.301 (0.83),3.311 (1.01),3.537 (0.47),3.551 (0.50),3.622(0.67),3.640(0.40),3.648(0.46),3.670(0.75),3.686(0.80),3.698(0.69),3.713(0.60), 4.379 (0.57),4.392 (0.56),5.650 (0.52),5.668 (0.75),5.687 (0.50),6.456 (0.90),6.460 (0.90),6.476 (0.94),6.480(0.99),6.583(1.08),6.603(1.29),6.613(1.51),6.617(1.96),6.981(1.37),7.000(2.27), 7.019(1.17),7.263(1.88),8.205(1.10),8.222(1.07),8.716(3.74). Example97 N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide Example73(70mg,188µmol)waspurifiedbychiralHPLCtogive: Example97(25mg,e.e.>95%).Rt=4.57min Example98(23mg,e.e.>95%).Rt=5.44mins Analytical Method: Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3µ, 100x4.6; eluentA:methyl tert‐butyl ether + 0.1 vol% diethylamine; eluent B: ethanol; isocratic: 95%A+5%B;flow:1.4ml/min;temperature:25°C;UV:280nm Preparative Method: Instrument: PrepCon Labomatic HPLC‐3; Column: YMC Cellulose SB 10µ, 250x50;eluentA:methyl tert‐butylether+0.1vol%diethylamine;eluentB:ethanol+0.1vol% diethylamine;isocratic:95%A+5%B;flow:80ml/min;temperature:25°C;UV:280nm ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.570(4.93),1.588(5.00),1.823(16.00),1.928(0.57),1.941 (0.60),1.959(0.43),2.179(0.46),2.196(0.55),2.210(0.49),2.331(13.92),2.348(0.45),2.518(0.65), 2.523 (0.40),3.298 (0.66),3.308 (0.74),3.325 (1.11),3.519 (0.43),3.525 (0.53),3.532 (0.43),3.537

(0.58),3.544(0.52),3.558(0.40),3.597(0.41),3.616(0.87),3.634(0.49),3.641(0.61),3.663(0.87), 3.678 (0.91),3.689 (0.78),3.705 (0.69),4.391 (0.59),4.404 (0.58),5.578 (0.67),5.597 (0.98),5.615 (0.66),7.032(2.76),7.059(0.70),7.065(0.52),7.076(0.58),7.083(1.35),7.088(1.03),7.105(0.75), 7.112 (0.79),7.122 (1.56),7.128 (1.78),7.145 (1.92),7.149 (1.36),8.190 (1.12),8.207 (1.12),8.300 (1.12),8.319(1.09),8.646(4.19). Example98 N‐[(3R)‐1‐(4‐{[(1S)‐1‐(3,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide Seeexample97fordetails. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.571(4.85),1.589(4.97),1.825(16.00),1.907(0.52),1.926 (0.58),1.940(0.60),1.957(0.44),2.175(0.50),2.191(0.56),2.206(0.50),2.330(14.07),2.518(0.79), 2.523 (0.50),3.311 (0.76),3.321 (0.97),3.551 (0.57),3.558 (0.40),3.565 (0.66),3.571 (0.63),3.583 (0.77),3.600(1.00),3.618(0.53),3.625(0.52),3.638(0.82),3.654(0.91),3.665(0.79),3.680(0.69), 4.395 (0.60),4.409 (0.58),5.574 (0.67),5.592 (0.98),5.610 (0.67),7.026 (2.78),7.059 (0.68),7.065 (0.51),7.076(0.58),7.082(1.32),7.088(1.00),7.105(0.79),7.111(0.83),7.121(1.55),7.126(1.77), 7.143(1.91),7.148(1.36),8.196(1.16),8.214(1.14),8.297(1.15),8.316(1.10),8.646(4.11). Example99 N‐[(3R)‐1‐(4‐{[(1S)‐1‐(2,6‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide Example74(80mg,190µmol)waspurifiedbychiralHPLCtogive: Example99(25mg,30%,e.e.>95%).Rt=5.00min Example100(29mg,34%,e.e.>95%).Rt=3.31mins

Analytical Method: Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3µ, 100x4.6; eluentA:methyl tert‐butyl ether +0.1 vol%diethylamine;eluentB:ethanol; isocratic: 95%A+5%B;flow:1.4ml/min;temperature:25°C;UV:280nm Preparative Method: Instrument: PrepCon Labomatic HPLC‐3; Column: YMC Cellulose SB 10µ, 250x50;eluentA:methyl tert‐butylether+0.1vol%diethylamine;eluentB:ethanol+0.1vol% diethylamine;isocratic:95%A+5%B;flow:80ml/min;temperature:25°C;UV:280nm ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.695(4.49),1.713(4.49),1.831(16.00),1.918(0.59),1.931 (0.60),1.950(0.44),2.074(1.34),2.173(0.47),2.190(0.56),2.204(0.51),2.220(0.40),2.266(14.03), 2.277 (0.57),2.518 (0.72),2.523 (0.51),3.294 (0.69),3.304 (0.76),3.321 (1.07),3.535 (0.57),3.543 (0.40),3.549(0.64),3.555(0.58),3.569(0.50),3.575(0.49),3.594(0.96),3.602(0.41),3.612(0.54), 3.620 (0.60),3.628 (0.83),3.644 (0.96),3.655 (0.80),3.670 (0.69),4.399 (0.59),4.412 (0.58),5.625 (0.63),5.642(0.89),5.659(0.60),6.984(1.40),6.993(0.41),7.005(2.91),7.018(0.42),7.026(1.65), 7.117 (2.91),7.261 (0.71),7.265 (0.57),7.277 (0.48),7.282 (1.11),7.286 (0.49),7.297 (0.56),7.302 (0.63),8.203(1.16),8.219(1.13),8.389(1.03),8.406(0.98),8.603(4.05). Example100 N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2,6‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide Seeexample99fordetails. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.693(4.37),1.711(4.42),1.825(16.00),1.922(0.56),1.936 (0.59),1.954(0.42),2.174(0.48),2.191(0.57),2.205(0.50),2.221(0.40),2.267(13.53),2.283(0.44), 2.518 (0.55),3.299 (0.70),3.309 (0.74),3.326 (0.97),3.511 (0.43),3.517 (0.54),3.524 (0.43),3.530 (0.57),3.537(0.52),3.603(0.88),3.610(0.41),3.621(0.50),3.629(0.65),3.637(0.82),3.653(0.94), 3.665 (0.78),3.680 (0.69),4.395 (0.57),4.409 (0.57),5.631 (0.61),5.649 (0.87),5.666 (0.58),6.984 (1.36),7.005(2.87),7.026(1.61),7.118(2.89),7.259(0.68),7.264(0.56),7.280(1.07),7.297(0.52), 7.301(0.58),8.197(1.13),8.214(1.11),8.387(1.05),8.403(1.01),8.603(4.11). Example101 N‐[(3R)‐1‐(4‐{[(1R)‐1‐(2,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide

Example75(80mg,190µmol)waspurifiedbychiralHPLCtogive: Example101(32mg,38%,e.e.>95%).Rt=3.34min Example102(32mg,38%,e.e.>95%).Rt=4.41mins Analytical Method: Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3µ, 100x4.6; eluentA:methyl tert‐butyl ether + 0.1 vol% diethylamine; eluent B: ethanol; isocratic: 95%A+5%B;flow:1.4ml/min;temperature:25°C;UV:280nm Preparative Method: Instrument: PrepCon Labomatic HPLC‐3; Column: YMC Cellulose SB 10µ, 250x50;eluentA:methyl tert‐butylether+0.1vol%diethylamine;eluentB:ethanol+0.1vol% diethylamine;isocratic:95%A+5%B;flow:80ml/min;temperature:25°C;UV:280nm ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.231(0.59),1.570(4.90),1.588(4.94),1.825(16.00),1.931 (0.59),1.945(0.61),1.963(0.45),2.184(0.47),2.200(0.56),2.216(0.50),2.305(14.24),2.322(0.63), 2.327 (0.72),2.332 (0.50),2.518 (2.73),2.523 (1.69),2.665 (0.43),2.669 (0.61),2.673 (0.43),3.306 (0.90),3.316(1.26),3.526(0.45),3.532(0.54),3.545(0.61),3.551(0.52),3.565(0.41),3.604(0.43), 3.623 (0.90),3.641 (0.50),3.648 (0.63),3.671 (0.88),3.687 (0.95),3.698 (0.81),3.713 (0.72),4.395 (0.61),4.410(0.61),5.732(0.63),5.750(0.97),5.768(0.63),7.056(2.96),7.094(0.45),7.108(0.50), 7.116 (0.88),7.126 (0.65),7.136 (0.63),7.145 (0.43),7.216 (0.72),7.226 (0.77),7.239 (1.24),7.250 (1.62),7.257(1.17),7.262(0.93),7.266(0.70),7.273(1.11),7.281(0.54),8.194(1.15),8.210(1.15), 8.309(1.20),8.328(1.15),8.642(4.36). Example102 N‐[(3R)‐1‐(4‐{[(1S)‐1‐(2,5‐difluorophenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide Seeexample101fordetails. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.572(5.06),1.589(5.07),1.830(16.00),1.929(0.63),1.943 (0.65),1.960(0.48),2.179(0.53),2.195(0.63),2.210(0.55),2.226(0.44),2.304(14.05),2.518(0.63),

3.320 (0.92),3.330 (1.31),3.552 (0.40),3.558 (0.63),3.572 (0.72),3.578 (0.72),3.587 (0.72),3.605 (1.09),3.623(0.59),3.630(0.54),3.645(0.89),3.660(0.98),3.671(0.84),3.687(0.75),4.387(0.40), 4.401 (0.66),4.413 (0.64),5.726 (0.67),5.744 (1.02),5.762 (0.67),7.049 (3.02),7.091 (0.48),7.105 (0.54),7.113(0.93),7.123(0.69),7.133(0.67),7.143(0.44),7.213(0.76),7.225(0.83),7.231(0.76), 7.237 (1.37),7.247 (1.54),7.254 (1.26),7.260 (1.00),7.271 (0.98),7.277 (0.59),8.204 (1.24),8.221 (1.20),8.308(1.24),8.327(1.18),8.643(4.30). Example103 3‐[(1R)‐1‐({6‐[(3R)‐3‐acetamidopyrrolidin‐1‐yl]‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ yl}amino)ethyl]benzoicacid ToasolutionofExample65(21.2mg,47.3µmol)inMeOH(2ml)wasadded1MNaOH(2ml).Stirred at RT for 16h.) Reaction concentrated under reduced pressure and the residuewas purified by preparativeHPLC(basicmethod)togivethetitledcompound(13.8mg,64%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.571(4.77),1.588(4.82),1.815(16.00),1.915(0.63),1.928 (0.67),1.946(0.46),2.163(0.51),2.178(0.65),2.194(0.57),2.209(0.44),2.333(14.27),2.522(0.81), 3.307 (1.33),3.316 (1.51),3.334 (1.99),3.343 (2.31),3.478 (1.15),3.490 (1.03),3.499 (1.08),3.504 (1.14),3.516(1.07),3.524(0.94),3.536(0.74),3.576(0.61),3.595(1.11),3.613(0.71),3.620(0.83), 3.638 (1.17),3.654 (1.11),3.666 (0.95),3.681 (0.84),4.368 (0.42),4.381 (0.69),4.395 (0.69),5.629 (0.72),5.647(1.04),5.667(0.70),7.103(3.09),7.203(1.12),7.222(2.51),7.241(1.46),7.363(1.41), 7.383 (1.14),7.704 (1.78),7.722 (1.65),7.971 (2.63),8.227 (1.41),8.244 (1.40),8.398 (1.29),8.418 (1.24),8.608(4.76). Example104 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(hydroxymethyl)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]pyrrolidin‐3‐yl}acetamide

Toa solutionofExample65 (22mg,49µmol) inTHF (3ml)andNaBH4 (14.8mg,392µmol)was addedandstirredatRTfor1h.TothereactionmixturewasaddedMeOH(3ml)andstirredatRTfor 3h.ThereactionwasconcentratedandtheresiduewaspurifiedbypreparativeHPLC(basicmethod) togivethetitledcompound(3.4mg,16%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.569(5.26),1.587(5.32),1.821(16.00),1.902(0.45),1.920 (0.71),1.933(0.75),1.951(0.56),2.173(0.66),2.189(0.75),2.204(0.68),2.221(0.52),2.334(14.38), 2.669 (0.41),3.288 (1.00),3.298 (1.31),3.315 (1.92),3.492 (0.42),3.517 (0.74),3.530 (0.78),3.537 (0.69),3.550(0.52),3.588(0.48),3.606(1.04),3.624(0.62),3.631(0.73),3.647(1.09),3.662(1.05), 3.674 (0.90),3.689 (0.79),4.374 (0.46),4.386 (0.78),4.400 (0.77),4.471 (5.94),5.611 (0.77),5.629 (1.13),5.647(0.75),7.065(3.32),7.149(1.24),7.167(1.60),7.248(0.92),7.267(2.36),7.286(3.19), 7.289 (2.65),7.308 (0.67),7.402 (2.60),8.194 (1.37),8.211 (1.37),8.316 (1.41),8.336 (1.39),8.618 (4.71). Example105 N‐[(3R)‐1‐(4‐{[(1R)‐1‐(3‐hydroxyphenyl)ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl)pyrrolidin‐ 3‐yl]acetamide Inavessel flushedwithargonwasadded tBuBrettPhosPdG3 (8.19mg,9.59µmol), tBuBrettPhos (4.65mg,9.59µmol),Cs2CO3(43.7mg,134µmol)andExample62(45.0mg,95.9µmol).Thevessel wasflushedagainwithArgonandtoluene(1.2ml)and2,2‐difluoroethan‐1‐ol(61µl,960µmol)were added. The reactionmixturewas heated at 80°C for 16h. The reactionmixturewas dilutedwith EtOAc,washedwithwater, filtered throughahydrophobicmembranconcentratedundervacuum. Theresiduewaspurifiedbysilicachromatography(DCM:EtOH)togiveExample105(5mg,13%)and Example106(10mg,22%) ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.850 (0.66),0.867 (1.18),0.872 (0.87),0.887 (1.18),0.905 (1.63),0.924(0.69),1.107(1.28),1.232(1.49),1.256(0.52),1.278(0.76),1.295(0.76),1.316(0.49), 1.349(1.28),1.537(4.69),1.555(4.69),1.820(16.00),1.921(0.59),1.934(0.62),1.952(0.42),2.075 (0.83),2.172(0.45),2.188(0.56),2.202(0.49),2.318(0.49),2.323(1.08),2.327(1.56),2.332(1.56), 2.339(14.30),2.518(4.65),2.523(3.16),2.540(0.52),2.660(0.45),2.665(0.97),2.669(1.35),2.674 (0.94),2.679(0.45),3.285(0.76),3.295(0.94),3.505(0.56),3.511(0.62),3.519(0.56),3.532(0.59), 3.539 (0.52),3.606 (0.87),3.623 (0.49),3.631 (0.59),3.646 (0.87),3.661 (0.94),3.673 (0.80),3.688

(0.69),4.249(0.42),4.371(0.42),4.386(0.62),4.398(0.59),5.555(0.62),5.574(0.90),5.592(0.62), 6.591 (1.01),6.595 (1.01),6.597 (0.97),6.611 (1.04),6.615 (1.11),6.813 (2.12),6.818 (1.49),6.836 (1.21),6.855(1.39),7.064(2.88),7.086(1.67),7.105(2.57),7.124(1.25),8.088(2.08),8.185(1.21), 8.202(1.18),8.251(1.25),8.271(1.15),8.624(4.23),9.304(2.74). Example106 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(2,2‐difluoroethoxy)phenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]pyrrolidin‐3‐yl}acetamide SeeExample105fordetails. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(0.69),1.563(4.39),1.581(4.42),1.820(16.00),1.922 (0.55),1.936(0.57),2.174(0.48),2.191(0.53),2.207(0.46),2.322(1.01),2.333(13.97),2.518(2.95), 2.522 (2.01),2.664 (0.70),2.668 (0.95),2.673 (0.67),3.294 (0.67),3.304 (0.83),3.516 (0.42),3.521 (0.52),3.528(0.42),3.534(0.56),3.541(0.49),3.609(0.84),3.627(0.46),3.634(0.57),3.653(0.94), 3.668 (0.88),3.679 (0.76),3.695 (0.67),4.244 (0.78),4.252 (0.81),4.281 (1.59),4.289 (1.55),4.317 (0.84),4.326(0.74),4.388(0.57),4.402(0.56),5.591(0.60),5.609(0.88),5.628(0.60),6.230(0.69), 6.358 (0.62),6.366 (1.40),6.375 (0.64),6.502 (0.59),6.859 (0.80),6.861 (0.83),6.865 (0.84),6.868 (0.85),6.881(0.95),6.886(1.02),7.052(5.41),7.060(1.59),7.068(1.48),7.247(1.57),7.268(2.60), 7.288(1.17),8.186(1.16),8.203(1.13),8.262(1.16),8.282(1.12),8.626(3.97). Example107 N‐[(3R)‐1‐(4‐{[(1R)‐1‐{3‐[(E)‐2‐ethoxyethenyl]phenyl}ethyl]amino}‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl)pyrrolidin‐3‐yl]acetamide To a solution of Example 62 (600 mg, 1.28 mmol) in dioxane (8.1 ml) was added 2‐[(E)‐2‐ ethoxyethenyl]‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (253mg, 1.28mmol), followed by K2CO3 (589mg, 4.26mmol) and Pd(PPh3)4 (123mg, 107 µmol) andwater (1.62ml). The reactionwas heated at 90°C for 16h. The reaction was concentrated and purified by silica chromatography (EtOH:DCM)togivethetitledcompound(480mg,81%). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.222 (4.24),1.239 (9.16),1.256 (4.35),1.562 (4.62),1.579 (4.65),1.819(16.00),1.919(0.59),1.931(0.65),1.949(0.46),2.171(0.49),2.187(0.59),2.202(0.54), 2.218(0.41),2.323(1.30),2.327(1.95),2.331(1.86),2.341(13.89),2.518(10.73),2.523(7.46),2.665 (1.30),2.669(1.76),2.673(1.27),3.286(0.73),3.296(0.76),3.518(0.59),3.531(0.65),3.551(0.43), 3.586 (0.43),3.605 (0.95),3.623 (0.54),3.630 (0.65),3.647 (1.00),3.662 (0.97),3.673 (0.84),3.689 (0.76),3.846(1.16),3.864(3.81),3.881(3.81),3.899(1.16),4.385(0.65),4.400(0.68),5.574(0.70), 5.593 (0.95),5.611 (0.65),5.794 (2.24),5.827 (2.38),7.055 (2.97),7.143 (0.76),7.148 (1.05),7.153 (1.05),7.169(4.08),7.177(2.73),7.188(1.11),7.202(2.89),7.213(0.46),7.314(2.30),8.185(1.30), 8.202(1.24),8.261(1.24),8.280(1.19),8.622(4.27). Table4:Examples108‐115 Using themethoddescribed forExample25: Intermediate11was treatedwith thecorresponding phenylethan‐1‐aminesortheirhydrochloridesaltsandgavethedesiredcompoundsafterpreparative HPLCpurification(basicmethod)and/oroptionallysilicachromatography.

Table5:Examples116‐122 Using themethoddescribed forExample25: Intermediate12was treatedwith thecorresponding phenylethan‐1‐aminesortheirhydrochloridesaltsandgavethedesiredcompoundsafterpreparative HPLCpurification(basicmethod)and/oroptionallysilicachromatography.

Table6:Examples123‐129 Using themethoddescribed forExample25: Intermediate13was treatedwith thecorresponding phenylethan‐1‐aminesortheirhydrochloridesaltsandgavethedesiredcompoundsafterpreparative HPLCpurification(basicmethod)and/oroptionallysilicachromatography.

Table7:Examples130‐136 Using themethoddescribed forExample25: Intermediate14was treatedwith thecorresponding phenylethan‐1‐aminesortheirhydrochloridesaltsandgavethedesiredcompoundsafterpreparative HPLCpurification(basicmethod)and/oroptionallysilicachromatography.

Table8:Examples137‐257 Using the method described for Example 3: Example 2 was treated with nitrogen containing nucleophile at 130°C. The desired compoundswere obtainied after preparativeHPLC purification (basicmethod)and/oroptionallysilicachromatography.

Example258 methyl4‐(2‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethoxy)benzoate A mixture of Example 2 (50.0 mg, 143 µmol), methyl 4‐[2‐(piperazin‐1‐yl)ethoxy]benzoate hydrochloride(144mg,428µmol)andDIPEA(150µl,860µmol)inDMSO(1ml)washeatedat130°C for16h.The titledcompoundwas isolated (10mg,20%)afterpreparativeHPLCpurification (basic method). 1H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.594 (1.73),1.605 (4.49),1.612 (2.38),1.623 (4.38),2.302 (12.90),2.318(0.66),2.322(1.18),2.327(1.56),2.332(1.15),2.336(0.55),2.401(4.33),2.518(6.52), 2.523 (4.11),2.539 (0.60),2.665 (3.26),2.669 (3.62),2.674 (3.84),2.688 (2.33),2.725 (3.21),2.800 (1.18),2.813(2.41),2.827(1.21),3.582(2.79),3.813(16.00),4.231(1.32),4.245(2.68),4.259(1.26), 5.750 (1.01),5.768 (1.23),5.786 (0.71),7.069 (0.55),7.076 (4.16),7.081 (1.29),7.094 (1.40),7.099 (4.79),7.237(2.58),7.275(0.82),7.295(1.75),7.314(1.01),7.373(1.07),7.445(2.52),7.488(0.71), 7.504 (1.18),7.523 (0.58),7.632 (0.55),7.650 (1.12),7.667 (0.77),7.898 (0.68),7.905 (4.74),7.911 (1.37),7.923(1.34),7.928(4.27),7.935(0.47),7.945(0.60),8.426(1.10),8.445(1.04),8.659(4.16). Example259 4‐(2‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐ 6‐yl]piperazin‐1‐yl}ethoxy)benzoicacid To a solution of Example 258 (8.20mg, 13.8 µmol) inMeOH (2ml)was added 1MNaOH (2ml), additional MeOH (1ml) needed for hom*ogeneous solution. Stirred at RT for 16h. Reaction was concentratedunder reducedpressure to removeMeOH.Dissolved inDMSO:water (1:1)The titled compoundwasisolated(3.4mg,40%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.605(5.44),1.623(5.45),2.301(16.00),2.322(0.47),2.326 (0.52),2.518(1.82),2.522(1.17),2.668(4.18),2.677(3.07),2.784(1.43),2.799(2.90),2.813(1.53), 3.383 (2.18),3.578 (4.14),4.193 (1.62),4.207 (3.21),4.221 (1.57),5.751 (0.87),5.769 (1.34),5.787 (0.85),6.985(3.99),7.008(4.09),7.101(1.25),7.237(2.74),7.272(0.99),7.291(2.13),7.310(1.23), 7.372 (1.10),7.467 (3.18),7.483 (0.87),7.499 (1.31),7.517 (0.64),7.651 (0.70),7.669 (1.28),7.687 (0.64),7.858(5.09),7.862(1.65),7.875(1.64),7.879(4.58),8.513(1.21),8.532(1.14),8.656(5.55). Example260 6‐(methanesulfonyl)‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐ amine AmixtureofExample10(50.0mg,143µmol)andsodiummethanesulfinate(72.9mg,714µmol)in DMSO (1ml)washeatedat130°C for16h.The titled compoundwas isolated (14mg,23%)after preparativeHPLCpurification(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.625 (1.19),1.643 (1.20),2.482 (4.12),2.518 (0.67),2.523 (0.44),3.313(4.58),3.331(16.00),5.758(4.13),7.607(0.44),7.846(0.49),9.089(1.10),9.105(0.97). Example261

6‐[(3R)‐3‐aminopyrrolidin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐aminehydrochloridesalt x.HCl Toanice‐cooledsolutionofExample250(960mg,1.86mmol)indioxane(4.1ml)wasaddedHCLin dioxane(4.1ml,4.0M,16mmol)andstirredfor3h.Thereactionwasconcentratedunderreduced pressuretogivethetitledcompound(904mg)whichwasusedwithoutfurtherpurification. ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.748 (2.93),1.765 (2.93),2.374 (0.53),2.392 (0.44),2.518 (0.95),2.523(0.71),2.539(11.48),3.161(8.17),3.561(0.42),3.599(0.49),3.678(0.48),3.710(0.67), 3.750 (0.58),3.770 (0.48),3.788 (0.74),3.803 (0.82),3.818 (0.46),3.834 (0.46),3.983 (0.54),5.758 (16.00),5.978(0.63),5.996(0.94),6.013(0.59),7.105(1.06),7.241(2.23),7.329(0.50),7.348(1.07), 7.376 (1.06),7.542 (0.51),7.559 (0.84),7.900 (0.72),7.942 (0.49),7.959 (0.61),8.534 (0.83),8.864 (2.51). Example262 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}cyclopropanecarboxamide Toasolutionofexample261(50.0mg,110µmol)andcyclopropanecarboxylicacid(18µl,220µmol) inDMF(830µl)wasaddedDIPEA(96µl,550µmol)andpropylphosphonicanhydridesolution(T3P)in DMF(130µl,50%purity,220µmol).Tothereactionwasaddedafewdropsofwaterandthethe titledcompound(29mg,52%)wasisolatedafterpreparativeHPLC(bascmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.638 (1.36),0.643 (1.84),0.654 (1.40),0.656 (1.63),0.663 (1.86),0.669(1.89),0.686(2.52),0.699(1.20),0.712(0.46),1.107(0.61),1.231(0.74),1.551(0.64), 1.558 (0.74),1.570 (1.12),1.582 (0.67),1.589 (0.76),1.603 (5.13),1.621 (5.06),1.959 (0.59),1.973 (0.64),1.991(0.46),2.197(0.48),2.214(0.61),2.230(0.54),2.245(0.41),2.290(16.00),2.322(0.56), 2.326 (0.72),2.332 (0.51),2.518 (3.04),2.522 (1.87),2.539 (0.41),2.664 (0.49),2.669 (0.69),2.673 (0.51),3.295(0.72),3.306(0.89),3.536(0.49),3.542(0.58),3.549(0.48),3.556(0.62),3.562(0.56),

3.635 (0.41),3.653 (0.90),3.674 (1.17),3.689 (1.07),3.700 (1.00),3.716 (0.76),4.410 (0.39),4.425 (0.66),4.437(0.66),5.762(0.77),5.780(1.18),5.798(0.77),7.088(3.16),7.100(1.28),7.237(2.53), 7.275 (0.87),7.294 (1.92),7.313 (1.12),7.372 (1.02),7.482 (0.66),7.500 (1.09),7.518 (0.54),7.627 (0.59),7.645(1.09),7.663(0.54),8.402(1.35),8.420(2.61),8.436(1.41),8.636(4.72). Example263 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}‐2,2‐difluoroacetamide UsingthemethoddescribedforExample262:Example261(60mg,132µmol)anddifluoroaceticacid (17µl,260µmol)gavethetitledcompound(39mg,56%)afterpreparativeHPLC(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.107 (8.91),1.605 (5.01),1.622 (5.05),2.056 (0.61),2.069 (0.66),2.088(0.47),2.253(0.53),2.270(0.70),2.293(16.00),2.322(0.54),2.327(0.55),2.518(2.15), 2.523 (1.31),2.539 (0.64),2.669 (0.50),3.401 (0.72),3.411 (0.76),3.428 (0.82),3.438 (0.82),3.543 (0.50),3.549(0.59),3.562(0.66),3.568(0.59),3.582(0.42),3.628(0.42),3.646(0.92),3.663(0.53), 3.672 (0.65),3.725 (0.82),3.741 (1.01),3.752 (0.87),3.768 (0.77),4.190 (0.57),4.507 (0.65),4.520 (0.65),5.763(0.78),5.781(1.20),5.800(0.77),6.079(1.61),6.214(3.89),6.348(1.41),7.100(4.19), 7.237 (2.49),7.276 (0.88),7.295 (1.92),7.314 (1.11),7.372 (1.02),7.484 (0.66),7.501 (1.13),7.520 (0.56),7.629(0.61),7.646(1.10),7.664(0.55),8.398(1.32),8.416(1.27),8.644(4.72),9.160(1.21), 9.178(1.19). Example264 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}‐2‐methoxyacetamide Using themethoddescribed forExample262:Example261 (50mg,110µmol)andmethoxyacetic acid (19.9mg, 221 µmol) gave the titled compound (35mg, 61%) after preparative HPLC (basic method).

¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.107 (0.99),1.602 (2.93),1.620 (2.94),2.289 (9.20),2.327 (0.42),2.518(1.78),2.522(1.10),2.669(0.42),3.302(16.00),3.364(0.58),3.377(0.52),3.524(0.43), 3.647 (0.41),3.698 (0.49),3.714 (0.58),3.724 (0.52),3.741 (0.45),3.829 (4.30),4.495 (0.43),4.509 (0.42),5.761(0.45),5.779(0.69),5.798(0.45),7.076(1.85),7.100(0.69),7.237(1.45),7.274(0.50), 7.293 (1.13),7.312 (0.65),7.373 (0.60),7.500 (0.64),7.647 (0.64),8.119 (0.80),8.137 (0.79),8.390 (0.76),8.409(0.73),8.630(2.77). Example265 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}oxetane‐3‐carboxamide Using themethod described for Example 262: Example 261 (50mg, 110 µmol) and oxetane‐3‐ carboxylicacid(22.5mg,221µmol)gavethetitledcompound(31mg,53%)afterpreparativeHPLC (basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.107 (1.39),1.232 (0.90),1.601 (5.07),1.619 (5.07),1.940 (0.62),1.953(0.64),1.971(0.45),2.202(0.51),2.217(0.62),2.233(0.56),2.249(0.41),2.288(16.00), 2.322 (0.66),2.326 (0.90),2.332 (0.64),2.518 (3.21),2.522 (1.90),2.539 (0.43),2.664 (0.60),2.669 (0.83),2.673(0.62),3.304(0.88),3.315(1.16),3.539(0.60),3.552(0.66),3.559(0.60),3.572(0.49), 3.582 (0.47),3.600 (1.01),3.618 (0.53),3.626 (0.58),3.694 (0.79),3.710 (1.03),3.722 (1.50),3.725 (1.26),3.743(1.71),3.763(1.01),4.459(0.64),4.472(0.64),4.593(5.37),4.611(7.94),4.613(4.98), 4.628 (3.32),4.632 (3.19),4.646 (0.41),5.760 (0.77),5.778 (1.22),5.796 (0.77),7.081 (3.14),7.100 (1.22),7.236(2.57),7.276(0.90),7.295(1.95),7.314(1.11),7.372(1.05),7.483(0.66),7.501(1.11), 7.519 (0.53),7.627 (0.60),7.645 (1.09),7.663 (0.53),8.245 (1.35),8.262 (1.33),8.395 (1.30),8.414 (1.24),8.630(4.77). Example266 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}‐1‐methylazetidine‐3‐carboxamide

Using the method described for Example 262: Example 261 (50 mg, 110 µmol) and 1‐ methylazetidine‐3‐carboxylic acid (25.4mg, 221 µmol) gave the titled compound (12.5mg, 21%) afterpreparativeHPLC(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.103 (1.38),1.107 (1.89),1.224 (1.03),1.230 (1.16),1.601 (4.38),1.619(4.45),1.826(0.75),1.926(0.50),1.940(0.52),2.160(11.15),2.183(0.67),2.198(0.63), 2.214(0.52),2.288(16.00),2.322(0.84),2.327(0.75),2.332(0.55),2.518(2.88),2.523(1.76),2.539 (0.56),2.665(0.50),2.669(0.72),2.673(0.52),3.038(0.50),3.055(1.15),3.072(1.99),3.077(1.47), 3.087 (1.35),3.104 (0.75),3.122 (0.59),3.268 (1.36),3.278 (1.60),3.294 (2.06),3.346 (7.98),3.460 (0.74),3.496(0.67),3.510(0.65),3.516(0.69),3.523(0.75),3.531(0.65),3.537(0.76),3.542(0.73), 3.556 (0.55),3.592 (0.48),3.610 (0.88),3.618 (0.75),3.628 (0.80),3.636 (0.85),3.644 (0.65),3.679 (0.81),3.694(0.98),3.706(0.96),3.721(0.80),4.415(0.53),4.428(0.52),5.759(0.80),5.779(1.19), 5.796 (0.79),7.064 (0.84),7.074 (2.45),7.100 (1.39),7.236 (2.80),7.275 (0.82),7.295 (1.76),7.314 (1.04),7.372(1.20),7.483(0.79),7.500(1.33),7.518(0.67),7.628(0.64),7.646(1.14),7.665(0.59), 8.161(0.90),8.178(0.90),8.398(1.20),8.416(1.16),8.629(3.85). Example267 methyl{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}carbamate ToamixtureofExample261(50mg,110µmol),triethylamine(77µl,550µmol),DMAP(0.3mg)in DCE(830µl)wasstirredatRTfor16h.Thereactionmixturewasaddedwater,extractedwithDCM, washedwithsat.NaCl.Theorganicswerefilteredthroughahydrophobicfilterandconcentrated.The titledcompound(13mg,24%)afterpreparativeHPLC(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.107 (1.81),1.231 (0.85),1.603 (5.33),1.621 (5.42),1.952 (0.54),1.966(0.61),1.987(0.52),2.187(0.54),2.205(0.67),2.219(0.63),2.237(0.46),2.288(16.00), 2.322 (0.81),2.327 (1.09),2.331 (0.83),2.518 (7.66),2.523 (5.33),2.539 (1.65),2.665 (0.74),2.669 (1.09),2.673(0.81),3.512(0.72),3.552(6.68),3.606(0.59),3.624(0.96),3.642(0.63),3.648(0.70), 3.675 (0.83),3.691 (0.96),3.702 (0.85),3.718 (0.74),4.203 (0.46),4.219 (0.76),4.231 (0.72),4.245 (0.44),5.759(1.28),5.778(1.26),5.796(0.83),7.068(3.35),7.101(1.28),7.237(2.61),7.274(0.98), 7.293 (2.11),7.312 (1.22),7.373 (1.11),7.483 (0.72),7.500 (1.22),7.517 (0.65),7.570 (0.83),7.586 (0.83),7.628(0.67),7.646(1.20),7.664(0.61),8.393(1.31),8.411(1.31),8.625(5.01). Example268 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]pyrrolidin‐3‐yl}methanesulfonamide UsingthemethoddescribedforExample262:Example261(50mg,110µmol)andmethanesulfonyl chloride (17 µl, 220µmol) gave the titled compound (27mg, 46%) after preparativeHPLC (basic method). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.107 (2.65),1.231 (0.47),1.609 (4.33),1.626 (4.34),1.999 (0.48),2.012(0.54),2.030(0.47),2.290(14.09),2.309(0.63),2.322(0.73),2.326(0.89),2.332(0.54), 2.518(2.21),2.522(1.33),2.669(0.55),3.004(16.00),3.318(0.48),3.363(0.71),3.377(0.71),3.389 (0.76),3.403(0.76),3.459(0.62),3.467(0.48),3.477(0.41),3.485(0.77),3.625(0.54),3.632(0.44), 3.639 (0.47),3.646 (0.45),3.761 (0.66),3.777 (0.84),3.787 (0.71),3.803 (0.66),4.105 (0.62),4.120 (0.60),5.763(0.67),5.781(1.03),5.799(0.66),7.084(2.75),7.101(1.07),7.237(2.13),7.274(0.76), 7.293 (1.66),7.312 (0.96),7.373 (0.89),7.483 (0.60),7.499 (1.99),7.514 (1.48),7.630 (0.51),7.648 (0.93),7.667(0.47),8.407(1.13),8.426(1.07),8.636(4.14). Example269 N‐{(3R)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]p yrrolidin‐3‐yl}cyclopropanesulfonamide Using the method described for Example 262: Example 261 (50 mg, 110 µmol) and cyclopropanesulfonyl chloride (22 µl, 220 µmol) gave the titled compound (31 mg, 51%) after preparativeHPLC(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.946 (0.72),0.952 (1.27),0.960 (2.24),0.963 (2.18),0.972 (2.54),0.977(3.04),0.987(1.21),0.990(1.23),0.993(1.39),0.997(1.95),1.016(0.43),1.107(3.52), 1.231 (0.43),1.608 (5.02),1.626 (5.03),2.010 (0.44),2.028 (0.54),2.041 (0.62),2.059 (0.55),2.290 (16.00),2.322(1.03),2.327(0.84),2.332(0.80),2.518(2.56),2.523(1.58),2.539(0.67),2.635(0.71), 2.639 (0.47),2.651 (1.16),2.659 (0.67),2.665 (1.11),2.669 (1.00),3.384 (0.78),3.397 (0.80),3.410 (0.86),3.423(0.84),3.464(0.71),3.471(0.56),3.482(0.47),3.488(0.88),3.634(0.62),3.639(0.51), 3.647 (0.54),3.653 (0.51),3.772 (0.74),3.789 (0.96),3.799 (0.82),3.816 (0.74),4.115 (0.43),4.131 (0.76),4.147(0.74),5.763(0.78),5.780(1.21),5.798(0.76),7.085(3.17),7.101(1.25),7.237(2.52), 7.273 (0.87),7.293 (1.93),7.312 (1.12),7.373 (1.04),7.483 (0.64),7.501 (1.11),7.518 (0.56),7.539 (1.83),7.556(1.77),7.630(0.60),7.648(1.10),7.665(0.55),8.401(1.30),8.420(1.25),8.637(4.81). Table9:Examples270‐278 Generalmethod:Toasolutionofthecarboxylicacid(230µmol)inDMF(1ml)wasaddedHATU(230 µmol) and stirred for 15mins, thenDIPEA (766 µmol) and Example 148 (75mg, 153 µmol)were added.ThereactionwasstirredatRT.ThecompoundsinTable9werethenpurifiedbypreparative HPLC(basicmethod)and/orsilicachromatograpy.

Example279 10‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]piperazin‐1‐yl}‐10‐oxodecanoicacid ToasolutionofExample278(195mg,317µmol) inMeOH(5.5)andTHF(1.5ml)underArgonwas addedLiOH(1Minwater,1.9ml).ThereactionwasstirredatRTfor16handthenneutralizedbythe additionof2MHClandconcentrated.Theresiduewaspurifiedbysilicachromatographytogivethe titlecompound(185mg,92%). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.033 (1.69),1.051 (3.72),1.068 (1.55),1.269 (4.16),1.465 (0.73),1.482(1.16),1.498(1.22),1.515(1.03),1.688(1.77),1.704(1.81),1.907(0.63),2.167(1.77), 2.185 (3.41),2.204 (1.61),2.351 (1.10),2.370 (1.69),2.388 (0.99),2.444 (1.45),2.518 (4.86),2.523 (3.25),2.539(16.00),3.162(0.69),3.170(0.76),3.409(0.57),3.427(1.00),3.444(0.96),3.622(4.67), 3.705 (0.84),7.104 (0.81),7.240 (1.75),7.309 (0.49),7.328 (1.04),7.347 (0.59),7.376 (0.75),7.520 (0.41),7.537(0.69),8.777(0.80). Example280

4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐ N,N‐dimethylpiperazine‐1‐carboxamide Toasolutionofdimethylcarbamylchloride(25.7mg,239µmol)inanhydrousTHF(1ml)wasadded triethylamine(67µl,480µmol)followedbytheslowadditionofExample148(78mg,159µmol).The reactionwasstirredatRTfor2handthenafewdropsofwaterwereadded‐Thetitledcompound(36 mg,45%)wasisolatedafterpreparativeHPLC(basicmethod). ¹H‐NMR(400MHz,CHLOROFORM‐d)δ[ppm]:1.041(0.50),1.262(0.58),1.283(0.79),1.727(1.41), 1.743(1.40),2.540(6.00),2.907(16.00),3.427(1.04),3.439(1.43),3.444(1.12),3.452(1.42),3.618 (1.24),3.634(1.26),3.642(0.81),6.505(0.42),6.792(0.45),6.929(0.91),7.067(0.43),7.219(0.75), 7.238(0.43),7.518(0.42),8.893(1.48). Example281 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[4‐(methanesulfonyl)piperazin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine ToasolutionofExample148(88mg,180µmol)inDCM(1.1.ml)wasaddedtriethylamine(75µl,540 µmol)followedbytheslowadditionofmethanesulfonylchloride(30.9mg,270µmol).Thereaction wasstirredatRT for2hand thena fewdropsofwaterwereadded‐The titledcompound (65mg, 72%)wasisolatedafterpreparativeHPLC(basicmethod). ¹H‐NMR(400MHz,CHLOROFORM‐d)δ[ppm]:1.040(0.74),1.194(0.58),1.261(0.59),1.282(5.18), 1.299(0.55),1.730(5.23),1.748(5.24),2.543(14.92),2.844(16.00),3.403(3.13),3.415(4.63),3.427 (3.69),3.730(3.57),3.743(4.20),3.755(3.07),5.773(0.75),5.791(1.23),5.809(0.91),5.878(0.75), 5.895 (0.56),6.552 (3.05),6.783 (1.07),6.920 (2.15),7.058 (1.02),7.196 (0.86),7.216 (1.89),7.235 (1.09),7.497(0.68),7.514(1.18),7.533(1.19),7.553(1.20),7.571(0.59),8.893(4.07). Example282

2‐amino‐1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}ethan‐1‐one ToasolutionofExample148(1g,2.04mmol)andN‐BocGlycine(537mg,3.07mmol)inDMF(20ml) underargonwasaddedDIPEA(1.78ml,10.2mmol)andHATU(1.165g,3.07mmol)andstirredatRT for 16h. The reactionwasdilutedwith EtOAc,washedwithwater, sat.NaCl,driedoverNa2SO4, filteredandconcentratedunderreducedpressure.TheBoc‐protectedproductwaspurifiedbysilica chromatography(DCM:EtOH). TheBoc‐protectedproductwas treatedwith4MHCl indioxane, concentrated and aportionwas purifiedbypreparativeHPLC(basicmethod)togivethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.612(5.02),1.630(5.00),2.309(16.00),2.322(0.79),2.327 (0.76),2.332(0.56),2.518(2.20),2.523(1.50),2.665(0.46),2.669(0.65),2.673(0.47),3.411(7.92), 3.563 (2.70),3.603 (1.56),3.613 (1.53),3.652 (1.25),3.663 (1.36),5.755 (0.76),5.773 (1.17),5.791 (0.76),7.102(1.14),7.238(2.50),7.278(0.87),7.297(1.88),7.317(1.08),7.374(1.01),7.481(2.98), 7.507 (1.10),7.525 (0.53),7.636 (0.59),7.654 (1.07),7.672 (0.54),8.456 (1.22),8.475 (1.16),8.684 (4.80). Example283 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]piperazin‐1‐yl}‐2‐(methylamino)ethan‐1‐one ToasolutionofExample148(1g,2.04mmol)andN‐BocSarcosine(580mg,3.07mmol)inDMF(20 ml)underargonwasaddedDIPEA(1.78ml,10.2mmol)andHATU(1.165g,3.07mmol)andstirredat RTfor16h.ThereactionwasdilutedwithEtOAc,washedwithwater,sat.NaCl,driedoverNa2SO4, filteredandconcentratedunderreducedpressure.TheBoc‐protectedproductwaspurifiedbysilica chromatography(DCM:EtOH).

TheBoc‐protectedproductwas treatedwith4MHCl indioxane, concentrated and aportionwas purifiedbypreparativeHPLC(basicmethod)togivethetitledcompound. ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.612(3.51),1.630(3.49),2.296(16.00),2.310(11.42),2.322 (0.55),2.327(0.51),2.518(1.24),2.523(0.83),2.669(0.41),3.385(5.64),3.576(0.99),3.608(3.19), 3.645 (1.01),3.658 (1.07),5.755 (0.55),5.773 (0.84),5.791 (0.53),7.102 (0.83),7.238 (1.78),7.278 (0.63),7.297(1.33),7.317(0.77),7.374(0.73),7.482(2.16),7.507(0.78),7.636(0.42),7.655(0.75), 8.456(0.87),8.474(0.83),8.684(3.40). Example284 3‐amino‐1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]piperazin‐1‐yl}propan‐1‐one ToasolutionofExample148(1g,2.04mmol)andN‐Bocß‐Alanine(580mg,3.07mmol)inDMF(20 ml)underargonwasaddedDIPEA(1.78ml,10.2mmol)andHATU(1.165g,3.07mmol)andstirredat RTfor16h.ThereactionwasdilutedwithEtOAc,washedwithwater,sat.NaCl,driedoverNa2SO4, filteredandconcentratedunderreducedpressure.TheBoc‐protectedproductwaspurifiedbysilica chromatography(DCM:EtOH). TheBoc‐protectedproductwas treatedwith4MHCl indioxane, concentrated and aportionwas purifiedbypreparativeHPLC(basicmethod)togivethetitledcompound. ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.613 (5.18),1.631 (5.16),1.751 (0.48),2.300 (1.31),2.310 (16.00),2.322(1.32),2.327(1.51),2.332(1.09),2.336(0.49),2.457(1.81),2.473(4.64),2.518(4.52), 2.523 (3.04),2.660 (0.44),2.665 (0.96),2.669 (1.39),2.673 (0.97),2.678 (0.42),2.757 (2.15),2.773 (4.15),2.789(1.71),3.547(1.41),3.630(7.37),3.652(2.07),5.756(0.82),5.774(1.24),5.792(0.78), 7.103 (1.26),7.238 (2.67),7.279 (0.93),7.298 (1.98),7.317 (1.14),7.374 (1.11),7.483 (3.14),7.508 (1.17),7.525(0.56),7.637(0.64),7.654(1.13),7.672(0.58),8.454(1.25),8.472(1.18),8.684(4.93). Example285 1‐{4‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]piperazin‐1‐yl}‐3‐(methylamino)propan‐1‐one To a solution of Example 148 (1g, 2.04mmol) andN‐(tert‐butoxycarbonyl)‐N‐methyl‐beta‐alanine (623mg,3.07mmol)inDMF(20ml)underargonwasaddedDIPEA(1.78ml,10.2mmol)andHATU (1.165g,3.07mmol)andstirredatRT for16h.The reactionwasdilutedwithEtOAc,washedwith water, sat.NaCl,driedoverNa2SO4, filteredand concentratedunder reducedpressure.TheBoc‐ protectedproductwaspurifiedbysilicachromatography(DCM:EtOH). TheBoc‐protectedproductwas treatedwith4MHCl indioxane, concentrated and aportionwas purifiedbypreparativeHPLC(basicmethod)togivethetitledcompound. ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.230 (0.72),1.614 (5.39),1.631 (5.29),1.751 (0.92),1.897 (0.52),2.311(16.00),2.330(14.82),2.518(4.60),2.523(2.81),2.540(0.68),2.560(1.21),2.577(2.64), 2.594 (1.64),2.665 (0.88),2.669 (1.14),2.673 (0.83),2.747 (1.79),2.763 (2.96),2.780 (1.22),3.412 (0.85),3.424(0.69),3.480(0.43),3.552(1.81),3.634(8.43),5.759(3.01),5.774(1.33),5.792(0.84), 7.103 (1.28),7.239 (2.76),7.278 (1.03),7.298 (2.12),7.317 (1.21),7.375 (1.14),7.488 (3.84),7.508 (1.39),7.526(0.65),7.638(0.73),7.656(1.28),7.674(0.63),8.462(1.37),8.479(1.28),8.686(5.28). Table10:Examples286‐289 UsingthemethoddescribedforExample20:Example10wastreatedwiththecorrespondingamines or their hydrochloride salts and gave the desired compounds after preparativeHPLC purification (basicmethod)and/orsilicachromatography.

Example290 6‐fluoro‐2‐methyl‐N‐{(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐ amine Using themethoddescribed forExample1using6‐fluoro‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ol (735 mg, 4.1mmol) and (1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethan‐1‐amine (1.00 g, 4.92mmol) gavethetitledcompound(919mg,58%)aftersilicachromatography(Hexane:EtOAc). 1H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.559(5.53),1.576(5.57),2.382(16.00),2.518(2.36),2.522 (1.58),2.616(6.32),5.677(0.83),5.694(1.28),5.712(0.83),7.341(0.67),7.360(1.52),7.380(0.89), 7.542 (1.63),7.560 (1.32),7.750 (1.49),7.769 (1.34),8.138 (2.47),8.141 (2.47),8.715 (4.00),8.883 (1.22),8.900(1.19). Table11:Examples291‐295 UsingthemethoddescribedforExample25:Example10wastreatedwiththecorrespondingamines or their hydrochloride salts and gave the desired compounds after preparativeHPLC purification (basicmethod)and/orsilicachromatography.

Example296 6‐fluoro‐2,8‐dimethyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine ToasolutionofExample10(250mg,714µmol)inDMSO(5ml)wasaddedDBU(213µl,1.4mmol) andnitromethane (193µl,3.6mmol) and stirred for4days atRT. The reactionwasdilutedwith waterandthesolidcollectedbyfiltrationandwashedwithwater.Thesolidwasdriedtogivethetitle compound(260mg,95%). 1H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.153 (0.82),1.171 (1.59),1.189 (0.82),1.603 (5.61),1.621 (5.61),1.986(3.24),2.429(16.00),2.518(1.22),2.523(0.74),2.539(1.06),2.724(11.33),4.016(0.71), 4.034 (0.70),5.592 (0.75),5.609 (1.14),5.628 (0.74),5.758 (2.79),7.544 (0.46),7.563 (1.48),7.582 (1.74),7.591(1.88),7.611(0.55),7.740(1.27),7.758(1.00),7.818(2.04),7.889(2.05),7.892(2.07), 8.639(1.19),8.658(1.16). Table12:Examples297‐300 Using themethod described for Example 25: Example 296 was treated with the corresponding amines or their hydrochloride salts and gave the desired compounds after preparative HPLC purification(basicmethod)and/orsilicachromatography.

Example301 6‐fluoro‐2,8‐dimethyl‐N‐{(1R)‐1‐[2‐methyl‐3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐ amine To a solutionofExample290 (250mg,868µmol) inDMSO (4.8ml)was addedDBU (205µl,1.4 mmol)andnitromethane (186µl,3.4mmol)andstirred for4daysatRT.Thereactionwasdiluted withwaterandthesolidcollectedbyfiltrationandwashedwithwater.Thesolidwasdriedtogive thetitlecompound(243mg,89%). 1H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.550 (5.96),1.567 (6.02),1.987 (0.41),2.327 (0.61),2.389 (16.00),2.539(4.42),2.615(7.78),2.669(0.66),2.708(12.68),5.665(0.92),5.683(1.45),5.700(0.92), 7.333 (0.80),7.353 (1.78),7.372 (1.06),7.535 (1.93),7.555 (1.60),7.739 (1.77),7.759 (1.61),7.932 (2.66),8.760(1.45),8.777(1.42). Table13:Examples302‐307 Using themethod described for Example 25: Example 301 was treated with the corresponding amines or their hydrochloride salts and gave the desired compounds after preparative HPLC purification(basicmethod)and/orsilicachromatography.

Example308 6‐chloro‐2‐methyl‐N‐{(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}pyrido[3,4‐d]pyrimidin‐4‐amine ToasolutionofIntermediate15(2.00g,9.71mmol) inDMF(40ml)wereaddedtriethylamine(4.7 ml, 34 mmol), 4‐(dimethylamino)pyridine (1 crystal) and 2,4,6‐tri(propan‐2‐yl)benzene‐1‐sulfonyl chloride(3.24g,10.7mmol)atRT.ThereactionmixturewasstirredatRTfor1hour.Then(1R)‐1‐[3‐ (trifluoromethyl)phenyl]ethan‐1‐aminehydrochloride (2.66g,11.7mmol)wasaddedandstirredat room temperature for 16 hoursThe reactionmxiturewas dilutedwithwater and extractedwith EtOAc.Theorganicphasewaswashedwithwaterandbrine,driedoveranhydroussodiumsulfate andconcentrated togivea residue.The residuewaspurifiedby silicagelcolumnchromatography (petroleumether:ethylacetatetogivethetitledcompound(3.2g,84%). 1H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.605(5.96),1.622(5.97),2.423(16.00),2.518(1.39),2.523 (0.89),5.589(0.71),5.607(1.08),5.625(0.70),7.548(0.50),7.567(1.59),7.586(1.75),7.597(1.94), 7.617(0.61),7.749(1.40),7.767(1.11),7.825(2.30),8.481(4.08),8.831(4.99),8.849(1.11). Table14:Examples309‐314 Usingthegeneralmethod:ToasolutionofExample308(100mg,263µmol)intetrahydrofuran(1.9 ml)wasaddedtheboronicacidorpinacolborateester(1.2eq),potassiumphosphate(2Minwater, 2 eq) and methanesulfonato(2‐dicyclohexylphosphino‐2',4',6'‐tri‐i‐propyl‐1,1'‐biphenyl)(2'‐amino‐ 1,1'‐biphenyl‐2‐yl)palladium(II)(0.1eq)atRT.Thereactionmixturewasstirredat70°Cfor16hours underanitrogenatmosphere.The reactionwasdilutedwithwaterandextractedwithEtOAc.The desired compoundswere isolatedafterpreparativeHPLCpurification (basicmethod)and/or silica chromatography.

Table15:Examples315‐318 Following themethod described here for Example 315, the Examples in Table 14were used to preparetheircorrespondinganalogsinTable15. Example315:ToasolutionofExample311(180mg,445µmol)inMeOH(4ml)wasaddedpalladium onactivatedcharcoal(10%,0.1eq).Thereactionvesselwasflushedwithhydrogenandstirredfor4h at RT. The reaction was filtered through Celite, and the filtrate was concentrated. The desired compoundswere isolated after preparativeHPLC purification (acidic or basicmethod) and/or by silicachromatography.

Example319 methyl2‐methyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidine‐6‐ carboxylate

ToasolutionofExample308(3.00g,8.18mmol),triethylamine(2.3ml,16mmol)inMeOH(60ml) was added [1,1'‐bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (598mg, 818 µmol) at RT. Thereactionmixturewasstirredat80°Cfor18hoursundercarbonmonoxideatmosphere(50psi). Thereactionmixturewasfilteredandthefiltratewaspurifiedbysilicagelcolumnchromatography (petroleumether:EtOAc)togivethetitlecompound(820mg,24%). Example320 2‐methyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidine‐6‐carboxamide Ammoniagaswasbublingtoethanoltogiveacolorlesssolutionat‐65°C.Tothesolutionwasadded Example319(100mg,251µmol)atRT.Thereactionmixturewasstirredina30mlsealedtubeat45 °Cfor16hoursThereactionmixturewasconcentratedtogivearesidue.Theresiduewaspurifiedby preparative HPLC [Instrument:ACSWH‐GX‐C; ColumnPhenomenex luna C18 150*25mm* 10µm; eluentA:water (0.225% formicacid inwater),eluentB:acetonitrile;gradient:0‐10min25‐55%B; flow25ml/min; temperature:RT;Detector:UV220/254nm.] togive the title compound (55mg, 58%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.617(6.33),1.634(6.55),2.324(0.62),2.452(16.00),2.666 (0.48),5.629(1.09),5.647(1.63),5.665(1.14),7.545(0.77),7.563(2.11),7.587(3.72),7.731(2.32), 7.764 (2.24),7.782 (1.94),7.852 (3.38),8.211 (2.19),8.379 (0.55),8.952 (4.68),9.055 (4.64),9.213 (1.76),9.231(1.82). Example321 N,2‐dimethyl‐4‐({(1R)‐1‐[3‐(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4‐d]pyrimidine‐6‐ carboxamide

Toasolutionofmethylamineinethanol(2M)wasaddedExample319(120mg,307µmol)atroom temperature.Thereactionmixturewasheatedinasealedtubeat40°Cfor16hours.Thereaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC [Instrument:ACSWH‐GX‐C; Column: Phenomenex Luna C18 150*25mm*10µm; eluent A: water (0.225%formicacid inwater),eluentB:acetonitrile;gradient:0‐10min25‐55%B;flow25ml/min; temperature:RT;Detector:UV220/254nm.]togivethetitlecompound(32mg,26%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.624(6.20),1.642(6.35),2.452(16.00),2.864(7.76),2.876 (8.04),5.633(0.99),5.651(1.50),5.669(1.01),7.547(0.60),7.566(1.94),7.585(3.48),7.589(3.39), 7.609 (0.81),7.768 (1.81),7.785 (1.49),7.856 (3.12),8.407 (0.54),8.858 (1.47),8.870 (1.49),8.956 (5.09),9.023(4.83),9.241(1.66),9.260(1.65). Example322 1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐methylphenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐ yl]piperidine‐4‐carbonitrile Using themethoddescribed forExample25: Intermediate16 (50mg,186µmol)was treatedwith (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐amine hydrochloride (49.4 mg, 223 µmol) and gavethetitledcompound(53mg,62%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.544 (4.76),1.561 (4.83),1.802 (0.71),1.808 (0.73),1.831 (0.85),1.854(0.41),2.004(0.84),2.318(16.00),2.518(1.48),2.523(1.21),2.534(7.42),3.121(0.45), 3.131 (0.63),3.142 (0.85),3.153 (0.62),3.164 (0.41),3.385 (0.68),3.411 (1.02),3.438 (0.72),3.873 (0.86),3.906(0.76),5.715(0.69),5.732(1.05),5.750(0.68),7.078(0.91),7.216(1.93),7.282(0.65), 7.300 (1.63),7.320 (1.13),7.353 (0.79),7.382 (1.64),7.400 (1.05),7.462 (2.93),7.623 (1.26),7.641 (1.12),8.464(1.13),8.483(1.09),8.645(4.51). Example323

N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐6‐[(2S)‐2,4‐dimethylpiperazin‐1‐yl]‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐amine UsingthemethoddescribedforExample25:Intermediate17(35.0mg,128µmol)wastreatedwith (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐amine hydrochloride (34.7 mg, 154 µmol) and gavethetitledcompound(51mg,86%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.859 (0.88),0.967 (2.64),1.109 (2.22),1.132 (5.97),1.144 (2.86),1.149(6.06),1.208(0.45),1.224(0.58),1.603(5.21),1.621(5.18),1.989(0.45),2.010(0.70), 2.017(0.72),2.038(0.47),2.164(0.75),2.173(0.87),2.192(0.92),2.201(0.87),2.230(10.75),2.298 (16.00),2.318(0.49),2.323(0.92),2.327(1.22),2.331(0.87),2.336(0.40),2.518(5.31),2.523(3.58), 2.660 (0.41),2.665 (0.87),2.669 (1.20),2.673 (0.83),2.747 (1.05),2.774 (0.96),2.903 (0.73),2.931 (0.68),3.070(0.49),3.078(0.70),3.101(0.85),3.109(0.77),3.132(0.49),3.164(0.51),3.906(0.70), 3.937 (0.64),4.684 (0.62),5.757 (0.77),5.775 (1.19),5.793 (0.77),7.103 (1.19),7.240 (2.48),7.278 (0.87),7.298(1.92),7.317(1.13),7.344(3.07),7.375(1.05),7.487(0.66),7.504(1.13),7.522(0.55), 7.635(0.62),7.653(1.11),7.672(0.55),8.411(1.24),8.430(1.20),8.663(4.82). Example324 {1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐ 4‐methylpiperazin‐2‐yl}methanol(mixtureofstereoisomers) UsingthemethoddescribedforExample25:Intermediate18(33.0mg,145µmol)wastreatedwith (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐amine hydrochloride (34.7 mg, 154 µmol) and gavethetitledcompound(32mg,55%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.967 (0.55),1.109 (1.44),1.598 (4.22),1.605 (4.42),1.616 (4.36),1.623(4.10),1.974(0.46),2.004(1.93),2.014(1.28),2.023(1.17),2.032(1.55),2.233(14.08), 2.290 (11.34),2.296 (11.41),2.518 (16.00),2.523 (10.44),2.673 (2.26),2.877 (0.98),2.903 (0.91), 3.072 (0.53),3.109 (2.04),3.136 (1.60),3.779 (0.79),3.919 (0.51),3.950 (0.54),3.998 (0.45),4.550

(0.76),4.741(0.81),4.753(0.83),5.747(0.66),5.755(0.74),5.765(1.03),5.773(1.04),5.783(0.71), 5.791 (0.65),7.103 (1.22),7.239 (2.48),7.272 (0.69),7.281 (0.72),7.291 (1.48),7.300 (1.51),7.310 (0.92),7.319(0.87),7.341(2.18),7.361(2.16),7.374(1.22),7.502(1.31),7.635(0.80),7.653(1.42), 7.671(0.72),8.408(0.96),8.420(1.19),8.437(0.92),8.633(3.50),8.640(3.50). Example325 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[2‐(trifluoromethyl)‐5,6‐ dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine Using themethoddescribed forExample25: Intermediate19 (30mg,86µmol)was treatedwith (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐aminehydrochloride(23mg,103µmol)andgave thetitledcompound(15mg,33%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.107 (3.17),1.225 (0.55),1.348 (0.42),1.632 (5.40),1.650 (5.34),2.325(16.00),2.518(6.33),2.523(4.14),2.660(0.42),2.665(0.91),2.669(1.29),2.673(0.93), 2.678 (0.42),4.205 (2.79),4.215 (3.02),4.224 (2.01),4.825 (3.65),4.830 (3.69),5.760 (0.82),5.778 (1.25),5.796(0.80),7.107(1.20),7.243(2.51),7.285(0.91),7.303(2.01),7.323(1.14),7.379(1.06), 7.495 (0.70),7.512 (1.18),7.530 (0.57),7.623 (3.25),7.648 (0.68),7.666 (1.18),7.684 (0.59),7.836 (3.00),7.839(3.15),8.490(1.33),8.509(1.29),8.741(4.92). Example326 N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methyl‐6‐[2‐(trifluoromethyl)‐5,6‐ dihydro[1,2,4]triazolo[1,5‐a]pyrazin‐7(8H)‐yl]pyrido[3,4‐d]pyrimidin‐4‐amine Using themethoddescribed forExample25: Intermediate20 (30mg,85µmol)was treatedwith (1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethan‐1‐aminehydrochloride(23mg,102µmol)andgave thetitledcompound(15mg,31%)afterpreparativeHPLCpurification(basicmethod).

¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.636(5.12),1.653(5.03),2.330(16.00),2.518(7.79),2.523 (4.89),2.665(1.21),2.669(1.66),2.673(1.18),4.302(1.12),4.314(2.28),4.328(1.69),4.441(1.49), 4.455 (2.14),4.983 (4.47),5.762 (0.73),5.779 (1.18),5.797 (0.76),7.108 (1.12),7.243 (2.39),7.286 (0.87),7.305(1.91),7.324(1.10),7.379(1.01),7.498(0.67),7.515(1.12),7.532(0.56),7.649(0.65), 7.669(1.29),7.679(3.32),8.488(1.27),8.506(1.21),8.757(4.72). Example327 6‐(cyclobutyloxy)‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐amine To sodiumhydride (60%dispersiononmineraloil,28.5mg,714µmol)underArgonwasaddeda solutionofcyclobutanol(51.5mg,714µmol)inNMP(2ml)andstirredfor5minatRT.ThenExample 2(50mg,143µmol)wasaddedandthereactionheatedusingamicrowaveat180°Cfor20min.The reactionmixturewas dilutedwithwater and extractedwith EtOAc. The combined organicswere washedwithsat.NaCl,filteredthroughahydrophobicfilterandconcentrated.Thetitlecompound (6.7mg, 12%)was isolated after preparative HPLC purification alongwith the ring‐opened side‐ product(seeExample328,1.5mg,3%). ¹H‐NMR (400MHz,DMSO‐d6)δ [ppm]:1.107 (0.46),1.228 (0.71),1.394 (0.41),1.418 (0.75),1.443 (0.87),1.463(0.58),1.495(5.88),1.512(5.90),1.695(0.54),1.705(0.75),1.721(0.61),2.298(0.59), 2.318 (1.78),2.323 (1.71),2.327 (1.61),2.340 (2.65),2.361 (1.63),2.364 (1.64),2.386 (0.99),2.412 (16.00),2.518(3.94),2.523(2.71),2.539(0.75),2.665(0.48),2.669(0.66),2.673(0.48),4.715(0.89), 4.736 (1.24),4.754 (0.86),5.729 (0.83),5.746 (1.29),5.764 (0.84),6.962 (1.03),7.100 (2.00),7.205 (1.11),7.224(2.48),7.238(1.12),7.243(1.55),7.437(1.61),7.456(1.34),7.617(1.47),7.635(1.35), 8.218(2.88),8.744(4.28),8.767(1.39),8.785(1.35). Example328 6‐butoxy‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐d]pyrimidin‐4‐ amine Isolatedasaside‐product(seeExample327). 1H‐NMR (400MHz,DMSO‐d6)δ [ppm]:0.832 (0.50),0.850 (0.77),0.947 (4.12),0.965 (9.91),0.984 (4.82),1.229(2.06),1.347(0.53),1.496(1.46),1.511(6.55),1.528(6.09),1.553(1.00),1.807(0.57), 1.824 (1.56),1.842 (2.13),1.859 (1.36),1.878 (0.50),2.322 (1.03),2.326 (1.20),2.331 (0.86),2.382 (16.00),2.412(2.06),2.522(4.32),2.664(0.77),2.669(1.03),2.673(0.77),2.692(0.60),2.722(0.53), 2.856 (0.43),3.300 (0.47),3.898 (0.47),3.913 (1.06),3.936 (1.13),3.952 (0.47),4.425 (0.50),4.441 (1.16),4.464(1.10),4.481(0.47),5.814(0.83),5.831(1.26),5.850(0.83),6.999(1.03),7.136(1.96), 7.236 (1.23),7.256 (2.40),7.275 (2.16),7.458 (1.73),7.477 (1.33),7.664 (1.46),7.683 (1.36),8.201 (2.86),8.218(0.43),8.738(4.39),8.776(1.33),8.794(1.26). Table15:Examples329‐337 Following themethod described here for Example 327, the following Examples in Table 15were preparedeitherastheirmono‐ordi‐substitutedanalogs.

Example338 6‐[(azetidin‐3‐yl)oxy]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐methylpyrido[3,4‐ d]pyrimidin‐4‐aminehydrochloride x.HCl ToasolutionofExample332(13.4mg,26.6µmol) indioxane(130µl)wasaddedaHClsolution in dioxane (4M,130µmol)and stirredatRT for1h.The reactionwas concentrated togive the title compound(13mg). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(16.00),1.232(0.51),1.593(0.96),1.669(2.47),1.686 (2.49),1.709(1.27),1.727(1.17),1.907(0.50),2.332(0.76),2.423(6.04),2.431(6.05),2.518(4.08), 2.523 (2.61),2.579 (2.11),2.673 (0.75),3.384 (0.82),3.675 (0.45),4.064 (0.40),5.248 (0.50),5.281 (0.40),5.706(0.40),5.792(0.53),5.810(0.53),7.096(0.51),7.103(0.78),7.231(1.04),7.238(1.62), 7.290 (0.44),7.307 (0.96),7.326 (0.57),7.357 (0.73),7.367 (0.58),7.375 (1.10),7.512 (0.53),7.529 (0.88),7.549(0.49),7.573(0.43),7.826(0.44),8.620(0.84),8.879(0.51),9.557(3.01). Example339 tert‐butyl{(3‐trans)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐ methylpyrido[3,4‐d]pyrimidin‐6‐yl]‐4‐fluoropyrrolidin‐3‐yl}carbamate(mixtureofstereoisomers) ToasolutionofExample2(50.0mg,143µmol)inDMSO(1.3ml)wasaddedtert‐butyl[rac‐(trans)‐4‐ fluoropyrrolidin‐3‐yl]carbamate (58.3mg,285µmol)andTEA (80µl,570µmol).The reactionwas heatedat110°Cfor16h.Anotherportionoftheaminewasadded(58.3mg,285µmol)andTEA(80 µl,570µmol)wereaddedandheatedat130°Cfor16h.Thereactionwasallowedtocoolandthen purifiedbypreparativeHPLC(basicmethod)togivethetitledcompound(23mg,28%). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(2.26),1.404(16.00),1.612(4.71),1.630(4.52),2.273 (0.50),2.300(10.47),2.327(0.45),2.401(0.69),2.518(1.82),2.522(1.09),2.725(0.51),3.489(0.51), 3.501 (0.49),3.517 (0.61),3.746 (0.64),3.762 (0.74),3.776 (1.11),3.803 (0.71),5.155 (0.55),5.284 (0.55),5.763(0.55),5.780(0.82),5.796(0.53),7.102(1.09),7.148(2.78),7.237(2.25),7.273(0.75), 7.293 (1.64),7.312 (0.97),7.373 (0.96),7.454 (0.61),7.469 (0.61),7.486 (0.71),7.503 (1.08),7.521 (0.54),7.632(0.54),7.650(0.99),7.668(0.55),8.409(1.13),8.427(1.10),8.655(3.98). Example340 6‐[(trans)‐3‐amino‐4‐fluoropyrrolidin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐aminehydrochloride(mixtureofstereoisomers) Using themethod described for Example 338: Example 339 (17.1mg, 32.0µmol) gave the titled compound(16.6mg). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(16.00),1.143(0.40),1.223(1.20),1.231(0.61),1.740 (3.25),1.757(3.26),2.323(0.47),2.327(0.65),2.332(0.46),2.518(2.97),2.523(2.22),2.537(7.42), 2.665 (0.46),2.669 (0.64),2.673 (0.45),2.737 (0.40),3.841 (0.68),3.919 (0.65),3.934 (1.02),3.950 (0.76),3.965(0.69),3.982(0.41),4.160(0.55),5.510(0.59),5.634(0.61),5.983(0.68),5.992(0.63), 6.000 (0.48),7.109 (0.92),7.244 (1.87),7.338 (0.87),7.357 (1.88),7.378 (1.79),7.551 (0.73),7.568 (1.21),7.585(0.59),7.941(0.73),8.730(0.89),8.790(0.74),8.844(1.61),8.860(1.31). Example341 tert‐butyl{(cis)‐1‐[4‐({(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}amino)‐2‐methylpyrido[3,4‐ d]pyrimidin‐6‐yl]‐4‐fluoropyrrolidin‐3‐yl}carbamate(mixtureofstereoisomers) UsingthemethoddescribedforExample339:Example2(17.1mg,32.0µmol)treatedwithtert‐butyl [rac‐(cis)‐4‐fluoropyrrolidin‐3‐yl]carbamate (58.3mg,285µmol)gave the titled compound (16mg, 20%)afterpreparativeHPLCpurification(basicmethod). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.231(0.46),1.433(16.00),1.608(2.37),1.626(2.37),2.294 (4.13),2.298(4.49),2.326(0.43),2.518(1.77),2.522(1.09),2.669(0.42),3.314(0.59),3.828(0.65), 3.847 (0.68),3.870 (0.50),5.774 (0.60),7.102 (0.61),7.121 (1.22),7.238 (1.26),7.291 (0.68),7.374 (0.67),7.400(0.42),7.502(0.51),7.647(0.56),8.402(0.48),8.420(0.48),8.648(2.34). Example342 6‐[(cis)‐3‐amino‐4‐fluoropyrrolidin‐1‐yl]‐N‐{(1R)‐1‐[3‐(difluoromethyl)‐2‐fluorophenyl]ethyl}‐2‐ methylpyrido[3,4‐d]pyrimidin‐4‐aminehydrochloride(mixtureofstereoisomers) Using themethod described for Example 338: Example 341 (13.3mg, 24.9µmol) gave the titled compound(13mg). ¹H‐NMR(400MHz,DMSO‐d6)δ[ppm]:1.107(16.00),1.224(1.24),1.232(0.79),1.731(3.65),1.748 (3.62),2.323(0.77),2.327(1.07),2.332(0.77),2.518(7.03),2.523(8.51),2.665(0.79),2.669(1.11), 2.673 (0.77),3.504 (0.41),3.526 (0.77),3.542 (0.81),3.565 (0.45),3.899 (0.45),3.935 (0.69),3.965 (0.52),3.974(0.49),3.999(0.41),4.064(0.52),4.088(0.69),4.109(0.58),5.482(0.64),5.620(0.62), 5.953 (0.47),5.969 (0.67),5.985 (0.47),7.107 (1.01),7.243 (2.10),7.336 (0.69),7.355 (1.52),7.378 (1.42),7.552(0.69),7.569(1.18),7.587(0.60),7.891(0.58),8.827(2.34).

EXPERIMENTALSECTION–BIOLOGICALASSAYS Examplesweretestedinselectedbiologicalassaysoneormoretimes.Whentestedmorethanonce, dataarereportedaseitheraveragevaluesorasmedianvalues,wherein ^ theaveragevalue,alsoreferredtoasthearithmeticmeanvalue,representsthesumofthe valuesobtaineddividedbythenumberoftimestested,and ^ themedian value represents themiddle number of the group of valueswhen ranked in ascendingordescendingorder.Ifthenumberofvaluesinthedatasetisodd,themedianis themiddlevalue.Ifthenumberofvaluesinthedatasetiseven,themedianisthearithmetic meanofthetwomiddlevalues. Examples were synthesized one or more times. When synthesized more than once, data from biologicalassays representaveragevaluesormedianvaluescalculatedutilizingdatasetsobtained fromtestingofoneormoresyntheticbatch. In vitro metabolic stability in human liver microsomes. The in vitro metabolic stability of test compoundswasdeterminedbyincubatingthemat1µMinasuspensionoflivermicrosomesin100 mMphosphatebuffer,pH7.4(NaH2PO4xH2O+Na2HPO4x2H2O)andataproteinconcentration of0.5mg/mLat37°C.Themicrosomeswereactivatedbyaddingaco‐factormixcontaining8mM Glucose‐6‐phosphate,4mMMgCl2,0.5mMNADPand1 IU/mlG‐6‐P‐Dehydrogenase inphosphate buffer,pH7.4.Themetabolicassaywasstartedshortlyafterwardsbyaddingthetestcompoundto the incubationatafinalvolumeof1mL.Organicsolvent inthe incubationswas limitedto≤0.01% dimethylsulfoxide (DMSO) and ≤1% acetonitrile. During incubation, the microsomal suspensions were continuously shakenat580 rpmandaliquotswere takenat2,8,16,30,45and60min, to which equal volumes of coldmethanolwere immediately added. Sampleswere frozen at ‐20 °C overnight,subsequentlycentrifugedfor15minutesat3000rpmandthesupernatantwasanalyzed withanAgilent1200HPLC‐systemwithLC/MS‐MSdetection.Thehalf‐lifeofa testcompoundwas determined from the concentration‐time plot. From the half‐life the intrinsic clearances and the hepaticinvivobloodclearance(CL)andmaximaloralbioavailability(Fmax)werecalculatedusingthe ‘well stirred’ livermodel togetherwith the additional parameters liver blood flow, specific liver weightandmicrosomalproteincontent.Thefollowingparametervalueswereused:Liverbloodflow 1.32L/h/kg,specificliverweight21g/kg,microsomalproteincontent40mg/g. Invitrometabolicstabilityinrathepatocytes. HepatocytesfromHan/Wistarratswereisolatedviaa2‐stepperfusionmethod.Afterperfusion,the liverwascarefully removed from the rat: the livercapsulewasopenedand thehepatocyteswere gently shaken out into a Petri dish with ice‐coldWilliams’medium E (WME). The resulting cell

suspensionwasfilteredthroughsterilegazein50mlfalcontubesandcentrifugedat50×gfor3min atroomtemperature.Thecellpelletwasresuspendedin30mlWMEandcentrifugedtwicethrough aPercoll®gradientat100×g.ThehepatocyteswerewashedagainwithWMEandresuspended in mediumcontaining5%FCS.Cellviabilitywasdeterminedbytrypanblueexclusion.Forthemetabolic stabilityassaylivercellsweredistributedinWMEcontaining5%FCStoglassvialsatadensityof1.0 × 106 vital cells/ml. The test compound was added to a final concentration of 1 µM. During incubation, the hepatocyte suspensionswere continuously shaken at 580 rpm and aliquotswere takenat2,8,16,30,45and90min, towhichequalvolumesofcoldmethanolwere immediately added.Sampleswere frozenat ‐20 °Covernight,subsequentlycentrifuged for15minutesat3000 rpmandthesupernatantwasanalyzedwithanAgilent1200HPLC‐systemwithLC/MS‐MSdetection. Thehalf‐lifeofatestcompoundwasdeterminedfromtheconcentration‐timeplot.Fromthehalf‐life theintrinsicclearancesandthehepaticinvivobloodclearance(CL)andmaximaloralbioavailability (Fmax)werecalculatedusingthe ‘wellstirred’ livermodeltogetherwiththeadditionalparameters liverblood flow, specific liverweight and amountof liver cells in vivo and in vitro.The following parametervalueswereused:Liverbloodflow4.2L/h/kg,specific liverweight32g/kg, livercells in vivo1.1x108cells/gliver,livercellsinvitro1.0x106/ml. Caco‐2PermeabilityAssay. Caco‐2cells(purchasedfromDSMZBraunschweig,Germany)wereseededatadensityof4.5×10⁴ cells/wellon24‐wellinsertplates,0.4µmporesize,andgrownfor15dinDMEMsupplementedwith 10%FCS,1%GlutaMAX(100×,Gibco),100U/mLpenicillin,100µg/mLstreptomycin(Gibco)and1% non‐essential amino acids (100×). Cells were maintained at 37°C in a humidified 5% CO₂ atmosphere.Mediumwaschangedevery2–3d.Beforethepermeationassaywasrun,theculture mediumwasreplacedbyFCS‐freeHEPEScarbonatetransportbuffer(pH7.2)Fortheassessmentof monolayer integrity, the transepithelialelectrical resistancewasmeasured.Test compoundswere predissolved in DMSO and added either to the apical or basolateral compartment at a final concentrationof2µM.Beforeandafter incubationfor2hat37°C,samplesweretakenfromboth compartments and analyzedby LC‐MS/MS afterprecipitationwithMeOH.Permeability (P_app)was calculated in the apical to basolateral (A → B) and basolateral to apical (B → A) direcƟons. The apparentpermeabilitywascalculatedusingfollowingequation:P_app=(V_r/P₀)(1/S)(P₂/t),whereV_r is thevolumeofmediuminthereceiverchamber,P₀isthemeasuredpeakareaofthetestdruginthe donorchamberatt=0,Sisthesurfaceareaofthemonolayer,P₂isthemeasuredpeakareaofthe testdrug intheacceptorchamberafter incubation for2h,andt isthe incubationtime.Theefflux ratiobasolateral (B) to apical (A)was calculated asP_appB–A/P_appA–B. In addition, the compound recoverywascalculated.Asanassaycontrol,referencecompoundswereanalyzedinparallel.

6,7‐dimethoxy‐N‐[(1R)‐1‐(1‐naphthyl)ethyl]quinazolin‐4‐amine, whichwasusedtocalibratetheassay,waspreparedasfollows: To4‐chloro‐6,7‐dimethoxyquinazoline(100mg,0.445mmol,commerciallyavailable)in1.7mLDMSO wasadded(1R)‐1‐(1‐naphthyl)ethanamine(76mg,0.445mmol,commerciallyavailable)andN‐ethyl‐ N‐isopropylpropan‐2‐amine(202µl,1.16mmol).Thereactionwasstirredat100°Covernight,cooled toambienttemperatureandfiltered.Afterremovalofthesolventunderreducedpressurethecrude productwaspurifiedviaHPLCchromatographytoyieldthetitlecompound(118mg,73%).¹H‐NMR (400MHz,DMSO‐d6),d[ppm]=1.72(3H),3.90(6H),6.32‐6.41(1H),7.09(1H),7.46‐7.58(3H),7.64‐ 7.69(1H),7.78(2H),7.92‐7.97(1H),8.18‐8.24(2H),8.28(1H). Theinvitroactivityofthecompoundsofthepresentinventioncanbedemonstratedinthefollowing assays: Biochemicalassay1:hK‐RasG12CinteractionassaywithhSOS1 Thisassayquantifiestheequilibrium interactionofhumanSOS1(hSOS1)withhumanK‐Ras^G12C(hK‐ RasG12C). Detection of the interaction is achieved by measuring hom*ogenous time‐resolved fluorescenceresonanceenergytransfer(HTRF)fromantiGST‐Europium(FRETdonor)boundtoGST‐ K‐RasG12Ctoanti‐6His‐XL665boundtoHis‐taggedhSOS1(FRET‐acceptor). Theassaybuffercontaines5mMHEPESpH7.4 (Applichem),150mMNaCl (Sigma),10mMEDTA (Promega),1mMDTT(Thermofisher),0.05%BSAFractionV,pH7.0,(ICNBiomedicals),0.0025%(v/v) Igepal(Sigma)and100mMKF(FLUKA). The expression and purification ofN‐terminalGST‐tagged hK‐RasG12C andN‐terminalHis‐tagged hSOS1 isdescribedbelow.Concentrationsofproteinbatchesusedareoptimized tobewithin the linearrangeoftheHTRFsignal.ARasworkingsolutionispreparedinassaybuffercontainingtypically 10 nM GST‐hK‐RasG12C and 2 nM antiGST‐Eu(K) (Cisbio, France). A SOS1 working solution is prepared in assaybuffer containing typically20nMHis‐hSOS1 and10nM anti‐6His‐XL665 (Cisbio, France).An inhibitorcontrolsolution isprepared inassaybuffercontaining10nManti‐6His‐XL665 withouthSOS1.

Fiftynlofa100‐fold concentrated solutionof the test compound inDMSOare transferred intoa blackmicrotitertestplate(384or1536,GreinerBio‐One,Germany).Forthis,eitheraHummingbird liquidhandler(Digilab,MA,USA)oranEchoacousticsystem(Labcyte,CA,USA)isused. Allstepsoftheassayareperformedat20°C.Avolumeof2.5µloftheRasworkingsolutionisadded to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After 2 min preincubation,2.5µloftheSOS1workingsolutionareaddedtoallwellsexceptforthosewellsatthe sideofthetestplatethataresubsequentlyfilledwith2.5µloftheinhibitorcontrolsolution.After60 min incubation the fluorescence ismeasuredwith a Pherastar (BMG, Germany) using the HTRF module(excitation337nm,emission1:620nm,emission2:665nm). Theratiometricdata(emission2dividedbyemission1)arenormalizedusingthecontrols(DMSO= 0%inhibition,inhibitioncontrolwellswithinhibitorcontrolsolution=100%inhibition).Compounds aretested induplicatesatupto11concentrations (forexample20µM,5,7µM,1,6µM,0,47µM, 0,13µM,38nM,11nM,3,1nM,0,89nM,0,25nMand0,073nM).IC50valuesarecalculatedby4‐ Parameterfittingusingacommercialsoftwarepackage(GenedataScreener,Switzerland). Biochemicalassay2:hK‐RasG12CactivationassaybyhSOS1athighGTPconcentration ThisassayquantifieshumanSOS1‐mediatednucleotideexchangeofhumanK‐Ras^G12C(hK‐RasG12C) preloadedwith a fluorescent GTP‐analog and in presence of an excess of free GTP. Loaded hK‐ RasG12CgeneratesahighHTRF‐signalbyenergytransferfromantiGST‐Terbium(FRETdonor)bound to hK‐Ras to the loaded fluorescent GDP analog (FRET‐acceptor). hSOS1 activity exchanges the fluorescentGDPfornon‐fluorescentGTPandthereforeleadstoareductionoftheHTRFsignal. The fluorescent GDP‐analog EDA‐GDP‐Dy647P1 (2’/3’‐O‐(2‐Aminoethyl‐carbamoyl)‐guanosine‐5’‐ diphosphate labelledwithDy647P1 (DyomicsGmbH,Germany)) issynthesizedby JenaBiosciences GmbH(Germany)andsuppliedasa1mMaqueoussolution. The expression and purification ofN‐terminalGST‐tagged human K‐RasG12C andN‐terminalHis‐ taggedhumanSOS1isdescribedbelow.Concentrationsofproteinbatchesusedareoptimizedtobe withinthelinearrangeoftheHTRFsignal. PreparationofGST‐taggedhK‐RasG12C loadedwithfluorescentnucleotide isperformedasfollows: incubationof11.5µMhK‐Ras^G12Cwith5‐foldexcessGDP‐Dy647nucleotide (54µM) in500µlNLS‐ buffer (RASactivationKit JenaBioscience,Kat.#PR‐950) for10minat37°C.Additionof20µl1M MgCl₂ (Sigma) to final 40mM and store on ice. Purification into buffer (10mM HEPES pH 7.4 (Applichem),150mMNaCl(Sigma),5mMMgCl₂(Sigma))byuseofaPD‐Minitrapdesaltingcolumn (GEHealthcare).Concentrationof1mlpurifiedhK‐Ras‐GDP‐Dy647isapprox.4‐5µM.

Theassaybuffercontaines10mMHEPESpH7.4 (Applichem),150mMNaCl (Sigma),5mMMgCl₂ (Sigma),1mMDTT(Thermofisher),0.05%BSAFractionV,pH7.0,(ICNBiomedicals),0.0025%(v/v) Igepal(Sigma). A Ras working solution is prepared in assay buffer containing typically 80 nM loaded GST‐hK‐ RasG12C‐EDA‐GDP‐Dy647P1 and 2 nM antiGST‐Tb (Cisbio, France). A hSOS1 working solution is prepared in assay buffer containing typically 8nM His‐hSOS1 and 100 µM GTP (Jena Bioscience, Germany). An inhibitor control solution is prepared in assay buffer containing the same concentrationofhSOS1withoutGTP. Alternatively,theinhibitorcontrolsolutionispreparedbysupplementingthehSOS1workingsolution with 20 µM of 6,7‐dimethoxy‐N‐[(1R)‐1‐(1‐naphthyl)ethyl]quinazolin‐4‐amine which is used to calibratetheassay. Fiftynlofa100‐fold concentrated solutionof the test compound inDMSOare transferred intoa blackmicrotitertestplate(384or1536,GreinerBio‐One,Germany).Forthis,eitheraHummingbird liquidhandler(Digilab,MA,USA)oranEchoacousticsystem(Labcyte,CA,USA)isused. Allstepsoftheassayareperformedat20°C.Avolumeof2.5µloftheRasworkingsolutionisadded to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After 2 min preincubation,2.5µlofthehSOS1workingsolutionareaddedtoallwellsexceptforthosewellsat the sideof the testplate thatare subsequently filledwith2.5µlof the inhibitor control solution. After20min incubation the fluorescence ismeasuredwithaPherastar (BMG,Germany)using the HTRFmodule(excitation337nm,emission1:620nm,emission2:665nm). Theratiometricdata(emission2dividedbyemission1)arenormalizedusingthecontrols(DMSO= 0%inhibition,inhibitioncontrolwellswithinhibitorcontrolsolution=100%inhibition).Compounds aretested induplicatesatupto11concentrations (forexample20µM,5,7µM,1,6µM,0,47µM, 0,13µM,38nM,11nM,3,1nM,0,89nM,0,25nMand0,073nM).IC50valuesarecalculatedby4‐ Parameterfittingusingacommercialsoftwarepackage(GenedataScreener,Switzerland). Biochemicalassay3:hK‐RasG12CactivationassaybyhSOS1 K‐Ras isasmallGTPase thatcanbindGDPandGTP.Theguaninenucleotideexchange factorSOS1 catalyzestheactivationofK‐RasbypromotingtheexchangeofGDPtoGTP.SOS1bindstoK‐Ras‐GDP therebyopening theGDP‐bindingpocket to facilitateGDP release.Rebindingofexcessnucleotide leads to dissociation of the K‐Ras‐SOS1 intermediate complex leaving K‐Ras loaded with the nucleotide. ThisassayquantifieshumanSOS1‐(hSOS1‐)mediatedloadingofhumanK‐Ras^G12C‐GDP(hK‐RasG12C‐ GDP) with a fluorescent GTP‐analog. Detection of successful loading is achieved by measuring

hom*ogenous time‐resolved fluorescence resonance energy transfer (HTRF) from antiGST‐Terbium (FRETdonor)bound toGST‐hK‐RasG12C (seebelow) to the loaded fluorescentGTP analog (FRET‐ acceptor). The fluorescent GTP‐analog EDA‐GTP‐Dy647P1 (2’/3’‐O‐(2‐Aminoethyl‐carbamoyl)‐guanosine‐5’‐ triphosphate labelledwithDy647P1 (DyomicsGmbH,Germany)) issynthesizedby JenaBiosciences GmbH(Germany)andsuppliedasa1mMaqueoussolution. Theassaybuffercontaines10mMHEPESpH7.4 (Applichem),150mMNaCl (Sigma),5mMMgCl₂ (Sigma),1mMDTT(Thermofisher),0.05%BSAFractionV,pH7.0,(ICNBiomedicals),0.0025%(v/v) Igepal(Sigma). The expression and purification ofN‐terminalGST‐tagged human K‐RasG12C andN‐terminalHis‐ taggedhSOS1isdescribedbelow.Concentrationsofproteinbatchesusedareoptimizedtobewithin the linearrangeof theHTRFsignal.AhRasworkingsolution isprepared inassaybuffercontaining typically100nMGST‐hK‐RasG12Cand2nMantiGST‐Tb(Cisbio,France).AhSOS1workingsolutionis prepared in assay buffer containing typically 20nM hSOS1 and 200 nM EDA‐GTP‐Dy647P1. An inhibitorcontrolsolution isprepared inassaybuffercontaining200nMEDA‐GTP‐Dy647P1without hSOS1. Fiftynlofa100‐fold concentrated solutionof the test compound inDMSOare transferred intoa blackmicrotitertestplate(384or1536,GreinerBio‐One,Germany).Forthis,eitheraHummingbird liquidhandler(Digilab,MA,USA)oranEchoacousticsystem(Labcyte,CA,USA)isused. Allstepsoftheassayareperformedat20°C.Avolumeof2.5µlofthehRasworkingsolutionisadded to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After 10 min preincubation,2.5µlofthehSOS1workingsolutionareaddedtoallwellsexceptforthosewellsat the sideof the testplate thatare subsequently filledwith2.5µlof the inhibitor control solution. After30min incubation the fluorescence ismeasuredwithaPherastar (BMG,Germany)using the HTRFmodule(excitation337nm,emission1:620nm,emission2:665nm). Theratiometricdata(emission2dividedbyemission1)arenormalizedusingthecontrols(DMSO= 0%inhibition,inhibitioncontrolwellswithinhibitorcontrolsolution=100%inhibition).Compounds aretested induplicatesatupto11concentrations (forexample20µM,5,7µM,1,6µM,0,47µM, 0,13µM,38nM,11nM,3,1nM,0,89nM,0,25nMand0,073nM).IC50valuesarecalculatedby4‐ Parameterfittingusingacommercialsoftwarepackage(GenedataScreener,Switzerland). Biochemicalassay4:hK‐RasG12CactivationassaybyhSOS2 This assay quantifies hSOS2‐mediated loading of hK‐Ras^G12C‐GDP (hK‐RasG12C‐GDP) with a fluorescentGTP‐analog.Detectionofsuccessfulloadingisachievedbymeasuringhom*ogenoustime‐

resolvedfluorescenceresonanceenergytransfer(HTRF)fromantiGST‐Terbium(FRETdonor)bound toGST‐hK‐RasG12CtotheloadedfluorescentGTPanalog(FRET‐acceptor). The fluorescent GTP‐analog EDA‐GTP‐Dy647P1 (2’/3’‐O‐(2‐Aminoethyl‐carbamoyl)‐guanosine‐5’‐ triphosphate labelledwithDy647P1 (DyomicsGmbH,Germany)) issynthesizedby JenaBiosciences GmbH(Germany)andsuppliedasa1mMaqueoussolution. Theassaybuffercontaines10mMHEPESpH7.4 (Applichem),150mMNaCl (Sigma),5mMMgCl₂ (Sigma),1mMDTT(Thermofisher),0.05%BSAFractionV,pH7.0,(ICNBiomedicals),0.0025%(v/v) Igepal(Sigma). The expression and purification ofN‐terminalGST‐tagged hK‐RasG12C andN‐terminalHis‐tagged hSOS2 isdescribedbelow.Concentrationsofproteinbatchesusedareoptimized tobewithin the linear range of the HTRF signal. A hRasworking solution is prepared in assay buffer containing typically100nMGST‐hK‐RasG12Cand2nMantiGST‐Tb(Cisbio,France).AhSOS2workingsolutionis prepared in assay buffer containing typically 20nM hSOS2 and 200 nM EDA‐GTP‐Dy647P1. An inhibitorcontrolsolution isprepared inassaybuffercontaining200nMEDA‐GTP‐Dy647P1without hSOS2. Fiftynlofa100‐fold concentrated solutionof the test compound inDMSOare transferred intoa blackmicrotitertestplate(384or1536,GreinerBio‐One,Germany).Forthis,eitheraHummingbird liquidhandler(Digilab,MA,USA)oranEchoacousticsystem(Labcyte,CA,USA)isused. Allstepsoftheassayareperformedat20°C.Avolumeof2.5µlofthehRasworkingsolutionisadded to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After 10 min preincubation,2.5µlofthehSOS2workingsolutionareaddedtoallwellsexceptforthosewellsat the sideof the testplate thatare subsequently filledwith2.5µlof the inhibitor control solution. After30min incubation the fluorescence ismeasuredwithaPherastar (BMG,Germany)using the HTRFmodule(excitation337nm,emission1:620nm,emission2:665nm). Theratiometricdata(emission2dividedbyemission1)arenormalizedusingthecontrols(DMSO= 0%inhibition,inhibitioncontrolwellswithinhibitorcontrolsolution=100%inhibition).Compounds aretested induplicatesatupto11concentrations (forexample20µM,5,7µM,1,6µM,0,47µM, 0,13µM,38nM,11nM,3,1nM,0,89nM,0,25nMand0,073nM).IC50valuesarecalculatedby4‐ Parameterfittingusingacommercialsoftwarepackage(GenedataScreener,Switzerland). EGFRkinaseassay EGFRinhibitoryactivityofcompoundsofthepresentinventionisquantifiedemployingtheTR‐FRET basedEGFRassayasdescribedinthefollowingparagraphs.

EpidermalGrowthFactorReceptor(EGFR)affinitypurifiedfromhumancarcinomaA431cells(Sigma‐ Aldrich, # E3641) is used as kinase.As substrate for the kinase reaction the biotinylated peptide biotin‐Ahx‐AEEEEYFELVAKKK(C‐terminusinamidform)isusedwhichcanbepurchasede.g.formthe companyBiosyntanGmbH(Berlin‐Buch,Germany). For theassay50nLofa100foldconcentratedsolutionof the testcompound inDMSO ispipetted intoablacklowvolume384wellmicrotiterplate(GreinerBio‐One,Frickenhausen,Germany),2µLof asolutionofEGFRinaqueousassaybuffer[50mMHepes/HClpH7.0,1mMMgCl₂,5mMMnCl₂,0.5 mM activated sodium ortho‐vanadate, 0.005% (v/v) Tween‐20] are added and the mixture is incubatedfor15minat22°Ctoallowpre‐bindingofthetestcompoundstotheenzymebeforethe startofthekinasereaction.Thenthekinasereactionisstartedbytheadditionof3µLofasolutionof adenosine‐tri‐phosphate (ATP, 16.7µM => final conc. in the 5 µL assay volume is 10 µM) and substrate(1.67µM=>finalconc.inthe5µLassayvolumeis1µM)inassaybufferandtheresulting mixture is incubated fora reaction timeof20minat22°C.TheconcentrationofEGFR isadjusted dependingoftheactivityoftheenzymelotandischosenappropriatetohavetheassayinthelinear range, typicalconcentrationareabout3U/ml.Thereaction isstoppedby theadditionof5µlofa solutionofHTRFdetection reagents (0.1µM streptavidine‐XL665 [CisBiointernational] and1nM PT66‐Tb‐Cryptate, an terbium‐cryptate labelled anti‐phospho‐tyrosine antibody from Cis Biointernational [instead of the PT66‐Tb‐cryptate PT66‐Eu‐Chelate from Perkin Elmer can also be used]) in an aqueous EDTA‐solution (80mM EDTA,0.2% (w/v)bovine serum albumin in50mM HEPESpH7.5). Theresultingmixtureisincubated1hat22°Ctoallowthebindingofthebiotinylatedphosphorylated peptide to the streptavidine‐XL665 and the PT66‐Eu‐Chelate. Subsequently the amount of phosphorylatedsubstrate isevaluatedbymeasurementof theresonanceenergytransfer from the PT66‐Tb‐Cryptatetothestreptavidine‐XL665.Therefore,thefluorescenceemissionsat620nmand 665 nm after excitation at 337 nm are measured in a HTRF reader, e.g. a Pherastar (BMG Labtechnologies,Offenburg,Germany)oraViewlux(Perkin‐Elmer).Theratiooftheemissionsat665 nmandat622nmistakenasthemeasurefortheamountofphosphorylatedsubstrate.Thedataare normalised(enzymereactionwithout inhibitor=0% inhibition,allotherassaycomponentsbutno enzyme=100%inhibition).Usuallythetestcompoundsaretestedonthesamemicrotiterplatein11 differentconcentrationsintherangeof20µMto0.072nM(e.g.20µM,5.7µM,1.6µM,0.47µM, 0.13µM,38nM,11nM,3.1nM,0.89nM,0.25nMand0.072nM,thedilutionseriesareprepared separatelybefore theassayon the levelof the100fold concentrated solutions inDMSOby serial dilutions,theexactconcentrationsmayvarydependingonthepipettorused)induplicatevaluesfor eachconcentrationandIC50valuesarecalculatedbya4parameterfit.

Cellularassays 3D‐SoftagarMiaPaca‐2(ATCCCRL‐1420)andNCI‐H1792(ATCCCRL‐5895) Day1:Softagar (SelectAgar, Invitrogen,3% inddH2Oautoclaved) isboiledand temperedat48°C. Medium(MiaPaca‐2:DMEM/Ham'sF12;[Biochrom;#FG4815,withstableGlutamine]10%FCSand 2.5%HorseSerum,H1792:RPMI1640;[Biochrom;#FG1215,withstableGlutamineand10%FCS])is tempered to37°C;Agar (3%) isdiluted1:5 inmedium (=0.6%) and50µl/wellplated into96well plates(Corning,#3904),waitatroomtemperatureuntiltheagarissolid.3%agarisdilutedto0.25% inmedium (1:12 dilution) and tempered at 42°C. Cells are trypsinized, counted and tempered at 37°C;cells(MiaPaCa‐2:125‐150,NCI‐H1792:1000)areresuspendedin100µl0.25%Agarandplated. Waitatroomtemperatureuntiltheagarissolid.Overlaywellswith50µlmedium.Platesisterwells inseparateplatefortimezerodetermination.Allplatesareincubatedovernight37°Cand5%CO2. Day2:Measurementof timezerovalues:Add40µlCellTiter96AqueousSolution (Promega)per well,(lightsensitive)andincubateinthedarkat37°Cand5%CO2.Absorptionismeasuredat490nm andreferencewavelength660nm.DMSO‐predilutedtestcompoundsareaddedwithHPDispenser toafinalDMSOconcentrationof0.3%. Day 10:Measurement of test compound and control treated wells with Cell Titer 96 AQueous accordingtotimezero.TheIC50valuesweredeterminedusingthefourparameterfit. ActiveRASinCalu‐1cells(CLS300141) 40.000 Calu‐1 cells are seeded in 96well plate (NUNC161093) for 48h at 37°C/5%CO2 (10%FBS (S0615), DMEM/Ham's F‐12 (Biochrom; # FG 4815), 2mM L‐Glutamine). After that, medium is changedtoFBS‐freemediumandthecellswereincubatedforfurther24hat37°C/5%CO2.Cellsare treatedwithvaryingconcentrationsofDMSO‐predilutedtestcompounds(final0.1%)for30minat 37°C/5%CO2. Supernatant with test compounds is discarded and, after that, treated cells are stimulatedwith100ng/ml EGF (Sigma#E9644,diluted in serum freemedium) for3minutes.Cells weretreatedwith lysisbufferandallnextstepswereperformedon iceaccordingtothesupplier's manualofG‐LISAKit(CytoskeletonBK131,RasActivationAssay).Finally,thecontentofactiveRasis measuredbydetectingtheabsorbanceat490nm(TecanSunrise).ThevalueofEGF‐stimulatedcells issetas100%,whereasthevalueofuntreatedcells issetas0%.TheIC50valuesweredetermined usingthefourparameterfit. ActiveRasinHelacells(ATCCCCL‐2) 30.000Helacellsareseededin96wellplatefor96hat37°C(10%FBS,DMEM/Ham'sF‐12,2mML‐ Glutamine).Afterthat,mediumischangedintoFBS‐freemediumfor24h.Cellsaretreatedwith varyingconcentrationsoftestcompoundsfor30min.Afterthat,treatedcellsarestimulatedwith

100ng/mlEGFfor2minutes.Cellsaretreatedwithlysisbufferandallnextstepsareperformedon iceaccordingtothesupplier'smanualofG‐LISAKit(CytoskeletonBK131,RasActivationAssay). Finally,thecontentofactiveRasismeasuredbydetectingtheabsorbanceat490nm.Thevalueof EGF‐stimulatedcellsissetas100%,whereasthevalueofuntreatedcellsissetas0%.Theresults givenas%reflectingtheinhibitionofformationofactiveRascomparedtocontrol. TheIC50valuesaredeterminedusingthefourparameterfit. pERKHTRFinMOLM‐13(DMSZACC554) 10000MOLM‐13cellsareseededinHTRF384welllowvolumeplate(Greinerbio‐one#784080)in medium(RPMI1640+10%FCS).After24hours,cellsaretreatedwithvaryingconcentrationsoftest compoundsfor1h.Nextstepsareperformedtothesupplier'smanualAdvancedphospho‐ERK1/2 (#64AERPEH)Cisbioone‐plateassayprotocol.ThecontentofpERKismeasuredwithPHERAstarHTRF protocol,calculatedRatio*1000. ThecalculatedratioofDMSO‐treatedcellsissetas100%andthecalculatedratioofnegativecontrol issetas0%(maximumpossibleeffect).TheresultsgivenasIC50reflectingtheinhibitionof formationofpERKcomparedtoDMSOcontrolandnegativecontrolandnormalizedaccordingtocell number. TheIC50valuesaredeterminedbymeansofa4parameterfit. pERKHTRFinCalu‐1(CLS300141) 5000Calu‐1cellsareseededinHTRF384welllowvolumeplate(Greinerbio‐one#784080)inmedium (McCoy's5A+10%FCS).After24hours,cellsaretreatedwithvaryingconcentrationsoftest compoundsfor24h.Nextstepsareperformedtothesupplier'smanualAdvancedphospho‐ERK1/2 (#64AERPEH)Cisbioone‐plateassayprotocol.ThecontentofpERKismeasuredwithPHERAstarHTRF protocol,calculatedRatio*1000. ThecalculatedratioofDMSO‐treatedcellsissetas100%andthecalculatedratioofnegativecontrol issetas0%(maximumpossibleeffect).TheresultsgivenasIC50reflectingtheinhibitionof formationofpERKcomparedtoDMSOcontrolandnegativecontrolandnormalizedaccordingtocell number. TheIC50valuesaredeterminedbymeansofa4parameterfit. pERKHTRFinK‐562(ATCCCCL‐243) 10000K‐562cellsareseededinHTRF384welllowvolumeplate(Greinerbio‐one#784075)in medium(RPMI1640+10%FCS)andtreatedwithvaryingconcentrationsoftestcompoundsfor1h. Nextstepsareperformedtothesupplier'smanualAdvancedphospho‐ERK1/2(#64AERPEH)Cisbio

one‐plateassayprotocol.ThecontentofpERKismeasuredwithPHERAstarHTRFprotocol,calculated Ratio*1000. ThecalculatedratioofDMSO‐treatedcellsissetas100%andthecalculatedratioofnegativecontrol issetas0%(maximumpossibleeffect).TheresultsgivenasIC50reflectingtheinhibitionof formationofpERKcomparedtoDMSOcontrolandnegativecontrolandnormalizedaccordingtocell number. TheIC50valuesaredeterminedbymeansofa4parameterfit. pERKassayinNCI‐H358cells(ATCCCRL‐5807)forcombinationexperiments 5000NCI‐H358 cells are seeded inHTRF 384well low volume plate (Greiner bio‐one #784080) in medium(RPMI+10%FCS).After24h,cellsaretreatedfor1hwithcomponentAandwithcomponent B for single compound treatments (final concentration ranges covering theexpected IC50values), and in nine different fixed‐ratio combinations of compound A (D1) and compound B (D2) (0.9xD1+0.1xD2, 0.8xD1+0.2xD2, 0.7xD1+0.3xD2, 0.6xD1+0.4xD2, 0.5xD1+0.5xD2, 0.4xD1+0.6xD2, 0.3xD1+0.7xD2,0.2xD1+0.8xD2,0.1xD1+0.9xD2)usingaTecanHPdigitaldispenser. Nextstepsareperformed to thesupplier'smanualAdvancedphospho‐ERK1/2 (#64AERPEH)Cisbio one‐plateassayprotocol.ThecontentofpERKismeasuredwithPHERAstarHTRFprotocol,calculated Ratio*1000. IC50 values (inhibitory concentration at 50% ofmaximal effect) are determined bymeans of a 4 parameterfitonmeasurementdatawhicharenormalizedtovehicle(DMSO)treatedcells(=100%) andmeasurementreadingstakenimmediatelybeforecompoundexposure(=0%).IC50isobolograms are plottedwith the actual concentrations of the two compounds on the x‐ and y‐axis, and the combinationindex(CI)iscalculatedaccordingtothemedian‐effectmodelofChou‐Talalay(ChouT.C. 2006Pharmacol.Rev.).ACIof<0.8isdefinedasmorethanadditive(synergistic)interaction,andaCI of>1.2isdefinedasantagonisticinteraction. P‐EGFRassay(In‐CellWestern)inHelacells(ATCCCCL‐2) After stimulationwith EGF, the EGF receptor autophosphorylates at Y1173. In‐cellWestern assay simultaneouslydetecttwotargetsat700and800nmusingtwospectrallydistinctnear‐infrareddyes. Withaspecificantibody,phosphorylatedEGFRcanbequantifiedandthesamplescanbenormalized withtotalEGFRantibodyparallel. 25000Helacellsareseededin96wellplate(NUNC161093)for24hat37°C/5%CO2(10%FBS(S0615), DMEM/Ham'sF‐12(Biochrom;#FG4815),2mML‐Glutamine).Afterthat,mediumischangedtoFBS‐ freemediumandthecellsareincubatedforfurther24hat37°C/5%CO2.

CellsaretreatedwithvaryingconcentrationsofDMSO‐predilutedtestcompounds(final0.1%)for30 minutesandfinallywith100ng/mlEGF(Sigma#E9644,dilutedinserumfreemedium)for2minutes. CellsaretreatedaccordingthemanualofEGFRNearInfraredIn‐CellELISAKit(Pierce#62210).Ifnot specified,allbuffersandantibodiesarepartofthiskit. Cellsare fixedwith4% formaldehyde,washed twicewith100µlperwellwithTRIS‐buffered saline withSurfact‐Amps20,permeabilizedwith100µlTRIS‐bufferedsalinewithSurfact‐AmpsX‐100,wash againwith100µlTRIS‐bufferedsaline,andfinally200µlblockingbufferareaddedfor60minutesat roomtemperature.Fixedandwashedcellsareincubatedwithprimaryantibodymix(P‐EGFR;EGFR) overnightat2‐8°C.Afterwashingwith100µlTRIS‐bufferedsalinewithSurfact‐Amps20,secondary IRDye‐labeledantibodymix(DyLight800GoatAnti‐Rabbit IgG,PierceSA5‐35571;DyLight680Goat Anti‐Mouse IgG,Pierce35518) isadded for1hat room temperatureandwashedagain.Platesare scannedwithLiCorOdysseyInfraredImagerat800nmforP‐EGFRandat700nmfortotalEGFR.The quotientof800nmand700nmforEGFonlytreatedcells issetas100%andthequotientof800nm and700nmofuntreatedcellsissetas0%.TheIC50valuesaredeterminedusingthefourparameter fit. pERKassayinNCI‐H358cells(ATCCCRL‐5807)forcombinationexperiments NCI‐H358humannon‐small cell lung tumor cells (ATCCCRL‐5807)arepropagated inahumidified 37°CincubatorinRPMI1640growthmedium(ThermoFisherGibco,#61870‐010)supplementedwith 10%fetalcalfserum(Biochrom,#S0615).ForanalysisofcombinationeffectsbetweencompoundA andcompoundB,cellsareplatedin384‐wellplates(Greinerbio‐one,#784080)atadensityof20,000 cellsperwellin8microLofgrowthmediumsupplementedwith10%fetalcalfserum.After24h,cells are treated with component A and with component B for single compound treatments (final concentration ranges covering the expected IC50 values), and in nine different fixed‐ratio combinations of compound A (D1) and compound B (D2) (0.9xD1+0.1xD2, 0.8xD1+0.2xD2, 0.7xD1+0.3xD2, 0.6xD1+0.4xD2, 0.5xD1+0.5xD2, 0.4xD1+0.6xD2, 0.3xD1+0.7xD2, 0.2xD1+0.8xD2, 0.1xD1+0.9xD2)usingaTecanHPdigitaldispenser.Thecellsareincubatedfor60minutesat37°C.4 microL/wellofa freshlypreparedsolutionof0.6nanog/microLofepidermalgrowth factor (Sigma, #E9644)inRPMI1640mediumareaddedusingaThermoFisherMultidropdevice(finalconcentration 200 nanog/milliL). The cells are incubated for another 3 minutes immediately followed by the detectionoftotalERK1/2andphosphorylatedERK1/2atpositionsThr202/Tyr204usingcommercial HTRFdetectionkits(Cisbio:totalERK1/2,64NRKPEG;phospho‐ERK1/2,64AERPEH)andaPHERAstar microplate readerdevice (BMG Labtech).Cell lysis anddetection areperformed according to the manufacturer’srecommendations.TheratioofphosphorylatedERK1/2 to totalERK1/2proteinare calculatedand IC50values (inhibitory concentrationat50%ofmaximaleffect)aredeterminedby meansofa4parameterfitonmeasurementdatawhicharenormalizedtovehicle(DMSO)treated cells(=100%). IC50 isobologramsareplottedwiththeactualconcentrationsofthetwocompounds on the x‐ and y‐axis, and the combination index (CI) is calculated according to themedian‐effect modelofChou‐Talalay(ChouT.C.2006Pharmacol.Rev.).ACIof<0.8isdefinedasmorethanadditive (synergistic)interaction,andaCIof>1.2isdefinedasantagonisticinteraction. Table 1: IC₅₀ values of some examples in the K‐RasG12C – SOS interaction assay, in K‐RasG12C activationbySOS,inK‐RasactivationbySOShighGTPandinK‐Ras‐wtactivationbySOS

Asexemplified in table1, thecompoundsof thepresent invention inhibit thebindingofhSOS1 to hKRAS,whichwasmeasuredinthebiochemicalhK‐RasG12C‐hSOS1interactionassay(assay1).The ability to inhibit the hKRAS‐hSOS1 interaction results in the inhibitionofhKRAS activationby the compounds,asmeasured inbiochemicalassay3,whichquantifies thehSOS1‐mediatednucleotide exchangefromhK‐RasG12C‐GDPtohK‐RasG12CloadedwithafluorescentGTP‐analog.Furthermore, thecompoundsofthepresentinventionshowtheabilitytoinhibitthenucleotideexchangereaction catalyzedbyhSOS1 inthepresenceofahighconcentrationof50µMGTP,asmeasured inassay2. ThisabilityincreasesthechancethatthecompoundswillbeabletoinhibithSOS1mediatedhKRAS‐ activation inside cells,wherehighGTP concentrations arepresent. The chemical structureof the compoundsofthepresentinventionissimilartoknowninhibitorsofEGFR‐kinase.Asshownintable 1,mostcompoundsare inactiveagainstEGFR‐kinaseup to thehighestconcentrationmeasured in theassay(>20µM). Theassaydataofthe largenumberofcompounds intable1givesevidencethatcompoundswhich haveapharmacologicalprofileastestedaccordingtoassays1to3andasdescribedinthepreceding paragraphwillbe generallyuseful to inhibithSOS1mediatedhKRAS‐activation inside cells,where highGTPconcentrationsarepresentandactivityagainstEGFR‐kinaseup tohighestconcentrations (>20µM)willnotbemeasuredintheassay. Thereforeaneven furtheraspectof thepresent invention refers to theuseofacompoundwhich inhibitsthebindingofhSOS1tohumanH‐orN‐orK‐RASincludingtheirclinicallyknownmutations and which inhibits the nucleotide exchange reaction catalyzed by hSOS1 in the presence of a concentration of 20 µMor lower, but which is substantially inactive against EGFR‐kinase at concentrations of 20 µM or lower for the preparation of a medicament for the treatment or prophylaxisofahyperproliferativedisorder. Particularly this aspect refers to the use of a compound which inhibits the binding of hSOS1 specificallytohK‐RasG12Cproteinandwhichinhibitsthenucleotideexchangereactioncatalyzedby hSOS1 in the presence of a concentration of 20 µMor lower, butwhich is substantially inactive againstEGFR‐kinaseatconcentrationsof20µMorlowerforthepreparationofamedicamentforthe treatmentorprophylaxisofahyperproliferativedisorder. ExpressionofhK‐RasG12C,hSOS1,hSOS1_12andhSOS2inE.coli: The applied DNA expression constructs encoding the following protein sequences and its corresponding DNA sequences were optimized for expression in E. coli and synthesized by the GeneArtTechnologyatLifeTechnologies: HumanK‐Ras(P01116‐2): hK‐RasG12C(aminoacid1‐169) HumanSOS1(Q07889): hSOS1(aminoacid564‐1049) hSOS1_12: (amino acid 564‐1049which is fused at itsN‐terminuswith the amino acid sequence GAMA HumanSOS2(Q07890): hSOS2(aminoacid564‐1043) These expressions construct additionally encoded att‐site sequences at the 5´and 3´ ends for subcloningintovariousdestinationvectorsusingtheGatewayTechnologyaswellasaTEV(Tobacco EtchVirus)proteasesiteforproteolyticcleavageoftagsequences.Theapplieddestinationvectors were: pD‐ECO1 (an in‐house derivate of the pET vector series from Novagen with ampicillin resistancegene)whichprovidesanN‐terminalfusionofa*gST‐tagtotheintegratedgeneofinterest. pD‐ECO5(alsoanin‐housederivativeofthepETvectorserieswithampicillinresistancegene)which providesaN‐terminalfusionofaHis10‐tagtotheintegratedgene.Togeneratethefinalexpression vectorstheexpressionconstructofhK‐Ras_G12CwasclonedintopD‐ECO1.hSOS1,hSOS1_12aswell ashSOS2were cloned intopD‐ECO5. The resultingexpression vectorswere termedpD‐ECO1_hK‐ RasG12C,pD‐ECO5_hSOS1,pD‐ECO5_hSOS1_12,pD‐ECO5_hSOS2 Sequences: GST‐hK‐RasG12C(G12CmutationaccordingtonumberinginP01116‐2)

E.coliExpression: The expression vectors were transformed into E. coli strain BL21 (DE3). Cultivation of the transformedstrainsforexpressionwasdonein10Land1Lfermenter. TheculturesweregrowninTerrificBrothmedia(MPBiomedicals,Kat.#113045032)with200ug/mL ampicillinatatemperatureof37°Ctoadensityof0.6(OD600),shiftedtoatemperatureof27°C(for hK‐Rasexpressionvectors)or17°C (forhSOSexpressionvectors), inducedforexpressionwith100 mMIPTGandfurthercultivatedfor24hours. Purification After cultivation the transformedE. coliwereharvestedby centrifugationand the resultingpellet wassuspendedinalysisbuffer(seebelow)andlysedbypassingthree‐timesthroughahighpressure device(Microfluidics).The lysatewascentrifuged(49000g,45min,4°C)andthesupernatantused forfurtherpurification. AnÄktachromatographysystemwasusedforallfurtherchromatographysteps. PurificationofGST‐hK‐RasG12Cforbiochemicalassays E. coli culture (transformedwith pD‐ECO1_hK‐RasG12C) from a 10L fermenterwas lysed in lysis buffer (50mM Tris HCl 7.5, 500mM NaCl,1mM DTT, 0,5% CHAPS, Complete Protease Inhibitor co*cktail‐(Roche)).Asa first chromatography step the centrifuged lysatewas incubatedwith50mL Glutathione Agarose 4B (Macherey‐Nagel; 745500.100) in a spinner flask (16 h, 10°C). The GlutathioneAgarose4Bloadedwithproteinwastransferredtoachromatographycolumnconnected toanÄktachromatographysystem.Thecolumnwaswashedwithwashbuffer(50mMTrisHCl7.5, 500mMNaCl, 1mM DTT) and the bound protein elutedwith elution buffer (50mM Tris HCl 7.5, 500mMNaCl,1mMDTT,15mMGlutathione).Themainfractionsoftheelutionpeak(monitoredby OD280)werepooled. Forfurtherpurificationbysize‐exclusionchromatographytheaboveeluatevolumewasappliedtoa columnSuperdex200HRprepgrade(GEHealthcare)andtheresultingpeakfractionsoftheeluted fusionproteinwerecollected.ThefinalyieldofhK‐RasG12Cwasabout50mgpurifiedfusionprotein

per L culture and the finalproduct concentrationwas about1mg/mL.Nativemass spectrometry analysesofthefinalpurifiedK‐RasG12Cdemonstrateditshom*ogeneousloadwithGDP. PurificationofHis10‐hSOS1andHis10‐hSOS2forbiochemicalassays E. coli transformed with pD‐ECO5_hSOS1 or pD‐ECO5_hSOS2 were cultured and induced in a fermenter,harvested and lysed in lysisbuffer (25mMTrisHCl7.5,500mMNaCl,20mM Imidazol, Complete EDTA‐free (Roche)). For immobilized metal ion affinity chromatography (IMAC) the centrifuged lysate (50 000 xg, 45min, 4°C) was incubated with 30mL Ni‐NTA (Macherey‐Nagel; #745400.100) in a spinner flask (16 h, 4°C) and subsequently transferred to a chromatography column connected to an Äkta chromatography system. The columnwas rinsedwithwash buffer (25mM Tris HCl 7.5, 500mM NaCl, 20mM Imidazol) and the bound protein elutedwith a linear gradient (0‐100%)ofelutionbuffer (25mMTrisHCl7.5,500mMNaCl,300mM Imidazol).Themain fractions of the elution peak (monitored by OD280) containing hom*ogenous His10‐hSOS were pooled.ThefinalyieldofHis10‐hSOS1wasabout110mgpurifiedproteinperLcultureandthefinal productconcentrationwasabout2mg/mL.ForHis10‐hSOS2thefinalyieldwas190mgperLculture andtheproductconcentration6mg/mL. PurificationofhSOS1_12 Toproducetag‐freehSOS1_12thesameprocessconsistingof4chromatographystepsapplyingan ÄktasystemwasusedasdecribedherebelowforhSOS1. His10‐hSOS1_12wasexpressedinE.colitransformedwithpD‐ECO5_hSOS1_12asdescribedabove. For IMAC the centrifuged lysatewas directly applied to a 30mL (or 50mL) columnwithNi‐NTA (Macherey‐Nagel) in anÄkta system, rinsedwithwash buffer (25mM TrisHCl 7.5, 500mMNaCl, 20mMImidazol)andtheboundproteinwaselutedwithalineargradient(0‐100%)ofelutionbuffer (25mM Tris HCl 7.5, 500mM NaCl, 300mM Imidazol). The main fractions of the elution peak (monitoredbyOD280)werepassedoveraHiPrepDesaltingcolumn(GE;#17‐5087‐01)tochangeto thecleavagebuffer(25mMTrisHCl7.5,150mMNaCl,1mMDTT).Theadjustedproteinsolutionwas treatedwithpurifiedHis‐TEVprotease(ratiohSOS1:TEV,w/w,30:1)for16hat4°Candafterwards passedoveraNi‐NTAcolumn toremovenon‐cleavedhSOS1protein,cleaved tagandHis‐TEV.The pooledflowthroughfractionswiththeprocessedhSOS1wereconcentratedusingaAmiconUltra15 Ultracel‐10 device (Centrifugal Filter 10000NMWL;Merck‐Millipore #UFC901024) and applied to size‐exclusion chromatography columnwith Superdex 200HR prep grade (GEHealthcare) in SEC buffer(25mMTrisHCl7.5,100mMNaCl).Thefinalyieldoftag‐freeproteinforSOS1_12wasabout 245mgper litercellculturewas.Thefinalproduct(tag‐free)concentrationforhSOS1_12was30.7 mg/mL. ComplexformationandCrystallizationofhSOS1_12withSOS1inhibitors The catalyticdomainofhuman SOS1 (hSOS1) in complexwith inhibitors canbe crystallizedusing constructhSOS1_12.ItisidenticaltotheconstructpublishedbyFreedmanetal.(Ref.1).Itcomprises ofhSOS1residuesGlu564toThr1049withanadditionalfouraminoacids(Gly‐Ala‐Met‐Ala)attheN‐ terminusandisshowninFiguresX1andX2below.Forinhibitor‐complexformation,frozenaliquots ofthehSOS1_12protein(concentration30.7mg/ml)inbuffer(25mMTrisHCl7.5/50mMNaCl/1mM DTT)arethawedandtherespectiveSOS1 inhibitor isaddedbeforesettingupofthecrystallization experiment(co‐crystallizationapproach)orsoakedintopre‐formedapocrystals(soakingapproach). Fortheco‐crystallizationapproach,theinhibitorisaddedfroma200mMDMSOstocksolutiontoa finalinhibitorconcentrationof2mMandthemixisincubatedovernightat4°C.Thecomplexcanbe crystallized using the Hanging Drop method. Crystals grow at 20°C. Drops are made from 1µl hSOS1_12:inhibitormix,1µlreservoirsolution(20‐30%%(v/v)ethylenglycole)and0.2µlseedstock. TheseedstockwasgeneratedfromhSOS1crystalspreviouslyobtainedinaninitialscreenusingthe samehSOS1_12constructandareservoirsolutionof25%ethyleneglycol.Forthesoakingapproach, apoSOS1crystals(grownusingthesameprocedureasdescribedabove,justwithoutadditionofan inhibitor)aresoakedfor2to24hourswith2mMligand. DataCollectionandProcessing SOS1‐inhibitorcrystalsaredirectlyshockfrozen in liquidnitrogen.Diffractiondatasetscollectedat synchrotronscanbeprocessedusingtheprogramsXDSandXDSAPP. Structuredeterminationandrefinement ThecrystalformdescribedherewasfirstobtainedandsolvedforahSOS1_12crystalgrown inthe presenceofanother inhibitorof the same chemical series, froma reservoir solution composedof 25%ethyleneglycol.ThisinitialstructurewassolvedusingtheMolecularReplacementmethodwith theprogramPHASERfromtheCCP4programsuiteandthepublishedstructureofhSOS1(PDBentry 2ii0,Ref.1)assearchmodel.ThedatasetsforfurtherSOS1:inhibitorcrystalstructurescanbesolved byMolecularReplacementusingPHASERandanearlierin‐houseSOS1:inhibitorco‐complexstructure as startingmodel.3Dmodels for the inhibitorsaregeneratedusing theprogramDiscoveryStudio (company Biovia) and parameter files for crystallographic refinement and model building are generated using software PRODRG. The inhibitors can be builtmanually built into the electron densitymaps using the program COOT, followed by several cycles of refinement (using program REFMACaspartoftheCCP4programsuite)andrebuildinginCOOT. FigureX1:SequenceofhSOS1_12withN‐terminalHistag(His10‐hSOS1_12)beforecleavagebyTEV protease.