Anticancer macrocyclic quinazoline-based inhibitors of the ineraction between ras and SOS1

Abstract

The present invention covers macrocyclic heterocyclic compounds of general formula (I), in which R1, R2, R4, R5, L, X and Y are as defined herein, pharmaceutical compositions comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative or genetic disorders.

Description

[0001] MACROCYCLIC HETEROCYCLES

[0002] The present disclosure relates to macrocyclic heterocycles, formulations comprising the macrocyclic heterocycles and their use in pharmaceutical applications.

[0003] The present invention covers macrocyclic heterocyclic compounds of general formula (I) as described and defined herein, pharmaceutical compositions and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative or genetic disorders, as a sole agent or in combination with other active ingredients.

[0004] BACKGROUND

[0005] The present invention covers macrocyclic heterocyclic compounds of general formula (I) which inhibit RAS-SOS1 interaction.

[0006] 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 to encode four different RAS proteins of 21 kDa size: H-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.

[0007] 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 respectively. 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 signaling events of diverse functions, e.g. cytoskeletal rearrangements, cell proliferation and differentiation. 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 hydrolyze 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.

[0008] 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 (SOS) proteins, SOS1 and SOS2, 4 different isoforms of RAS guanine nucleotide releasing proteins (RAS- GRP1-4) and two RAS guanine nucleotide releasing factors (RAS-GRF1 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.

[0009] 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 & Faller 2013 Expert Opin. Ther. Targets). Marketed cancer drugs are available that inhibit RAF, EGFR or MEK.

[0010] 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 K-RAS-G12C mutant might have the benefit of reduced side effects, as the wildtype K-RAS proteins are not 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 or early development 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.

[0011] WO 2018 / 172250 (Bayer Pharma AG) describes 2-methyl-quinazoline like as inhibiting RAS-SOS interaction. WO 2018 / 115380 (Boehringer Ingelheim) describes benzylamino substituted quinazolines like as SOS1 inhibitors.

[0012] WO 2021 / 228028 (Chia Tai TianQing Parmaceutical Group) describes compounds of the following formula as SOS 1 -inhibitors. Chinese patent application CN 114685488 describes compounds of the following formula: also as SOSl-inibitors. Just recently also macrocyclic SOS1 inhibitors have been disclosed in WO 2023 / 205701 Al by Kumquat Biosciences:

[0013] It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.

[0014] In particular, the compounds of the present invention have surprisingly been found to effectively and selectively inhibit the RAS-SOS1 interaction (Biochemical assay: hK-RAS-G12C interaction assay with hSOSl) and may therefore be used for the treatment or prophylaxis of hyperproliferative or genetic disorders, in particular cancer.

[0015] DESCRIPTION of the INVENTION

[0016] In accordance with a first aspect, the present invention covers compounds of general formula (I): in which

[0017] X represents C-R3or N;

[0018] Y represents C-R3or N; wherein X and Y are both independently from each other C-R3or one of X and Y is N and the other one of X and Y is C-R3;

[0019] R1represents C1-6-alkyl or C3-6-cycloalkyl wherein in both one carbon atom can be replaced by an oxygen or N-CH3, N-CH2-CH3, N-CH2-CH2-CH3, N-CH(CH3)2, or N-

[0020] C(O)-CH3, except for the carbon atoms in the C3-6-cycloalkyl residue that are directly attached to the aromatic bicyclus and wherein epoxides and aziridines are excluded; or

[0021] -Cl, -Br;

[0022] C1-3alkyl substituted with at least one or more F; or

[0023] -N(R7)2, wherein both R7can be selected independently from each other and wherein only one R7can be C3-6cycloalkyl as defined below for R7; or are independently from each other -H, -CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); or

[0024] ring carbon atom can optionally be substituted with

[0025] 1 or 2 -CH3, -F or -OH, or a mixture thereof; or R2represents -H; C1-4 alkyl optionally substituted with -F and / or -OH wherein -F and -OH are not bound to the same carbon atom; -O-C1-4optionally substituted with -

[0026] F; -CN or halogen;

[0027] R3represents -H, -F, -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, -O-CH3or

[0028] R4represents -H, -Cl, -F, -CH3, -CH2-CH3, -NH2, wherein the residues containing a carbon atom can optionally be substituted with one or more -F;

[0029] R5represents -CH3, -CH2F, -CHF2, -CH2-CH3or -C« CH;

[0030] R6represents -H, -CH3, -CH2-CH3, -CH(CH3)2or , -C(O)-CH3,

[0031] -C(O)-OC(CH3)3, optionally substituted with -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;

[0032] R7represents

[0033] -H;

[0034] C1-3alkyl optionally substituted with 1 or more -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom; or C3-6cycloalkyl, in which one carbon atom can be optionally replaced by an oxygen atom, wherein epoxides and residues that generate -N-C-O- motifs are excluded; or

[0035] A moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or - O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;

[0036] R8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, ;

[0037] R9represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F, under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;

[0038] R10represents -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F;

[0039] L represents

[0040] , wherein

[0041] X’ is selected from -C(Ra)(Ra)-, -O-, -C(O)-, -N(R8)-, -S-, -S(O)- or -S(O)2-;

[0042] Y’ is selected from -C(Ra)(Ra)-, -C(O)-;

[0043] Z’ is selected from -C(Ra)(Ra)-, -O-, -N(R8)-;

[0044] Rais selected independently from each other from -H, -F, -CH3, -CHF2or -CF3with the condition that a maximum of four Raare not -H; or

[0045] Rais when two Rathat are bound to the same or to two neighboring atom(s) form a 3 to 5 membered ring, wherein the 3 to 5 membered ring can be substituted with 1 or more -F and wherein L can comprise only one 3 to 5 membered ring; wherein X’, Y’ and Z’ are selected in the way that L does not contain more than one - sulfur atom or -C(O)- and none of the following structures are present -O-O-, -O-N-, -N- N-, -O-CH2-N-, -N-CH2-N-, -O-CH2-O-,

[0046] -C(O)-S-, -C(O)-NH-S-, -O-S(O)2-; or

[0047] , wherein the double bond between X’ ’ and

[0048] X’ ’ can be in E or Z configuration and

[0049] X” represents -CRaa;

[0050] Y” represents -C(Rab)(Rab);

[0051] Z”represents -O-, -N(R6)- or -CH2-;

[0052] Raarepresents -H, -CH3;

[0053] Rabrepresents independently from each other -H, -F, -CH3, -CHF2,

[0054] -CF3or , or in which both Rabtogether with the carbon atom they are attached to form a three membered ring, wherein when Z” is -O- or -N(R6)- residue Rabis not -F; R11and R12independently from each other represent Ci-4-alkyl, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH2(CH3)2, or -N(R8)(R8); or

[0055] R11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13), S(O)2and in which each remaining carbon atom in the 4 to 6 membered heterocycloalkyl residue can optionally be substituted by 1 or 2 -CH3, or by 1 -CH2-CH3; or a 5 to 6 membered heterocycloalkenyl;

[0056] R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2,

[0057] -C(O)-CH3, -C(O)-OC(CH3)3, -S(O)2-CH3, ;

[0058] T represents O or N(R6);

[0059] U represents CH2, O, S or N(R6);

[0060] V represents C=O or S(O)2;

[0061] W represents CH2, O or N(R13); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0062] DEFINITIONS

[0063] The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and / or variables are permissible.

[0064] The term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or sulfur or oxygen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.

[0065] When groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent. As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom, to a sulfur atom or to a phosphor via a double bond.

[0066] The term “ring substituent” means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.

[0067] The term “comprising” when used in the specification includes “consisting of’.

[0068] If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.

[0069] The term “halogen atom” means a fluorine, chlorine or bromine atom, particularly a fluorine or chlorine atom.

[0070] The term “C1-C6-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl,

[0071] 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,

[0072] 1.2-dimethylbutyl or 1,3 -dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec -butyl isobutyl, or tert- butyl group, more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.

[0073] The term “C1-C6-haloalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C6-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C1-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,

[0074] 2.2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or l,3-difluoropropan-2-yl.

[0075] The term “C1-C6-alkoxy” means a linear or branched, saturated, monovalent group of formula (C1-C6-alkyl)-O-, in which the term “Ci-Ce-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.

[0076] The term “C2-C6-alkenyl” means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 to 4 carbon atoms (“C2-C4-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then it is possible for said double bonds to be isolated from, or conjugated with, each other.

[0077] The term “C2-C6-alkynyl” means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkynyl”). Said C2-C6-alkynyl group is, for example, ethynyl, prop-l-ynyl, prop-2-ynyl (or “propargyl”), but-l-ynyl, but-2-ynyl, but-3-ynyl, pent-l-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-l-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl,

[0078] 1-methylbut-3-ynyl, l-methylbut-2-ynyl, 3-methylbut-l-ynyl, l-ethylprop-2-ynyl, 3-methylpent-4-ynyl,

[0079] 2-methylpent-4-ynyl, l-methylpent-4-ynyl, 2-methylpent-3-ynyl, l-methylpent-3-ynyl,

[0080] 4-methylpent-2-ynyl, l-methylpent-2-ynyl, 4-methylpent-l-ynyl, 3-methylpent-l-ynyl,

[0081] 2-ethylbut-3-ynyl, l-ethylbut-3-ynyl, l-ethylbut-2-ynyl, 1 -propylprop-2-ynyl, l-isopropylprop-2-ynyl,

[0082] 2.2-dimethylbut-3-ynyl, l,l-dimethylbut-3-ynyl, I , I -dimcthylbut-2-ynyl or 3,3-dimethylbut-l-ynyl group. Particularly, said alkynyl group is ethynyl.

[0083] The term “C3-C6-cycloalkyl” means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms (“C3-C6-cycloalkyl”). Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, or a bicyclic hydrocarbon ring.

[0084] The term “C3-C8-cycloalkoxy” means a saturated, monovalent, mono- or bicyclic group of 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, cycloheptyloxy or cyclooctyloxy group.

[0085] The terms “4- to 7-membered heterocycloalkyl” and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, P, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom or a phosphor atom.

[0086] Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1 ,2-oxazolidinyl,

[0087] 1.3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl,

[0088] 1.4-dioxanyl or 1 ,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or

[0089] 1.4-oxazepanyl, for example.

[0090] Particularly, “4- to 6-membered heterocycloalkyl” means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen or phosphor atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen or phosphor atom and optionally one further ring heteroatom from the series: N or O.

[0091] The term “heterospirocycloalkyl” means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.

[0092] Said heterospirocycloalkyl group is, for example, 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, or one of the further homologous 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]- and spiro[4.6]-.

[0093] The term “bridged heterocycloalkyl” means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which “bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.

[0094] 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, azabicyclo[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]decyl or azabicyclo[4.2.2]decyl.

[0095] The term “heteroaryl” means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and / or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).

[0096] Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, 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, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

[0097] In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g. : tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. Particularly, the heteroaryl group is a quinazoline or a pyrido pyrimidine group.

[0098] The term “C1-C6”, as used in the present text, e.g. in the context of the definition of “C1-C6-alkyl”, “C1-C6-haloalkyl”, “C1-C6- alkoxy” or “C1-C6-haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.

[0099] Further, as used herein, the term “C3-C6”, as used in the present text, e.g. in the context of the definition of “C3-C6-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.

[0100] By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0101] The compounds of the present invention contain at least one or more asymmetric centre(s), depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.

[0102] Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

[0103] Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The at least one asymmetric centre of the compounds of the invention is located at the carbon atom to which R5and the secondary amin are attached and is present in (R) configuration in an enantiomeric excess of at least 95%, 96%, 97%, 98% or • 99%. Compounds of the present invention may contain further asymmetric centres. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

[0104] The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or 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 crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization, optimally chosen to maximize the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

[0105] In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0106] The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.

[0107] Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

[0108] The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and / or co- precipitates.

[0109] The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

[0110] Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.

[0111] The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.

[0112] A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with 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,

[0113] 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.

[0114] Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminum or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N- methyl morpholine, arginine, lysine, 1,2- ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N, N-dimcthyl-glucaminc, N-cthyl- glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino- 1,3 -propanediol, 3-amino-l,2- propanediol, 4-amino-l,2,3-butanetriol, or a salt with a quaternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl) ammonium, tetra(n- butyl) ammonium, N-bcnzyl-N,N,N-trimcthylammonium, choline or benzalkonium.

[0115] Those skilled in the art will further recognize that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.

[0116] The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

[0117] In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and / or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HQ", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.

[0118] This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and / or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition.

[0119] Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.

[0120] In accordance with a second embodiment of the first aspect, the present invention relates to compounds according to formula (I) in which:

[0121] X represents C-R3or N;

[0122] Y represents C-R3or N; wherein X and Y are both independently from each other C-R3or one of X and Y is N and the other one of X and Y is C-R3;

[0123] R1represents -Cl, Br; or

[0124] C1-3alkyl substituted with at least one or more F; or

[0125] -N(R7)2, wherein both R7can be selected independently from each other and wherein only one R7can be C3-6cycloalkyl as defined below for R7; or are independently from each other -H,

[0126] -CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); or or or wherein each ring carbon atom can optionally be substituted with

[0127] 1 or 2 -CH3, -F or -OH, or a mixture thereof; or

[0128] ; or Rdrepresents -CH3, -CH2-CH3, -CH(CH3)2or

[0129] R2represents H; C1-4alkyl optionally substituted with -F and / or -OH wherein -F and -OH are not bound to the same carbon atom; -O-C1-4optionally substituted with -

[0130] F; -CN or halogen;

[0131] R3represents -H, -F, -CH3, -CF2H, -CH2-CH3, -CH(CH3)2, or ;

[0132] R4represents -H, -Cl, -F, -CH3, -NH2, wherein the residues containing a carbon atom can optionally be substituted with one or more -F;

[0133] R5represents -CH3, -CH2F, -CHF2, -CH2-CH3or -C« CH;

[0134] R6represents -H, -CH3, -CH2-CH3, -CH(CH3)2, , -C(O)-CH3,

[0135] -C(O)-OC(CH3)3;

[0136] R7represents a moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or -O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;

[0137] R8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, ;

[0138] R9represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F, under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;

[0139] R10represents -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F;

[0140] L represents

[0141] , wherein

[0142] X’ is selected from -C(Ra)(Ra)-, -O-, -C(O)-, -N(R8)-, -S-, -S(O)- or -S(O)2-;

[0143] Y’ is selected from -C(Ra)(Ra)-, -C(O)-;

[0144] Z’ is selected from -C(Ra)(Ra)-, -O-, -N(R8)-;

[0145] Rais selected independently from each other from -H, -F, -CH3, -CHF2or -CF3with the condition that a maximum of four Raare not -H; or

[0146] Rais when two Rathat are bound to the same or to two neighboring atom(s) form a 3 to 6 membered ring, wherein the 3 to 6 membered ring can be substituted with 1 or more -F and wherein L can comprise only one 3 to 6 membered ring; wherein X’, Y’ and Z’ are selected in the way that L does not contain more than one sulfur atom or -C(O)- and none of the following structures are present -O-O-, -O-N-, -N- N-, -O-CH2-N-, -N-CH2-N-, -O-CH2-O- or

[0147] -C(O)-S-, -C(O)-NH-S-, -O-S(O)2-; or

[0148] , wherein the double bond between X’ ’ and

[0149] X’ ’ can be in E or Z configuration and

[0150] X” represents -CRaa;

[0151] Y” represents -C(Rab)(Rab);

[0152] Z”represents -O-, -N(R6)- or -CH2-;

[0153] Raarepresents -H, -CH3;

[0154] Rabrepresents independently from each other -H, -F, -CH3, -CHF2,

[0155] -CF3or , or in which both Rabtogether with the carbon atom they are attached to form a three membered ring, wherein when Z” is -O- or -N(R6)- residue Rabis not -F; R11and R12independently from each other represent Ci 4-alkyl; or

[0156] R11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13), S(O)2and in which each remaining carbon atom in the 4 to 6 membered heterocycloalkyl residue can optionally be substituted by 1 or 2 -CH3; or a 5 membered heterocycloalkenyl;

[0157] R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2,

[0158] -C(O)-CH3, -C(O)-OC(CH3)3, -S(O)2-CH3, ;

[0159] T represents O or N(R6);

[0160] U represents CH2, O, S or N(R6);

[0161] V represents C=O, S(O)2;

[0162] W represents O or N(R13); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0163] In accordance with a third embodiment of the first aspect, the present invention relates to compounds according to formula (I), supra, in which:

[0164] X represents C-R3or N;

[0165] Y represents C-R3or N; wherein X and Y are both independently from each other C-R3or one of X and Y is N and the other one of X and Y is C-R3;

[0166] -N(R7)2, wherein both R7can be selected independently from each other and wherein only one R7can be C3-6cycloalkyl as defined below for R7; or are independently from each other -H,

[0167] -CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); or or or , wherein each ring carbon atom can optionally be substituted with 1 or

[0168] 2 -CH3, -F or -OH, or a mixture thereof; or

[0169] , wherein R represents -CH3; R2represents H; C1-4alkyl optionally substituted with -F and / or -OH wherein -F and -OH are not bound to the same carbon atom; ; -O-C1-4optionally substituted with -

[0170] F; CN or halogen;

[0171] R3represents -H, -F, -CH3, -CF2H, -CH2-CH3, or ;

[0172] R4represents -H, -Cl, -F, -CH3, wherein the residues containing a carbon atom can optionally be substituted with one or more -F;

[0173] R5represents -CH3, -CHF2or -C• CH;

[0174] R7represents a moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or -O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;

[0175] R8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2,

[0176] L represents

[0177] , wherein

[0178] X’ is selected from -C(Ra)(Ra)-, -O-, -C(O)-, -N(R8)-, -S-, -S(O)- or -S(O)2-;

[0179] Y’ is selected from -C(Ra)(Ra)-, -C(O)-;

[0180] Z’ is selected from -C(Ra)(Ra)-, -O-, -N(R8)-;

[0181] Rais selected independently from each other from -H, -F, -CH3,

[0182] -CHF2or -CF3 with the condition that a maximum of four Raare not -H; or

[0183] Rais when two Rathat are bound to the same or to two neighboring atom(s) form a 3 to 4 membered ring, wherein the 3 to 4 membered ring can be substituted with 1 or more -F and wherein L can comprise only one 3 to 4 membered ring; wherein X’, Y’ and Z’ are selected in the way that L does not contain more than one - sulfur atom or -C(O)- and none of the following structures are present -O-O-, -O-N-, -N- N-, -O-CH2-N-, -N-CH2-N-, -O-CH2-O-, -C(O)-S-, -C(O)-NH-S-, -O-S(O)2-, -O-C(O)-; or

[0184] , wherein the double bond between X’ ’ and

[0185] X’ ’ can be in E or Z configuration and

[0186] X” represents -CRaa;

[0187] Y” represents -C(Rab)(Rab);

[0188] Z”represents -O-, -N(R6)- or -CH2-;

[0189] Raarepresents -H, -CH3;

[0190] Rabrepresents independently from each other -H, -F, -CH3, -CHF2,

[0191] -CF3or , or in which both Rabtogether with the carbon atom they are attached to form a three membered ring, wherein when Z” is -O- or -N(R6)- residue Rabis not -F;

[0192] R11and R12independently from each other represent C1-3-alkyl; or

[0193] R11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O or N(R13);

[0194] R13represents -H, -CH3, -CH2CH3, -CH(CH3)2, -C(O)-CH3,

[0195] T represents O;

[0196] U represents CH2, O or N-CH3;

[0197] V represents C=O, S(O)2;

[0198] W represents O or N(R13); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

[0199] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:

[0200] R1represents C1-6-alkyl or C3-6-cycloalkyl wherein in both one carbon atom can be replaced by an oxygen or N-CH3, N-CH2-CH3, N-CH2-CH2-CH3, N-CH(CH3)2, or N-C(O)-CH3, except for the carbon atoms in the C3-6-cycloalkyl residue that are directly attached to the aromatic bicycle and wherein epoxides and aziridines are excluded; or - Cl, -Br; or

[0201] -OH, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH(CH3)2, preferably

[0202] -O-CH3, -O-CH2-CH3, -O-CH(CH3)2,

[0203] C1-3alkyl substituted with at least one or more F.

[0204] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:

[0205] R1represents -N(R7)2, wherein both R7can be selected independently from each other and wherein only one R7can be C3-6cycloalkyl as defined below for R7; or are independently from each other -H, -CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); or h ring carbon atom can optionally be substituted with

[0206] 1 or 2 -CH3, -F or -OH or a mixture thereof; or

[0207] R6represents -H, -CH3, -CH2-CH3, -CH(CH3)2, , -C(O)-CH3or -C(O)-O(CH3)3, optionally substituted with -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;

[0208] R7represents

[0209] -H;

[0210] C1-3alkyl optionally substituted with 1 or more -F under the condition that

[0211] -F is not bound to a carbon atom that is directly next to a nitrogen atom; or C3-6cycloalkyl, in which one carbon atom can be optionally replaced by an oxygen atom, wherein epoxides and residues that generate -N-C-O- motifs are excluded; or a moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or - O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;

[0212] R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(O)-CH3,

[0213] W represents CH2, O or N(R13), preferably O or N(R13).

[0214] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:

[0215] R1represents

[0216]

[0217] R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(O)-CH3,

[0218] -C(O)-O(CH3)3, -S(O)2-CH3, , preferably -H, -CH3, -CH2CH3,

[0219] -CH(CH3)2, -C(O)-CH3,

[0220] W represents CH2, O or N(R13), preferably O or N(R13).

[0221] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:

[0222] R1represents

[0223] ; and

[0224] R8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2,

[0225] R11and R12independently from each other represent Ci-4-alkyl, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH2(CH3)2, or -N(R8)(R8), preferably C1-3- alkyl; or

[0226] R11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13), S(O)2and in which each remaining carbon atom in the 4 to 6 membered heterocycloalkyl residue can optionally be substituted by 1 or 2 -CH3, or by 1 -CH2-CH3, preferably together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13); or a 5 to 6 membered heterocycloalkenyl;

[0227] R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(O)-CH3,

[0228] -C(O)-O(CH3)3, -S(O)2-CH3, preferably -H, -CH3, -CH2CH3,

[0229] -CH(CH3)2, -C(O)-CH3,

[0230] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:

[0231] R1represents

[0232] R9represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F, under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;

[0233] R10represents -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F;

[0234] V represents C=O or S(O)2.

[0235] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which: R1represents wherein Rdrepresents -CH3, -CH2-CH3, -CH(CH3)2or

[0236] R6represents -H, -CH3, -CH2-CH3, -CH(CH3)2, , -C(O)-CH3or

[0237] -C(O)-O(CH3)3optionally substituted with -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;

[0238] T represents O or N(R6) and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

[0239] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:

[0240] X represents C-R3;

[0241] Y represents C-R3; and

[0242] R3represents -H, -F, -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, -O-CH3or preferably -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

[0243] In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:

[0244] X represents N;

[0245] Y represents C-R3; and

[0246] R3represents -H, -F, -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, -O-CH3or

[0247] , preferably -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

[0248] In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.

[0249] The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.

[0250] The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.

[0251] The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.

[0252] Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action and pharmacokinetic profile, both of which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit SOS1 and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably hyperproliferative disorders and in particular cancer in humans and animals.

[0253] Compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and / or cell division, and / or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disorder.

[0254] Hyperproliferative or genetic disorders include, but are not limited to, for example: solid and liquid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include sarcomas, lymphomas, leukaemias and multiple myeloma.

[0255] Examples of breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0256] Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0257] Examples of brain cancers include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.

[0258] Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

[0259] Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

[0260] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0261] 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), and mixed hepatocellular cholangiocarcinoma.

[0262] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0263] Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.

[0264] 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 nervous system.

[0265] Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0266] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0267] Multiple myeloma include, but are not limited to, IgG myeloma, IgA myeloma, IgM myeloma, IgD myeloma, IgE myeloma, Bence Jones myeloma, nonsecretory myeloma, solitary plasmacytoma, extramedullary myeloma and asymptomatic myeloma.

[0268] These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

[0269] The term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.

[0270] The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.

[0271] Generally, the use of chemotherapeutic agents and / or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:

[0272] 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone,

[0273] 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,

[0274] 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans,

[0275] 5. provide for a higher response rate among treated patients,

[0276] 6. provide for a longer survival time among treated patients compared to standard chemotherapy treatments,

[0277] 7. provide a longer time for tumour progression, and / or

[0278] 8. yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

[0279] In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and / or surgical intervention.

[0280] 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 compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with at least one compound of general formula (I) of the present invention. Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.

[0281] The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.

[0282] In other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.

[0283] In other embodiments, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signaling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signaling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.

[0284] In one aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell concomitantly with 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 administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.

[0285] In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

[0286] In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular hyperproliferative disorders and particularly cancer.

[0287] The pharmaceutical activity of the compounds according to the invention can be explained by their activity as inhibitor for SOS1 and in particular their activity in inhibiting SOS1 and KRAS interaction. In a particular embodiment SOS1 and KRAS G12C interaction is inhibited.

[0288] In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular hyperproliferative or genetic disorders, particularly cancer disorders.

[0289] In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular hyperproliferative or genetic disorders, particularly cancer disorders, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.

[0290] In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipient(s), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.

[0291] The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes. It is possible for the compounds according to the invention to have systemic and / or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

[0292] For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

[0293] 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 modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric 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-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and / or amorphised and / or dissolved form into said dosage forms.

[0294] Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

[0295] Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

[0296] The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

[0297] • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),

[0298] • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid polyethylene glycols, paraffins),

[0299] • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),

[0300] • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

[0301] • isotonicity agents (for example glucose, sodium chloride),

[0302] • adsorbents (for example highly-disperse silicas),

[0303] • viscosity-increasing agents, gel formers, thickeners and / or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),

[0304] • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol®)),

[0305] • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),

[0306] • 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, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, poly acrylates, polymethacrylates such as, for example, Eudragit®)),

[0307] • capsule materials (for example gelatine, hydroxypropylmethylcellulose),

[0308] • synthetic polymers (for example polylactides, polyglycolides, poly acrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

[0309] • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), • penetration enhancers,

[0310] • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

[0311] • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0312] • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

[0313] • flavourings, sweeteners, flavour- and / or odour-masking agents.

[0314] The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

[0315] Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyperproliferative or genetic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[0316] Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

[0317] EXPERIMENTAL SECTION

[0318] NMR peak forms are stated as they appear in the spectra, possible higher order effects may have not been considered.

[0319] The1H-NMR data of selected compounds are listed in the form of1H-NMR peak lists. Therein, for each signal peak the • value in ppm is given, followed by the signal intensity, reported in round brackets. The • value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: • i (intensity]), •2 (intensity^), ... , •i (intensity;), ... , »n(intensityn).

[0320] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A1H-NMR peaklist is similar to a classical1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities,13C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by- product fingerprints". An expert who calculates the peaks of the target compound by known methods (ACD spectrus, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%.

[0321] Chemical names were generated using the ACD / Name software from ACD / Labs or ChemDraw by PerkinElmer. In some cases generally accepted names of commercially available reagents were used in place of ACD / Name or ChemDraw generated names.

[0322] The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

[0323] Table 1: Abbreviations

[0324] The following table lists the abbreviations used herein.

[0325] Other abbreviations have their meanings customary per se to the skilled person. The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

[0326] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[0327] EXPERIMENTAL SECTION - GENERAL PART

[0328] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[0329] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane / ethyl acetate, DCM / methanol or DCM / ethanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and / or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0330] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

[0331] EXPERIMENTAL SECTION - GENERAL PROCEDURES

[0332] The compounds of the present invention can be prepared as described in the following section. The schemes and the procedures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in the schemes can be modified in various ways. The order of transformations exemplified in the schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents can be achieved before and / or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metalation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in "Protective Groups in Organic Synthesis", 4"' edition, Wiley 2006). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a "one -pot" reaction, as is well-known to the person skilled in the art.

[0333] The syntheses of the compounds of the present invention are preferably carried out according to the general synthetic sequences, shown in schemes 1-10.

[0334] Scheme 1 Scheme 1: Synthesis route for the preparation of compounds of general formula (I) in which PG represents a protecting group, T represents a leaving group or R1, LG represents a leaving group, Z represents O or NR8, and L’ together with Z represents L, whereas L, R1, R2, R4, R5, R8, X, and Y are defined as in general formula (I).

[0335] Compounds of general formula (I) can be prepared by cyclization of hydroxypyrimidine derivatives (XLIX) by using dehydrative conjugation methods. Such methods are known using coupling reagents like benzotriazol- l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and benzotriazol- 1- yl-oxytripyrrolidinophosphonium hexafluorophosphate (pyBOP), see the teachings of J. Org. Chem., 2007, 72, 10194; Advanced Synthesis & Catalysis, 2018, 360, 4764; Bioorg. Med. Chem., 2019, 27, 931; WO 2011028741 Al; are in the public domain.

[0336] Alternatively, compounds of general formula (I) can be formed in a two-step process, whereby the hydroxyl group of compounds of general formula (XLIX) are converted to a leaving group, such as Cl using phosphorus oxytrichloride, or Br using phosphorus oxytribromide, or tosylate typically 4- methylbenzene-1 -sulfonyl chloride, a base such as for example triethylamine or potassium carbonate and / or DMAP in an organic solvent such as for example dichloromethane or acetonitrile. For examples, see Org. Lett., 2011, 4374 or Bioorg. Med. Chem. Lett., 2013, 2663 and references therein.

[0337] Subsequently the compounds of general formula (L) can be converted to compounds of general formula (I), using an intramolecular nucleophilic substitution reaction (SNAr) with the amine function present in compounds of formula (L), in analogy to intermolecular SNAr reactions which are well-documented in the public domain and are known to those skilled in the art.

[0338] Compounds of general formula (XLIX) can be prepared from compounds of formula (III) by deprotection of the amine, which is typically protected with Boc or similar protection groups known to the person skilled in the art.

[0339] Compounds of general formula (III) can be prepared by pyrimidine formation from bis-amides (IV) in analogy to literature procedures. Typically, derivative (IV) could be reacted with a base such as for example sodium hydroxide or sodium ethoxide in a solvent such as for example water or ethanol, respectively at elevated temperature. For example, see Monatshefte Fur Chemie, 1987, 118, 399; WG2007 / 134986, WO2013 / 016999; WO2012 / 028578 and references therein.

[0340] Bis amides (IV) can be obtained by standard amide couplings of amino amides (V) and carboxylic acid derivatives (VI).

[0341] Furthermore, compounds of general formula (I) can be prepared by cyclization of pyrimidine derivatives (VII) by intramolecular SNAr reaction of the nucleophile represented by Z-H which can be OH or NR8H replacing the leaving group (LG), preferably Cl under conditions known to the person skilled in the art. Typically, alcohol derivatives of general formula (VII) with Z equals O are treated with bases like LDA in solvents like dioxane at elevated temperatures. Typically, amine derivatives of general formula (VII) with Z equals NR8H are treated at elevated temperatures in solvents like DMF or NMP.

[0342] Compounds of general formula (VII) can be prepared from SNAr reaction of pyrimidine derivatives (IX) with amines (X) and subsequent deprotection of the products of said SNAr reaction represented by general formula (VIII). Furthermore, cyclization can lead to compounds of general formula (II), which can be further converted to compounds of general formula (I) by transition metal catalysed coupling of the aryl halide (Hal) of (II) with nucleophiles like alcohols, amines, lactams, sultams, phosphinoxides, or suitable organometal derivatives. Typically, R1can be introduced by the general procedures J, K, L, M, or N which are described below. Furthermore, a suitable R1can be present in compounds of general formula (V) or (IX), for example if R1is alkoxy. In some cases, R1can be introduced, which is subsequently converted to R1by protecting group manipulations and / or derivatisation of R1. For example, R1can contain a protected amine, which is then deprotected and further substituted by alkylation or acylation, using

[0343] Scheme 2: Synthesis route for the preparation of certain compounds (lb), in which L, R1, R2, R3, R4, R5are defined as in general formula (I), and R3is not H.

[0344] Certain compounds represented by general formula (la), bearing a substituent R3which is not H can be prepared by literature known methods, e.g. Minisci-type reactions or reactions with nitromethane and DBU for introduction of a methyl group. The introduction of R3can be performed either on halogen- substituted pyridopyrimidines (Ila) (Route A) to obtain aryl halides of general formula (lib) which can be further converted to compounds of general formula (lb) by transition metal catalysed coupling of said aryl halides with e.g. alcohols, amines, lactams, sultams, phosphinoxides, or boronic acid derivatives. Alternatively, the sequence of these transformations can be switched (Route B), whereas each general formula (la), (lb), (Ila), and (lib) represent certain subtypes of general formula (I).

[0345] Scheme 3

[0346] Scheme 3 Synthesis route for the preparation of compounds of general formula (IX) in which T represents a leaving group or R1, LG represents a leaving group, preferably Cl, and R1 is defined as in general formula (I).

[0347] Compounds of general formula (IX) can be prepared by literature known methods from amino- carboxamides amides (XII) and urea at elevated temperature, leading to bis-hydroxypyrimidine derivatives (XI), which can be transferred into the corresponding leaving group substituted pyrimidines (IX), e.g. using phosphoric trichloride and thus resulting in the corresponding 2,4-dichloropyrimidine derivatives.

[0348] Scheme 4

[0349] Scheme 4 Synthesis route for the preparation of certain compounds of general formula (X) in which PG represents a protecting group, PG’ represents an orthogonal protecting group, Z represents O or NR8, and L’ together with Z represents L, whereas L, R2, R4, R5, R8, and Raare defined as in general formula (I).

[0350] Certain compounds of general formula (X) can be prepared from phenols (XIV) by O-alkylation or Mitsunobu reaction with suitable alkyl halides or alcohols, respectively, thus leading to ethers (XIII), which, after removal of the protection group, e.g. silyl ethers for Z = O or carbamate-based protecting groups like Boc for Z = NR8, lead to the desired compounds of general formula (X). The phenol derivatives (XIV) can be prepared by introduction of the chiral phenethylamine by reacting MOM-protected phenol derivative (XVII) with BuLi and sulfinamide (XXXI). Simultaneous removal of the MOM ether and cleavage of the sulfinamide lead to compounds of general formula (XV), which can be selectively protected with a suitable protecting group PG’, leading to intermediates (XIV). PG’ can be chosen to be orthogonal to protecting group PG, e.g. a Boc group, an Fmoc group, or a SEM group can be used to allow a selective cleavage in the presence of PG based on the nature of PG. The principle of orthogonal protecting groups is known to a person skilled in the art.

[0351] Scheme 5

[0352] Scheme 5 Synthesis route for the preparation of certain compounds of general formula (X) in which PG represents a protecting group, Z represents O or NR8, and L’ together with Z represents L, whereas L, R2, R4, R5, R8, and Raare defined as in general formula (I).

[0353] Certain compounds of general formula (X) can be prepared from aryl fluorides (XXI) by SNAr with amines leading to aniline derivatives (XX). The ketone in (XX) can be converted into sulfinimines (XIX) in analogy to the numerous literature procedures. For example the reaction can be performed at ambient temperature using titanium(IV) ethoxide or titanium(IV) isopropoxide in an organic solvent such as for example THF. For examples, see Chem. Rev. 2010, 110, 3600-3740; Chem. Soc. Rev. 2009, 38, 1162— 1186; Tetrahedron 2004, 60, 8003 or WO2019 / 122129 and the references therein. The sulfinimines (XIX) can be converted to the corresponding sulfinamides (XVIII) 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 an organic solvent such as for example ethanol, methanol or THF. 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 such as for example diisobutylaluminium 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. Alternatively, the sulfinamides (XVIII) can be obtained from the corresponding sulfinimines using L-selectride in an organic solvent such as THF. Such transformations are known to those skilled in the art. For examples, see J. Org. Chem. 2006, 71, 6859 an / or J. Org. Chem. 2007, 72, 626 and the references therein. Based on the nature of the reducing agent and the chirality of the sulfur atom in the sulfinimine, the reduction is stereoselective and the preferred stereoisomer of the phenethylamine can be obtained as major product. Typically, the diastereomers of the sulfinamide are separated by chromatography on this stage to obtain the pure R-isomer of compounds of formula (X). The (R)-sulfinamides (XVIII) can be converted to the corresponding (R)-amines (X) in analogy to the numerous literature procedures. For example, the reaction can be performed using hydrogenchloride (HC1) in an aprotic organic solvent such as dioxane to give the corresponding HC1 salts. Basic aqueous work up gives the free NFL amine. For a review about sulfinimine and sulfinamide chemistry, see for example Chem. Rev. 2010, 110, 3600-3740; Chem. Soc. Rev. 2009, 38, 1162-1186; Tetrahedron 2004, 60, 8003 or W02013 / 030138 and the references therein.

[0354] Scheme 6

[0355] Scheme 6 Synthesis route for the preparation of certain compounds of general formula (X) in which Hal represents a halogen atom, preferably Br or I, PG represents a protecting group, and L’ together with Z represents L, whereas L, R2, R4, R5, and Raare defined as in general formula (I).

[0356] Certain compounds of formula (X) can be prepared from aryl halides (XXX) by Sonogashira coupling with acetylene derivatives (XXIX). The chiral phenethylamine can be introduced as described for compounds of formula (XVIII) in Scheme 5, thus leading to sulfinamides (XXVI). A sequence of deprotection, leading to amino alcohols (XXV), hydrogenation of the alkyne to obtain compounds of formula (XXIV), and selective protection of the alcohol leads to compounds of general formula (X).

[0357] Alternatively, partial hydrogenation of (XXVI) leads to olefins (XXIII), which can be further transferred into compounds of formula (X) by full deprotection and subsequent selective protection of the alcohol function of amino alkenol derivatives represented by general formula (XXII). Scheme 7

[0358] Scheme 7 Synthesis route for the preparation of certain compounds of general formula (X) in which Z represents O, PG represents a protecting group, and L’ together with Z represents L, whereas L, R2, R4, R5, and Raare defined as in general formula (I).

[0359] Certain compounds of general formula (X) can be obtained from coupling of ethyl-difluoroiodacetate (XXXVI) and benzyl bromide (XXXVII), typically mediated by sub stoichiometric amounts of copper in DMSO as solvent at ambient temperature. The obtained product (XXXV) can be reduced to alcohol (XXXIV) and protected to obtain aryl bromide (XXXIII). The chiral phenethylamine can be introduced by metal halogen exchange, followed by reaction of the aryl metal species with sulfinimine (XXXI). The resulting sulfinamide (XXXII) leads to certain compounds of general formula (X) after selective cleavage of the sulfinamide.

[0360] Scheme 8

[0361] Scheme 8 Synthesis route for the preparation of certain compounds of general formula (VI) in which PG represents a protecting group, and PG’ represents an orthogonal protecting group, whereas L, R2, R4, R5, and Raare defined as in general formula (I).

[0362] Certain compounds of general formula (VI) can be prepared from phenol derivative (XL) by O-alkylation or Mitsunobu reaction with the respective alkyl halides or alcohols, respectively. The obtained aryl ethers (XLII), (XLI), and (XXXIX) can be transferred to the compounds of general formula (VI) either by saponification of esters (XLII), hydrolysis of nitriles (XLI), or hydroboration of alkenes (XXXIX) followed by oxidation of the resulting alcohols (XXXVIII), using methods described in the literature and known to a person skilled in the art. Scheme 9

[0363] Scheme 9 Synthesis route for the preparation of certain compounds of general formula (VI) in which PG represents a protecting group, whereas L, R2, R4, R5, and Raare defined as in general formula (I). Certain compounds of general formula (VI) can be synthesised from aryl bromides of general formula (XLIV) by transition metal catalysed reactions, e.g. Heck reaction, Stille reaction, or Suzuki reaction of the aryl bromide with suitable alkenes or alkenyl metal derivatives, leading to styrenes (XLIII). Hydrogenation to obtain aryl alkyl esters (XLII) and subsequent saponification furnish the respective compounds of formula (VI).

[0364] Scheme 10

[0365]

[0366] Scheme 10 Synthesis route for the preparation of certain compounds of general formula (VI) in which PG represents a protecting group, whereas L, R2, R4, R5, and Raare defined as in general formula (I).

[0367] Certain compounds of general formula (VI) can be prepared from benzylic alcohols represented by general formula (XLVIII) by O-alkylation with the respective alkyl halides or alkyl sulfonates, leading to benzyl ethers (XLVII). The chiral phenethylamine can be introduced by metal halogen exchange, followed by reaction of the aryl metal species with sulfinimine (XXXI). The resulting sulfinamides (XL VI) can be transferred into the alcohols (XLV) by selective O-deprotection. For example, silyl protecting groups like TBS can be selectively cleaved in the presence of the sulfinamide using TBAF. Oxidation by methods known to persons skilled in the art of the resulting alcohol leads to carboxylic acid derivatives of general formula (VI). For example, oxidation of the alcohol to the corresponding carboxylic acid can be achieved using catalytic amounts of tetrapropylammonium perruthenate in acetonitrile at 0 °C.

[0368] Analytical LC-MS

[0369] Method 1 :

[0370] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH Cl 8 1.7 pm, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1- 99% B, 1.6-2.0 min 99% B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.

[0371] Method 2: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH Cl 8 1.7 pm, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml / min; temperature: 60 °C; DAD scan: 210-400 nm.

[0372] Method 3 Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith© Flash RP-18E 25*2 mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml / min; temperature: 50 °C; PDA: 220nm&254nm.

[0373] Preparative HPLC a) Autopurifier: acidic method

[0374] System: Waters Autopurification system: Pump 2545, Sample Manager 2767,

[0375] CFO, DAD 2996, ELSD 2424, SQD

[0376] Column: XBrigde Cl 8 5.0 pm 100x30 mm

[0377] Solvent: A = H2O + 0.1 %vol. HCOOH (99%)

[0378] B = acetonitrile

[0379] Gradient: 0-0.5 min 5% B 25 ml / min, 0.51-5.5 min 10-100% B 70 ml / min, 5.51-6.5 min, 100% B, 70 ml / min

[0380] Temperature: RT

[0381] Solution: max. 250 mg / max. 2.5 ml DMSO or DMF

[0382] Injection: 1 x 2.5 ml

[0383] Detection: DAD scan range 210-400 nm, MS ESI+, ESI-, scan range 160-1000 m / z b) Autopurifier: basic method

[0384] System: Waters Autopurification system: Pump 2545, Sample Manager 2767,

[0385] CFO, DAD 2996, ELSD 2424, SQD

[0386] Column: XBrigde Cl 8 5.0 pm 100x30 mm

[0387] Solvent: A = H2O + 0.2%vol. NH3(32%)

[0388] B = acetonitrile

[0389] Gradient: 0-0.5 min 5% B 25 ml / min, 0.51-5.5 min 10-100% B 70 ml / min, 5.51-6.5 min, 100% B, 70 ml / min

[0390] Temperature: RT

[0391] Solution: max. 250 mg / max. 2.5 ml DMSO or DMF

[0392] Injection: 1 x 2.5 ml

[0393] Detection: DAD scan range 210-400 nm, MS ESI+, ESI-, scan range 160-1000 m / z

[0394] General synthetic procedures

[0395] General Procedure A

[0396] The phenol derivative (1 equiv.) was dissolved in DMF (0.2 M), then K2CO3(3 equiv.) was added, followed by the alkyl halide (1.5 equiv.). The reaction mixture was heated at 60 °C for 18 hours for alkyl bromides and 80 °C for alkyl chlorides. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (x3). The combined organic extracts were washed with brine (x2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained material can be used without purification.

[0397] General Procedure B

[0398] The ester was dissolved in a mixture of THF : 1 M alkali metal hydroxide (1 : 1) and stirred at room temperature for 2-18 hours. The reaction mixture was neutralised to pH 7 with aqueous citric acid, then extracted into EtOAc (x3). The combined org. phases were dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained material can be used in the next step without purification.

[0399] General Procedure C

[0400] Acid (1 equiv.), amine (1.2 equiv.), NMI (2.0 equiv.), and TCFH (2.0 equiv.) were dissolved in N,N• dimethylacetamide (0.2 M) and stirred at room temperature for up to 24 hours. The reaction mixture was diluted with EtOAc, washed with water, and brine (x2). The org. phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography afforded the title compound.

[0401] General Procedure D

[0402] Starting material (1 equiv.) was dissolved in EtOH (0.01 M), then NaOEt (21w% in EtOH, 1.1 equiv.) was added and stirred at room temperature for 30 minutes. The reaction was quenched with water and extracted into EtOAc (x3). The combined org. phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography afforded the title compound.

[0403] General Procedure E

[0404] N-Boc protected amine (1 equiv.) was dissolved in a mixture of 10 : 1 DCM : TFA (0.1 M) and stirred at room temperature for 18 hours. Additional THF can be added as required. The reaction mixture was concentrated under reduced pressure, dissolved in DCM and washed with sat. aq. NaHCO3solution (x3). The org. phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. The obtained product was used without further purification.

[0405] General Procedure F

[0406] N-Boc protected amine (1 equiv.) was suspended in 1,4-dioxane or EtOH (0.4 M), then HC1 (4 M in 1,4- dioxane, 10 equiv.) was added and stirred at room temperature for 2-24 hours. The solvent was removed under reduced pressure to afford the title compound. The obtained product was used without further purification.

[0407] General Procedure G The starting material (1 equiv.) and BOP (1.3 equiv.) were dissolved in DMF (0.01 M), then DIPEA (1.5 equiv.) and DBU (4 equiv.) were added and stirred at room temperature for 3-24 hours. The reaction was quenched with brine and extracted into either DCM or EtOAc (x3). The combined org. phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography afforded the title compound.

[0408] General Procedure H

[0409] To a solution of halide (1.0 eq.) and dimethylphosphinoxide (1.0 - 1.1 eq.) in MeCN was added triethylamine (3.5 eq.) and palladium catalyst ((Pd(PPh3)4or Pd(dppf)Cl2-CH2Cl2, 0.2 eq.). The reaction mixture was purged with argon and stirred at 100 °C overnight. The mixture was filtered and concentrated. Purification by HPLC or prep. TLC yielded the desired compound.

[0410] General Procedure I

[0411] Pyridopyrimidine substrate (1 eq.) was dissolved in DMSO at RT. Nitromethane (5 eq.) was added, followed by l,8-diazabicyclo[5.4.0]undec-7-en (2 eq.). The mixture was stirred at RT for 1-5 days until conversion was sufficient as monitored by LCMS. The crude reaction mixture was directly purified by preparative HPLC purification (acidic or basic method) to give the desired compound.

[0412] General Procedure J

[0413] To a solution of pyridopyrimidine halide substrate (1.0 eq.) and nucleophile (1.5 eq.) in 1,4-dioxane was added K2CO3(4.0 eq.), trans-N,N•-dimethylcyclohexane-l,2-diamine (0.4 eq. - 0.6 eq.) and Cui (0.25 eq. - 0.4 eq.). The reaction mixture was purged with argon and stirred at 100 °C overnight. The mixture was filtered and concentrated. Purification by HPLC yielded the desired compound.

[0414] General Procedure K

[0415] To a solution of pyridopyrimidine halide (1.0 eq.) and dialkylphosphinoxide (1.0 - 1.1 eq.) in MeCN was added triethylamine (3.5 eq.) and palladium catalyst ((Pd(PPh3)4or Pd(dppf)Cl2-CH2Cl2, 0.2 eq.). The reaction mixture was purged with argon and stirred at 100 °C overnight. The mixture was filtered and concentrated. Purification by HPLC or prep. TLC yielded the desired compound.

[0416] General Procedure L

[0417] To a solution of halide (1.0 eq.) and amine (1.2-2.0 eq.) in 1,4-dioxane was added sodium tert-butoxide (2.0 - 4.0 eq.), Pd2(dba)3(0.05 - 0.5 eq), and XPhos (0.1 - 1 eq.). The reaction was purged with argon and stirred at 100 °C for 3 hours. The mixture was filtered and concentrated. Purification by HPLC yielded the desired compound.

[0418] General Procedure M

[0419] To a solution of an aromatic halide (1.0 eq.) and nucleophile (4.0 - 5.0 eq.) in 1,4-dioxane was added potassium carbonate (2.0 - 3.0 eq.), trans-N,N•-dimethylcyclohexane-l,2-diamine (1.0 - 1.5 eq.) and copper(I) iodide (1.0 eq.). The reaction mixture was purged with argon and stirred at 100 °C to 110 °C overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by HPLC (afterwards in some cases preparative TLC was used) yielding the desired compound.

[0420] EXPERIMENTAL SECTION - INTERMEDIATES

[0421] Intermediate 1

[0422] 6-chloropyrido[3,4-d]pyrimidine-2,4(lH,3H)-dione

[0423] A mixture of 5-amino-2-chloropyridine-4-carboxylic acid (25.0 g, 145 mmol) and urea (34.8 g, 579 mmol) was heated to 170 °C for 3 h. Then, the mixture was cooled to 100 °C, water was added and the mixture was heated at 100 °C for 1 h. The resulting precipitate was collected by filtration at rt and dried at 75 °C under reduced pressure for 5 days. The titled compound was obtained as a solid (21.3 g, 74 % yield).

[0424] LC-MS (Method 1): Rt= 0.58 min; MS (ESIneg): m / z = 196 [M-H]

[0425] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 2.518 (1.06), 2.523 (0.71), 7.536 (0.74), 7.769 (15.20), 7.771 (16.00), 7.920 (0.82), 8.353 (15.35), 11.622 (0.79).

[0426] Intermediate 2

[0427] 2,4,6-trichloropyrido[3,4-d]pyrimidine

[0428] A mixture of 6-chloropyrido[3,4-d]pyrimidine-2,4(lH,3H)-dione (5.00 g, 25.3 mmol), DIPEA (22 ml, 130 mmol) and phosphoric trichloride (50 ml, 540 mmol) was heated at 100 °C overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc and extracted with sat. aq. NaHCO3solution and brine. The org. phase was dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (2.10 g, 35 % yield) as a solid.

[0429] LC-MS (Method 1): Rt= 1.15 min; MS (ESIpos): m / z = 234 [M+H]+1H-NMR (400 MHz, DMSO-d6) • [ppm]: 2.518 (1.22), 2.522 (0.79), 5.337 (1.55), 7.974 (15.20), 8.851 (16.00), 8.853 (14.94).

[0430] Intermediate 3 methyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy]butanoate

[0431] To a suspension of tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (743 mg, 2.43 mmol) and K2CO3(1.01 g, 7.30 mmol) in DMF (15 mL), methyl 4-bromobutanoate (0.46 mL, 3.65 mmol) was added and the mixture was stirred at 60 °C for 3 hours. The reaction mixture was poured onto water and extracted into EtOAc (3x). The combined org. phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the titled compound (1.25 g, quant.) as a pale yellow oil, which was used without further purification.

[0432] LC-MS (Method 2): Rt= 1.38 min; MS (ESIpos): m / z = 406 [M+H]+

[0433] 1H NMR (400 MHz, DMSO-rfc) • ppm 1.15 - 1.33 (m, 8 H) 1.33 - 1.51 (m, 10 H) 1.98 - 2.08 (m, 5 H) 2.38 - 2.48 (m, 1 H) 2.52 - 2.57 (m, 3 H) 2.68 - 2.74 (m, 7 H) 2.89 (s, 7 H) 3.30 - 3.35 (m, 1 H) 3.38 - 3.44 (m, 1 H) 3.53 - 3.62 (m, 7 H) 3.78 - 3.88 (m, 1 H) 3.95 - 4.08 (m, 1 H) 4.09 - 4.18 (m, 1 H) 4.94 (br t, 1 H) 7.32 (t, 1 H) 7.51 - 7.60 (m, 2 H) 7.70 (br d, 1 H) 7.95 (s, 2 H).

[0434] Intermediate 4

[0435] 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenoxy]butanoic acid Methyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenoxy]butanoate (270 mg, 666 μmol) was dissolved in THF (2.7 ml), then aq. NaOH solution (3.3 ml, 1.0 M, 3.3 mmol) was added and the mixture was stirred ar rt for 18 hours. The reaction mixture was neutralized to pH=7 using aq. citric acid solution and extracted into EtOAc (3x). The combined org. phases were filtered through hydrophobic filter paper and concentrated under reduced pressure to obtain the titled compound (260 mg, 100 % yield), which was used without further purification.

[0436] LC-MS (Method 1): Rt= 1.24 min; MS (ESIpos): m / z = 392 [M+H]+

[0437] 1H NMR (400 MHz, DMSO-rfc) • ppm 1.15 - 1.31 (m, 6 H) 1.35 (s, 7 H) 1.91 (s, 3 H) 1.96 - 2.03 (m, 3 H) 2.41 - 2.47 (m, 2 H) 3.81 - 3.94 (m, 1 H) 4.03 (q, 1 H) 4.13 (br d, 1 H) 4.95 (br t, 1 H) 7.32 (t, 1 H) 7.50 - 7.60 (m, 2 H) 7.71 (br d, 1 H) 12.06 (br s, 2 H).

[0438] Intermediate 5 tert-butyl { ( 1 R)- 1 - [2- { 4- [(4-carbamoyl-6-methoxypyridin-3-yl)amino] -4-oxobutoxy } -3- (trifluoromethyl)phenyl] ethyl } carbamate

[0439] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy]butanoic acid (210 mg, 537 μmol), 5-amino-2-methoxypyridine-4-carboxamide (108 mg, 644 μmol), and HATU (306 mg, 805 μmol) were dissolved in DMF (4.2 ml), then DIPEA (280 pl, 1.6 mmol) was added. The reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with water and sat. aq. NaHCO3solution, and extracted into EtOAc (3x). The combined org. phase was filtered through hydrophobic filter paper and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (310 mg, quant.).

[0440] LC-MS (Method 2): Rt= 1.20 min; MS (ESIpos): m / z = 541 [M+H]+

[0441] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (1.96), 1.172 (3.69), 1.190 (1.85), 1.256 (2.35), 1.273 (2.54), 1.345 (10.13), 1.988 (6.22), 2.044 (1.17), 2.092 (0.79), 2.518 (2.43), 2.523 (1.72), 2.570 (0.70), 2.729 (3.69), 2.888 (4.42), 3.739 (4.05), 3.853 (3.11), 3.859 (16.00), 3.879 (0.53), 3.899 (0.49), 3.999 (0.47), 4.017 (1.34), 4.035 (1.37), 4.053 (0.43), 4.969 (0.39), 5.805 (0.56), 6.924 (0.88), 7.050 (0.41), 7.078 (1.69), 7.307 (0.58), 7.326 (1.23), 7.346 (0.71), 7.535 (1.24), 7.555 (1.18), 7.582 (0.50), 7.692 (0.76), 7.713 (1.47), 7.887 (0.79), 7.951 (0.56), 8.278 (0.64), 8.844 (1.09), 10.438 (0.88).

[0442] Intermediate 6 tert-butyl [( 1 R)- 1 - { 2- [3 -(6-methoxy-4-oxo-3 ,4-dihydropyrido[3 ,4-d]pyrimidin-2-yl)propoxy] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[0443] T ert-butyl { ( 1 R) - 1 - [2 - { 4 - [(4-carbamoyl-6-methoxypyridin-3 -yl)amino] -4-oxobutoxy } -3-

[0444] (trifluoromethyl)phenyl] ethyl} carbamate (20.0 mg, 37.0 μmol) was dissolved in POCh (34 pl) and stirred at rt for 3 days. The reaction mixture was quenched with sat. aq. NaHCO3solution and extracted into EtOAc (3x). The combined org. phase was filtered through hydrophobic filter paper and concentrated under reduced pressure. Purification by HPLC (basic method) yielded the titled compound (13 mg, 83 % yield).

[0445] LC-MS (Method 2): Rt= 0.93 min; MS (ESIneg): m / z = 421.0 [M-H]

[0446] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.072 (1.26), 1.109 (0.41), 1.465 (3.14), 1.482 (3.12), 1.752 (0.56), 1.903 (7.20), 2.251 (1.04), 2.268 (1.51), 2.285 (1.09), 2.313 (1.60), 2.829 (1.21), 2.848 (1.91), 2.866 (1.02), 2.887 (0.50), 2.960 (0.62), 3.048 (0.63), 3.814 (0.96), 3.934 (16.00), 3.964 (1.01), 3.979 (0.51), 4.032 (0.83), 4.053 (0.65), 4.619 (0.77), 4.636 (0.75), 7.257 (4.74), 7.408 (0.70), 7.428 (1.44), 7.448 (0.84), 7.659 (1.53), 7.678 (1.30), 8.014 (1.08), 8.034 (1.03), 8.715 (4.50).

[0447] Intermediate 7 tert-butyl { ( 1 R) - 1 - [2-fluoro-3 -(trifluoromethyl)phenyl] ethyl } carbamate

[0448] To a solution of (lR)-l-[2-fluoro-3-(trifluoromethyl)phenyl]ethan-l-amine hydrogen chloride (1 / 1) (1.00 g, 4.10 mmol) and Et3N (1.7 ml, 12 mmol) in DCM (10 ml) was added di-tert-butyl dicarbonate (1.07 g, 4.93 mmol) and the reaction mixture was stirred at rt for 3 days. The mixture was washed with sat. aq. NaHCO3solution and brine and then dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) gave the titled compound (1.21 g, 96 % yield).

[0449] LC-MS (Method 2): Rt= 1.37 min; MS (ESIneg): m / z = 306 [M-H]

[0450] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (0.87), 1.303 (7.60), 1.321 (7.84), 1.353 (16.00), 2.518 (0.69), 2.523 (0.45), 4.907 (0.48), 4.925 (0.67), 4.943 (0.45), 7.388 (0.68), 7.407 (1.53), 7.427 (0.91), 7.636 (1.18), 7.653 (1.82), 7.668 (0.98), 7.687 (0.78), 7.707 (1.37), 7.725 (0.69).

[0451] Intermediate 8 tert-butyl { ( 1 R) - 1 - [2-hydroxy-3 -(trifluoromethyl)phenyl] ethyl } carbamate

[0452] A mixture of tert-butyl {(lR)-l-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamate (1.16 g, 2.45 mmol), 2-(methylsulfonyl)ethanol (1.52 g, 12.3 mmol) and CS2CO3(4.00 g, 12.3 mmol) in DMF (15 ml) was stirred at 40 °C for 5 days. The reaction mixture was quenched by addition of water and extracted with DCM / iPrOH (3 / 1; 3x). The combined org. layers were dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (81.0 mg, 11 % yield).

[0453] LC-MS (Method 2): Rt= 0.94 min; MS (ESIneg): m / z = 304 [M-H]

[0454] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.084 (0.41), 1.172 (0.47), 1.190 (0.47), 1.233 (1.12), 1.261

[0455] (12.52), 1.278 (12.61), 1.353 (16.00), 1.987 (0.41), 2.084 (2.51), 2.518 (1.95), 2.523 (1.30), 4.994 (1.33), 5.012 (1.86), 5.029 (1.27), 5.759 (0.74), 6.967 (2.51), 6.986 (5.28), 7.005 (2.89), 7.392 (4.04), 7.395

[0456] (4.52), 7.411 (3.87), 7.414 (3.93), 7.478 (4.19), 7.481 (4.13), 7.497 (4.01), 7.604 (0.92), 9.627 (1.45). Intermediate 9 tert-butyl { ( 1 R)- 1 - [2-(2- { [tert-butyl(diphenyl)silyl] oxy } ethoxy)-3- (trifluoromethyl)phenyl] ethyl } carbamate

[0457] A mixture of tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (350 mg, 1.15 mmol) and K2CO3(475 mg, 3.44 mmol) in DMF (7.0 ml) was stirred at rt for 10 min before (2- bromoethoxy)(tert-butyl)diphenylsilane (625 mg, 1.72 mmol) was added. The reaction mixture was stirred at 60 °C overnight. The mixture was diluted with EtOAc, washed with water (2x) and brine, dried over Na2SO4. filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) gave the titled compound (225 mg, 33 % yield).

[0458] LC-MS (Method 2): Rt= 1.85 min; MS (ESIpos): m / z = 588 [M+H]+

[0459] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.794 (0.57), 0.861 (0.51), 0.950 (8.38), 1.005 (1.04), 1.021 (16.00), 1.033 (2.12), 1.083 (1.64), 1.179 (2.25), 1.196 (2.15), 1.231 (0.54), 1.259 (3.42), 1.278 (0.60), 1.360 (11.83), 1.390 (0.44), 2.518 (1.11), 2.523 (0.73), 3.960 (0.63), 3.975 (0.73), 3.986 (1.01), 4.002 (0.85), 4.516 (0.41), 5.202 (0.44), 6.558 (1.68), 7.326 (0.47), 7.345 (1.08), 7.363 (0.82), 7.374 (0.98), 7.378 (1.01), 7.386 (2.12), 7.391 (1.96), 7.397 (0.76), 7.402 (0.82), 7.412 (1.08), 7.418 (2.50), 7.434 (3.29), 7.452 (3.04), 7.459 (1.99), 7.464 (1.30), 7.468 (1.11), 7.476 (1.42), 7.487 (0.41), 7.539 (0.98), 7.556 (0.82), 7.584 (0.60), 7.602 (0.57), 7.671 (1.08), 7.674 (0.63), 7.680 (1.23), 7.682 (1.80), 7.687 (1.36), 7.689 (1.71), 7.695 (1.71), 7.703 (2.66), 7.717 (2.62), 7.731 (1.39), 10.855 (1.26). Intermediate 10

[0460] ( 1 R)- 1 - [2-(2- { [tert-butyl(diphenyl)silyl]oxy } ethoxy)-3-(trifluoromethyl)phenyl]ethan- 1 -amine

[0461] To a solution of tert-butyl {(lR)-l-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethoxy)-3- (trifluoromethyl)phenyl] ethyl} carbamate (452 mg, 769 μmol) and Et3SiH (25 μl, 150 μmol) in DCM (6.0 ml) was added TFA (590 μl, 7.7 mmol) at 0 °C and the mixture was stirred at rt overnight. The reaction was quenched by addition of aq. NH3solution (25%) and DCM. The org. phase was separated and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc followed by DCM / EtOH) gave the titled compound (214 mg, 57 % yield). LC-MS (Method 2): Rt= 1.75 min; MS (ESIpos): m / z = 488 [M+H]+

[0462] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.025 (1.65), 1.033 (16.00), 1.213 (2.59), 1.229 (2.62), 2.518

[0463] (1.16), 2.523 (0.75), 3.952 (0.52), 3.971 (1.76), 3.987 (0.45), 4.102 (0.49), 4.500 (0.49), 4.516 (0.49),

[0464] 5.758 (1.12), 7.324 (0.67), 7.416 (0.45), 7.423 (0.64), 7.438 (2.14), 7.456 (3.00), 7.461 (2.21), 7.465

[0465] (1.09), 7.469 (0.49), 7.476 (1.01), 7.507 (0.56), 7.511 (0.56), 7.527 (0.49), 7.530 (0.45), 7.684 (1.95), 7.687 (1.80), 7.703 (1.87), 7.706 (1.39), 7.892 (0.49), 7.895 (0.49), 7.912 (0.45).

[0466] Intermediate 11

[0467] N- { (1R)- 1 - [2-(2- { [tert-butyl(diphenyl)silyl]oxy }ethoxy)-3-(trifluoromethyl)phenyl]ethyl } -2,6- dichloropyrido[3,4-d]pyrimidin-4-amine

[0468]

[0469] To a solution of 2,4,6-trichloropyrido[3,4-d]pyrimidine (107 mg, 456 μmol) and (lR)-l-[2-(2-{ [tert- butyl(diphenyl)silyl]oxy}ethoxy)-3-(trifluoromethyl)phenyl]ethan-l-amine (212 mg, 435 μmol) in DMF (3.4 ml) was added EpN (300 pl) and the mixture was stirred at rt overnight. The reaction was quenched by addition of EtOAc and water. The org. phase was washed with water (2x) and brine, dried over Na2SCh. filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) gave the titled compound (288 mg, 92 % yield).

[0470] LC-MS (Method 2): Rt= 1.86 min; MS (ESIpos): m / z = 685 [M+H]+

[0471] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.983 (16.00), 1.170 (0.74), 1.443 (1.93), 1.460 (1.93), 1.985 (1.33), 2.518 (2.07), 2.523 (1.19), 3.311 (0.44), 3.414 (0.44), 4.070 (0.74), 4.079 (0.74), 4.085 (0.89),

[0472] 5.753 (0.44), 5.815 (0.44), 7.312 (0.74), 7.336 (0.59), 7.340 (0.59), 7.357 (1.63), 7.376 (2.52), 7.395 (1.33), 7.402 (1.04), 7.408 (0.89), 7.412 (0.59), 7.419 (1.04), 7.426 (0.89), 7.590 (0.59), 7.607 (0.59), 7.652 (1.48), 7.656 (1.48), 7.672 (2.81), 7.676 (2.37), 7.691 (1.33), 7.695 (0.89), 7.742 (0.59), 7.762 (0.59), 8.662 (1.93), 8.897 (2.22), 9.462 (0.59), 9.478 (0.59).

[0473] Intermediate 12

[0474] 2- [2- { ( 1 R)- 1 - [(2,6-dichloropyrido[3 ,4-d]pyrimidin-4-yl)amino]ethyl } -6- (trifluoromethyl)phenoxy]ethan- 1 -ol To a solution of N-{(lR)-l-[2-(2-{ [tert-butyl(diphenyl)silyl]oxy}ethoxy)-3- (trifluoromethyl)phenyl]ethyl}-2,6-dichloropyrido[3,4-d]pyrimidin-4-amine (286 mg, 417 μmol) in THF (2.7 ml) was added a TBAF solution (IM in THF, 630 pl) and the reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated and purification by flash column chromatography (hexane / EtOAc) gave the titled compound (172 mg, 92 % yield).

[0475] LC-MS (Method 2): Rt= 1.25 min; MS (ESIpos): m / z = 447 [M+H]+

[0476] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.153 (3.59), 1.170 (7.18), 1.189 (3.59), 1.229 (0.65), 1.257 (0.33), 1.351 (0.33), 1.529 (15.67), 1.546 (16.00), 1.986 (14.69), 2.523 (4.24), 3.431 (0.65), 3.783 (0.65), 3.800 (1.63), 3.813 (4.57), 3.825 (5.22), 3.836 (3.59), 3.846 (1.96), 3.861 (0.33), 3.954 (1.63), 3.964 (2.61), 3.977 (2.61), 3.989 (2.94), 3.998 (2.29), 4.016 (3.27), 4.034 (3.27), 4.051 (0.98), 4.633 (1.63), 4.648 (2.29), 4.660 (2.29), 4.673 (1.96), 4.684 (1.31), 4.971 (4.24), 4.985 (9.80), 4.998 (3.92), 5.741 (0.65), 5.757 (2.29), 5.775 (3.59), 5.791 (2.29), 5.808 (0.65), 7.275 (2.61), 7.294 (5.55), 7.314 (2.94), 7.578 (4.90), 7.594 (4.24), 7.741 (4.57), 7.758 (4.24), 8.662 (13.71), 8.886 (15.02), 9.442 (3.92), 9.459 (3.59).

[0477] Intermediate 13

[0478] (15R)-2-chloro-15-methyl-ll-(trifluoromethyl)-8,9,15,16-tetrahydro-6,17-(azeno)pyrido[3,4- g] [ 1 ,4,6, 10]benzodioxadiazacyclotridecine

[0479] To a solution of 2-[2-{(lR)-l-[(2,6-dichloropyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-6- (trifluoromethyl)phenoxy]ethan-l-ol (145 mg, 324 μmol) in 1,4-dioxane (18 ml) was added an LDA solution (2M in THF / heptane / ethylbenzene, 180 pl). The reaction mixture was stirred at 80 °C for 1 h. The mixture was quenched by addition of aq. sat. NH4CI solution, extracted with EtOAc and concentrated under reduced pressure. Purification by prep. TLC (hexane / EtOAc) yielded the titled compound (89.0 mg, 67 % yield).

[0480] LC-MS (Method 2): Rt= 1.25 min; MS (ESIpos): m / z = 411 [M+H]+

[0481] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.774 (1.00), 0.793 (2.40), 0.811 (1.17), 0.817 (0.95), 0.834 (1.00), 0.842 (0.95), 0.860 (1.45), 0.870 (0.45), 0.878 (0.67), 1.003 (2.12), 1.032 (1.84), 1.082 (4.91), 1.099 (0.61), 1.153 (3.07), 1.171 (6.19), 1.189 (3.18), 1.230 (0.39), 1.258 (6.24), 1.390 (0.67), 1.403 (0.50), 1.419 (0.78), 1.438 (0.61), 1.441 (0.56), 1.529 (1.06), 1.547 (1.17), 1.580 (16.00), 1.598 (16.00), 1.986 (11.65), 2.083 (1.11), 2.518 (3.85), 2.522 (2.51), 3.636 (1.39), 3.667 (1.39), 3.823 (0.50), 3.998

[0482] (0.89), 4.015 (2.56), 4.033 (2.51), 4.051 (0.84), 4.520 (1.23), 4.536 (1.45), 4.553 (1.62), 4.568 (1.62),

[0483] 4.815 (2.06), 4.821 (2.01), 4.848 (1.67), 4.853 (1.62), 4.982 (0.50), 5.073 (1.67), 5.089 (1.73), 5.104

[0484] (1.67), 5.120 (1.45), 5.758 (7.08), 6.000 (0.45), 6.017 (1.67), 6.034 (2.40), 6.051 (1.62), 6.069 (0.45),

[0485] 7.261 (2.34), 7.281 (5.02), 7.300 (2.79), 7.559 (4.29), 7.563 (4.68), 7.578 (4.18), 7.582 (3.85), 7.739

[0486] (4.07), 7.742 (4.07), 7.758 (3.85), 7.762 (3.51), 8.298 (13.27), 8.664 (14.38), 8.886 (0.72), 9.576 (3.68), 9.592 (3.57), 10.516 (0.95), 10.637 (1.00), 10.853 (2.68), 11.153 (0.45).

[0487] Intermediate 14

[0488] (15R)-2-chloro-4,15-dimethyl-ll-(trifluoromethyl)-8,9,15,16-tetrahydro-6,17-(azeno)pyrido[3,4- g] [ 1 ,4,6, 10]benzodioxadiazacyclotridecine

[0489] To a solution of (15R)-2-chloro-15-methyl-ll-(trifluoromethyl)-8,9,15,16-tetrahydro-6,17- (azeno)pyrido[3,4-g][l,4,6,10]benzodioxadiazacyclotridecine (25.0 mg, 60.9 μmol) in DMSO (500 pl) was added DBU (19 pl, 121 μmol) and nitromethane (16 pl, 301 μmol) and the mixture was stirred at rt for 2 days. The mixture was diluted with DMSO and purification by HPLC (basic method) yielded the titled compound (14.9 mg, 58 % yield).

[0490] LC-MS (Method 2): Rt= 1.34 min; MS (ESIpos): m / z = 425 [M+H]+

[0491] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.572 (6.42), 1.590 (6.47), 2.518 (1.86), 2.522 (1.16), 2.599 (16.00), 3.636 (0.55), 3.667 (0.57), 4.504 (0.52), 4.519 (0.60), 4.537 (0.68), 4.552 (0.66), 4.813 (0.82), 4.821 (0.81), 4.847 (0.67), 4.854 (0.64), 5.077 (0.67), 5.093 (0.69), 5.108 (0.69), 5.124 (0.58), 6.012 (0.93), 6.030 (0.91), 7.252 (0.94), 7.271 (2.01), 7.291 (1.10), 7.551 (1.77), 7.556 (1.95), 7.571 (1.62), 7.575 (1.58), 7.735 (1.56), 7.739 (1.56), 7.754 (1.49), 7.758 (1.34), 8.121 (4.79), 9.478 (0.57).

[0492] Intermediate 15

[0493] (S2S) -N- { ( 1 E) - 1 - [2-bromo-3 -(trifhroromethyl)phenyl] ethylidene } -2-methylpropane-2-sulfinamide l-[2-Bromo-3-(trifluoromethyl)phenyl]ethan-l-one (5.91 g, 22.1 mmol) was dissolved in THF (61 mL) under argon atmosphere. (S2S)-2-Methylpropane-2-sulfinamide (5.36 g, 44.3 mmol) was added, followed by titanium(IV)ethoxide (19 ml, 89 mmol). The mixture was heated to 80 °C overnight. Water was added to the reaction mixture, which was further diluted with EtOAc and then filtered. The mixture was further diluted with water and the organic phase was separated. The aq. phase was extracted with EtOAc and the organic phases were combined. The organic phase was dried and the solvent was evaporated. The residue was purified by flash column chromatography on silica using hexane / EtOAc as eluent to give the title compound (6.94 g, 85% yield).

[0494] LC-MS (Method 2): Rt= 1.34 min; MS (ESIpos): m / z = 372.2 [M+H]+

[0495] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.141 (4.85), 1.159 (15.03), 1.167 (2.48), 1.172 (1.21), 1.189 (0.67), 1.215 (16.00), 1.986 (0.67), 2.437 (5.26), 2.469 (1.69), 2.642 (5.80), 7.603 (1.39), 7.621 (0.70), 7.685 (1.52), 7.697 (2.00), 7.817 (0.51), 7.823 (0.53), 7.834 (0.61), 7.840 (0.50), 7.891 (0.56), 7.902 (0.76), 7.915 (0.43).

[0496] Intermediate 16

[0497] (S2S)-N- { (1R)- 1 -[2-bromo-3-(trifluoromethyl)phenyl]ethyl } -2-methylpropane-2-sulfinamide

[0498] (S2S)-N-{(lE)-l-[2-Bromo-3-(trifluoromethyl)phenyl]ethylidene}-2-methylpropane-2-sulfinamide (9.90 g, 26.7 mmol) was dissolved in THF (99 mL) under argon atmosphere. The mixture was cooled to -78 °C. L-Selectride (53 ml, 1.0 M in THF, 53 mmol) was added dropwise and the mixture was stirred at -78 °C for 2 hours. The mixture was allowed to warm to RT overnight. The mixture was cooled with an ice bath and carefully quenched with sat. aq. NH4CI solution. The mixture was stirred for 1 hour at RT and then extracted twice with EtOAc. The combined organic phases were dried and the solvent evaporated. The residue was purified by flash column chromatography on silica using hexane / EtOAc as eluent to give the title compound (5.10 g, 51% yield).

[0499] LC-MS (Method 2): Rt= 1.29 min; MS (ESIpos): m / z = 374.4 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.105 (16.00), 1.448 (2.10), 1.465 (2.05), 1.987 (0.59), 5.683 (0.51), 5.697 (0.49), 7.616 (0.56), 7.729 (0.46), 7.733 (0.53), 7.844 (0.42), 7.847 (0.41).

[0500] Intermediate 17

[0501] ( 1 R) - 1 - [2-bromo-3 -(trifluoromethyl)phenyl] ethan- 1 -amine — hydrogen chloride ( 1 / 1 )

[0502] (S2S)-N-{(lR)-l-[2-Bromo-3-(trifluoromethyl)phenyl]ethyl}-2-methylpropane-2-sulfinamide (7.60 g, 20.4 mmol) was dissolved in 1,4-dioxane (250 mL). Hydrogen chloride (51 ml, 4.0 M in 1,4-dioxane, 200 mmol) was added and the mixture was stirred at RT for 3 hours. The solvent and all volatiles were evaporated. Toluene was added and all volatiles were again evaporated. This step was repeated 2 more times to give the title compound (6.9 g) as crude mixture that was used in the next step without any further purification.

[0503] LC-MS (Method 2): Rt= 1.12 min; MS (ESIpos): m / z = 268.1 [M+H]+

[0504] Intermediate 18 tert-butyl { ( 1 R) - 1 - [2-bromo-3 -(trifluoromethyl)phenyl] ethyl } carbamate

[0505] (lR)-l-[2-Bromo-3-(trifluoromethyl)phenyl]ethan-l-amine — hydrogen chloride (1 / 1) (2.90 g, 90 % purity, 8.57 mmol) was suspended in CH2Cl2(29 mL). Triethylamine (4.8 ml, 34 mmol) was added and the mixture was cooled to 0 °C. Di-tert-butyl dicarbonate (2.24 g, 10.3 mmol) was added and the mixture was allowed to warm to RT and was stirred overnight. Sat. aq. NaHCO3solution was added. The organic phase was separated and washed with brine and then dried. The solvent was evaporated. The residue was purified by flash column chromatography on silica using hexane / EtOAc as eluent to give the title compound (3.40 g).

[0506] LC-MS (Method 2): Rt= 1.40 min; MS (ESIneg): m / z = 366.3 [M-H] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.107 (1.28), 1.258 (3.60), 1.276 (3.30), 1.349 (16.00), 5.043 (0.52), 5.062 (0.71), 5.079 (0.47), 7.583 (0.55), 7.602 (1.24), 7.621 (1.02), 7.707 (4.44), 7.727 (3.10), 7.781 (0.77), 7.799 (0.75).

[0507] Intermediate 19 ethyl (4E)-5- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenyl]pent-4-enoate

[0508] Tert-butyl {(lR)-l-[2-bromo-3-(trifluoromethyl)phenyl]ethyl]carbamate (1.50 g, 4.07 mmol) was dissolved in DMF (30 mL). Tri-2-tolylphosphine (1.24 g, 4.07 mmol), palladium(II)acetate (457 mg, 2.04 mmol) and sodium acetate (668 mg, 8.15 mmol) were added and the atmosphere was exchanged to argon. Ethyl pent-4-enoate (1.8 ml, 12 mmol) was added and the mixture was stirred at 130 °C for 21 hours. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic phases were dried and the solvent was evaporated. The residue was purified by flash column chromatography on silica using hexane / EtOAc as eluent to give the title compound (1.95 g) as a mixture (~3:1) of two isomers of the double bond. The mixture was used without further purification in the next step.

[0509] Major Isomer:

[0510] LC-MS (Method 2): Rt= 1.52 min; MS (ESIpos): m / z = 416.3 [M+H]+

[0511] Minor Isomer:

[0512] LC-MS (Method 2): Rt= 1.50 min; MS (ESIpos): m / z = 416.3 [M+H]

[0513] Intermediate 20 ethyl 5-[2-{(lR)-l - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifhioromethyl)phenyl] pentanoate

[0514]

[0515] Ethyl (4E)-5-[2-{(lR)-l-[(tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenyl]pent-4-enoate (L90 g, 4.57 mmol) was dissolved in EtOH (280 mL) under argon atmosphere. Palladium on carbon (Pd / C) (3.12 g, 10 % purity, 1.37 mmol) was added. The atmosphere was exchanged to hydrogen gas and the mixture was strongly stirred at RT for 65 hours. The hydrogen gas atmosphere was exchanged to argon and the mixture was filtered. The solids were washed with additional ethanol. The combined organic phases were evaporated to give a residue (1.19 g, 71% purity, 44% yield) as a crude mixture of the title compound that was used in the next step without further purification.

[0516] LC-MS (Method 2): Rt= 1.53 min; MS (ESIpos): m / z = 418.3 [M+H]+

[0517] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.035 (1.06), 1.049 (0.45), 1.052 (2.62), 1.070 (1.18), 1.155 (7.69), 1.159 (1.85), 1.173 (16.00), 1.176 (2.90), 1.190 (7.35), 1.194 (1.43), 1.204 (1.76), 1.280 (5.86), 1.297 (6.07), 1.338 (14.66), 1.431 (0.52), 1.444 (0.50), 1.508 (0.70), 1.525 (0.68), 1.670 (1.06), 1.687

[0518] (1.82), 1.701 (1.66), 1.907 (0.75), 2.085 (0.43), 2.323 (0.40), 2.328 (0.68), 2.333 (1.68), 2.351 (3.34),

[0519] 2.368 (1.72), 2.518 (1.48), 2.523 (0.92), 2.660 (0.67), 2.665 (0.66), 2.669 (0.62), 2.674 (0.47), 2.685

[0520] (0.42), 2.727 (4.86), 2.729 (4.94), 2.888 (6.55), 3.428 (0.43), 3.445 (0.43), 3.729 (0.42), 3.743 (0.41),

[0521] 4.021 (1.90), 4.039 (6.01), 4.046 (0.85), 4.057 (5.97), 4.064 (0.79), 4.074 (1.87), 4.884 (0.55), 7.383 (0.60), 7.402 (1.41), 7.421 (0.90), 7.533 (1.63), 7.551 (1.27), 7.584 (0.79), 7.603 (0.70), 7.688 (1.13), 7.708 (0.96), 7.950 (0.78).

[0522] Intermediate 21

[0523] 5 - [2 - { ( 1 R) - 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenyl]pentanoic acid

[0524]

[0525] Ethyl 5-[2-{(lR)-l-[(tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenyl]pentanoate (1.16 g, 2.78 mmol) was dissolved in EtOH (7 mL). Potassium hydroxide (6.9 ml, 2.0 M in water, 14 mmol) was added and the mixture was stirred at RT for 2 hours. The mixture was diluted with water and citric acid (908 mg, 4.72 mmol) was added to adjust the pH to 6-7. The aq. phase was diluted with brine and extracted with EtOAc (3 times). The combined organic phases were dried and the solvent was evaporated to give the title compound (1.08 g, 79% purity, 79% yield) which was used in the next step without further purification.

[0526] LC-MS (Method 2): Rt= 0.76 min; MS (ESIneg): m / z = 388.2 [M-H]

[0527] Intermediate 22 tert-butyl { ( 1 R) - 1 - [2 - { 5 - [(4-carbamoyl-6-chloropyridin-3 -yl)amino] -5 -oxopentyl } -3 - (trifluoromethyl)phenyl] ethyl } carbamate 5-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenyl]pentanoic acid (1.03 g, 2.64 mmol), 5-amino-2-chloropyridine-4-carboxamide (545 mg, 3.17 mmol) and chloro(dimethylamino)-N,N- dimethylmethaniminiumhexafluoridophosphate(l-) (1.48 g, 5.29 mmol) were dissolvedin DMA (31 mL). 1 -Methyl- IH-imidazole (420 pl, 5.3 mmol) was added and the mixture was stirred for 3 days at RT. The mixture was diluted with EtOAc and washed with brine. The organic phase was separated and dried. The solvent was evaporated and the residue was purified by flash column chromatography on silica using a mixture of hexane and EtOAc as eluent to give the title compound (1.10 g, 90 % purity, 69 % yield).

[0528] LC-MS (Method 2): Rt= 1.32 min; MS (ESIpos): m / z = 543.4 [M+H]+

[0529] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.794 (0.73), 0.862 (0.48), 1.006 (0.68), 1.034 (0.61), 1.083 (1.52), 1.154 (4.19), 1.172 (8.13), 1.190 (4.18), 1.259 (2.72), 1.269 (5.56), 1.285 (6.40), 1.312 (16.00), 1.340 (1.82), 1.468 (0.60), 1.775 (2.03), 1.907 (5.62), 1.987 (13.17), 2.085 (0.49), 2.216 (0.75), 2.371 (0.79), 2.433 (1.48), 2.450 (2.75), 2.468 (1.95), 2.523 (2.66), 2.686 (1.11), 2.721 (0.40), 2.802 (1.45), 2.912 (0.59), 2.961 (1.19), 3.729 (0.52), 3.743 (0.48), 3.999 (1.06), 4.017 (3.17), 4.035 (3.15), 4.053 (1.00), 4.894 (0.64), 7.379 (0.81), 7.399 (1.79), 7.419 (1.16), 7.530 (2.08), 7.549 (1.60), 7.568 (0.92), 7.587 (0.89), 7.681 (1.25), 7.699 (1.04), 7.784 (4.31), 8.085 (1.44), 8.481 (1.22), 9.283 (3.23), 10.851 (0.81), 10.952 (1.70).

[0530] Intermediate 23 tert-butyl [( 1 R)- 1 - { 2- [4-(6-chloro-4-hydroxypyrido[3 ,4-d]pyrimidin-2-yl)butyl] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[0531] T ert-butyl { ( 1 R) - 1 - [2 - { 5 - [(4-carbamoyl-6-chloropyridin-3 -yl)amino] -5 -oxopentyl } -3-

[0532] (trifluoromethyl)phenyl] ethyl} carbamate (1.10 g, 2.03 mmol) was dissolved in EtOH (100 mL) at RT. NaOEt (830 pl, 21 % purity in EtOH, 2.2 mmol) was added and the mixture was stirred at RT for 1 hour. The reaction mixture was used directly in the next step without further purification or work-up.

[0533] LC-MS (Method 2): Rt= 1.06 min; MS (ESIpos): m / z = 525.3 [M+H]+

[0534] Intermediate 24

[0535] 2-(4-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}butyl)-6-chloropyrido[3,4-d]pyrimidin-4-ol

[0536] Tert-butyl [( 1R)- 1 - { 2-[4-(6-chloro-4-hydroxypyrido[3,4-d]pyrimidin-2-yl)butyl] -3-

[0537] (trifluoromethyl)phenyl} ethyl] carbamate (1.06 g, 2.02 mmol) (crude mixture) was dissolved in EtOH (100 mL). Hydrogen chloride (5.1 ml, 4.0 M in 1,4-dioxane, 20 mmol) was added and the mixture was stirred at RT overnight. Additional hydrogen chloride (2.5 ml, 4.0 M in 1,4-dioxane, 10 mmol) was added and the mixture was stirred at RT for 2 days. Additional hydrogen chloride (2.5 ml, 4.0 M in 1,4-dioxane, 10 mmol) was added and the mixture was stirred at RT overnight. Sat. aq. NaHCO3solution was added and the aq. phase was extracted with EtOAc (3 times). The combined organic phases were dried and the solvent was evaporated. The residue was purified by flash column chromatography (basic column) using a mixture of CH2Cl2and EtOH as eluent to give the title compound (600 mg, 1.25 mmol, 62% yield).

[0538] LC-MS (Method 2): Rt= 0.79 min; MS (ESIpos): m / z = 425.4 [M+H]+

[0539] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.100 (16.00), 1.496 (2.08), 1.513 (2.12), 1.917 (0.49), 2.518 (0.40), 2.684 (1.48), 2.703 (0.55), 2.722 (0.97), 2.741 (0.54), 3.071 (5.29), 3.946 (2.27), 7.542 (0.73), 7.561 (0.43), 7.700 (0.80), 7.718 (0.62), 7.950 (2.70), 7.951 (2.76), 8.007 (0.63), 8.026 (0.56), 8.578 (0.78), 8.863 (2.68), 8.865 (2.63).

[0540] Intermediate 25 tert-butyl 4-[(15R)-15-methyl-ll-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-(azeno)pyrido[4,3- d] [2,6]benzodiazacyclotridecin-2-yl] -4-oxo- 1 ,41ambda5-azaphosphinane- 1 -carboxylate

[0541] (15R)-2-Chloro-15-methyl-ll-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-(azeno)pyrido[4,3- d][2,6]benzodiazacyclotridecine (60.0 mg, 147 μmol) and tert-butyl 4-oxo- l,41ambda5-azaphosphinane- 1-carboxylate (35.6 mg, 162 μmol) were dissolved in MeCN (3 mL) under argon atmosphere. [1,1•- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (24.1 mg, 29.5 μmol) and triethylamine (72 pl, 520 μmol) were added and the mixture was stirred at 100 °C for 18 hours. The mixture was cooled to RT, diluted with CH2Cl2, filtered and the solvent was evaporated. The residue was purified by flash column chromatography on silica using CH2Cl2 / EtOH as eluent to give the title compound (55.0 mg, 98% purity, 62% yield).

[0542] LC-MS (Method 2): Rt= 1.44 min; MS (ESIpos): m / z = 590.4 [M+H]+

[0543] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.800 (0.60), 1.035 (1.49), 1.041 (0.49), 1.052 (3.32), 1.070 (2.67), 1.087 (0.66), 1.158 (0.94), 1.203 (0.76), 1.444 (16.00), 1.585 (1.75), 1.603 (1.79), 2.523 (0.73),

[0544] 2.727 (6.51), 2.888 (7.82), 3.362 (0.43), 3.404 (0.46), 3.417 (0.44), 3.422 (0.88), 3.435 (0.90), 3.439

[0545] (0.90), 3.452 (0.82), 4.346 (0.48), 4.359 (0.92), 4.372 (0.45), 7.362 (0.65), 7.519 (0.76), 7.537 (0.63),

[0546] 7.806 (0.57), 7.825 (0.52), 7.950 (1.11), 8.915 (0.69), 8.932 (0.69), 9.062 (1.63), 9.685 (0.51), 9.699

[0547] (0.49).

[0548] Intermediate 26

[0549] 4-[(15R)-15-methyl-ll-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-(azeno)pyrido[4,3- d][2,6]benzodiazacyclotridecin-2-yl]-l,41ambda5-azaphosphinan-4-one — hydrogen chloride (1 / 1)

[0550] Tert-butyl 4-[(15R)-15-methyl-l l-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-(azeno)pyrido[4,3- d][2,6]benzodiazacyclotridecin-2-yl]-4-oxo-l,41ambda5-azaphosphinane-l-carboxylate (53.0 mg, 89.9 μmol) was dissolved in 1,4-dioxane (1.2 mL). At RT, hydrogen chloride (220 pl, 4.0 M in 1,4-dioxane, 900 μmol) was added and the mixture was stirred overnight. All volatiles were evaporated under reduced pressure to give the crude material as residue that was used in the next step without further purification (55.3 mg, crude material).

[0551] LC-MS (Method 2): Rt= 1.19 min; MS (ESIpos): m / z = 490.4 [M+H]+

[0552] Intermediate 27

[0553] (15R)-15-methyl-2-(methylsulfanyl)-l l-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-

[0554] (azeno)pyrido[4,3-d] [2,6]benzodiazacyclotridecine

[0555] (15R)-2-Chloro-15-methyl-ll-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-(azeno)pyrido[4,3- d][2,6]benzodiazacyclotridecine (50.0 mg, 123 μmol) was dissolved in 1,4-dioxane (2 mL). Pd2(dba)3(11.3 mg, 12.3 μmol) was added, followed by Xantphos (14.2 mg, 24.6 μmol, N,N-diisopropylethylamine (64 pl, 370 μmol) and sodium methanethiolate (12.9 mg, 184 μmol). The resulting mixture was heated to 100 °C for 18 hours. The mixture was diluted with CH2Cl2and filtered. The filtrate was collected and the solvent was evaporated. The crude product (91.0 mg) was used in the next step without further purification.

[0556] LC-MS (Method 2): Rt= 1.46 min; MS (ESIpos): m / z = 419.3 [M+H]+

[0557] Intermediate 28 ethyl (2RS ,4E) -5 - [2 - { ( 1 R) - 1 - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenyl] -2- methylpent-4-enoate (mixture of diastereomers)

[0558] Tert-butyl {(lR)-l-[2-bromo-3-(trifluoromethyl)phenyl]ethyl}carbamate (500 mg, 1.36 mmol) was dissolved in DMF (10 mL) under argon atmosphere. Tri-2-tolylphosphine (413 mg, 1.36 mmol), palladium(II)acetate (152 mg, 679 μmol) and sodium acetate (223 mg, 2.72 mmol) were added. The atmosphere was exchanged to argon and ethyl (2RS)-2-methylpent-4-enoate (660 μl, 4.1 mmol) was added. The mixture was heated to 130 °C overnight. The mixture was poured into water. The aq. phase was extracted with EtOAc. The organic phase was dried and the solvent was evaporated. The residue was purified by flash column chromatography on silica to give the title compound as a mixture of two diastereomers (1:1) and minor additional isomers of the double bond (566 mg, 80% purity, 78% yield).

[0559] Major isomers 1+2:

[0560] LC-MS (Method 2): Rt= 1.63 min; MS (ESIpos): m / z = 430 [M+H]+

[0561] Minor Isomers 3+4:

[0562] LC-MS (Method 2): Rt= 1.61 min; MS (ESIpos): m / z = 430 [M+H]+

[0563] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.074 (2.19), 1.092 (2.44), 1.094 (2.23), 1.103 (2.41), 1.109 (2.42), 1.112 (3.88), 1.120 (2.53), 1.127 (4.49), 1.130 (2.74), 1.145 (2.58), 1.154 (1.11), 1.161 (0.99), 1.172 (1.42), 1.176 (1.37), 1.178 (1.35), 1.190 (0.99), 1.194 (1.69), 1.204 (2.61), 1.211 (1.47), 1.219 (5.60), 1.222 (6.10), 1.237 (9.75), 1.254 (3.97), 1.268 (2.13), 1.285 (2.41), 1.297 (2.78), 1.333 (16.00), 1.394 (0.54), 1.532 (2.37), 1.564 (0.49), 1.580 (0.49), 1.791 (4.36), 1.877 (0.79), 1.987 (0.87), 2.304

[0564] (0.52), 2.318 (0.47), 2.323 (0.75), 2.327 (1.00), 2.332 (0.80), 2.371 (1.07), 2.427 (0.73), 2.444 (0.40),

[0565] 2.518 (2.49), 2.523 (1.68), 2.597 (1.56), 2.665 (0.73), 2.669 (0.97), 2.673 (0.72), 3.975 (0.42), 3.983

[0566] (0.52), 3.993 (1.27), 4.001 (1.55), 4.011 (1.27), 4.019 (1.52), 4.029 (0.43), 4.036 (0.52), 4.112 (1.64),

[0567] 4.130 (4.37), 4.148 (4.03), 4.166 (1.19), 5.699 (0.89), 6.093 (0.87), 6.097 (0.94), 6.808 (0.68), 7.401

[0568] (0.64), 7.428 (0.56), 7.448 (0.99), 7.459 (0.97), 7.468 (0.87), 7.478 (0.64), 7.527 (0.76), 7.549 (0.83),

[0569] 7.573 (1.85), 7.591 (1.38), 7.667 (0.60), 7.682 (0.67), 7.698 (0.56), 7.708 (0.47), 7.721 (1.36), 7.741

[0570] (1.06). Intermediate 29 ethyl (2RS)-5- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenyl] -2- methylpentanoate (mixture of diastereomers)

[0571] Ethyl (2RS ,4E)-5- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenyl] -2- methylpent-4-enoate (466 mg, 1.09 mmol) was dissolved in EtOH (40 mL). Platinum(IV)oxide hydrate (~8O-81% Pt, ADAMS’ CATALYST)

[0572] (26.6 mg, 109 μmol) was added. The atmosphere was exchanged to hydrogen gas (1 atm) and the mixture was stirred overnight at RT. The mixture was filtered, the solvent was evaporated and the residue was redissolved in MeOH (30 mL). Platinum(IV)oxide hydrate (-80-81% Pt, ADAMS’ CATALYST) (26.6 mg, 109 μmol) was added and the atmosphere was exchanged to hydrogen gas (1 atm). The mixture was stirred for 3 days at RT. The mixture was filtered and the solvent was evaporated. The residue was purified by flash column chromatography to give the title compound as a mixture of two diastereomers (1:1) (319 mg, 60% purity, 41% yield).

[0573] Isomer 1+2:

[0574] LC-MS (Method 2): Rt= 1.55 min; MS (ESIpos): m / z = 432 [M+H]+

[0575] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.076 (4.95), 1.081 (4.80), 1.093 (5.09), 1.099 (5.01), 1.130 (0.55), 1.147 (4.76), 1.149 (4.26), 1.154 (1.85), 1.164 (9.24), 1.166 (7.82), 1.172 (2.60), 1.182 (4.52),

[0576] 1.184 (3.91), 1.190 (1.34), 1.196 (0.58), 1.273 (6.13), 1.290 (6.22), 1.301 (1.41), 1.337 (16.00), 1.395

[0577] (1.04), 1.532 (0.92), 1.564 (0.66), 1.580 (0.45), 1.695 (0.81), 1.722 (0.91), 1.988 (2.33), 2.323 (0.56),

[0578] 2.327 (0.82), 2.332 (0.60), 2.452 (0.46), 2.471 (0.87), 2.518 (2.40), 2.523 (1.55), 2.627 (0.46), 2.660

[0579] (0.76), 2.665 (1.03), 2.669 (1.15), 2.673 (0.75), 3.585 (1.82), 3.590 (1.98), 4.017 (1.48), 4.022 (0.84),

[0580] 4.035 (3.65), 4.040 (2.46), 4.053 (3.26), 4.058 (2.35), 4.071 (1.01), 4.076 (0.72), 4.858 (0.50), 7.383

[0581] (0.68), 7.402 (1.55), 7.422 (0.97), 7.532 (1.83), 7.550 (1.49), 7.566 (0.42), 7.591 (1.00), 7.609 (0.83),

[0582] 7.684 (1.20), 7.705 (1.01). Intermediate 30

[0583] (2RS)-5- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenyl] -2-methylpentanoic acid (mixture of diastereomers)

[0584] Ethyl (2RS)-5- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenyl] -2- methylpentanoate (319 mg, 739 μmol) was dissolved in EtOH (4 mL) and THF (8 mL). Lithium hydroxide (3.7 ml, 1.0 M in water, 3.7 mmol) was added and the mixture was stirred overnight at RT. The solvent was evaporated and the residue redissolved in water. Citric acid (10% in water) was added to adjust the pH to approx. 5. The aq. phase was extracted with EtOAc. The organic phase was dried and the solvent was evaporated to give the title compound as a mixture of two diastereomers (283 mg, 90% purity, 85% yield) which was used in the next step without further purification.

[0585] Isomer 1+2:

[0586] LC-MS (Method 2): Rt= 0.83 min; MS (ESIpos): m / z = 404 [M+H]+

[0587] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.054 (2.82), 1.065 (2.58), 1.071 (3.13), 1.082 (2.50), 1.154 (4.48), 1.166 (0.90), 1.171 (8.08), 1.183 (0.47), 1.190 (4.18), 1.280 (2.40), 1.284 (2.61), 1.297 (2.65),

[0588] 1.301 (2.97), 1.337 (8.80), 1.695 (0.47), 1.711 (0.50), 1.906 (0.57), 1.987 (16.00), 2.322 (0.41), 2.327

[0589] (0.46), 2.518 (0.91), 2.523 (0.59), 2.669 (0.49), 2.673 (0.41), 3.999 (1.11), 4.017 (3.41), 4.034 (3.38),

[0590] 4.052 (1.09), 7.384 (0.42), 7.403 (0.95), 7.423 (0.60), 7.533 (1.12), 7.551 (0.92), 7.578 (0.49), 7.597

[0591] (0.47), 7.693 (0.68), 7.711 (0.58), 12.082 (0.42).

[0592] Intermediate 31 tert-butyl { (1R)- 1 - [2- { (4RS)-5-[(4-carbamoyl-6-chloropyridin-3-yl)amino] -4-methyl-5 -oxopentyl } -3- (trifluoromethyl)phenyl] ethyl] carbamate (mixture of diastereomers)

[0593]

[0594] (2RS)-5-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenyl]-2-methylpentanoic acid (283 mg, 701 μmol), 5-amino-2-chloropyridine-4-carboxamide (144 mg, 842 μmol) and chloro(dimethylamino)-N,N-dimethylmethaniminium hexafluoridophosphate(l-) (394 mg, 1.40 mmol) were dissolved in DMA (3 mL). 1 -Methyl- IH-imidazole (110 pl, 1.4 mmol) was added and the mixture was stirred overnight at RT. The mixture was poured into water and the aq. phase was extracted with EtOAc. The organic phase was washed with brine and then dried. The solvent was evaporated. The residue was purified by flash column chromatography on silica to give the title compound as a mixture of two diastereomers (1:1) (438 mg, 80% purity, 90% yield). Isomer 1+2:

[0595] LC-MS (Method 2): Rt= 1.42 min; MS (ESIpos): m / z = 557 [M+H]+

[0596] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.144 (0.67), 1.149 (0.67), 1.161 (0.70), 1.166 (0.65), 1.264 (0.52), 1.277 (1.33), 1.304 (1.32), 1.955 (10.66), 2.685 (11.89), 2.781 (10.16), 2.941 (16.00), 7.812 (0.45).

[0597] Intermediate 32 tert-butyl [(lR)-l-{2-[(4RS)-4-(6-chloro-4-hydroxypyrido[3,4-d]pyrimidin-2-yl)pentyl]-3-

[0598] (trifluoromethyl)phenyl} ethyl] carbamate (mixture of diastereomers)

[0599] Tert-butyl {(lR)-l-[2-{(4RS)-5-[(4-carbamoyl-6-chloropyridin-3-yl)amino]-4-methyl-5-oxopentyl}-3- (trifluoromethyl)phenyl] ethyl] carbamate (391 mg, 701 μmol) was dissolved in EtOH (10 mL) and sodium ethoxide (290 pl, 21 % purity in EtOH, 770 μmol) was added. The mixture was stirred at RT for 2 hours. This crude reaction mixture was used directly in the next step in the same solvent.

[0600] Isomer 1:

[0601] LC-MS (Method 2): Rt= 1.14 min; MS (ESIpos): m / z = 549 [M+H]+

[0602] Isomer 2:

[0603] LC-MS (Method 2): Rt= 1.17 min; MS (ESIpos): m / z = 549 [M+H]+

[0604] Intermediate 33

[0605] 2- [(2RS)-5- { 2- [( 1 R)- 1 -aminoethyl] -6-(trifluoromethyl)phenyl }pentan-2-yl] -6-chloropyrido[3 ,4- d]pyrimidin-4-ol (mixture of diastereomers)

[0606] To tert-butyl [(lR)-l-{2-[(4RS)-4-(6-chloro-4-hydroxypyrido[3,4-d]pyrimidin-2-yl)pentyl]-3- (trifluoromethyl)phenyl} ethyl] carbamate (378 mg, 701 μmol) in EtOH (10 mL) (crude reaction mixture from previous step) was added hydrogen chloride (1.8 ml, 4.0 M in 1,4-dioxane, 7.0 mmol) and the mixture was stirred at RT for 3 days. Sat. aq. NaHCO3solution was added and the mixture was extracted with EtOAc. The organic phase was dried and the solvent was evaporated to give the title compound as a crude mixture (247 mg, 90% purity, 72% yield) that was used directly in the next step without further purification.

[0607] Isomer 1+2:

[0608] LC-MS (Method 2): Rt= 0.87 min; MS (ESIpos): m / z = 439 [M+H]+

[0609] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.035 (9.04), 1.052 (16.00), 1.070 (9.16), 1.141 (1.68), 1.147 (1.67), 1.157 (1.79), 1.164 (1.56), 1.251 (1.73), 1.259 (1.73), 1.269 (1.86), 1.276 (1.61), 1.955 (2.44),

[0610] 2.518 (0.66), 2.523 (0.45), 2.686 (8.57), 2.781 (2.22), 2.828 (0.45), 2.846 (0.41), 2.941 (3.41), 3.410

[0611] (3.16), 3.428 (8.57), 3.445 (7.87), 3.463 (3.07), 7.363 (0.51), 7.372 (0.49), 7.485 (0.62), 7.490 (0.56),

[0612] 7.505 (0.49), 7.821 (0.78), 7.840 (0.72), 7.896 (1.36), 7.898 (1.45), 7.903 (1.50), 8.803 (1.39), 8.807

[0613] (1.52), 8.809 (1.47).

[0614] Intermediate 34

[0615] 3- { [2-bromo-6-(trifluoromethyl)phenyl]methoxy }propan- 1 -ol

[0616] [2-Bromo-6-(trifluoromethyl)phenyl]methanol (2.00 g, 7.84 mmol) was dissolved in dry DMF (40 mL). At 0°C, sodium hydride (690 mg, 60 % purity in mineral oil, 17.3 mmol) was added in portions and the mixture stirred for 30 minutes at 0°C. Then, 3-bromopropan-l-ol (850 pl, 9.4 mmol) was added dropwise over 5 minutes and the mixture stirred for 30 minutes at 0°. Water was added and the mixture was extracted with ethyl acetate. The combined org. layers were washed with brine, filtered through a hydrophobic filter and concentrated in vacuo. Purification by flash column chromatography (hexane / EtOAc / CH2Cl2 / EtOH) yielded the titled compound (1.62 g 66 % yield).

[0617] LC-MS (Method 2): Rt= 1.11 min; MS (ESIpos): m / z = 313 [M+H]+ Intermediate 35

[0618] (3-{ [2-bromo-6-(trifluoromethyl)phenyl]methoxy}propoxy)(tert-butyl)dimethylsilane

[0619] 3-{ [2-Bromo-6-(trifluoromethyl)phenyl]methoxy}propan-l-ol (1.62 g, 5.17 mmol) was dissolved in dry dichloromethane (16 ml). The mixture was cooled to 0 °C. Imidazole (704 mg, 10.3 mmol) and tert- butyl(chloro)dimethylsilane (990 pl, 5.4 mmol) were added and the mixture was stirred for 15 minutes at 0°C and overnight at RT. Water and DCM were added and the org. phase was washed with brine, dried over a hydrophobic filter and concentrated in vacuo. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (2.10 g, 35 % yield).

[0620] LC-MS (Method 2): Rt= 1.85 min; MS (ESIpos): m / z = 427 [M+H]+

[0621] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.838 (16.00), 1.675 (0.60), 1.690 (0.93), 1.705 (0.62), 3.553 (0.63), 3.568 (1.31), 3.583 (0.60), 3.610 (0.66), 3.626 (1.37), 3.641 (0.64), 4.592 (1.47), 7.494 (0.48), 7.778 (0.51), 7.797 (0.44), 7.990 (0.48), 8.010 (0.45).

[0622] Intermediate 36

[0623] (S2S)-N-[(lRS)-l-{2-[(3-{ [tert-butyl(dimethyl)silyl] oxy } propoxy)methyl] -3 -

[0624] (trifluoromethyl)phenyl} ethyl] -2-methylpropane-2-sulfinamide (mixture of diastereomers)

[0625] (3-{ [2-Bromo-6-(trifluoromethyl)phenyl]methoxy}propoxy)(tert-butyl)dimethylsilane (1.08 g, 2.52 mmol) was dissolved in THF (13 ml) and cooled to -78 °C. n-BuLi (1.1 ml, 2.5 M in hexane, 2.8 mmol) was added and the mixture was stirred for 1 h at -78 °C. Then (S2S)-N-[(lE)-ethylidene]-2-methylpropane- 2-sulfinamide (1.9 ml, 2.0 M in THF, 3.8 mmol) was added over 5 minutes and the mixture stirred for 1 h at -78 °C and was warmed up to RT within 1 h. Saturated aqueous sodium chloride sol. was added at 0 °C and the mixture was extracted with ethyl acetate. The combined organic layers were filtered through a hydrophobic filter and concentrated in vacuo. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (877 mg, 70 % yield).

[0626] LC-MS (Method 2): Rt= 1.74 min; MS (ESIpos): m / z = 496 [M+H]+

[0627] Intermediate 37

[0628] (S2S)-N-[(lRS)-l-{2- [(3 -hydroxypropoxy)methyl] -3 -(trifluoromethyl)phenyl } ethyl] -2-methylpropane- 2-sulfinamide (mixture of diastereomers)

[0629] (S2S)-N-[(lRS)-l-{2-[(3-{ [tert-butyl(dimethyl)silyl] oxy } propoxy)methyl] -3 -

[0630] (trifluoromethyl)phenyl} ethyl] -2-methylpropane-2-sulfinamide (877 mg, 1.77 mmol) was dissolved in THF. TBAF (2.7 ml, 1.0 M in THF, 2.7 mmol) was added and the mixture stirred for 1.5 h at 50 °C. The mixture was concentrated in vacuo. Purification by flash column chromatography (hexane / EtOAc / EtOH) yielded the titled compound (666 mg, 99 % yield).

[0631] LC-MS (Method 2): Rt= 1.11 min; MS (ESIpos): m / z = 382 [M+H]

[0632] Intermediate 38

[0633] 3-( { 2- [( 1 RS)- 1 - { [(S)-2-methylpropane-2-sulfinyl] amino } ethyl] -6- (trifluoromethyl)phenyl } methoxy)propanoic acid

[0634] (S2S)-N-[(lRS)-l-{2- [(3 -Hydroxypropoxy)methyl] -3 -(trifluoromethyl)phenyl } ethyl] -2-methylpropane- 2-sulfinamide (666 mg, 1.75 mmol) was dissolved in MeCN (7 ml). NMO monohydrate (2.36 g, 17.5 mmol) and tetrapropylammonium perruthenate (61.4 mg, 175 μmol) were added at 0 °C and the mixture stirred for 60 minutes at 0 °C. The mixture was quenched with 2-propanol at 0 °C and stirred for 30 minutes at this temperature. The reaction mixture was concentrated in vacuo. Purification by flash column chromatography (CH2Cl2 / EtOH) yielded the titled compound in two fractions (623 mg, 70 % purity, 63 % yield and 135 mg, 90 % purity, 18 % yield).

[0635] LC-MS (Method 2): Rt= 0.68 min; MS (ESIpos): m / z = 396 [M+H]+

[0636] Intermediate 39

[0637] 2- [2-( { 2- [( 1 RS)- 1 -aminoethyl] -6-(trifluoromethyl)phenyl } methoxy)ethyl] -6-chloropyrido[3 ,4- d]pyrimidin-4(3H)-one

[0638] 3-( { 2- [( 1 RS)- 1 - { [(S)-2-Methylpropane-2-sulfinyl] amino } ethyl] -6- (trifluoromethyl)phenyl}methoxy)propanoic acid (200 mg, 506 μmol), 5-amino-2-chloropyridine-4- carboxamide (104 mg, 607 μmol), TCFH (284 mg, 1.01 mmol) and 1 -methyl- IH-imidazole (81 pl, 1.0 mmol) were dissolved in DMA (3.3 ml) and stirred overnight at room temperature. EtOAc was added and the mixture was washed with water (3x) and brine (lx). The organic layer was filtered through a hydrophobic filter and concentrated in vacuo. The residue was purified by HPLC (basic method). The obtained material (66.7 mg) was dissolved in MeCN (670 pl) and water (670 pl). NH4OH was added and the mixture stirred for 4 h at 40 °C. The mixture was concentrated in vacuo to give the title compound (60.8 mg, 95 % yield). The crude mixture was directly used in the next step.

[0639] LC-MS (Method 2): Rt= 0.71 min; MS (ESIpos): m / z = 427 [M+H]+

[0640] Intermediate 40

[0641] 1 - { 2- [(2- { [tert-butyl(diphenyl)silyl]oxy } ethyl)amino] -3-(trifluoromethyl)phenyl } ethan- 1 -one

[0642]

[0643] To a solution of l-[2-fluoro-3-(trifluoromethyl)phenyl]ethan-l-one (3.00 g, 14.6 mmol) in DMF (20 ml) under argon was added 2-{ [tert-butyl(diphenyl)silyl]oxy}ethan-l-amine (6.54 g, 21.8 mmol) and N,N- diisopropylethylamine (5.1 ml, 29 mmol). The reaction mixture was stirred at 80 °C for 1 h. Water and EtOAc were added. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine, were dried and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (4.70 g, 67 % yield).

[0644] LC-MS (Method 2): Rt= 1.80 min; MS (ESIpos): m / z = 487 [M+H]+

[0645] Intermediate 41

[0646] (S2S)-N-[(lE)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl] oxy } ethyl) amino] -3 -

[0647] (trifluoromethyl)phenyl } ethylidene] -2-methylpropane-2-sulfinamide

[0648] To a solution of l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3-(trifluoromethyl)phenyl}ethan- 1-one (6.50 g, 80 % purity, 10.7 mmol) and (S2S)-2-methylpropane-2-sulfinamide (2.60 g, 21.4 mmol) was added titanium(IV) ethoxide (9.0 ml, 43 mmol). The reaction mixture was stirred at 80 °C for 2 days. The reaction mixture was diluted with EtOAc. Water was slowly added. The reaction mixture was filtered. The aqueous phase was extracted with EtOAc. The combined organic phases were dried and concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (4.90 g, 78 % yield). LC-MS (Method 2): Rt= 1.76 min; MS (ESIneg): m / z = 588 [M-H]

[0649] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.883 (7.55), 0.965 (0.94), 1.070 (0.59), 1.097 (0.79), 1.103 (0.86), 1.154 (4.24), 1.172 (10.79), 1.179 (8.84), 1.190 (4.96), 1.987 (16.00), 2.518 (0.54), 2.615 (3.10), 3.207 (0.53), 3.219 (0.53), 3.669 (0.44), 3.681 (0.79), 3.694 (0.44), 3.999 (1.20), 4.017 (3.62), 4.035 (3.55), 4.053 (1.13), 7.024 (0.48), 7.383 (0.54), 7.400 (1.60), 7.417 (1.68), 7.436 (1.06), 7.453 (0.97), 7.515 (1.21), 7.521 (1.34), 7.525 (1.29), 7.534 (1.24), 7.628 (0.46).

[0650] Intermediate 42

[0651] (S2S)-N-[(lR)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3-(trifluoromethyl)phenyl}ethyl]-

[0652] 2-methylpropane-2-sulfinamide

[0653] To a solution of (S2S)-N-[(lE)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3- (trifluoromethyl)phenyl}ethylidene]-2-methylpropane-2-sulfinamide (1.37 g, 2.33 mmol) in THF (13 ml) at -78 °C was added L-Selectride (4.7 ml, 1.0 M in THF, 4.7 mmol). The reaction mixture was stirred at - 78 °C for 2 h and at room temperature overnight. Sat. aq. NaHCO3solution was added at 0 °C. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (900 mg, 65 % yield).

[0654] LC-MS (Method 2): Rt= 1.75 min; MS (ESIpos): m / z = 592 [M+H]+

[0655] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.817 (0.64), 0.844 (0.55), 1.012 (14.25), 1.024 (0.50), 1.052 (16.00), 1.154 (1.05), 1.172 (2.03), 1.190 (0.96), 1.428 (1.72), 1.444 (1.70), 1.988 (3.92), 2.518 (1.11), 2.523 (0.77), 3.821 (0.50), 3.834 (1.01), 3.847 (0.47), 4.017 (0.82), 4.035 (0.81), 5.420 (0.62), 5.434 (0.58), 7.197 (0.60), 7.289 (0.69), 7.427 (0.45), 7.432 (0.43), 7.442 (1.26), 7.446 (1.50), 7.461 (2.44), 7.465 (2.80), 7.469 (1.03), 7.473 (0.52), 7.481 (0.90), 7.486 (0.63), 7.490 (0.62), 7.506 (0.51), 7.509 (0.47), 7.641 (1.24), 7.646 (2.00), 7.650 (1.39), 7.655 (0.83), 7.660 (1.52), 7.665 (1.78), 7.669 (0.84), 7.715 (0.47), 7.732 (0.44). Intermediate 43

[0656] 2-[(lR)-l-aminoethyl]-N-(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)-6-(trifluoromethyl)aniline hydrogen chloride (1 / 1) To a solution of (S2S)-N-[(lR)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3- (trifluoromethyl)phenyl} ethyl] -2-methylpropane-2-sulfinamide (4.50 g, 7.62 mmol) in 1,4-dioxane (66 ml) was added HC1 (9.5 ml, 4.0 M in 1,4-dioxane, 38 mmol). The reaction mixture was stirred for 1 h and concentrated to give the title compound (4.72 g, quant.).

[0657] LC-MS (Method 2): Rt= 1.78 min; MS (ESIpos): m / z = 488 [M+H]+

[0658] Intermediate 44

[0659] N-[(lR)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3-(trifluoromethyl)phenyl}ethyl]-2,6- dichloropyrido[3,4-d]pyrimidin-4-amine To a mixture of 2,4,6-trichloropyrido[3,4-d]pyrimidine (753 mg, 3.21 mmol) and 2-[(lR)-l-aminoethyl]- N-(2-{ [tert-butyl(diphenyl)silyl]oxy }ethyl)-6-(trifluoromethyl)aniline hydrogen chloride (1 / 1) (2.00 g, 84 % purity, 3.21 mmol) in DMF (20 mL) was added triethylamine (2.2 ml, 16 mmol). The reaction mixture was stirred overnight. Water and EtOAc were added. The organic phase was washed with water and brine, dried and concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (1.45 g, 86 % yield).

[0660] LC-MS (Method 2): Rt= 1.85 min; MS (ESIpos): m / z = 685, 686 [M+H]+

[0661] Intermediate 45

[0662] 2- [2- { ( 1 R)- 1 - [(2,6-dichloropyrido[3 ,4-d]pyrimidin-4-yl)amino]ethyl } -6-(trifluoromethyl)anilino] ethan- l-ol

[0663] To a mixture of N-[(lR)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3- (trifluoromethyl)phenyl}ethyl]-2,6-dichloropyrido[3,4-d]pyrimidin-4-amine (1.45 g, 2.12 mmol) in THF (59 mL) under argon was added TBAF (3.2 mL, 1 M in THF) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (700 mg, 74 % yield).

[0664] LC-MS (Method 2): Rt= 1.21 min; MS (ESIneg): m / z = 444 [M-H]

[0665] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (3.00), 1.172 (6.48), 1.190 (3.33), 1.229 (0.76), 1.550 (15.98), 1.567 (16.00), 1.987 (11.93), 2.518 (6.47), 2.523 (4.10), 2.679 (0.68), 3.063 (0.56), 3.076 (1.17), 3.093 (1.94), 3.106 (1.97), 3.124 (1.41), 3.136 (0.72), 3.445 (0.59), 3.457 (1.33), 3.468 (1.35), 3.478 (1.77), 3.488 (1.76), 3.508 (1.21), 3.521 (0.69), 3.602 (0.60), 3.614 (1.53), 3.627 (2.37), 3.641 (3.68), 3.653 (3.21), 3.663 (1.88), 3.674 (2.32), 3.680 (1.73), 3.686 (2.01), 3.692 (2.25), 3.705 (1.65), 3.719 (0.92), 3.731 (0.51), 3.999 (0.89), 4.017 (2.72), 4.034 (2.72), 4.052 (0.87), 4.201 (1.69), 4.218 (2.25), 4.235 (1.56), 4.811 (4.78), 4.824 (11.04), 4.837 (4.56), 5.711 (0.53), 5.729 (2.16), 5.745 (3.21), 5.762 (2.04), 7.159 (2.66), 7.179 (5.53), 7.198 (3.00), 7.509 (4.99), 7.512 (5.45), 7.528 (4.72), 7.532 (4.58), 7.720 (4.60), 7.738 (4.26), 8.625 (11.36), 8.874 (12.55), 9.380 (3.63), 9.397 (3.53).

[0666] Intermediate 46

[0667] 6-bromo-N - [( 1 R) - 1 - { 2 - [ (2 - { [tert-butyl(diphenyl)silyl] oxy } ethyl) amino] -3 - (trifluoromethyl)phenyl } ethyl] -2-chloro-7 -fluoroquinazolin-4-amine

[0668] To a mixture of 6-bromo-2,4-dichloro-7-fluoroquinazoline (95.0 mg, 321 μmol) and 2-[(lR)-l- aminoethyl]-N-(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)-6-(trifluoromethyl)aniline hydrogen chloride (1 / 1) (200 mg, 84 % purity, 321 μmol) in DMF (2 mL) was added triethylamine (220 pl, 1.6 mmol). The reaction mixture was stirred overnight. Water and EtOAc were added. The organic phase was washed with water and brine, dried and concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (100 mg, 42 % yield).

[0669] LC-MS (Method 1): Rt= 1.90 min; MS (ESIpos): m / z = 748 [M+H]+

[0670] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.982 (16.00), 1.083 (0.44), 1.154 (1.59), 1.172 (3.21), 1.189 (1.47), 1.258 (1.04), 1.323 (0.81), 1.507 (1.79), 1.524 (1.79), 1.987 (5.67), 2.518 (0.84), 2.523 (0.54),

[0671] 2.729 (4.66), 2.888 (5.32), 3.999 (0.47), 4.017 (1.11), 4.035 (1.14), 5.739 (0.43), 7.215 (0.70), 7.351

[0672] (0.43), 7.355 (0.61), 7.372 (1.42), 7.376 (0.92), 7.383 (0.46), 7.391 (1.37), 7.405 (1.38), 7.412 (0.59),

[0673] 7.416 (0.98), 7.422 (1.34), 7.428 (0.82), 7.433 (1.54), 7.450 (0.86), 7.519 (0.62), 7.523 (0.66), 7.539

[0674] (0.58), 7.542 (0.56), 7.597 (1.50), 7.622 (2.44), 7.626 (1.61), 7.643 (1.56), 7.646 (1.01), 7.653 (1.53), 7.658 (1.36), 7.663 (0.45), 7.673 (1.32), 7.677 (0.90), 7.725 (0.57), 7.742 (0.53), 7.950 (0.66), 8.991

[0675] (0.98), 9.009 (0.96), 9.126 (0.52), 9.143 (0.51), 10.851 (0.47).

[0676] Intermediate 47

[0677] 2- [2- { ( 1 R)- 1 - [(6-bromo-2-chloro-7 -fhroroquinazolin-4-yl) amino] ethyl } -6- (trifluoromethyl) anilino] ethan- 1 -ol

[0678] To a mixture of 6-bromo-N-[(lR)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3- (trifluoromethyl)phenyl} ethyl] -2-chloro-7-fluoroquinazolin-4-amine (100 mg, 134 μmol) in THF (3.7 mL) under argon was added TBAF (0.2 mL, 1 M in THF) at room temperature. The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (77.0 mg, quant.).

[0679] LC-MS (Method 1): Rt= 1.38 min; MS (ESIpos): m / z = 507 [M+H]+

[0680] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (4.68), 1.171 (9.93), 1.189 (4.79), 1.230 (0.41), 1.540 (9.12), 1.557 (9.10), 1.987 (16.00), 2.031 (0.42), 2.518 (3.60), 2.522 (2.31), 3.078 (0.62), 3.096 (1.03), 3.108 (1.06), 3.127 (0.76), 3.480 (0.75), 3.492 (0.75), 3.501 (0.99), 3.511 (0.98), 3.521 (0.65), 3.532 (0.69), 3.544 (0.41), 3.616 (0.80), 3.629 (1.21), 3.642 (1.90), 3.655 (1.63), 3.666 (1.13), 3.677 (1.19), 3.684 (0.91), 3.689 (1.05), 3.696 (1.17), 3.708 (0.87), 3.723 (0.48), 3.998 (1.14), 4.016 (3.34), 4.034 (3.23), 4.052 (1.00), 4.216 (1.06), 4.236 (1.28), 4.250 (0.95), 4.808 (2.22), 4.821 (4.96), 4.834 (2.13), 5.721 (1.36), 5.739 (2.09), 5.756 (1.33), 7.154 (1.52), 7.174 (3.17), 7.193 (1.72), 7.497 (2.85), 7.501 (3.06), 7.517 (2.68), 7.520 (2.50), 7.606 (7.21), 7.630 (6.90), 7.715 (2.55), 7.731 (2.37), 8.998 (4.89), 9.017 (4.81), 9.113 (2.32), 9.131 (2.23).

[0681] Intermediate 48

[0682] (15R)-2-bromo-3-fluoro-15-methyl-ll-(trifluoromethyl)-9,10,15,16-tetrahydro-8H-6,17-

[0683] (azeno)dibenzo[d,i] [1 ,3,7, 1 l]oxatriazacyclotridecine

[0684] To a solution of 2-[2-{(lR)-l-[(6-bromo-2-chloro-7-fluoroquinazolin-4-yl)amino]ethyl}-6- (trifluoromethyl)anilino]ethan-l-ol (77.0 mg, 152 μmol) in 1,4-dioxane (10 ml) was added lithium diisopropylamide (110 pl, 2M in THF / heptane / ethylbenzene, 230 μmol). The reaction mixture was heated at 80 °C fur 2 h. Sat. aq. NaHCO3solution was added. The reaction mixture was extracted with EtOAc, dried and concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (50.0 mg, 70 % yield).

[0685] LC-MS (Method 1): Rt= 1.24 min; MS (ESIpos): m / z = 473 [M+H]+

[0686] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.950 (0.43), 1.154 (4.82), 1.172 (10.19), 1.190 (4.88), 1.233 (0.48), 1.610 (3.85), 1.627 (3.84), 1.907 (2.29), 1.988 (16.00), 2.318 (0.88), 2.518 (8.18), 2.523 (5.60), 2.660 (0.92), 2.729 (0.64), 2.888 (0.44), 3.565 (1.22), 3.999 (1.40), 4.017 (3.58), 4.034 (3.31), 4.053 (1.05), 5.860 (0.64), 6.894 (0.89), 6.913 (1.85), 6.933 (0.99), 7.302 (4.26), 7.328 (4.04), 7.381 (1.63), 7.385 (1.79), 7.402 (1.55), 7.405 (1.54), 7.570 (1.58), 7.573 (1.62), 7.589 (1.55), 8.683 (1.49), 8.703 (1.45), 9.124 (0.98), 9.138 (0.90).

[0687] Intermediate 49

[0688] 6-bromo-N - [( 1 R) - 1 - { 2 - [ (2 - { [tert-butyl(diphenyl)silyl] oxy } ethyl) amino] -3 - (trifluoromethyl)phenyl } ethyl] -2-chloropyrido [2, 3 -d] pyrimidin-4-amine

[0689] To a mixture of 6-bromo-2,4-dichloropyrido[2,3-d]pyrimidine (300 mg, 1.08 mmol) and 2-[(lR)-l- aminoethyl]-N-(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)-6-(trifluoromethyl)aniline hydrogen chloride (1 / 1) (670 mg, 84 % purity, 1.08 mol) in DMF (6.7 mL) was added triethylamine (750 pl, 5.4 mmol). The reaction mixture was stirred overnight. Water and EtOAc were added. The organic phase was washed with water and brine, dried and concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound 550 mg (70 % yield).

[0690] LC-MS (Method 1): Rt= 1.82 min; MS (ESIpos): m / z = 731 [M+H]+

[0691] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.986 (16.00), 1.007 (3.97), 1.072 (4.50), 1.113 (0.60), 1.153 (1.77), 1.171 (3.79), 1.189 (1.85), 1.384 (0.49), 1.401 (0.48), 1.507 (1.81), 1.524 (1.79), 1.986 (6.15), 2.727 (3.89), 2.887 (4.49), 3.564 (4.60), 3.998 (0.51), 4.016 (1.30), 4.034 (1.25), 5.744 (0.44), 7.215 (0.73), 7.357 (0.43), 7.361 (0.59), 7.377 (1.44), 7.381 (0.94), 7.387 (0.44), 7.393 (1.07), 7.396 (1.47), 7.408 (1.38), 7.413 (0.97), 7.417 (1.05), 7.422 (1.07), 7.426 (1.52), 7.434 (1.88), 7.443 (0.62), 7.451 (1.07), 7.453 (0.89), 7.456 (0.85), 7.461 (0.61), 7.526 (0.64), 7.530 (0.68), 7.547 (0.59), 7.550 (0.56), 7.624 (1.56), 7.627 (1.60), 7.633 (0.55), 7.636 (0.58), 7.640 (1.25), 7.644 (1.93), 7.647 (1.16), 7.655 (1.72), 7.659 (1.80), 7.663 (0.66), 7.674 (1.32), 7.678 (0.94), 7.736 (0.58), 7.754 (0.54), 7.950 (0.55), 9.052 (2.05), 9.059 (1.98), 9.266 (1.53), 9.272 (1.43), 9.308 (0.54), 9.325 (0.52).

[0692] Intermediate 50

[0693] 2- [2- { ( 1 R)- 1 - [(6-bromo-2-chloropyrido[2,3-d]pyrimidin-4-yl)amino]ethyl } -6- (trifluoromethyl) anilino] ethan- 1 -ol

[0694] To a mixture of 6-bromo-N-[(lR)-l-{2-[(2-{ [tert-butyl(diphenyl)silyl]oxy}ethyl)amino]-3- (trifluoromethyl)phenyl}ethyl]-2-chloropyrido[2,3-d]pyrimidin-4-amine (625 mg, 857 μmol) in THF (24 mL) under argon was added TBAF (1.3 mL, 1 M in THF) at room temperature. The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (284 mg, 68 % yield).

[0695] LC-MS (Method 1): Rt= 1.17 min; MS (ESIpos): m / z = 490 [M+H]+

[0696] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (0.71), 1.171 (1.56), 1.189 (0.82), 1.230 (0.67), 1.351 (0.43), 1.540 (15.58), 1.557 (15.61), 1.987 (2.34), 2.031 (0.40), 2.336 (0.96), 2.518 (8.57), 2.522 (5.32), 2.678 (0.96), 3.065 (0.58), 3.095 (1.76), 3.108 (1.82), 3.126 (1.28), 3.138 (0.67), 3.283 (0.41), 3.297 (0.97), 3.306 (1.70), 3.378 (0.82), 3.384 (0.47), 3.391 (0.43), 3.454 (0.51), 3.466 (1.21), 3.476 (1.24), 3.487 (1.61), 3.497 (1.65), 3.506 (1.09), 3.517 (1.09), 3.528 (0.61), 3.604 (0.49), 3.616 (1.28), 3.630 (1.99), 3.643 (3.13), 3.655 (2.68), 3.667 (1.83), 3.677 (1.99), 3.684 (1.53), 3.690 (1.77), 3.696 (1.92), 3.707 (1.41), 3.722 (0.76), 3.734 (0.40), 4.016 (0.52), 4.034 (0.54), 4.204 (1.79), 4.222 (2.20), 4.237 (1.61), 4.815 (3.56), 4.827 (7.90), 4.839 (3.40), 5.708 (0.56), 5.726 (2.34), 5.743 (3.61), 5.760 (2.27), 5.776 (0.50), 7.155 (2.61), 7.174 (5.40), 7.193 (2.92), 7.506 (4.80), 7.509 (5.14), 7.525 (4.55), 7.529 (4.26), 7.723 (4.32), 7.740 (4.02), 9.056 (13.35), 9.062 (16.00), 9.273 (12.01), 9.279 (10.88), 9.296 (3.98), 9.314 (3.79).

[0697] Intermediate 51

[0698] (15R)-2-bromo-15-methyl-l l-(trifluoromethyl)-9,10,15,16-tetrahydro-8H-6,17-(azeno)pyrido[2,3- g] [4, 1 ,6, 10]benzoxatriazacyclotridecine

[0699] To a solution of 2-[2-{(lR)-l-[(6-bromo-2-chloropyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-6- (trifluoromethyl)anilino]ethan-l-ol (284 mg, 579 μmol) in 1,4-dioxane (39 ml) was added lithium diisopropylamide (580 pl, 2M in THF / heptane / ethylbenzene, 1.2 mol). The reaction mixture was heated at 80 °C for 8 h. Sat. aq. NaHCO3solution was added. The reaction mixture was extracted with EtOAc, dried and concentrated. Purification by flash column chromatography (hexane / EtOAc) yielded the titled compound (180 mg, 68 % yield).

[0700] LC-MS (Method 1): Rt= 1.06 min; MS (ESIpos): m / z = 454 [M+H]+

[0701] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.153 (4.75), 1.171 (9.68), 1.189 (4.68), 1.614 (8.32), 1.631 (8.29), 1.907 (3.02), 1.987 (16.00), 2.518 (2.14), 2.523 (1.38), 2.753 (0.57), 3.998 (1.87), 4.016 (4.22), 4.034 (4.18), 4.052 (1.50), 4.462 (0.71), 4.774 (0.67), 5.758 (1.86), 5.871 (1.42), 6.898 (1.85), 6.917 (3.75), 6.937 (2.01), 7.391 (3.35), 7.395 (3.54), 7.411 (3.21), 7.414 (3.08), 7.564 (3.31), 7.567 (3.35), 7.583 (3.24), 8.853 (8.13), 8.859 (9.06), 8.950 (4.12), 8.956 (3.78), 9.341 (1.90), 9.353 (1.78).

[0702] Intermediate 52 tert-butyl 4-[(15R)-3-fluoro-15-methyl-l l-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-

[0703] (azeno)dibenzo[b,g] [ 1 ,5] diazacyclotridecin-2-yl] -4-oxo- 1 ,41ambda5-azaphosphinane- 1 -carboxylate

[0704]

[0705] (15R)-2-Bromo-3-fluoro-15-methyl-ll-(trifluoromethyl)-7,8,9,10,15,16-hexahydro-6,17-

[0706] (azeno)dibenzo[b,g][l,5]diazacyclotridecine (100 mg, 214 μmol) and tert-butyl 4-oxo-l,41ambda5- azaphosphinane-1 -carboxylate (51.5 mg, 235 μmol) were dissolved in MeCN (5 mL). Triethylamine (100 pl, 750 μmol) and [l,l•-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with CH2Cl2(34.9 mg, 42.7 μmol) were added and the mixture was stirred at 100 °C for 18 hours. The mixture was cooled to RT, diluted with CH2Cl2and all volatiles were evaporated. The residue was purified by flash column chromatography on silica using hexane / EtOAc as eluent to give the title compound (144 mg, quant.) which was used in the next step without further purification.

[0707] LC-MS (Method 2): Rt= 1.45 min; MS (ESIpos): m / z = 607.5 [M+H]+

[0708] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.800 (0.46), 1.034 (4.33), 1.052 (10.10), 1.069 (5.42), 1.087 (0.55), 1.158 (0.70), 1.442 (16.00), 1.555 (0.44), 1.578 (1.79), 1.596 (1.78), 2.327 (0.46), 2.518 (1.84),

[0709] 2.523 (1.15), 2.665 (0.57), 2.669 (0.61), 2.673 (0.43), 2.887 (0.48), 3.362 (0.61), 3.404 (0.98), 3.417

[0710] (1.07), 3.421 (2.39), 3.433 (2.43), 3.438 (2.49), 3.451 (2.54), 3.456 (0.89), 3.469 (0.87), 4.348 (1.49),

[0711] 4.361 (2.89), 4.373 (1.39), 7.352 (0.71), 7.371 (0.78), 7.381 (0.54), 7.399 (0.46), 7.410 (0.46), 7.508

[0712] (0.80), 7.525 (0.67), 7.834 (0.54), 7.854 (0.48), 9.473 (0.44), 9.487 (0.43).

[0713] Intermediate 53 tert-butyl [( 1 R)- 1 - { 2- [5 -(4-bromo-2-carbamoyl-5-fluoroanilino)-5-oxopentyl] -3- (trifluoromethyl)phenyl } ethyl] carbamate 5-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenyl]pentanoic acid (925 mg, 2.38 mmol) and 2-amino-5-bromo-4-fluorobenzamide (775 mg, 3.33 mmol) were dissolved in DMA (19 mL). 1 -Methyl- IH-imidazole (470 pl, 5.9 mmol) and chloro(dimethylamino)-N,N- dimethylmethaniminium hexafluoridophosphate(l-) (1.67 g, 5.94 mmol) were added under argon atmosphere and the mixture was stirred at RT for 16 hours. The mixture was diluted with EtOAc and was washed with water. The organic phase was separated and dried. The residue was purified by flash column chromatography on silica using hexane / EtOAc as eluent to give the title compound (1.32 g, 93% purity, 86% yield).

[0714] LC-MS (Method 2): Rt= 1.46 min; MS (ESIpos): m / z = 606.3 [M+H]+

[0715] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.153 (4.53), 1.170 (9.03), 1.188 (4.37), 1.258 (1.84), 1.275 (1.82), 1.286 (0.88), 1.303 (5.48), 1.338 (0.71), 1.781 (0.65), 1.899 (1.30), 1.954 (0.53), 1.986 (16.00), 2.422 (0.43), 2.439 (0.78), 2.685 (7.61), 2.780 (0.50), 2.940 (0.84), 3.997 (1.11), 4.016 (3.41), 4.034 (3.43), 4.051 (1.12), 7.393 (0.59), 7.523 (0.68), 7.542 (0.57), 7.880 (0.51), 8.177 (0.85), 8.196 (0.84), 8.385 (0.46), 8.496 (1.15), 8.526 (1.12), 12.044 (0.55).

[0716] Intermediate 54 tert-butyl [( 1 R)- 1 - { 2- [4-(6-bromo-7 -fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)butyl] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[0717] T ert-butyl [(lR)-l-{2- [5 -(4-bromo-2-carbamoyl-5 -fluoroanilino)-5 -oxopentyl] -3 -

[0718] (trifluoromethyl)phenyl] ethyl] carbamate (1.32 g, 2.18 mmol) was dissolved in EtOH (100 mL). Sodium ethoxide (900 pl, 21 % purity, 2.4 mmol) was added and the mixture was stirred at RT for 1 hour. Water was added and the solvent was evaporated. The residue was dissolved in EtOAc and was washed with water and brine. The organic phase was separated and dried to give the title compound ( 1.02 g, 93 % purity, 74% yield) which was used without further purification.

[0719] LC-MS (Method 2): Rt= 1.42 min; MS (ESIpos): m / z = 588.3 [M+H]+ Intermediate 55

[0720] 2-(4- { 2- [( 1 R)- 1 -aminoethyl] -6-(trifluoromethyl)phenyl }butyl)-6-bromo-7 -fluoroquinazolin-4(3H)- one — hydrogen chloride (1 / 1)

[0721] Tert-butyl [( 1 R)- 1 - { 2- [4-(6-bromo-7 -fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)butyl] -3-

[0722] (trifluoromethyl)phenyl} ethyl] carbamate (1.06 g, 1.81 mmol) was dissolved in 1,4-dioxane (10 mL). Hydrogen chloride (9.0 ml, 4.0 M in 1,4-dioxane, 36 mmol) was added and the mixture was stirred at RT for 30 hours. Additional hydrogen chloride (4.5 ml, 4.0 M in 1,4-dioxane, 18 mmol) and CH2Cl2(10 mL) were added and the mixture was stirred at RT for 36 hours. All volatiles were evaporated. The residue was suspended in CH2Cl2(20 mL) and MTBE (30 mL) was added. The mixture was carefully concentrated under reduced pressure. The resulting precipitate was collected by filtration and dried to give the title compound (1.05 g, quant.) which was used in the next step without further purification.

[0723] LC-MS (Method 2): Rt= 1.14 min; MS (ESIpos): m / z = 488.2 [M+H]+

[0724] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.100 (0.45), 1.472 (1.41), 1.500 (16.00), 1.516 (15.84), 1.546 (1.62), 1.559 (1.45), 1.574 (1.24), 1.590 (0.93), 1.866 (1.03), 1.885 (2.89), 1.906 (3.87), 1.923 (2.64),

[0725] 1.940 (0.91), 2.322 (0.62), 2.327 (0.85), 2.331 (0.61), 2.407 (1.11), 2.518 (2.48), 2.523 (1.61), 2.665

[0726] (0.89), 2.669 (1.20), 2.674 (1.08), 2.684 (4.86), 2.705 (7.09), 2.723 (4.27), 2.744 (1.84), 2.774 (1.14),

[0727] 2.808 (0.44), 2.854 (1.04), 2.866 (1.18), 2.888 (1.55), 2.919 (0.81), 2.957 (0.48), 3.549 (1.23), 4.491

[0728] (4.29), 4.596 (2.82), 4.612 (3.03), 4.626 (2.37), 7.519 (2.64), 7.539 (5.65), 7.559 (3.30), 7.602 (10.65), 7.626 (10.67), 7.697 (6.05), 7.715 (4.77), 8.021 (5.08), 8.040 (4.64), 8.302 (12.06), 8.321 (11.71), 8.609 (6.26).

[0729] Intermediate 56 tert-butyl { ( 1 R) - 1 - [2 - { 5 - [ (5 -bromo-3 -carbamoylpyridin-2-yl)amino] -5 -oxopentyl } -3 - (trifluoromethyl)phenyl] ethyl } carbamate

[0730]

[0731] 5-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenyl]pentanoic acid (925 mg, 2.38 mmol) and 2-amino-5-bromopyridine-3-carboxamide (616 mg, 2.85 mmol) were dissolved in DMA (18 mL). 1 -Methyl- IH-imidazole (470 pl, 5.9 mmol) and chloro(dimethylamino)-N,N- dimethylmethaniminium hexafluoridophosphate(l-) (1.67 g, 5.94 mmol) were added and the mixture was stirred at RT for 16 hours. The mixture was diluted with EtOAC and washed with water. The aq. phase was extracted with EtOAc. The combined organic phase was separated and dried. The residue was purified by flash column chromatography on silica using hexane / EtOAc as eluent to give the title compound (1.02 g, 67% purity, 49% yield). LC-MS (Method 2): Rt= 1.28 min; MS (ESIpos): m / z = 587 [M+H]+

[0732] Intermediate 57 tert-butyl [( 1 R)- 1 - { 2- [4-(6-bromo-4-oxo-3 ,4-dihydropyrido[2,3-d]pyrimidin-2-yl)butyl] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[0733] Tert-butyl { ( 1 R) - 1 - [2- { 5 - [( 5 -bromo-3 -carbamoylpyridin-2-yl)amino] -5 -oxopentyl } -3- (trifluoromethyl)phenyl] ethyl} carbamate (1.02 g, 1.74 mmol) was dissolved in EtOH (80 mL). Sodium ethoxide (710 pl, 21 % purity, 1.9 mmol) was added and the mixture was stirred at RT for 1 hour. Water was added and the solvents were evaporated. The residue was redissolved in EtOAc and was washed with water and brine. The organic phase was separated and dried. The solvent was evaporated to give the title compound (577 mg, 87% purity, 51% yield) which was used without further purification.

[0734] LC-MS (Method 2): Rt= 1.02 min; MS (ESIpos): m / z = 571.3 [M+H]+

[0735] Intermediate 58

[0736] 2-(4-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}butyl)-6-bromopyrido[2,3-d]pyrimidin-4(3H)- one — hydrogen chloride (1 / 1)

[0737] Tert-butyl [(lR)-l-{2-[4-(6-bromo-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)butyl]-3-

[0738] (trifluoromethyl)phenyl} ethyl] carbamate (577 mg, 1.01 mmol) was dissolved in 1,4-dioxane (5.1 mL). Hydrogen chloride (5.1 ml, 4.0 M in 1,4-dioxane, 20 mmol) was added and the mixture was stirred at RT for 19 hours. All volatiles were evaporated and the residue was suspended in CH2Cl2(5 mL). MTBE (5 mL) was added and the mixture was carefully concentrated under reduced pressure. The resulting precipitate was collected by filtration and dried to give the title compound (533 mg, 89% purity, 93% yield) which was used without further purification.

[0739] LC-MS (Method 2): Rt= 0.88 min; MS (ESIpos): m / z = 471.2 [M+H]+

[0740] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.051 (0.55), 1.101 (16.00), 1.498 (1.57), 1.515 (1.61), 1.921 (0.40), 2.685 (0.47), 2.723 (0.48), 2.742 (0.82), 2.761 (0.50), 3.071 (6.04), 3.898 (1.02), 5.758 (1.04), 7.545 (0.56), 7.704 (0.61), 7.722 (0.48), 8.002 (0.49), 8.021 (0.45), 8.534 (0.61), 8.588 (1.72), 8.594 (1.80), 9.015 (1.61), 9.022 (1.73).

[0741] Intermediate 59

[0742] 1 - [2-(3 - { [tert-butyl(dimethyl)silyl]oxy }prop- 1 -yn- 1 -yl)-3-(trifluoromethyl)phenyl]ethan- 1 -one

[0743] In a 250 ml two neck flask under argon, l-[2-iodo-3-(trifluoromethyl)phenyl]ethan-l-one (CAS 2384365- 04-0, 9.45 g, 30.1 mmol) was dissolved in DMF (71 ml). To the solution, tert-butyl(dimethyl)[(prop-2- yn-l-yl)oxy] silane (12 ml, 60 mmol) and triethylamine (42 ml, 300 mmol) were added subsequently. Argon was bubbled through the mixture, before dichlorobis(triphenylphosphine)palladium (6.34 g, 9.03 mmol) and copper(I)iodide (3.44 g, 18.1 mmol) were added. The mixture was stirred at 85 °C overnight. After cooling, the mixture was combined with a second batch of the same reaction starting from 9.5 g (30.1 mmol) l-[2-iodo-3-(trifluoromethyl)phenyl]ethan-l-one, which was reacted under equivalent conditions. The combined mixtures were diluted with ethyl acetate and water, the phases were separated and the aqueous phase was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified twice by flash column chromatography (gradient: 100 % hexane to 20 % ethyl acetate in hexane) to yield the title compound (4.67 g, 22 %) as dark oil.

[0744] LC-MS (Method 2): Rt= 1.65 min; MS (ESIpos): m / z = 357 [M+H]+

[0745] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.629 (0.94), 0.765 (1.68), 0.771 (16.00), 0.778 (0.87), 2.521 (6.98), 2.559 (0.85), 4.493 (2.50), 7.571 (0.47), 7.777 (0.44), 7.817 (0.45).

[0746] Intermediate 60

[0747] (S2S)-N-{(lE)-l-[2-(3-{ [tert-butyl(dimethyl)silyl] oxy } prop- 1 -yn- 1 -yl) -3 -

[0748] (trifluoromethyl)phenyl]ethylidene}-2-methylpropane-2-sulfinamide In a 250 ml round bottom flask, to a mixture of l-[2-(3-{ [tert-butyl(dimethyl)silyl]oxy}prop-l-yn-l-yl)- 3-(trifluoromethyl)phenyl]ethan-l-one (4.67 g, 13.1 mmol) and (S2S)-2-methylpropane-2-sulfinamide (2.38 g, 19.7 mmol) in 100 ml THF under argon was added titanium(IV) ethoxide (8.2 ml, 39 mmol). The mixture was stirred at 80 °C overnight. After cooling, the mixture was diluted with water and ethyl acetate and stirred for 5 minutes. The formed precipitate was filtered off, and the phases of the filtrate were separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified twice by flash column chromatography (gradient: 100 % hexane to 50 % ethyl acetate in hexane) to yield the title compound (3.94 g, 65 %) as brown oil.

[0749] LC-MS (Method 2): Rt= 1.71 min; MS (ESIpos): m / z = 460 [M+H]+

[0750] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.769 (0.92), 0.776 (16.00), 0.783 (0.92), 1.028 (1.48), 1.111 (3.74), 2.355 (0.45), 2.592 (1.33), 4.470 (0.86).

[0751] Intermediate 61

[0752] (S2S)-N- { (1R)- 1 - [2-(3 - { [tert-butyl(dimethyl)silyl]oxy }prop- 1 -yn- 1 -yl)-3-

[0753] (trifluoromethyl)phenyl] ethyl } -2-methylpropane-2-sulfinamide

[0754] In a 250 ml round bottom flask, a mixture of (S2S)-N-{(lE)-l-[2-(3-{ [tert-butyl(dimethyl)silyl]oxy}prop- l-yn-l-yl)-3-(trifluoromethyl)phenyl]ethylidene}-2-methylpropane-2-sulfinamide (3.94 g, 8.57 mmol) in 100 ml THF under argon was cooled to -78 °C. To the mixture was then added lithium tri-sec- butylborohydride (IM in THF, 17 ml, 1.0 M, 17 mmol), and the mixture was stirred for 3 hours at -78 °C. The cooling bath was removed and the mixture was stirred for 2 hours at room temperature. To the mixture was then added saturated aqueous ammonium chloride sol. and the resulting mixture was stirred for 10 minutes, before it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified twice by flash column chromatography (gradient: 100 % hexane to 100 % ethyl acetate) to isolate the major isomer (1.18 g, 30 %) as brown oil. LC-MS (Method 2): Rt= 1.66 min; MS (ESIpos): m / z = 462 [M+H]+

[0755] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.756 (0.87), 0.763 (16.00), 0.770 (0.79), 0.966 (11.40), 1.323 (1.34), 1.339 (1.33), 4.514 (2.28), 5.477 (0.43), 5.492 (0.40), 7.455 (0.41), 7.525 (0.47).

[0756] A fraction containing a mixture of diastereomers formed during the reaction was used as reference for determination of the diastereomeric excess (d.e.) of the product by analytical SFC.

[0757] Instrument: Waters Acquity UPC2 QDA; column: Chiralpak IG 3 • m 100x4.6 mm; mobile phase A: carbon dioxide; mobile phase B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 95% A + 5% B; flow: 4 ml / min; temperature: 40.0 °C; backpressure: 1800 psi; wavelength: 220 nm

[0758] Isomer 1: Rt= 0.99 min; MS (ESIpos): m / z = 462 [M+H]+

[0759] Isomer 2: Rt= 1.13 min; MS (ESIpos): m / z = 462 [M+H]+

[0760] The title compound was isolated as isomer 1 with a d.e. of >99 %.

[0761] Intermediate 62

[0762] 3-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}prop-2-yn-l-ol hydrogen chloride (1 / 1)

[0763] In a 100 ml round bottom flask, to a solution of (S2S)-N-{ l-[2-(3-{ [tert-butyl(dimethyl)silyl]oxy }prop-l- yn-l-yl)-3-(trifluoromethyl)phenyl]ethyl}-2-methylpropane-2-sulfinamide (isomer 1) (1.18 g, 2.56 mmol) in 12 ml 1,4-dioxane under argon was added hydrochloric acid (6.4 ml, 4.0 M in 1,4-dioxane, 26 mmol) and the mixture was stirred for 3 hours at -78 °C. The cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and the residue was taken up in toluene and concentrated under reduced pressure three times. The procedure was repeated with the crude product to obtain full conversion. The crude product (752 mg) was directly used in the following reaction.

[0764] LC-MS (Method 2): Rt= 0.92 min; MS (ESIpos): m / z = 244 [M+H]+

[0765] Intermediate 63

[0766] 3-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}propan-l-ol hydrogen chloride (1 / 1)

[0767] In a 100 ml round bottom flask, to a solution of 3-{2-[l-aminoethyl]-6-(trifluoromethyl)phenyl}prop-2- yn-l-ol hydrogen chloride (1 / 1) (isomer 1) (715 mg, 2.56 mmol) in 25 ml ethanol under argon was added platinum(IV) oxide (290 mg, 1.28 mmol) and the mixture was stirred vigorously for 5 hours under a hydrogen atmosphere (balloon). The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was submitted again to the above described conditions and stirred under hydrogen until starting material was consumed. The mixture was filtered, the filtrate was concentrated under reduced pressure and the crude product (685 mg black oil) was used without further purification.

[0768] LC-MS (Method 2): Rt= 0.94 min; MS (ESIpos): m / z = 248 [M+H]+

[0769] Intermediate 64

[0770] ( 1 R)- 1 - [2- { 3- [(Triethylsilyl)oxy]propyl } -3-(trifluoromethyl)phenyl]ethan- 1 -amine

[0771] In a 100 ml round bottom flask, to a solution of 3-{2-[(l-aminoethyl]-6-(trifluoromethyl)phenyl}propan- l-ol (isomer 1) (632 mg, 2.56 mmol) in 28 ml dichloromethane under argon was added 2,6- dimethylpyridine (2.1 ml) and the mixture was cooled to 0 ° C, before triethylsilyl trifluoromethanesulfonate (2.9 ml, 13 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate sol. was then added and further stirred for 10 min. The phases were separated and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product (1.2 g dark oil) was used without further purification.

[0772] LC-MS (Method 2): Rt= 1.69 min; MS (ESIpos): m / z = 362 [M+H]+ Intermediate 65

[0773] 2,6-dichloro-N-{(lR)-l-[2-{3-[(triethylsilyl)oxy]propyl}-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4- d]pyrimidin-4-amine

[0774] In a microwave reactor, to a mixture of l-[2-{3-[(triethylsilyl)oxy]propyl}-3- (trifluoromethyl)phenyl]ethan-l -amine (isomer 1) (550 mg, 85 % purity, 1.29 mmol) and 2,4,6- trichloropyrido[3,4-d]pyrimidine (303 mg, 1.29 mmol) in 15 ml DMF under argon was added triethylamine (900 pl, 6.5 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and water and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (gradient: 100 % hexane to 50 % ethyl acetate in hexane) to yield the title compound (463 mg, 64 %) as red-brown oil.

[0775] LC-MS (Method 2): Rt= 1.84 min; MS (ESIpos): m / z = 559 [M+H]+

[0776] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.542 (1.80), 0.562 (6.59), 0.582 (7.34), 0.601 (2.54), 0.710 (0.45), 0.729 (0.86), 0.894 (8.21), 0.914 (16.00), 0.934 (6.29), 1.154 (0.43), 1.171 (0.88), 1.189 (0.45), 1.592 (2.76), 1.609 (2.75), 1.987 (1.54), 2.522 (1.57), 3.212 (0.66), 3.747 (0.43), 3.763 (0.63), 3.769 (0.52), 3.784 (0.71), 3.798 (0.45), 5.644 (0.58), 7.383 (0.46), 7.402 (1.01), 7.422 (0.60), 7.580 (1.08), 7.599 (0.86), 7.783 (0.97), 7.802 (0.86), 8.625 (2.26), 8.867 (2.55), 9.469 (0.68), 9.485 (0.67).

[0777] Intermediate 66

[0778] 3 - [2 - { ( 1 R) - 1 - [(2,6-dichloropyrido[3 ,4-d]pyrimidin-4-yl)amino]ethyl } -6- (trifluoromethyl)phenyl] propan- 1 -ol

[0779] In a 100 ml round bottom flask, to a solution of 2,6-dichloro-N-{ l-[2-{3-[(triethylsilyl)oxy]propyl}-3- (trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidin-4-amine (isomer 1) (463 mg, 827 μmol) in 23 ml THF was added tetra-n-butylammoniumfluoride (1.2 ml, 1.0 M in tetrahydrofuran, 1.2 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was then concentrated under reduced pressure and purified by flash column chromatography (gradient: 100 % hexane to 100 % ethyl acetate) to yield the title compound (363 mg, 99 %) as yellow oil.

[0780] LC-MS (Method 2): Rt= 1.25 min; MS (ESIpos): m / z = 445 [M+H]+

[0781] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (4.37), 1.172 (9.00), 1.189 (4.40), 1.600 (4.25), 1.617 (4.33), 1.645 (0.49), 1.659 (0.43), 1.987 (16.00), 2.518 (1.56), 2.523 (1.02), 2.829 (0.48), 3.185 (0.46),

[0782] 3.561 (0.51), 3.576 (1.11), 3.590 (1.52), 3.604 (1.12), 3.618 (0.48), 3.999 (1.20), 4.016 (3.56), 4.034

[0783] (3.49), 4.052 (1.12), 4.593 (1.17), 4.605 (2.77), 4.618 (1.12), 5.613 (0.53), 5.630 (0.79), 5.647 (0.52),

[0784] 5.758 (1.61), 7.377 (0.68), 7.396 (1.50), 7.416 (0.87), 7.578 (1.56), 7.595 (1.27), 7.782 (1.38), 7.800

[0785] (1.26), 8.625 (3.36), 8.864 (3.85), 9.454 (0.92), 9.470 (0.89).

[0786] Intermediate 67 l-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzene

[0787] To a solution of l-bromo-2-methyl-3-(trifluoromethyl)benzene (500 g, 2.09 mol) in acetonitrile was added N-bromosuccinimide (410 g, 2.30 mol ) at 25 °C. The mixture was stirred at 40°C for 4 hours under 450 nm, 600 W light. The mixture was quenched with saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 5: 1) to give l-bromo-2-(bromomethyl)-3- (trifluoromethyl)benzene (600 g, 95 % purity, 86 % yield) as a colorless oil.

[0788] 1H-NMR (400 MHz, CDCl3) • [ppm]: 7.82 (d, 1 H), 7.66 (d, 1 H), 7.30 (t, 1 H), 4.75 (s, 2 H). Intermediate 68 ethyl 3 - [2-bromo-6-(trifluoromethyl)phenyl] -2,2-difluoropropanoate

[0789] To a solution of l-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzene (10.0 g, 31.5 mmol) in 100 mL DMSO were added ethyl difluoro(iodo)acetate (8.26 g, 33 mmol) and copper (6.90 g, 10.9 mmol). The reaction mixture was stirred at 25 °C for 16 hours. The mixture was extracted with petroleum ether. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (300-400 mesh, petroleum ether: ethyl acetate = 100: 1 to 20: 1) to give ethyl 3-[2-bromo-6-(trifluoromethyl)phenyl]-2,2-difluoropropanoate (2.78 g, 11 % yield) as a colorless oil.

[0790] 1H-NMR (400 MHz, CDCl3) • [ppm]: 7.85 (d, 1 H), 7.70 (d, 1 H), 7.33 (t, 1 H), 4.36 (q, 2 H), 3.95 (t, 2 H), 1.36 (t, 3 H).

[0791] Intermediate 69

[0792] 3- [2-bromo-6-(trifluoromethyl)phenyl] -2,2-difluoropropan- 1 -ol

[0793] To a solution of ethyl 3-[2-bromo-6-(trifluoromethyl)phenyl]-2,2-difluoropropanoate (65.6 g, 95 % purity, 173 mmol) in 280 mL THF was added lithium borohydride (130 mL, 2.0 M in THF) at 0 °C under nitrogen atmosphere and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with saturated aq. ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate) to give 3-[2-bromo- 6-(trifluoromethyl)phenyl] -2,2-difluoropropan- l-ol 34.0 g (62 % yield) as a colorless oil.1H-NMR (400 MHz, CDCl3) • [ppm]: 7.86 (d, 1 H), 7.70 (d, 1 H), 7.30 (t, 1 H), 3.97-3.85 (m, 2 H), 3.84- 3.74 (m, 2 H), 2.03 (t, 1 H).

[0794] Intermediate 70

[0795] {3-[2-bromo-6-(trifluoromethyl)phenyl]-2,2-difluoropropoxy}(tert-butyl)diphenylsilane

[0796] To a solution of 3-[2-bromo-6-(trifluoromethyl)phenyl]-2,2-difluoropropan-l-ol (22.0 g, 95 % purity, 65.5 mmol) in 500 mL dichloromethane were added IH-imidazole (8.92 g, 131 mmol) and tert- butyl(chloro)diphenylsilane (27.0 g, 98.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to give {3-[2-bromo-6-(trifluoromethyl)phenyl]-2,2-difluoropropoxy}(tert- butyl)diphenylsilane (20.0 g, 95 % purity, 52 % yield) as a colorless oil.

[0797] 1H NMR (400 MHz, CDCl3) • [ppm] = 7.66 (d, 1 H), 7.62-7.55 (m, 4 H), 7.52 (d, 1H), 7.34-7.30 (m, 1 H), 7.29-7.27 (m, 3 H), 7.26-7.16 (m, 2 H), 7.07 (t, 1 H), 3.80-3.66 (m, 4 H), 0.99 (s, 9 H).

[0798] Intermediate 71

[0799] (S2R)-N- { (1R)- 1 - [2-(3 - { [tert-butyl(diphenyl)silyl]oxy } -2,2-difluoropropyl)-3-

[0800] (trifluoromethyl)phenyl] ethyl } -2-methylpropane-2-sulfinamide

[0801]

[0802] The reaction was performed by flow chemistry.

[0803] Instrument: Longer Pump YZ15; reactor: three-neck bottle; pump type: peristaltic pump.

[0804] Solution 1: [3-[2-bromo-6-(trifluoromethyl)phenyl]-2,2-difluoro-propoxy]-tert-butyl-diphenyl-silane (19.5 g, 93%, 32.5 mmol) in THF (195 mL);

[0805] Solution 2: n-butyllithium (30 mL, 1.6 M in hexanes, 49 mmol);

[0806] Solution 3: (S2R)-N-ethylidene-2-methylpropane-2-sulfinamide (7.18 g, 48.8 mmol) in THF (195 mL).

[0807] Solution 1 was pumped by pump 1 [SI, P1 11-049 mL / min] to flow reactor 1 [FLR1, PFA, Coils reactor, 1.588 (1 / 16”) mm, 0.636 mL, -40 °C]. The solution 2 was pumped by pump 2 [S2, P2, 1.671 mL / min] to flow reactor 1 [FLR1, PFA, Coils reactor, 1.588 (1 / 16”) mm, 0.636 mL, -40 °C]. The solution 3 was pumped by pump 3 [S3, P3, 10.376 mL / min] to flow reactor 2 [FLR2, PFA, Coils reactor, 1.588 (1 / 16”) mm, 0.636 mL, -40 °C]. The residence time of flow reactor 1 was [FLR1, 0.05 min]. The residence time of flow reactor 2 was [FLR2, 0.026 min]. The pump 1 and pump 2 were started at the same time. After 0.05 minutes, pump 3 was started. The reaction mixture was collected after running 0.026 mins. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate, gradient 10 : 1 to 1 : 1) to give the title compound (2.10 g, 95 % purity, 10 % yield) as the first eluting diastereomer. The undesired diastereomer was isolated separately and not used further.

[0808] 1H NMR (400 MHz, CDCl3) • [ppm] = 7.75-7.65 (m, 6 H), 7.49-7.39 (m, 7 H), 5.02-4.92 (m, 1 H), 3.87 (t, 2 H), 3.80-3.60 (m, 2 H), 3.40-3.27 (m, 1 H), 1.56-1.52 (m, 3 H), 1.20 (s, 9 H) , 1.12 (s, 9H).

[0809] Intermediate 72

[0810] ( 1 R)- 1 - [2-(3 - { [tert-butyl(diphenyl)silyl] oxy } -2,2-difluoropropyl)-3-(trifluoromethyl)phenyl] ethan- 1 - amine

[0811]

[0812] To a mixture of (S2R)-N-{(lR)-l-[2-(3-{ [tert-butyl(diphenyl)silyl]oxy}-2,2-difluoropropyl)-3- (trifluoromethyl)phenyl]ethyl}-2-methylpropane-2-sulfinamide (2.10 g, 95 % purity, 3.19 mmol) in water (8 mL) and tetrahydrofuran (16 mL) was added iodine (243 mg, 956 μmol) at room temperature. Then, the mixture was stirred at 50 °C for 16 hours. The mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient: petroleum ether / ethyl acetate = 2 : 1 to ethyl acetate / methanol 0 : 1) to give the title compound (540 mg, 98 % purity, 32 % yield) as colorless oil.

[0813] LC-MS (Method 3): Rt= 0.609 min; MS (ESIpos): m / z = 522.3 [M+H]+.

[0814] 1H NMR (400 MHz, DMSO-rfc) • [ppm] = 8.30-7.90 (m, 3 H), 7.82 (d, 1 H), 7.73-7.63 (m, 5 H), 7.58- 7.43 (m, 6 H), 4.78-4.68 (m, 1 H), 4.08-3.93 (m, 2 H), 3.91-3.70 (m, 2 H), 1.49 (d, 3 H), 1.05 (s, 9 H).

[0815] The absolute stereochemistry was determined using Mosher's method (e.g. described in Journal of Chemical Education 200885 (5), 698). The1H-NMR data for the corresponding Mosher amide indicate the absolute stereochemistry of the title compound to be “R”.

[0816] Intermediate 73

[0817] N- { (1R)- 1 - [2-(3 - { [tert-butyl(diphenyl)silyl]oxy } -2,2-difluoropropyl)-3-(trifluoromethyl)phenyl]ethyl } -

[0818] 2,6-dichloropyrido[3,4-d]pyrimidin-4-amine

[0819]

[0820] To a mixture of 2,4,6-trichloropyrido[3,4-d]pyrimidine (174 mg, 742 μmol) and (lR)-l-[2-(3-{ [tert- butyl(diphenyl)silyl]oxy}-2,2-difluoropropyl)-3-(trifluoromethyl)phenyl]ethan-l-amine (403 mg, 96 % purity, 742 μmol) in dichloromethane (5.0 ml) was added triethylamine (520 pl, 3.7 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and ethyl acetate. The organic phase was washed twice with water and one time with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient: 100 % hexane to 60 % ethyl acetate in hexane) to give the title compound (438 mg, 82 % yield) as colorless oil.

[0821] LC-MS (Method 2): Rt= 1.85 min; MS (ESIpos): m / z = 719 [M+H]+

[0822] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.973 (0.41), 1.034 (16.00), 1.153 (1.52), 1.171 (3.17), 1.189 (1.59), 1.646 (1.61), 1.663 (1.62), 1.986 (5.14), 2.518 (0.64), 2.523 (0.46), 3.989 (0.43), 3.998 (0.54),

[0823] 4.005 (0.46), 4.015 (1.26), 4.033 (1.29), 5.758 (0.51), 7.404 (0.47), 7.407 (0.69), 7.425 (1.72), 7.428

[0824] (1.13), 7.431 (0.60), 7.443 (1.61), 7.445 (1.59), 7.447 (1.62), 7.464 (1.76), 7.471 (1.49), 7.476 (0.63),

[0825] 7.480 (0.45), 7.487 (1.17), 7.557 (0.69), 7.577 (0.42), 7.664 (1.56), 7.668 (2.61), 7.671 (2.25), 7.674

[0826] (1.30), 7.677 (1.31), 7.679 (1.44), 7.684 (2.05), 7.687 (2.59), 7.691 (1.12), 7.696 (0.73), 7.889 (0.62),

[0827] 7.907 (0.55), 8.528 (1.18), 8.839 (1.45).

[0828] Intermediate 74

[0829] 3 - [2 - { ( 1 R) - 1 - [(2,6-dichloropyrido[3 ,4-d]pyrimidin-4-yl)amino]ethyl } -6-(trifluoromethyl)phenyl] -2,2- difluoropropan- 1 -ol To N- { (1R)- 1 - [2-(3 - { [tert-butyl(diphenyl)silyl]oxy } -2,2-difluoropropyl)-3-(trifluoromethyl)phenyl] - ethyl}-2,6-dichloropyrido[3,4-d]pyrimidin-4-amine (385 mg, 535 μmol) in THF (4.0 ml) was added tetra- n-butylammoniumfluoride (IM in THF, 800 pl) at room temperature and the mixture was stirred at 50 °C for 2 hours. The mixture was then concentrated in vacuo and the residue was subjected to flash column chromatography on silica (gradient: 100 % hexane to 90 % ethyl acetate), to yield the title compound (202 mg, 79 % yield).

[0830] LC-MS (Method 2): Rt= 1.26 min; MS (ESIpos): m / z = 481 [M+H]+

[0831] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.654 (12.35), 1.670 (12.28), 2.518 (1.80), 2.523 (1.24), 3.367 (0.48), 3.574 (0.75), 3.587 (0.81), 3.615 (0.90), 3.628 (0.86), 3.653 (0.74), 3.665 (0.78), 3.694 (0.86), 3.706 (0.84), 3.727 (2.08), 3.743 (2.25), 3.760 (3.51), 3.775 (3.66), 3.793 (1.94), 3.808 (1.82), 4.406 (0.61), 4.425 (0.60), 4.445 (0.63), 4.478 (0.74), 4.497 (0.64), 4.519 (0.62), 4.537 (0.52), 5.442 (0.48), 5.459 (1.93), 5.475 (2.96), 5.492 (1.94), 5.509 (0.50), 5.757 (2.01), 5.774 (3.74), 5.790 (9.05), 5.805 (3.65), 7.524 (2.19), 7.544 (5.02), 7.563 (3.06), 7.658 (5.13), 7.661 (5.61), 7.678 (4.09), 7.681 (3.83), 7.893 (4.56), 7.911 (4.09), 8.520 (13.30), 8.829 (16.00), 8.831 (15.76), 9.486 (3.41), 9.502 (3.30).

[0832] Intermediate 75

[0833] 2- { ( 1 R)- 1 - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenyl trifluoromethanesulfonate

[0834] To a solution of tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (3.75 g, 12.3 mmol) in dichloromethane (75 ml) was added pyridine (4.0 ml) at room temperature. The mixture was then cooled to 0 °C and trifluoromethanesulfonic anhydride (3.1 ml, 18 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. To the mixture was then added water and dichloromethane, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient: 100 % hexane to 50 % ethyl acetate in hexane), to yield the title compound (5.02 g, 93 % yield).

[0835] LC-MS (Method 2): Rt= 1.50 min; MS (ESIpos): m / z = 455 [M+NH4]+1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.141 (4.24), 1.258 (0.64), 1.318 (16.00), 1.362 (6.86), 1.380 (6.90), 1.479 (0.79), 2.518 (1.44), 2.523 (0.88), 4.987 (0.60), 5.003 (0.82), 5.019 (0.56), 7.771 (2.30), 7.790 (2.05), 7.888 (1.65), 7.905 (1.52), 7.963 (3.00), 7.966 (2.87), 7.983 (2.51).

[0836] Intermediate 76 tert-butyl { ( 1 R) - 1 - [2 - ( 3 - { [tert -butyl(dime thy 1) silyl] oxy } but- 1 -yn- 1 -y 1) - 3 - (trifluoromethyl)phenyl] ethyl} carbamate (mixture of diastereomers)

[0837] To a solution of 2-{(lR)-l-[(tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenyl trifluoromethanesulfonate (1.50 g, 3.43 mmol) and tert-butyl[(but-3-yn-2-yl)oxy]dimethylsilane (3.16 g, 17.1 mmol) in DMSO (19 ml) was added bis(triphenylphosphine)palladium(II) dichloride (1.20 g, 1.71 mmol), and copper(I) iodide (327 mg, 1.71 mmol) and the mixture was stirred at 70 °C overnight. To the mixture was then added water and ethyl acetate, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient: 100 % hexane to 70 % ethyl acetate in hexane) to yield the title compound (559 mg, 35 % yield).

[0838] LC-MS (Method 2): Rt= 1.78 min; MS (ESIpos): m / z = 472 [M+H]+

[0839] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.125 (6.75), 0.129 (4.15), 0.883 (16.00), 1.263 (0.60), 1.271 (0.62), 1.280 (0.61), 1.349 (3.83), 1.443 (1.25), 1.459 (1.26), 7.622 (0.77), 7.642 (0.56), 7.663 (0.52).

[0840] Intermediate 77

[0841] 4-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}but-3-yn-2-ol hydrogen chloride (1 / 1) (mixture of diastereomers)

[0842] To a solution of tert-butyl {(lR)-l-[2-(3-{ [tert-butyl(dimethyl)silyl]oxy}but-l-yn-l-yl)-3- (trifluoromethyl)phenyl] ethyl} carbamate (559 mg, 1.19 mmol) in 1,4-dioxane (10 ml) was added hydrochloric acid (3.0 ml, 4.0 M in 1,4-dioxane, 12 mmol), and the mixture was stirred at room temperature overnight, and 4 hours at 50 °C. The mixture was concentrated in vacuo and taken up in toluene and concentrated again three times. The crude product (365 mg, quant.) was obtained as black oil and used without further purification.

[0843] LC-MS (Method 2): Rt= 0.97 min; MS (ESIpos): m / z = 258 [M+H]+

[0844] Intermediate 78

[0845] 4-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}butan-2-ol — hydrogen chloride (1 / 1) (mixture of diastereomers)

[0846] To a solution of 4-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}but-3-yn-2-ol — hydrogen chloride (1 / 1) (350 mg, 1.19 mmol) in ethanol (35 ml) was added platinum(IV) oxide (135 mg, 596 μmol) and the mixture was stirred under hydrogen atmosphere at room temperature for 2.5 hours. The mixture was then filtered and concentrated in vacuo. The crude product (425 mg) was obtained as brown oil and used without purification.

[0847] LC-MS (Method 2): Rt= 1.01 min; MS (ESIpos): m / z = 262 [M+H]+

[0848] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.025 (0.97), 1.040 (1.10), 1.051 (0.43), 1.066 (0.41), 1.102 (4.74), 1.109 (5.11), 1.118 (4.99), 1.125 (4.62), 1.230 (0.56), 1.253 (0.56), 1.269 (0.54), 1.411 (0.50), 1.427 (0.51), 1.491 (0.51), 1.522 (3.96), 1.538 (6.78), 1.555 (3.65), 1.584 (0.50), 2.518 (0.93), 2.523 (0.62), 2.665 (0.55), 2.669 (0.69), 2.673 (0.57), 3.163 (16.00), 3.214 (0.79), 3.292 (0.55), 3.308 (1.08), 3.384 (1.27), 3.485 (0.42), 3.491 (0.59), 3.643 (1.51), 3.713 (0.59), 3.728 (0.79), 4.132 (1.11), 4.676 (0.71), 4.790 (0.55), 7.521 (0.97), 7.540 (2.11), 7.560 (1.31), 7.700 (2.11), 7.720 (1.60), 8.000 (1.75), 8.021 (1.61), 8.591 (1.85).

[0849] Intermediate 79 (lR)-l-[2-{3-[(triethylsilyl)oxy]butyl}-3-(trifluoromethyl)phenyl]ethan-l-amine (mixture of diastereomers)

[0850] To a solution of 4-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}butan-2-ol - hydrogen chloride (1 / 1) (355 mg, 1.19 mmol) (mixture of diastereomers) in dichloromethane (10 mL) was added 2,6-lutidine (970 μL). The mixture was cooled to 0 °C, before triethylsilyl trifluoromethanesulfonate (1.3 mL, 6.0 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature overnight. To the solution was then added saturated aqueous sodium hydrogen carbonate solution and stirred for 10 minutes. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product (715 mg) was obtained as dark oil and used without further purification in the next step.

[0851] Intermediate 80

[0852] 2,6-dichloro-N- { ( 1 R)- 1 - [2- { (3RS)-3- [(triethylsilyl)oxy] butyl } -3-

[0853] (trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidin-4-amine (mixture of diastereomers)

[0854]

[0855] To a mixture of 2,4,6-trichloropyrido[3,4-d]pyrimidine (280 mg, 1.19 mmol) and (lR)-l-[2-{(3RS)-3- [(triethylsilyl)oxy]butyl}-3-(trifluoromethyl)phenyl]ethan-l-amine (448 mg, 1.19 mmol) in DMF (8.0 ml) was added triethylamine (830 μl, 6.0 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient: 100 % hexane, to 50 % ethyl acetate in hexane) to give the title compound (493 mg, 72 % yield) as colorless oil.

[0856] LC-MS (Method 2): Rt= 1.88 min; MS (ESIpos): m / z = 573 [M+H]+

[0857] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.537 (1.30), 0.541 (1.31), 0.545 (0.59), 0.558 (4.60), 0.560 (3.97), 0.565 (1.01), 0.576 (5.78), 0.579 (6.34), 0.595 (7.22), 0.598 (3.44), 0.615 (2.67), 0.765 (0.49), 0.886 (0.87), 0.895 (8.01), 0.901 (8.00), 0.905 (2.15), 0.914 (15.82), 0.920 (16.00), 0.929 (1.27), 0.934 (6.16), 0.941 (5.84), 1.153 (0.63), 1.171 (1.85), 1.175 (3.14), 1.190 (3.27), 1.227 (3.36), 1.242 (3.09), 1.595 (2.98), 1.600 (3.21), 1.612 (3.40), 1.617 (3.38), 1.634 (0.64), 1.986 (1.87), 2.518 (1.57), 2.523 (1.03), 3.292 (0.41), 3.638 (0.52), 4.006 (0.47), 4.016 (0.74), 4.034 (0.80), 5.585 (0.51), 5.602 (0.76), 5.619 (0.50), 7.386 (0.47), 7.393 (0.88), 7.405 (0.88), 7.412 (0.58), 7.425 (0.50), 7.577 (1.00), 7.580 (0.99), 7.584 (0.97), 7.594 (0.80), 7.597 (0.82), 7.601 (0.84), 7.771 (0.82), 7.784 (0.86), 7.802 (0.69), 8.617 (2.10), 8.636 (2.00), 8.638 (2.00), 8.869 (4.70), 9.457 (0.58), 9.471 (0.89), 9.486 (0.55).

[0858] Intermediate 81

[0859] (2RS)-4- [2- { ( 1 R)- 1 - [(2,6-dichloropyrido[3 ,4-d]pyrimidin-4-yl)amino] ethyl } -6-

[0860] (trifluoromethyl)phenyl]butan-2-ol (mixture of diastereomers)

[0861] To 2,6-dichloro-N-{(lR)-l-[2-{(3RS)-3-[(triethylsilyl)oxy]butyl}-3-(trifluoromethyl)phenyl]-ethyl}- pyrido[3,4-d]pyrimidin-4-amine (493 mg, 860 μmol) in tetrahydrofuran (10 ml) was added tetra-n- butylammoniumfluoride (1.3 ml, 1.0 M in tetrahydrofuran, 1.3 mmol) at room temperature and the mixture was stirred at room temperature for 3 hours and at 50 °C for 4 h. The mixture was then concentrated in vacuo and the residue was subjected to flash column chromatography on silica gel (gradient: 100 % hexane to 100 % ethyl acetate) to yield the title compound (368 mg, 93 % yield) as light-brown solid.

[0862] LC-MS (Method 2): Rt= 1.32 min; MS (ESIpos): m / z = 459 [M+H]+

[0863] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.842 (0.74), 0.860 (1.77), 0.878 (0.95), 1.131 (10.77), 1.147 (10.58), 1.165 (0.81), 1.179 (10.40), 1.194 (10.59), 1.226 (1.63), 1.245 (0.55), 1.258 (0.64), 1.265 (0.53), 1.504 (0.92), 1.525 (1.24), 1.537 (1.46), 1.557 (1.15), 1.568 (0.98), 1.598 (11.06), 1.615 (11.13), 1.634 (0.84), 1.905 (0.48), 2.004 (0.46), 2.036 (0.77), 2.074 (1.27), 2.113 (0.61), 2.132 (0.56), 2.145 (0.59),

[0864] 2.336 (0.44), 2.518 (3.57), 2.522 (2.24), 2.705 (0.43), 2.730 (0.80), 2.763 (0.48), 2.943 (0.75), 2.975

[0865] (0.60), 3.021 (0.56), 3.043 (0.69), 3.291 (0.53), 3.296 (0.55), 3.351 (1.44), 3.769 (0.98), 3.780 (1.04),

[0866] 3.795 (1.08), 3.807 (1.10), 3.824 (0.75), 3.836 (0.41), 4.565 (5.19), 4.576 (4.86), 4.607 (4.94), 4.618

[0867] (4.78), 5.595 (1.04), 5.613 (1.75), 5.619 (1.45), 5.630 (1.40), 5.636 (1.79), 5.653 (1.06), 7.367 (2.32),

[0868] 7.386 (5.10), 7.406 (2.97), 7.572 (5.15), 7.591 (4.31), 7.765 (2.52), 7.775 (2.58), 7.784 (2.31), 7.792

[0869] (2.28), 8.637 (13.10), 8.865 (16.00), 8.867 (10.09), 8.875 (0.68), 9.442 (2.08), 9.450 (2.40), 9.459 (2.29), 9.467 (2.07).

[0870] Intermediate 82 l-(difluoromethyl)-2-(methoxymethoxy)benzene To a solution of 2-(methoxymethoxy)benzaldehyde (100 g, 95 % purity, 572 mmol) in dichloromethane (1.5 1) was added diethylaminosulfur trifluoride (230 ml, 1.7 mol) at 0 °C under nitrogen atmosphere and the mixture was stirred at 25 °C for 16 hours. The mixture was poured into saturated aq. sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (14% ethyl acetate in petroleum ether) to give l-(difluoromethyl)- 2-(methoxymethoxy)benzene (86.0 g, 95 % purity, 76 % yield) as a pale yellow oil.

[0871] 1H NMR (400 MHz, CDCl3) • [ppm] = 7.59 (d, 1 H), 7.42 (t, 1 H), 7.18 (d, 1 H), 7.14-7.08 (m, 1 H), 6.98 (t, 1 H), 5.25 (s, 2 H), 3.54 (s, 3 H).

[0872] Intermediate 83

[0873] (S2S)-N- { ( 1 R)- 1 - [3 -(difluoromethyl)-2-(methoxymethoxy)phenyl]ethyl } -2-methylpropane-2- sulfinamide

[0874] To a solution of l-(difluoromethyl)-2-(methoxymethoxy)benzene (56.1 g, 95 % purity, 283 mmol) in tetrahydrofuran (1.1 1) was added n-BuLi (2.5 M in tetrahydrofuran, 120 ml, 310 mmol) dropwise at -70 °C. The mixture was stirred at -70 °C for 1 hour. The reaction was warmed to 0 °C and stirred at 0 °C for 1.5 hours. Then, the mixture was cooled to -70°C, a solution of (S2S)-N-ethylidene-2-methylpropane-2- sulfinamide (62.6 g, 425 mmol) in tetrahydrofuran (80 ml) was added dropwise. The mixture was stirred at -70 °C for 30 min and then allowed to warm to rt and stirred for 1.5 hours. The reaction mixture was quenched with saturated aq. ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate, petroleum ether, 1 : 2) to give the title compound (31.0 g, 95 % purity, 31 % yield) as a pale yellow oil.

[0875] 1H NMR (400 MHz, CDCl3) • [ppm] = 7.54 (t, 2 H), 7.31-7.27 (m, 1 H), 6.97 (t, 1 H), 5.14-5.03 (m, 2 H), 5.02-4.96 (m, 1 H), 3.64 (s, 3 H), 3.51-3.43 (m, 1 H), 1.53 (t, 3 H), 1.2 (s, 9 H).

[0876] Intermediate 84

[0877] 2-[(lR)-l-aminoethyl]-6-(difluoromethyl)phenol hydrogen chloride (1 / 1)

[0878] To a solution of (S2S)-N-{(lR)-l-[3-(difhroromethyl)-2-(methoxymethoxy)phenyl]ethyl}-2- methylpropane-2-sulfinamide (31.0 g, 87.80 mmol, 95 % purity) in 1,4-dioxane (100 ml) was added 2 M hydrochloric acid in 1,4-dioxane (190 ml) at 25 °C. After stirring at 25 °C for 1 hour, the mixture was concentrated in vacuo and purified by trituration with methyl tertiary butyl ether. The mixture was filtered and the filter cake was dried in vacuo to give the title compound (18.60 g, 89 % purity, 84 % yield) as a pale yellow solid.

[0879] LC-MS (Method 3): Rt= 0.380 min; MS (ESIpos): m / z = 171.0 [M-NH2]+.

[0880] Intermediate 85 tert-butyl { ( 1 R) - 1 - [3 -(difluoromethyl)-2-hydroxyphenyl] ethyl } carbamate

[0881] To a solution of 2-[(lR)-l-aminoethyl]-6-(difluoromethyl)phenol hydrogen chloride (1 / 1) (18.60 g, 74.02 mmol, 89 % purity) in di-tert-butyl dicarbonate (200 ml) was stirred at 100 °C for 3 hours. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (ethyl acetate, petroleum ether, 1 : 13) to give the title compound (18.30 g, 73 % purity, 63 % yield) as a colorless oil.

[0882] LC-MS (Method 3): Rt= 0.634 min; MS (ESIpos): m / z = 232.0 [M-55]+.

[0883] Intermediate 86

[0884] (S2S)-N-[(lR)-l-{2-[(lZ)-3-{ [tert-butyl(dimethyl)silyl]oxy}prop-l-en-l-yl]-3-

[0885] (trifluoromethyl)phenyl } ethyl] -2-methylpropane-2-sulfinamide

[0886] To a solution of (S2S)-N-{ l-[2-(3-{ [tert-butyl(dimethyl)silyl]oxy}prop-l-yn-l-yl)-3- (trifluoromethyl)phenyl]ethyl}-2-methylpropane-2-sulfinamide (isomer 1) (585 mg, 1.27 mmol) in ethanol (35 ml) was added platinum(IV) oxide (144 mg, 634 μmol) and the mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. The mixture was then filtered and concentrated in vacuo. The crude product was obtained as brown oil (615 mg) and used without purification.

[0887] LC-MS (Method 2): Rt= 1.68 min; MS (ESIpos): m / z = 464 [M+H]+

[0888] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.034 (0.71), 0.040 (1.14), 0.873 (16.00), 0.924 (1.15), 0.986 (0.54), 1.131 (1.74), 1.149 (1.06), 1.159 (0.52), 1.192 (1.68), 5.844 (1.92), 7.599 (0.52), 7.692 (0.48).

[0889] Intermediate 87

[0890] (2Z)-3-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}prop-2-en-l-ol hydrogen chloride (1 / 1)

[0891] In a 100 ml round bottom flask, to a solution of (S2S)-N-[(lR)-l-{2-[(lZ)-3-{ [tert- butyl(dimethyl)silyl]oxy }prop- 1 -en- 1 -yl] -3-(trifluoromethyl)phenyl } ethyl] -2-methylpropane-2- sulfinamide (615 mg, 1.33 mmol) in 15 ml 1,4-dioxane under argon was added hydrochloric acid (3.3 ml, 4.0 M in 1,4-dioxane, 13 mmol) and the mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and the residue was taken up in toluene and concentrated under reduced pressure three times. The crude product (436 mg) was used without purification.

[0892] LC-MS (Method 2): Rt= 0.96 min; MS (ESIpos): m / z = 246 [M+H]+

[0893] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.026 (0.56), 1.042 (7.40), 1.064 (0.88), 1.099 (16.00), 1.101 (10.40), 1.110 (0.55), 1.132 (0.62), 1.154 (0.43), 1.231 (0.79), 1.289 (0.72), 1.387 (0.78), 1.399 (1.35), 1.415 (1.36), 1.488 (2.58), 1.504 (2.43), 1.526 (0.48), 2.297 (9.48), 2.327 (0.52), 2.518 (1.48), 2.523 (1.00), 2.669 (0.53), 3.457 (0.99), 3.468 (0.96), 3.486 (0.85), 3.522 (0.40), 3.643 (0.53), 3.662 (0.54), 3.676 (0.65), 3.689 (0.75), 3.701 (0.88), 3.720 (6.00), 4.566 (0.73), 6.057 (0.79), 6.075 (1.14), 6.086 (1.04), 6.103 (1.25), 6.119 (0.86), 6.535 (0.72), 6.565 (0.55), 7.142 (0.87), 7.160 (1.66), 7.162 (1.80), 7.180 (2.10), 7.230 (1.87), 7.235 (0.62), 7.248 (1.92), 7.267 (0.78), 7.626 (0.88), 7.645 (1.99), 7.664 (1.31), 7.760 (1.46), 7.778 (1.00), 7.915 (0.43), 7.932 (0.43), 7.991 (0.92), 8.011 (0.76), 8.418 (1.40), 8.583 (0.80).

[0894] Intermediate 88

[0895] ( 1 R) - 1 - [2- { ( 1 Z) - 3 - [(triethylsilyl)oxy ]prop- 1 -en- 1 -yl } -3 -(trifluoromethyl)phenyl] ethanamine

[0896] To a solution of (2Z)-3-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenyl}prop-2-en-l-ol hydrogen chloride (1 / 1) (374 mg, 1.33 mmol) in dichloromethane (10 ml) was added 2,6-lutidine (1.1 ml). The mixture was cooled to 0 °C before triethylsilyl trifluoromethanesulfonate (1.5 ml, 6.6 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature overnight. To the solution was then added saturated aqueous sodium hydrogen carbonate sol. and stirred for 10 minutes. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product (705 mg) was obtained as brown oil and used without purification.

[0897] LC-MS (Method 2): Rt= 1.64 min; MS (ESIpos): m / z = 360 [M+H]+

[0898] Intermediate 89

[0899] 2,6-dichloro-N-{(lR)-l-[2-{(lZ)-3-[(triethylsilyl)oxy]prop-l-en-l-yl}-3-(trifluoromethyl)phenyl]- ethyl } pyrido [3 ,4-d] pyrimidin-4-amine

[0900] In a 25 ml round bottom flask, to a mixture of l-[2-{(lZ)-3-[(triethylsilyl)oxy]prop-l-en-l-yl}-3- (trifluoromethyl)phenyl]ethan-l -amine (isomer 1) (478 mg, 1.33 mmol) and 2,4,6-trichloropyrido[3,4- d]pyrimidine (312 mg, 1.33 mmol) in 10 ml DMF under argon was added triethylamine (930 pl, 6.6 mmol) and the mixture was stirred for 1 hour at room temperature. The mixture was diluted with ethyl acetate and water and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (gradient: 100 % hexane to 50 % ethyl acetate in hexane) to yield the title compound (529 mg, 71 % yield) as red-brown solid.

[0901] LC-MS (Method 2): Rt= 1.82 min; MS (ESIpos): m / z = 557 [M+H]+

[0902] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.304 (3.22), 0.321 (3.63), 0.450 (3.30), 0.469 (7.74), 0.489 (8.20), 0.509 (3.44), 0.543 (0.80), 0.562 (1.96), 0.583 (2.03), 0.602 (0.75), 0.721 (6.56), 0.817 (10.49), 0.836 (16.00), 0.856 (7.56), 0.891 (1.99), 0.895 (2.46), 0.910 (2.71), 0.915 (4.33), 0.934 (1.80), 1.111 (0.71), 1.154 (1.05), 1.172 (2.03), 1.189 (1.08), 1.228 (1.25), 1.258 (0.65), 1.327 (0.60), 1.507 (2.47), 1.537 (1.33), 1.568 (4.97), 1.585 (4.62), 1.610 (0.90), 1.693 (0.51), 1.709 (0.49), 1.987 (3.37), 2.074 (0.56), 2.518 (5.35), 2.523 (3.55), 3.778 (0.98), 3.809 (1.64), 3.827 (1.63), 3.926 (1.18), 3.947 (0.84), 4.016 (0.97), 4.034 (1.29), 4.052 (0.71), 5.399 (1.19), 5.522 (0.58), 5.758 (0.55), 5.923 (0.58), 6.051 (1.01), 6.585 (0.60), 6.867 (1.30), 6.897 (1.25), 7.503 (2.15), 7.523 (1.93), 7.615 (2.01), 7.634 (1.70), 7.679 (0.97), 7.788 (2.59), 7.806 (2.84), 8.545 (3.03), 8.574 (0.50), 8.623 (0.74), 8.646 (1.12), 8.843 (3.12), 8.866 (1.15), 8.887 (1.28), 8.905 (0.71), 9.201 (0.62), 9.505 (1.36).

[0903] Intermediate 90

[0904] (2Z)-3-[2-{(lR)-l-[(2,6-dichloropyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-6-(trifluoromethyl)phenyl]- prop-2-en-l-ol

[0905] To 2, 6-dichloro-N - { ( 1 R) - 1 - [2 - { ( 1 Z) - 3 - [(triethylsilyl)oxy ]prop- 1 -en- 1 -yl } -3 -(trifluoromethyl) -phenyl] - ethyl}pyrido[3,4-d]pyrimidin-4-amine (525 mg, 942 μmol) in tetrahydrofuran (20 ml) was added tetra-n- butylammoniumfluoride (1.4 ml, 1.0 M, 1.4 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo and the residue was subjected to flash column chromatography on silica gel (gradient: 100 % hexane to 100 % ethyl acetate) to yield the title compound (410 mg, 98 % yield) as light -brown solid.

[0906] LC-MS (Method 2): Rt= 1.25 min; MS (ESIpos): m / z = 443 [M+H]+

[0907] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.812 (0.47), 0.820 (0.50), 0.845 (1.92), 0.863 (4.27), 0.881 (2.28), 0.903 (0.67), 1.110 (1.65), 1.145 (0.60), 1.153 (0.76), 1.171 (1.29), 1.189 (0.73), 1.229 (3.44), 1.248 (1.23), 1.258 (1.42), 1.266 (1.14), 1.285 (0.83), 1.327 (1.41), 1.351 (0.81), 1.496 (3.53), 1.511 (3.30), 1.529 (2.82), 1.562 (11.34), 1.579 (10.54), 1.599 (2.71), 1.616 (1.80), 1.906 (1.03), 1.986 (2.09), 2.073 (7.74), 2.318 (1.85), 2.518 (16.00), 2.523 (10.77), 2.660 (1.67), 3.298 (1.59), 3.302 (1.27), 3.384 (1.81), 3.392 (0.80), 3.572 (2.41), 3.588 (2.36), 3.748 (2.86), 4.034 (0.41), 4.147 (0.95), 4.401 (1.06),

[0908] 4.598 (0.46), 4.611 (1.00), 4.736 (4.24), 4.980 (0.60), 5.406 (3.16), 5.628 (0.49), 6.069 (2.45), 6.477

[0909] (0.78), 6.829 (2.93), 6.856 (2.77), 7.395 (0.47), 7.468 (3.36), 7.485 (5.36), 7.505 (3.18), 7.577 (0.72),

[0910] 7.606 (5.34), 7.625 (5.12), 7.716 (1.19), 7.782 (4.52), 7.801 (3.68), 8.556 (6.72), 8.595 (1.14), 8.626

[0911] (1.63), 8.678 (1.34), 8.844 (8.00), 8.855 (3.93), 8.863 (3.62), 8.865 (3.42), 9.259 (0.95), 9.472 (0.58),

[0912] 9.524 (3.30), 9.537 (3.13).

[0913] Intermediate 91

[0914] 6-bromo-2-chloro-N- { ( 1 R) - 1 - [2 - { 3- [(triethylsilyl)oxy]propyl } -3- (trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0915]

[0916] To a solution of (lR)-l-[2-{3-[(triethylsilyl)oxy]propyl}-3-(trifluoromethyl)phenyl]ethan-l-amine (300 mg, 85 % purity, 705 μmol) and 6-bromo-2,4-dichloropyrido[2,3-d]pyrimidine (197 mg, 705 μmol) in DMF (6 ml) was added triethylamine (490 pl) and the mixture was stirred at room temperature overnight. A second batch was prepared using the same amounts of starting materials. The combined crude products were diluted with ethyl acetate and water, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, gradient: 100 % hexane to 50 % ethyl acetate in hexane) to yield the title compound (279 mg, 65 % yield) as brown oil.

[0917] LC-MS (Method 2): Rt= 1.77 min; MS (ESIpos): m / z = 603 [M+H]+

[0918] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.546 (1.50), 0.565 (6.35), 0.574 (0.44), 0.585 (6.84), 0.605 (2.19), 0.712 (0.42), 0.732 (0.87), 0.897 (7.49), 0.905 (0.49), 0.908 (0.68), 0.917 (16.00), 0.925 (0.74),

[0919] 0.937 (5.90), 1.171 (0.41), 1.581 (2.24), 1.598 (2.23), 1.986 (0.76), 2.075 (2.19), 2.518 (0.80), 2.522

[0920] (0.53), 3.178 (0.45), 3.765 (0.45), 3.788 (0.53), 7.397 (0.83), 7.416 (0.48), 7.577 (0.86), 7.595 (0.69),

[0921] 7.785 (0.75), 7.804 (0.68), 9.053 (1.53), 9.058 (1.64), 9.274 (1.19), 9.280 (1.09), 9.385 (0.44), 9.400

[0922] (0.41).

[0923] Intermediate 92

[0924] 3-[2-{(lR)-l-[(6-bromo-2-chloropyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-6- (trifluoromethyl)phenyl] propan- 1 -ol

[0925] To 6-bromo-2-chloro-N- { ( 1 R) - 1 - [2 - { 3- [(triethylsilyl)oxy]propyl } -3-(trifluoromethyl)phenyl] - ethyl }pyrido[2,3-d]pyrimidin-4-amine (279 mg, 462 μmol) in tetrahydrofuran (5 ml) was added tetra-n- butylammoniumfluoride (690 pl, 1.0 M, 690 μmol) at room temperature and the mixture was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo and the residue was subjected to flash column chromatography on silica gel (gradient: 100 % hexane to 100 % ethyl acetate) to yield the title compound (215 mg, 95 % yield) as yellow solid.

[0926] LC-MS (Method 2): Rt= 1.18 min; MS (ESIpos): m / z = 489 [M+H]+

[0927] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (4.53), 1.172 (9.10), 1.189 (4.30), 1.589 (8.85), 1.606 (8.91), 1.629 (0.74), 1.647 (0.89), 1.660 (0.84), 1.678 (0.60), 1.692 (0.45), 1.987 (16.00), 2.074 (2.77), 2.147 (0.58), 2.164 (0.72), 2.178 (0.71), 2.518 (3.66), 2.523 (2.50), 2.659 (0.42), 2.806 (0.51), 2.831 (0.96), 2.863 (0.59), 3.158 (0.60), 3.181 (0.91), 3.212 (0.51), 3.552 (0.45), 3.564 (1.03), 3.579 (2.24), 3.593 (3.02), 3.607 (2.29), 3.622 (0.97), 3.633 (0.44), 3.999 (1.13), 4.016 (3.36), 4.034 (3.22), 4.053 (1.05), 4.593 (2.57), 4.606 (6.35), 4.619 (2.48), 5.615 (1.23), 5.632 (1.87), 5.649 (1.21), 5.759 (0.93), 7.372 (1.44), 7.392 (3.11), 7.412 (1.79), 7.576 (3.25), 7.593 (2.61), 7.784 (2.78), 7.802 (2.51), 9.053 (7.38), 9.059 (8.24), 9.276 (6.43), 9.282 (6.10), 9.369 (2.20), 9.387 (2.11).

[0928] Intermediate 93

[0929] 5-Amino-2-chloropyridine-4-carboxamide

[0930] 5-Amino-2-chloroisonicotinic acid (50.0 g, 290 mmol) was dissolved in DCM (500 mL), then CDI (56.4 g, 348 mmol) was added and stirred at room temperature for 2 hours. Then, NH4OH (20.3 g, 579 mmol) was added and stirred at room temperature for 16 hours. The reaction was quenched with water and extracted into EtOAc (x3). The combined org. phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with TBME to afford the title compound (23.3 g, 46% yield).

[0931] LC-MS (Method 2): Rt= 0.54 min; MS (ESIpos): m / z = 172.1 [M+H]+

[0932] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 2.518 (0.70), 2.523 (0.46), 6.672 (7.02), 7.537 (14.02), 7.594 (1.88), 7.922 (16.00), 8.115 (1.85).

[0933] Intermediate 94

[0934] 2-Amino-5-bromo-4-fluorobenzamide

[0935] 6-Bromo-7-fluoro-2H-3,l-benzoxazine-2,4(lH)-dione (10.0 g, 38.5 mmol) was dissolved in 1,4-dioxane (130 mL). Then, (NH4)2CO3(14.8 g, 154 mmol) was added and the reaction mixture was heated at 60 °C for 2.5 hours. The reaction mixture was cooled to room temperature and quenched with water and stirred for 1 hour. The resulting precipitate was filtered, washed with water and dried to afford the title compound (6.91 g, 77% yield) as a solid.

[0936] LC-MS (Method 2): Rt= 0.80 min; MS (ESIpos): m / z = 233 [M+H]+

[0937] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 2.518 (1.00), 2.523 (0.58), 5.758 (0.47), 6.601 (15.58), 6.629 (16.00), 7.016 (11.30), 7.212 (1.60), 7.845 (14.76), 7.865 (14.28).

[0938] Intermediate 95

[0939] 2- Amino-5 -bromopyridine-3 -carboxamide

[0940] Methyl 2-amino-5-bromopyridine-3-carboxylate (4.50 g, 19.5 mmol) was dissolved in n-PrOH (17 ml), then aq. NH4OH (30%, 40 ml, 270 mmol) was added and stirred at 90 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated to approximately 30 ml. The resulting mixture was diluted with water and stirred for 1 hour. The resulting precipitate was filtered, washed with water, and dried to afford the title compound (2.16 g, 46% yield, 90% purity). LC-MS (Method 1): Rt= 0.58 min; MS (ESIneg): m / z = 214 [M-H]

[0941] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.948 (0.74), 2.523 (1.16), 4.196 (0.46), 7.372 (4.63), 7.458 (1.68), 8.038 (1.58), 8.075 (0.59), 8.082 (0.57), 8.118 (0.48), 8.128 (4.84), 8.134 (13.22), 8.139 (16.00), 8.146 (5.44).

[0942] Intermediate 96

[0943] Methyl 2-(tert-butylamino)-6-methylpyridine-3-carboxylate

[0944] Methyl 2-chloro-6-methylpyridine-3-carboxylate (6.00 g, 32.3 mmol) was dissolved in NMP (50 mL). Tert-butylamine (7.09 g, 97.0 mmol) and DIPEA (11.0 mL, 65.0 mmol) were added and stirred overnight at 150 °C. Additional tert-butylamine (7.09 g, 65.0 mmol) was added and heated at 150 °C for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted into EtOAc (x3). The combined org. phases were filtered over hydrophobic filter paper and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (1.00 g, 14% yield).

[0945] LC-MS (Method 2): Rt= 1.56 min; MS (ESIpos): m / z = 223 [M+H]+

[0946] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.450 (16.00), 2.342 (6.18), 2.349 (0.71), 3.772 (8.84), 3.783 (0.96), 6.444 (0.98), 6.464 (0.99), 7.941 (1.40), 7.960 (1.36), 8.009 (0.56).

[0947] Intermediate 97

[0948] Methyl 5-bromo-2-(tert-butylamino)-6-methylpyridine-3-carboxylate

[0949] Methyl 2-(tert-butylamino)-6-methylpyridine-3-carboxylate (850 mg, 3.82 mmol) was dissolved in chloroform (14 mL) and cooled to 0°C. N-Bromosuccinimide (1.02 g, 5.74 mmol) was added and stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with 10% aq. sodium thiosulfate solution. The org. phase was filtered over hydrophobic filter paper and concentrated under reduce pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (1.20 g, quant.).

[0950] LC-MS (Method 2): Rt= 1.72 min; MS (ESIpos): m / z = 303 [M+H]+

[0951] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.441 (16.00), 2.468 (7.84), 2.518 (1.03), 2.523 (0.74), 2.926 (0.45), 2.938 (0.45), 3.797 (9.10), 3.804 (1.23), 7.959 (0.67), 8.088 (2.37).

[0952] Intermediate 98

[0953] 2-Amino-5-bromo-6-methylpyridine-3-carboxamide

[0954] 2-Amino-5-bromo-6-methylpyridine-3-carboxylic acid (CAS 1781727-71-6, 670 mg, 2.90 mmol) was dissolved in THF (7.0 ml), then N-(3-dimethylaminopropyl)-N•-ethylcarbodiimide hydrochloride (778 mg, 4.06 mmol), HOBt (533 mg, 3.48 mmol) and 4-methyl morpholine (640 μL, 5.8 mmol) were added and stirred at room temperature for 10 minutes. Then, aq. NH4OH (30%, 1.5 mL, 12 mmol) was added and stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and diluted with water, the resulting precipitate was filtered and dried to afford the title compound (280 mg, 42% yield).

[0955] LC-MS (Method 2): Rt= 0.71 min; MS (ESIpos): m / z = 230 [M+H]+1H-NMR (400 MHz, DMSO-d6) • [ppm]: 2.374 (16.00), 2.518 (1.09), 2.523 (0.70), 7.338 (1.49), 8.116 (4.74).

[0956] Intermediate 99

[0957] Methyl 2-(tert-butylamino)-6-methoxypyridine-3-carboxylate

[0958] Methyl 2-chloro-6-methoxypyridine-3-carboxylate (10.0 g, 49.6 mmol) was dissolved in NMP (60 mL), then tert-butylamine (14.5 g, 198 mmol) and DIPEA (17.0 mL, 99.0 mmol) were added and heated at 150 °C for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted into EtOAc (x3). The combined org. phases were filtered over hydrophobic filter paper and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (6.76 g, 57% yield).

[0959] LC-MS (Method 2): Rt= 1.49 min; MS (ESIpos): m / z = 239 [M+H]+

[0960] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.470 (16.00), 3.745 (8.82), 3.857 (7.88), 5.974 (1.80), 5.995 (1.89), 7.947 (1.89), 7.968 (1.88), 8.311 (0.55).

[0961] Intermediate 100

[0962] Methyl 5-bromo-2-(tert-butylamino)-6-methoxypyridine-3-carboxylate

[0963] Methyl 2-(tert-butylamino)-6-methoxypyridine-3-carboxylate (6.50 g, 27.3 mmol) was dissolved in chloroform (52 mL) and cooled to 0 °C, then NBS (7.28 g, 40.9 mmol) was added and stirred at room temperature for 3 hours. The mixture was quenched with sat. aq. Na2SiO3solution and extracted into DCM. The org. phase was filtered through hydrophobic filter paper and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (8.70 g, quant.).

[0964] LC-MS (Method 2): Rt= 1.62 min; MS (ESIpos): m / z = 318 [M+H]+

[0965] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.463 (16.00), 2.518 (1.76), 2.523 (1.34), 3.766 (8.34), 3.939 (8.58), 8.108 (4.60), 8.266 (0.72).

[0966] Intermediate 101

[0967] Methyl 2-amino-5-bromo-6-methoxypyridine-3-carboxylate

[0968] Methyl 5-bromo-2-(tert-butylamino)-6-methoxypyridine-3-carboxylate (8.70 g, 27.4 mmol) was dissolved in TFA (78 mL, 1.00 mol) and heated at 120 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (6.65 g, 93% yield).

[0969] LC-MS (Method 2): Rt= 1.17 min; MS (ESIpos): m / z = 262 [M+H]+

[0970] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.463 (1.46), 1.470 (0.90), 2.518 (0.95), 2.523 (0.61), 3.691 (1.12), 3.695 (1.21), 3.745 (0.56), 3.752 (4.59), 3.768 (15.54), 3.818 (4.80), 3.836 (0.46), 3.857 (0.44), 3.895 (16.00), 3.919 (0.48), 3.938 (0.65), 6.003 (0.90), 6.025 (1.00), 7.443 (1.00), 7.919 (0.96), 7.940 (0.72), 8.074 (5.03).

[0971] Intermediate 102

[0972] 2-Amino-5-bromo-6-methoxypyridine-3-carboxylic acid

[0973] Methyl 2-amino-5-bromo-6-methoxypyridine-3-carboxylate (5.65 g, 21.6 mmol) was dissolved in 1,4- dioxane (62 mL), lithium hydroxide monohydrate (5.45 g, 130 mmol) and water (4.2 mL) were added and the mixture was stirred at 50 °C for 18 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The aqueous solution was acidified with citric acid to pH 5 and the resulting precipitate was isolated by filtration. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (4.56 g, 85% yield).

[0974] LC-MS (Method 2): Rt= 0.43 min; MS (ESIneg): m / z = 245 [M-H]

[0975] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.172 (0.83), 1.907 (0.91), 1.987 (1.38), 2.518 (0.48), 3.710 (0.51), 3.808 (2.56), 3.884 (16.00), 5.971 (0.58), 5.993 (0.58), 7.895 (0.58), 7.916 (0.48), 8.044 (7.38).

[0976] Intermediate 103

[0977] 2-Amino-5-bromo-6-methoxypyridine-3-carboxamide

[0978] 2-Amino-5-bromo-6-methoxypyridine-3-carboxylic acid (500 mg, 2.02 mmol) was dissolved in THF (4.7 mL), then N-(3-dimethylaminopropyl)-N•-ethylcarbodiimide hydrochloride (543 mg, 2.83 mmol), HOBt (372 mg, 2.43 mmol) and 4-methyl morpholine (450 μL, 4.0 mmol) were added and stirred at room temperature for 10 minutes. Then, aq. NH4OH (30%, 1.1 mL, 8.1 mmol) was added and stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and diluted with water, the resulting precipitate was filtered and dried to afford the title compound (175 mg, 35% yield).

[0979] LC-MS (Method 2): Rt= 0.79 min; MS (ESIpos): m / z = 247 [M+H]+

[0980] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 2.518 (2.01), 2.523 (1.45), 3.853 (16.00), 7.591 (0.41), 8.186 (4.61).

[0981] Intermediate 104

[0982] 1 -(2-bromoethyl)cyclopropane- 1 -carboxylic acid

[0983] To 5-oxaspiro[2.4]heptan-4-one (700 mg, 6.24 mmol) was added HBr in acetic acid (6.0 ml, 33 %, 37 mmol) and the mixture was stirred at room temperature for 90 minutes. The mixture was poured into cold water resulting in a precipitate which was isolated by filtration and washed with water to afford the crude title compound (900 mg, 75% yield). The obtained material was used immediately in the next step without purification.

[0984] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.840 (4.59), 0.850 (13.99), 0.857 (16.00), 0.866 (5.88), 0.904 (0.45), 1.015 (0.42), 1.054 (5.54), 1.062 (15.01), 1.069 (12.75), 1.080 (4.44), 1.906 (1.00), 1.979 (7.88), 1.999 (9.15), 2.019 (8.32), 2.518 (0.92), 2.522 (0.57), 3.560 (10.67), 3.565 (1.95), 3.577 (8.28), 3.580 (10.15), 3.582 (9.04), 3.594 (1.82), 3.600 (9.89).

[0985] Intermediate 105 methyl 1 -(2-bromoethyl)cyclopropane- 1 -carboxylate l-(2-Bromoethyl)cyclopropane-l -carboxylic acid (100 mg, 518 μmol) was dissolved in MeOH (2.0 mL) and cooled to 0 °C. Then, thionyl chloride (57 pl, 780 μmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, then redissolved in MeCN and concentrated under reduced pressure (2x) to afford the title compound (90.0 mg, 84% yield). The obtained material was used without further purification.

[0986] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.908 (0.72), 0.919 (2.21), 0.926 (2.77), 0.935 (0.93), 1.090 (0.89), 1.099 (2.45), 1.107 (2.04), 1.118 (0.68), 2.026 (1.36), 2.045 (1.52), 2.065 (1.42), 3.551 (1.93), 3.568 (1.36), 3.570 (1.73), 3.572 (1.50), 3.588 (16.00).

[0987] Intermediate 106

[0988] Methyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenoxy]butanoate

[0989] General procedure A used.

[0990] Tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (743 mg, 2.43 mmol) was dissolved in DMF (15 ml), then K2CO3(1.01 g, 7.30 mmol) was added, followed by methyl 4- bromobutanoate (460 pl, 3.7 mmol). The reaction mixture was heated at 60 °C for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed with brine (2x), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (1.25 g, quantitative yield). The obtained material was used without purification.

[0991] LC-MS (Method 2): Rt= 1.38 min; MS (ESIpos): m / z = 406 [M+H]+

[0992] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.152 (1.37), 1.170 (2.77), 1.188 (1.46), 1.250 (1.06), 1.257 (0.82), 1.267 (1.13), 1.352 (4.79), 1.986 (4.70), 2.028 (0.84), 2.044 (1.02), 2.062 (0.70), 2.437 (0.67), 2.455 (1.09), 2.473 (0.58), 2.518 (0.74), 2.727 (13.14), 2.887 (16.00), 3.349 (1.26), 3.378 (0.69), 3.527 (0.76), 3.544 (1.54), 3.560 (0.73), 3.598 (4.72), 3.610 (6.75), 4.015 (1.09), 4.033 (1.10), 7.324 (0.56), 7.532 (0.57), 7.548 (0.49), 7.551 (0.49), 7.948 (2.03).

[0993] Intermediate 107

[0994] 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenoxy]butanoic acid

[0995] General procedure B used.

[0996] Methyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenoxy]butanoate ( 1.20 g, 2.96 mmol), KOH (15 mL, 1 M, 15 mmol), THF (14 mL) afforded the title compound (807 mg, 70% yield).

[0997] LC-MS (Method 2): Rt= 0.71 min; MS (ESIpos): m / z = 392 [M+H]+

[0998] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.153 (5.05), 1.171 (10.49), 1.182 (0.46), 1.189 (5.19), 1.258 (1.34), 1.275 (1.40), 1.354 (5.55), 1.977 (0.50), 1.986 (16.00), 1.994 (0.70), 2.012 (0.41), 2.422 (0.63), 2.441 (0.99), 2.459 (0.54), 2.518 (0.44), 3.998 (1.18), 4.016 (3.48), 4.034 (3.53), 4.052 (1.17), 7.322 (0.71), 7.342 (0.41), 7.529 (0.66), 7.532 (0.74), 7.549 (0.65), 7.552 (0.68), 7.695 (0.42).

[0999] Intermediate 108 methyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy] -2- methylbutanoate (mixture of diastereomers)

[1000] General procedure A used.

[1001] Tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (2.00 g, 6.55 mmol), methyl 4-chloro-2-methylbutanoate (1.4 ml, 9.8 mmol), K2CO3(2.72 g, 19.7 mmol), and DMF (40 mL) afforded the title compound (2.10 g, 76% yield).

[1002] LC-MS (Method 2): Rt= 0.95 min; MS (ESIpos): m / z = 250.1 [M+H]+

[1003] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.098 (1.50), 1.104 (0.46), 1.110 (0.77), 1.116 (1.72), 1.128 (0.75), 1.131 (0.87), 1.135 (0.45), 1.155 (6.00), 1.165 (2.05), 1.173 (7.49), 1.183 (1.83), 1.191 (1.76), 1.243 (1.06), 1.260 (1.16), 1.277 (0.45), 1.287 (0.47), 1.352 (4.14), 1.395 (5.49), 1.406 (0.44), 1.421 (0.74), 1.432 (0.98), 1.438 (0.64), 1.832 (0.51), 1.848 (0.64), 1.867 (0.74), 1.883 (0.75), 2.062 (0.60), 2.077 (0.44), 2.081 (0.77), 2.097 (0.75), 2.112 (0.41), 2.116 (0.56), 2.699 (0.50), 2.710 (0.44), 2.717 (0.79), 2.727 (2.62), 2.729 (2.84), 2.732 (0.85), 2.744 (0.97), 2.751 (0.53), 2.887 (2.95), 3.568 (0.59), 3.577 (0.46), 3.584 (0.91), 3.587 (0.78), 3.598 (0.80), 3.603 (1.23), 3.611 (6.79), 3.615 (16.00), 3.816 (1.28), 3.832 (2.49), 3.848 (1.33), 5.463 (1.13), 5.466 (1.07), 5.491 (1.10), 5.494 (1.18), 5.928 (1.03), 5.931 (1.06), 5.972 (1.21), 5.975 (1.14), 6.865 (0.71), 6.893 (0.74), 6.910 (0.68), 6.937 (0.63), 7.298 (0.56), 7.318 (1.21), 7.338 (0.75), 7.526 (0.61), 7.544 (0.46), 7.589 (1.00), 7.592 (1.06), 7.608 (0.76), 7.611 (0.73), 7.897 (0.75), 7.917 (0.71).

[1004] Intermediate 109

[1005] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy] -2-methylbutanoic acid (mixture of diastereomers)

[1006] General procedure B used.

[1007] Methyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenoxy] -2- methylbutanoate (2.10 g, 5.01 mmol), NaOH (25 ml, 1.0 M, 25 mmol), and THF (20 mL) afforded the title compound (2.00 g, 99% yield).

[1008] LC-MS (Method 2): Rt= 1.44 min; MS (ESIpos): m / z = 420.3 [M+H]+

[1009] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.030 (0.41), 1.039 (0.51), 1.136 (3.66), 1.144 (0.79), 1.152 (7.23), 1.166 (1.56), 1.170 (10.11), 1.188 (4.55), 1.256 (0.80), 1.268 (0.85), 1.273 (0.86), 1.353 (2.70), 1.362 (1.47), 1.395 (2.82), 1.783 (0.41), 1.799 (0.53), 1.818 (0.57), 1.834 (0.50), 1.986 (16.00), 2.076 (0.45), 2.092 (0.44), 2.594 (0.45), 2.610 (0.43), 3.836 (0.81), 3.852 (1.59), 3.868 (0.80), 3.998 (1.23), 4.015 (3.69), 4.033 (3.64), 4.051 (1.16), 5.454 (0.81), 5.456 (0.74), 5.482 (0.72), 5.484 (0.77), 5.927 (0.69), 5.929 (0.73), 5.971 (0.79), 5.974 (0.74), 6.887 (0.48), 6.915 (0.50), 6.931 (0.47), 6.959 (0.43), 7.297 (0.43), 7.317 (0.92), 7.336 (0.55), 7.590 (0.60), 7.593 (0.61), 7.610 (0.56), 7.613 (0.57), 7.898 (0.53), 7.918 (0.49).

[1010] Intermediate 110 tert-butyl {(lR)-l-[2-{ [l-(cyanomethyl)cyclopropyl]methoxy}-3-

[1011] (trifluoromethyl)phenyl] ethyl } carbamate

[1012] To a solution of [l-(hydroxymethyl)cyclopropyl] acetonitrile (500 mg, 4.50 mmol) in toluene (10 mL) was added tert-butyl {(lS)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (1.37 g, 4.50 mmol) and DIAD (1.82 g, 9.00 mmol) at 0 °C. Then, triphenylphosphine (2.36 g, 9.00 mmol) was added portion wise at 0 °C over 5 min. After addition, the mixture was stirred for 15 min, then stirred at 60°C for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography afforded the title compound (1.50 g, 67% yield).

[1013] LC-MS (Method 3): Rt= 0.67 min; MS (ESIpos): m / z = 421.1 [M+Na]+

[1014] Intermediate 111

[1015] ( 1 - { [2- { ( 1 R) - 1 - [(T ert-butoxycarbonyl)amino] ethyl } -6- (trifluoromethyl)phenoxy ] methyl } cyclopropyl)acetic acid

[1016] To a solution of tert-butyl {(lR)-l-[2-{ [l-(cyanomethyl)cyclopropyl]methoxy}-3- (trifluoromethyl)phenyl] ethyl} carbamate (1.00 g, 2.51 mmol) in EtOH (10 mL) was added aq. NaOH sol. (1.2 mL, 6 M, 35 mmol) and the mixture was stirred at 100 °C for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The water phase was acidified with aq. HC1 sol. to pH = 3~4, then extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (250 mg, 23% yield).

[1017] LC-MS (Method 1): Rt = 1.28 min; MS (ESIpos): m / z = 418.5 [M+H]+.

[1018] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.574 (5.80), 0.592 (1.17), 0.604 (1.42), 0.747 (0.74), 0.765 (0.62), 1.107 (0.59), 1.154 (0.94), 1.172 (1.82), 1.190 (1.10), 1.251 (4.64), 1.268 (4.72), 1.350 (16.00), 1.465 (1.95), 1.988 (0.99), 2.291 (0.77), 2.323 (0.82), 2.327 (1.30), 2.331 (1.45), 2.518 (2.11), 2.523

[1019] (1.47), 2.647 (0.98), 2.660 (0.46), 2.665 (0.68), 2.669 (0.87), 2.673 (0.66), 2.678 (0.45), 2.690 (0.77),

[1020] 3.566 (0.49), 3.877 (2.35), 4.944 (0.50), 4.962 (0.68), 4.981 (0.46), 7.295 (1.05), 7.314 (2.25), 7.334

[1021] (1.30), 7.509 (0.93), 7.521 (2.69), 7.524 (3.02), 7.540 (2.12), 7.543 (1.94), 7.695 (1.08), 7.713 (0.91),

[1022] 12.085 (1.62).

[1023] Intermediate 112 methyl 1 - { 2- [2 - { ( 1 R) - 1 - [(tert -butoxycarbonyl) amino] ethyl } -6- (trifluoromethyl)phenoxy ] ethyl } cyclopropane- 1 -carboxylate

[1024] General procedure A used.

[1025] Tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (924 mg, 3.03 mmol), methyl l-(2-bromoethyl)cyclopropane-l -carboxylate (940 mg, 4.54 mmol), K2CO3(1.25 g, 9.08 mmol), DMF (20 mL) afforded the title compound (1.30 g, 88% yield).

[1026] LC-MS (Method 2): Rt= 1.48 min; MS (ESIpos): m / z = 431 [M+H]+

[1027] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.917 (0.78), 0.925 (0.81), 1.098 (0.53), 1.106 (0.71), 1.112 (0.76), 1.116 (0.75), 1.235 (0.75), 1.253 (0.79), 1.331 (0.77), 1.356 (3.83), 1.395 (0.62), 1.428 (1.99), 2.729 (13.38), 2.887 (16.00), 3.568 (0.81), 3.573 (1.56), 3.577 (7.08), 3.587 (2.44), 7.314 (0.46), 7.518 (0.41), 7.521 (0.45), 7.950 (2.00).

[1028] Intermediate 113

[1029] 1 - { 2- [2 - { ( 1 R) - 1 - [(tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy] ethyl } cyclopropane- 1 - carboxylic acid

[1030] Methyl 1 - { 2- [2- { ( 1 R)- 1 - [(tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy]ethyl } - cyclopropane- 1 -carboxylate (1.30 g, 3.01 mmol) was dissolved in aq. NaOH sol. (15 ml, 1.0 M, 15 mmol) and MeOH (15 mL) and heated at 60 °C for 30 hours. The mixture was cooled to room temperature and acidified with IM KHSO4to pH 5, and extracted into EtOAc (3x). The combined org. phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (1.20 g, 95% yield). LC-MS (Method 2): Rt= 0.80 min; MS (ESIpos): m / z = 418 [M+H]+

[1031] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.720 (1.15), 0.728 (1.24), 0.737 (0.46), 0.831 (0.57), 0.838 (0.65), 0.847 (0.70), 0.875 (1.93), 0.988 (0.43), 0.997 (1.22), 1.005 (1.16), 1.014 (0.66), 1.020 (0.55), 1.029 (0.55), 1.072 (1.53), 1.081 (1.84), 1.090 (1.91), 1.105 (1.32), 1.151 (4.86), 1.164 (2.62), 1.169 (8.72), 1.187 (4.22), 1.227 (0.98), 1.246 (3.55), 1.263 (3.63), 1.297 (0.55), 1.306 (0.74), 1.315 (0.72), 1.328 (2.40), 1.355 (16.00), 1.387 (0.55), 1.425 (2.76), 1.616 (0.64), 1.634 (1.00), 1.653 (0.70), 1.906 (5.10), 1.914 (0.48), 1.985 (14.00), 2.029 (0.47), 2.121 (0.53), 2.128 (0.63), 2.144 (0.50), 2.518 (0.48), 2.930 (0.85), 3.495 (0.44), 3.576 (0.68), 3.990 (0.66), 3.996 (1.29), 4.007 (0.57), 4.014 (3.48), 4.032 (3.52), 4.041 (0.62), 4.050 (1.36), 4.207 (0.55), 4.222 (0.51), 4.935 (0.60), 4.938 (0.53), 4.952 (0.61), 4.969 (0.41), 7.290 (0.95), 7.309 (1.92), 7.328 (1.14), 7.514 (1.73), 7.518 (1.96), 7.534 (2.02), 7.537 (2.20), 7.558 (0.73), 7.687 (0.96), 7.707 (0.81), 12.157 (0.58).

[1032] Intermediate 114 methyl ( 1 S , 3 s ) - 3 - [2 - { ( 1 R) - 1 - [(tert-butoxycarbonyl) amino] ethyl } -6- (trifluoromethyl)phenoxy]cyclobutane- 1 -carboxylate

[1033] To a solution of methyl (lr,3r)-3-hydroxycyclobutane-l-carboxylate (1.00 g, 7.68 mmol) in toluene was added tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (2.35 g, 7.68 mmol) and DIAD (3.11 g, 15.4 mmol) at 0 °C. Then to the mixture was added triphenylphosphine (4.03 g, 15.4 mmol) at 0 °C over 5 minutes. After addition, the mixture was stirred at this temperature for 15 minutes and the resulting mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated in vacuo. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (1.95 g, 58% yield).

[1034] LC-MS (Method 3): Rt=1.07 min; MS (ESIpos): m / z = 440.2 [M+Na]+.

[1035] Intermediate 115 ( 1 S , 3 s ) - 3 - [2 - { ( 1 R) - 1 - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy ] cyclobutane- 1 - carboxylic acid

[1036] To a solution of methyl (lS,3s)-3-[2-{(lR)-l-[(tert-butoxycarbonyl)amino]ethyl}-6- (trifluoromethyl)phenoxy]cyclobutane-l -carboxylate (6.40 g, 87 % purity, 13.3 mmol) in THF (20 mL), water (20 mL) and MeOH (20 mL) was added lithium hydroxide monohydrate (1.12 g, 26.7 mmol) at room temperature. After stirring at 25 °C for 16 hours the mixture was diluted with water and was acidified to pH=5 with IM aq. hydrochloric acid sol., then extracted with EtOAc (3x). The combined org. phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (3.65 g, 66% yield). ee value: = 90 %

[1037] LC-MS (Method 2): Rt= 0.72 min; MS (ESIpos): m / z = 404.5 [M+H]+.

[1038] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (1.13), 1.172 (2.69), 1.186 (1.48), 1.190 (1.90), 1.250 (4.03), 1.266 (4.06), 1.358 (16.00), 1.414 (0.59), 1.988 (3.08), 2.378 (1.26), 2.399 (1.43), 2.518 (4.17), 2.523 (3.08), 2.570 (0.73), 2.603 (0.76), 2.732 (0.50), 4.017 (0.65), 4.035 (0.67), 4.281 (0.67), 7.285 (0.99), 7.305 (2.13), 7.324 (1.25), 7.515 (2.25), 7.535 (2.42), 7.679 (1.65), 7.698 (1.48), 12.285 (2.79).

[1039] Intermediate 116 tert-butyl { ( 1 R) - 1 - [2 - { [(2R) -pent-4-en-2-yl] oxy } -3 -(trifluoromethyl)phenyl] ethyl } carbamate To a solution of tert-butyl {(lR)-l-[2-hydroxy-3-(tnfluoromethyl)phenyl]ethyl}carbamate (3.00 g, 93 % purity, 9.14 mmol) in toluene (30 mL) was added (2S)-pent-4-en-2-ol (1.18 g, 13.7 mmol) and DIAD (3.70 g, 18.3 mmol) at 0 °C. Then to the mixture was added triphenylphosphine (4.79 g, 18.3 mmol) at 0 °C over 5 minutes. After addition, the mixture was stirred at this temperature for 15 minutes and the resulting mixture was stirred at 60°C for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The org. phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (3.20 g, 93% yield).

[1040] LC-MS (Method 3): Rt= 1.13 min; MS (ESIpos): m / z = 396.2 [M+Na]+.

[1041] Intermediate 117 tert-butyl { ( 1 R) - 1 - [2 - { [(2R) -5 -hydroxypentan-2-yl] oxy } -3 -(trifluoromethyl)phenyl] ethyl } carbamate

[1042] To a solution of tert-butyl {(lR)-l-[2-{ [(2R)-pent-4-en-2-yl]oxy}-3-(trifluoromethyl)- phenyl] ethyl} carbamate (1.00 g, 99 % purity, 2.65 mmol) in THF (45 mL) was added borane dimethyl sulfide complex (320 pl, 10 M, 3.2 mmol) at 0 °C under nitrogen atmosphere, then stirred at 25 °C for 2 hours. Upon completion, sodium perborate tetrahydrate (2.04 g, 13.3 mmol) in water (20 mL) was added dropwise. The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (730 mg, 69% yield).

[1043] LC-MS (Method 3): Rt = 0.77 min; MS (ESIpos): m / z = 406.4 [M+H]+

[1044] Intermediate 118

[1045] (4R) -4-[2-{(lR)-l - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy ]pentanoic acid

[1046]

[1047] To a solution of tert-butyl {(lR)-l-[2-{ [(2R)-5-hydroxypentan-2-yl]oxy}-3- (trifluoromethyl)phenyl] ethyl} carbamate (730 mg, 98 % purity, 1.83 mmol) in 1 ,2-dichloroethane (10 mL) were added 2,2,6,6-tetramethylpiperidine-l-oxyl (28.6 mg, 183 μmol), potassium chloride (13.6 mg, 183 μmol) and iron(III) nitrate nonahydrate (73.8 mg, 183 μmol) in portions at 25 °C. The mixture was stirred at 25 °C for 18 hours under oxygen atmosphere. The mixture was diluted with sat. aq. NH4CI sol. and extracted into DCM (3x). The combined org. phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (447 mg, 59% yield).

[1048] LC-MS (Method 3): Rt = 0.58 min; MS (ESIpos): m / z =428.2 [M+23]+.

[1049] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.030 (0.59), 1.104 (3.38), 1.117 (3.30), 1.159 (1.86), 1.235

[1050] (3.36), 1.251 (3.58), 1.357 (16.00), 1.846 (0.84), 1.865 (0.97), 1.889 (1.21), 1.907 (1.19), 1.925 (0.71), 2.376 (1.21), 2.393 (1.96), 4.411 (0.75), 4.424 (0.72), 5.002 (0.75), 7.255 (1.11), 7.275 (2.36), 7.294

[1051] (1.37), 7.478 (0.95), 7.499 (1.03), 7.516 (2.20), 7.535 (1.79), 7.681 (1.48), 7.699 (1.24).

[1052] Intermediate 119 tert-butyl {(lR)-l-[2-{ [(2S)-pent-4-en-2-yl]oxy}-3-(trifluoromethyl)phenyl]ethyl}carbamate

[1053] To a solution of tert-butyl {(lR)-l-[2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (500 mg, 1.64 mmol) in THF (5.0 mL) was added DIAD (993 mg, 4.91 mmol), triphenylphosphine (1.29 g, 4.91 mmol) and (2R)-pent-4-en-2-ol (423 mg, 4.91 mmol) at 0 °C. The mixture stirred at 25 °C for 18 hours. The mixture was concentrated under reduced pressure to give a residue. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (400 mg, 61% yield).

[1054] LC-MS (Method 3): Rt= 0.675 minute; MS (ESIpos): m / z = 396.2 [M+Na]+.

[1055] Intermediate 120 tert-butyl { ( 1 R)- 1 - [2- { [(2S)-5-hydroxypentan-2-yl]oxy } -3-(trifluoromethyl)phenyl] ethyl } carbamate

[1056] To a solution of tert-butyl {(lR)-l-[2-{ [(2S)-pent-4-en-2-yl]oxy}-3-(trifluoromethyl)phenyl]- ethyl} carbamate (7.30 g, 90 % purity, 17.6 mmol) in THF (100 mL) was added borane dimethyl sulfide complex (2.1 ml, 10 M, 21 mmol) at 0°C under nitrogen atmosphere and stirred for 2 hours. Upon completion, sodium perborate monohydrate (8.78 g, 88.0 mmol) in water (20 mL) was added dropwise and the mixture was stirred at 25 °C for 2 hours. The mixture was quenched with methanol and extracted with ethyl acetate. The org. phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (4.30 g, 80% yield).

[1057] 1H NMR (400 MHz, CDCl3) • 7.51 (dd, 1H), 7.48 (d, 1H), 7.17 (t, 1H), 5.36-5.11 (m, 1H), 4.98-4.83 (m, 1H), 4.50-4.33 (m, 1H), 3.67 (t, 2H), 2.20-2.06 (m, 1H), 1.77-1.69 (m, 1H), 1.66-1.57 (m, 2H), 1.43 (s, 9H), 1.36 (d, 3H), 1.30 (d, 3H).

[1058] Intermediate 121

[1059] (4S)-4-[2-{(lR)-l - [(tert-butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy ] pentanoic acid To a solution of tert-butyl {(lR)-l-[2-{ [(2S)-5-hydroxypentan-2-yl]oxy}-3- (trifluoromethyl)phenyl] ethyl] carbamate (5.90 g, 90 % purity, 13.6 mmol) in 1 ,2-dichloroethane (80 mL) were added 2,2,6,6-tetramethylpiperidine-l-oxyl (212 mg, 1.36 mmol) and potassium chloride (101 mg, 1.36 mmol) and iron(III) nitrate nonahydrate (548 mg, 1.36 mmol) in portions at 25 °C. The mixture was stirred at 25 °C for 18 hours under oxygen atmosphere. The reaction mixture was poured into water and extracted with dichloromethane. The org. phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / EtOAc) afforded the title compound (2.40 g, 42% yield).

[1060] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.084 (3.21), 1.102 (3.60), 1.240 (3.91), 1.257 (3.86), 1.369 (16.00), 1.837 (0.54), 1.855 (0.99), 1.873 (1.20), 1.891 (0.95), 1.908 (0.45), 2.358 (1.56), 2.376 (2.79), 2.396 (1.28), 4.560 (0.58), 4.574 (0.57), 4.945 (0.48), 4.962 (0.66), 4.980 (0.45), 7.245 (0.67), 7.264 (1.43), 7.283 (0.87), 7.487 (0.84), 7.513 (2.11), 7.516 (2.10), 7.533 (1.58), 7.660 (1.57), 7.679 (1.43), 12.138 (0.40).

[1061] Intermediate 122

[1062] Ethyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl) amino] ethyl } -4-fluoro-6-(trifluoromethyl)phenoxy]butanoate

[1063] General procedure A used.

[1064] Tert-butyl {(lR)-l-[5-fluoro-2-hydroxy-3-(trifluoromethyl)phenyl]ethyl}carbamate (2.20 g, 6.81 mmol), ethyl 4-bromobutanoate (1.46 mL, 10.2 mmol), K2CO3(2.82 g, 20.4 mmol), and DMF (45 mL) afforded the title compound (2.57 g, 86% yield).

[1065] LC-MS (Method 2): Rt= 1.46 min; MS (ESIpos): m / z = 438.4 [M+H]+.

[1066] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.153 (0.41), 1.169 (7.26), 1.176 (1.14), 1.187 (16.00), 1.205 (7.91), 1.256 (3.32), 1.273 (3.53), 1.311 (0.56), 1.358 (14.86), 1.382 (1.86), 1.434 (1.15), 1.477 (1.58), 1.986 (1.12), 2.003 (0.92), 2.019 (1.40), 2.037 (1.05), 2.518 (2.81), 2.523 (2.01), 3.831 (0.73), 3.853 (0.78), 4.044 (1.83), 4.062 (5.49), 4.079 (5.40), 4.097 (1.94), 4.117 (0.62), 4.133 (0.51), 4.896 (0.41), 4.914 (0.56), 5.757 (0.78), 7.440 (0.94), 7.447 (1.24), 7.460 (1.01), 7.468 (1.16), 7.518 (0.80), 7.542 (0.85), 7.549 (0.88), 7.577 (0.71).

[1067] Intermediate 123

[1068] 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -4-fluoro-6-(trifluoromethyl)phenoxy]butanoic acid

[1069] General procedure B used.

[1070] Ethyl 4- [2- { ( 1 R)- 1 - [(tert-butoxycarbonyl)amino]ethyl } -4-fluoro-6-(trifluoromethyl)phenoxy] -butanoate (2.57 g, 5.88 mmol), NaOH (29 ml, 1.0 M, 29 mmol), and THF (40 mL) afforded the title compound (2.19 g, 91% yield).

[1071] LC-MS (Method 2): Rt= 0.76 min; MS (ESIpos): m / z = 410 [M+H]+

[1072] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.150 (4.22), 1.168 (8.79), 1.173 (0.77), 1.186 (5.01), 1.202 (1.28), 1.224 (0.64), 1.260 (4.01), 1.277 (4.15), 1.309 (0.60), 1.356 (16.00), 1.379 (1.25), 1.475 (1.00), 1.753 (0.72), 1.962 (1.01), 1.983 (15.80), 1.991 (1.23), 2.015 (0.43), 2.375 (2.00), 2.394 (3.15), 2.412 (1.63), 2.518 (0.51), 3.578 (2.44), 3.585 (2.19), 3.589 (2.16), 3.595 (2.43), 3.601 (1.94), 3.606 (1.81), 3.610 (1.77), 3.612 (1.80), 3.811 (0.74), 3.828 (1.20), 3.848 (1.20), 3.864 (0.66), 3.996 (1.20), 4.014 (3.31), 4.031 (3.32), 4.049 (1.21), 4.060 (0.47), 4.078 (0.69), 4.095 (0.76), 4.112 (0.65), 4.912 (0.49), 4.930 (0.64), 4.947 (0.42), 7.428 (1.16), 7.435 (1.54), 7.448 (1.23), 7.456 (1.45), 7.515 (0.92), 7.521 (0.90), 7.544 (1.48), 7.564 (0.82).

[1073] Intermediate 124 tert-butyl { ( 1 R)- 1 - [2- { 4- [(4-carbamoyl-6-chloropyridin-3-yl)amino] -4-oxobutoxy } -3- (trifluoromethyl)phenyl] ethyl } carbamate

[1074] General procedure C used.

[1075] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy]butanoic acid (710 mg, 1.81 mmol), 5-amino-2-chloropyridine-4-carboxamide (374 mg, 2.18 mmol), NMI (290 pl, 3.6 mmol), and TCFH (1.02 g, 3.63 mmol) were dissolved in N,N• dimethylacetamide (18 mL) and stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc, washed with water, and brine (x2). The org. phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (621 mg, 60% yield).

[1076] LC-MS (Method 2): Rt= 1.72 min; MS (ESIpos): m / z = 545 [M+H]+

[1077] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (4.18), 1.171 (8.15), 1.189 (3.92), 1.250 (3.85), 1.267 (4.11), 1.331 (16.00), 1.354 (2.16), 1.987 (12.33), 2.105 (1.26), 2.386 (3.51), 2.518 (3.06), 2.522 (2.00), 2.601 (1.30), 2.620 (2.24), 2.638 (1.18), 2.924 (3.16), 3.345 (0.88), 3.883 (0.77), 3.905 (0.80), 3.998 (0.88), 4.016 (2.51), 4.034 (2.44), 4.052 (0.81), 4.186 (0.56), 4.942 (0.48), 4.959 (0.68), 4.977 (0.46), 7.305 (0.94), 7.324 (2.07), 7.343 (1.21), 7.529 (1.90), 7.532 (2.12), 7.549 (2.08), 7.553 (2.32), 7.575 (0.84), 7.690 (1.17), 7.710 (1.01), 7.787 (3.61), 8.094 (1.29), 8.484 (1.13), 9.167 (0.61), 9.274 (2.23), 10.992 (1.42).

[1078] Intermediate 125

[1079] Tert-butyl [( 1 R)- 1 - { 2- [3 -(6-chloro-4-hydroxypyrido[3 ,4-d]pyrimidin-2-yl)propoxy] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[1080]

[1081] General procedure D used.

[1082] Tert-butyl { ( 1 R)- 1 - [2- { 4- [(4-carbamoyl-6-chloropyridin-3-yl)amino] -4-oxobutoxy } -3-

[1083] (trifluoromethyl)phenyl] ethyl} carbamate (521 mg, 957 μmol) was dissolved in EtOH (50 mL), then NaOEt (341 mg, 21 % purity, 1.05 mmol) and stirred at room temperature for 24 hours. The reaction was quenched with water and extracted into EtOAc (3x). The combined org. phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (462 mg, 88% yield).

[1084] LC-MS (Method 2): Rt= 1.05 min; MS (ESIpos): m / z = 527 [M+H]+

[1085] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.082 (0.69), 1.099 (0.51), 1.113 (0.43), 1.170 (0.42), 1.230 (4.17), 1.248 (16.00), 1.320 (0.44), 1.354 (1.13), 1.906 (0.63), 1.986 (0.50), 2.263 (0.59), 2.279 (0.92), 2.293 (0.84), 2.308 (0.52), 2.518 (0.46), 2.874 (0.58), 2.891 (1.22), 2.914 (0.93), 2.933 (0.45), 3.916 (0.59), 3.938 (0.63), 4.261 (0.42), 4.939 (0.54), 7.295 (0.55), 7.314 (1.20), 7.334 (0.70), 7.524 (1.58), 7.540 (1.29), 7.543 (1.34), 7.665 (0.91), 7.684 (0.81), 7.931 (2.18), 8.840 (3.45), 12.733 (0.79).

[1086] Intermediate 126

[1087] 2-(3 - { 2- [( 1 R)- 1 -aminoethyl] -6-(trifluoromethyl)phenoxy }propyl)-6-chloropyrido[3 ,4-d]pyrimidin-4- ol — hydrogen chloride (1 / 1)

[1088] General procedure F used. Tert-butyl [( 1 R)- 1 - { 2- [3 -(6-chloro-4-hydroxypyrido[3 ,4-d]pyrimidin-2-yl)propoxy] -3-

[1089] (trifluoromethyl)phenyl} ethyl] carbamate (2.67 g, 5.07 mmol) was suspended in 1,4-dioxane (13 mL), then HC1 in 1,4-dioxane (13 ml, 4.0 M, 51 mmol) was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the resulting solid was triturated with TBME to afford the title compound (2.42 g, 98% yield). The obtained product was used without further purification.

[1090] LC-MS (Method 2): Rt= 0.78 min; MS (ESIpos): m / z = 427 [M+H]+

[1091] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.100 (12.99), 1.104 (1.37), 1.246 (0.44), 1.529 (12.15), 1.545 (12.25), 1.590 (0.51), 2.250 (0.70), 2.268 (1.70), 2.285 (2.53), 2.292 (2.54), 2.323 (1.00), 2.327 (1.30),

[1092] 2.518 (1.74), 2.523 (1.10), 2.665 (0.41), 2.669 (0.58), 2.876 (3.20), 2.895 (5.80), 2.913 (2.49), 3.070

[1093] (4.00), 3.944 (0.68), 3.961 (1.70), 3.967 (1.49), 3.983 (2.53), 3.999 (1.07), 4.019 (1.13), 4.034 (2.57),

[1094] 4.050 (1.45), 4.057 (1.66), 4.072 (0.65), 4.653 (3.05), 4.669 (3.98), 4.684 (4.22), 4.698 (3.89), 7.445

[1095] (2.05), 7.465 (4.29), 7.485 (2.38), 7.706 (3.60), 7.708 (3.96), 7.725 (3.31), 7.728 (3.18), 7.957 (16.00), 7.958 (15.86), 8.067 (3.38), 8.085 (3.16), 8.674 (4.52), 8.683 (4.48), 8.892 (14.41), 8.894 (14.37).

[1096] Intermediate 127

[1097] (15R)-2-chloro-15-methyl-ll-(trifluoromethyl)-8,9,15,16-tetrahydro-7H-6,17-(azeno)pyrido[3,4- g] [ 1 ,6, 10]benzoxadiazacyclotridecine

[1098] General procedure G used.

[1099] 2-(3 - { 2- [( 1 R)- 1 - Aminoethyl] -6-(trifluoromethyl)phenoxy }propyl)-6-chloropyrido[3 ,4-d]pyrimidin-4- ol — hydrogen chloride (1 / 1) (1.46 g, 3.14 mmol) and BOP (1.81 g, 4.08 mmol) were dissolved in DMF (73 mL), then DIPEA (1.4 ml, 7.9 mmol) and DBU (1.9 ml, 13 mmol) were added and stirred at room temperature for 3 days. The reaction was quenched with brine and extracted into either DCM or EtOAc (3x). The combined org. phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (841 mg, 62% yield).

[1100] LC-MS (Method 2): Rt= 1.35 min; MS (ESIpos): m / z = 409 [M+H]+

[1101] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.153 (3.52), 1.171 (7.46), 1.189 (3.66), 1.549 (6.11), 1.567 (6.16), 1.907 (16.00), 1.986 (12.25), 2.083 (0.51), 2.102 (0.43), 2.389 (0.56), 2.518 (1.09), 2.523 (0.78), 2.604 (0.50), 2.612 (1.09), 2.679 (0.45), 2.785 (0.42), 2.825 (0.72), 2.832 (0.69), 2.853 (0.69), 2.860 (0.54), 2.925 (0.58), 2.933 (0.81), 2.940 (1.31), 2.947 (0.65), 2.979 (0.40), 2.985 (0.42), 3.554 (0.66), 3.566 (0.60), 3.579 (0.67), 3.998 (0.89), 4.015 (2.63), 4.033 (2.52), 4.052 (0.81), 4.917 (0.40), 4.924 (0.49), 4.942 (0.78), 4.961 (0.44), 6.046 (0.77), 6.064 (1.10), 6.081 (0.75), 7.241 (0.90), 7.260 (1.92), 7.280 (1.07), 7.517 (1.72), 7.521 (1.86), 7.537 (1.59), 7.541 (1.50), 7.743 (1.49), 7.747 (1.51), 7.763 (1.42), 7.766 (1.30), 8.341 (4.96), 8.343 (5.45), 8.817 (4.98), 8.819 (5.70), 9.298 (1.46), 9.314 (1.40).

[1102] Intermediate 128

[1103] Tert-butyl {(lR)-l-[2-{4-[(4-carbamoyl-6-chloropyridin-3-yl)amino]-3-methyl-4-oxobutoxy}-3-

[1104] (trifluoromethyl)phenyl] ethyl} carbamate (mixture of diastereomers)

[1105] General procedure C used.

[1106] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy] -2-methylbutanoic acid (2.00 g, 4.93 mmol), 5-amino-2-chloropyridine-4-carboxamide (1.02 g, 5.92 mmol), TCFH (2.77 g, 9.87 mmol), NMI (790 pl, 9.9 mmol), and DMA (40 mL) afforded the title compound (1.50 g, 54% yield).

[1107] LC-MS (Method 2): Rt= 1.31 min; MS (ESIpos): m / z = 559.4 [M+H]+

[1108] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.083 (0.56), 1.153 (4.52), 1.170 (8.65), 1.188 (4.12), 1.203 (0.42), 1.220 (0.51), 1.232 (1.09), 1.243 (1.13), 1.250 (1.16), 1.258 (1.36), 1.308 (2.23), 1.315 (2.09), 1.907 (0.47), 1.986 (16.00), 3.998 (1.15), 4.016 (3.52), 4.034 (3.53), 4.051 (1.15), 5.756 (5.67), 7.513 (0.40), 7.823 (0.43).

[1109] Intermediate 129

[1110] Tert-butyl [( 1 R)- 1 - { 2- [3 -(6-chloro-4-oxo-3 ,4-dihydropyrido[3 ,4-d]pyrimidin-2-yl)butoxy] -3- (trifluoromethyl)phenyl} ethyl] carbamate (mixture of diastereomers)

[1111]

[1112] General procedure D used.

[1113] Tert-butyl { (1R)- 1 -[2- { 4-[(4-carbamoyl-6-chloropyridin-3-yl)amino] -3-methyl-4-oxobutoxy } -3-

[1114] (trifluoromethyl)phenyl] ethyl} carbamate (1.50 g, 2.68 mmol), NaOMe (1.1 ml, 21 % purity, 3.0 mmol), EtOH (75 mL) afforded the title compound (600 mg, 41% yield).

[1115] LC-MS (Method 2): isomer 1 Rt= 1.10 min; MS (ESIpos): m / z = 541.4 [M+H]+

[1116] LC-MS (Method 2): isomer 2 Rt= 1.15 min; MS (ESIpos): m / z = 541.4 [M+H]+.

[1117] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.147 (2.43), 1.153 (5.30), 1.170 (9.28), 1.188 (5.10), 1.205 (0.70), 1.224 (1.92), 1.336 (0.71), 1.343 (0.81), 1.353 (0.77), 1.361 (0.75), 1.986 (16.00), 3.997 (1.12),

[1118] 4.015 (3.30), 4.034 (3.20), 4.051 (1.06), 7.919 (0.56), 8.838 (0.63), 8.840 (0.61), 8.846 (0.52), 8.848

[1119] (0.50).

[1120] Intermediate 130

[1121] 2-(4-{2-[(lR)-l-Aminoethyl]-6-(trifluoromethyl)phenoxy}butan-2-yl)-6-chloropyrido[3,4-d]pyrimidin-

[1122] 4(3H)-one — hydrogen chloride (1 / 1) (mixture of diastereomers)

[1123] General procedure F used.

[1124] Tert-butyl [(lR)-l-{2-[3-(6-chloro-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-2-yl)butoxy]-3-

[1125] (trifluoromethyl)phenyl}ethyl]carbamate (600 mg, 1.11 mmol), HC1 in 1,4-dioxane (2.8 ml, 4.0 M, 11 mmol), and EtOH (30 mL) afforded the title compound (500 mg, 94% yield). LC-MS (Method 2): Rt= 0.80 min; MS (ESIpos): m / z = 441 [M+H]+

[1126] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.033 (7.22), 1.051 (16.00), 1.069 (6.79), 1.338 (2.65), 1.342 (2.75), 1.356 (2.78), 1.360 (2.67), 1.469 (1.95), 1.481 (2.29), 1.485 (2.39), 1.498 (1.88), 2.518 (0.98), 2.523 (0.67), 3.410 (2.19), 3.427 (7.75), 3.444 (7.18), 3.461 (2.35), 3.565 (0.50), 3.884 (0.52), 3.980 (0.58), 4.003 (0.44), 5.251 (0.48), 7.423 (0.50), 7.443 (1.08), 7.463 (0.62), 7.677 (1.14), 7.694 (0.97), 7.959 (3.86), 8.000 (0.53), 8.015 (0.66), 8.029 (0.50), 8.575 (1.31), 8.886 (2.42), 8.888 (2.49), 8.895 (2.17), 8.897 (2.18).

[1127] Intermediate 131

[1128] (7RS, 15R)-2-Chloro-7,15-dimethyl-l l-(trifluoromethyl)-8,9,15,16-tetrahydro-7H-6,17-

[1129] (azeno)pyrido[3,4-g][l,6,10]benzoxadiazacyclotridecine (mixture of diastereomers)

[1130] General procedure G used.

[1131] 2-(4-{2-[(lR)-l-Aminoethyl]-6-(trifluoromethyl)phenoxy}butan-2-yl)-6-chloropyrido[3,4-d]pyrimidin- 4(3H)-one— hydrogen chloride (1 / 1) (93.0 mg, 195 μmol), BOP (112 mg, 253 μmol), DBU (120 pl, 780 μmol), DIPEA (85 pl, 490 μmol), DMF (4.6 mL) afforded the title compound (45.0 mg, 55% yield).

[1132] LC-MS (Method 2): Rt= 1.46 min; MS (ESIpos): m / z = 423.3 [M+H]+

[1133] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.774 (1.27), 0.793 (3.38), 0.812 (1.59), 0.817 (1.38), 0.834 (1.29), 0.842 (1.19), 0.852 (0.41), 0.860 (1.82), 0.870 (0.47), 0.878 (0.77), 1.004 (2.75), 1.032 (2.49), 1.082 (6.25), 1.099 (0.82), 1.142 (0.41), 1.153 (5.08), 1.171 (9.21), 1.189 (4.27), 1.238 (0.63), 1.251 (5.25), 1.258 (9.00), 1.270 (5.30), 1.284 (0.67), 1.303 (5.34), 1.321 (5.45), 1.374 (0.43), 1.380 (0.45), 1.389 (0.74), 1.403 (0.59), 1.420 (0.85), 1.423 (0.71), 1.438 (0.66), 1.442 (0.65), 1.525 (0.49), 1.536 (0.45), 1.541 (0.55), 1.560 (5.57), 1.564 (5.21), 1.578 (5.66), 1.582 (5.12), 1.608 (0.48), 1.786 (0.46), 1.986 (16.00), 2.146 (0.45), 2.394 (0.65), 2.430 (0.79), 2.459 (0.45), 2.518 (2.26), 2.523 (1.50), 2.922 (0.42), 2.943 (0.50), 3.089 (0.40), 3.099 (0.54), 3.107 (0.52), 3.998 (1.21), 4.016 (3.72), 4.034 (3.76), 4.052 (1.23), 4.881 (0.62), 4.908 (0.60), 6.000 (0.54), 6.236 (0.62), 6.255 (0.97), 6.272 (0.61), 7.254 (0.96), 7.274 (2.06), 7.292 (1.17), 7.516 (2.45), 7.521 (2.63), 7.536 (2.23), 7.540 (2.09), 7.742 (1.06), 7.762 (0.99), 7.783 (1.11), 7.787 (1.09), 7.803 (1.04), 8.324 (7.81), 8.326 (7.97), 8.848 (4.56), 8.850 (4.91), 8.853 (4.63), 8.855 (4.25), 9.207 (1.03), 9.222 (1.00), 9.250 (1.15), 9.267 (1.10), 10.516 (1.43), 10.572 (0.52), 10.636 (1.74), 10.852 (4.52), 11.045 (0.43), 11.151 (0.57).

[1134] Intermediate 132 tert-butyl [( 1 R)- 1 - { 2- [( 1 - { 2- [(4-carbamoyl-6-chloropyridin-3-yl)amino] -2- oxoethyl } cyclopropyl)methoxy] -3-(trifluoromethyl)phenyl } ethyl] carbamate

[1135] General procedure C used.

[1136] ( 1 - { [2- { ( 1 R) - 1 - [(T ert-butoxycarbonyl)amino] ethyl } -6- (trifluoromethyl)phenoxy]methyl}cyclopropyl)acetic acid (237 mg, 568 μmol), 5-amino-2- chloropyridine-4-carboxamide (117 mg, 681 μmol), TCFH (319 mg, 1.14 mmol), NMI (91 pl, 1.1 mmol), and DMA (3.0 mL) afforded the title compound (304 mg, 89% yield).

[1137] LC-MS (Method 2): Rt= 1.37 min; MS (ESIpos): m / z = 571 [M+H]+

[1138] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.708 (1.26), 0.716 (1.78), 0.729 (2.30), 0.739 (1.62), 0.765 (0.75), 0.845 (0.60), 0.858 (0.59), 1.092 (0.86), 1.202 (5.34), 1.219 (5.48), 1.259 (16.00), 1.465 (0.52), 1.956 (8.51), 2.318 (0.48), 2.323 (1.00), 2.327 (1.38), 2.331 (0.98), 2.336 (0.45), 2.518 (4.05), 2.523 (2.70), 2.665 (1.19), 2.669 (1.64), 2.674 (1.48), 2.686 (10.69), 2.781 (8.16), 2.941 (12.05), 3.683 (1.25), 3.707 (1.31), 4.141 (0.80), 4.165 (0.72), 4.897 (0.44), 4.916 (0.63), 4.934 (0.42), 7.282 (0.74), 7.301 (1.64), 7.321 (0.94), 7.488 (0.92), 7.502 (2.16), 7.518 (1.48), 7.647 (1.02), 7.666 (0.85), 7.821 (3.31), 8.147 (1.29), 8.517 (1.08), 9.444 (3.03), 11.281 (1.58).

[1139] Intermediate 133

[1140] Tert-butyl { ( 1 R) - 1 - [2 - ( { 1 - [(6-chloro-4-hydroxypyrido[3 ,4-d]pyrimidin-2- yl)methyl] cyclopropyl } methoxy) -3 -(trifluoromethyl)phenyl] ethyl } carbamate

[1141] General procedure D used.

[1142] T ert-butyl [ ( 1 R) - 1 - { 2 - [ ( 1 - { 2- [(4-carbamoyl-6-chloropyridin-3 -yl)amino] -2-oxoethyl } - cyclopropyl)methoxy]-3-(trifluoromethyl)phenyl}ethyl]carbamate (500 mg, 876 μmol), NaOMe (360 pl, 21 % purity, 960 μmol), and EtOH (10 mL) afforded the title compound (484 mg, quantitative yield).

[1143] LC-MS (Method 2): Rt= 1.09 min; MS (ESIpos): m / z = 553 [M+H]+

[1144] Intermediate 134

[1145] 2- { [ 1 -( { 2- [( 1 R)- 1 - Aminoethyl] -6-(trifluoromethyl)phenoxy } methyl)cyclopropyl] methyl } -6- chloropyrido[3,4-d]pyrimidin-4-ol

[1146] Tert-butyl { ( 1 R) - 1 - [2 - ( { 1 - [(6-chloro-4-hydroxypyrido[3 ,4-d]pyrimidin-2-yl)methyl]cyclopropyl } - methoxy)-3-(trifluoromethyl)phenyl]ethyl}carbamate (484 mg, 875 μmol) was reacted with HC1 in 1,4- dioxane (2.2 ml, 4.0 M, 8.8 mmol) and stirred at room temperature for 16 hours. The reaction mixture was poured onto water and neutralised with sat. aq. NaHCO3solution, then extracted with EtOAc (3x). The combined org. phases were filtered through hydrophobic filter paper and concentrated under reduced pressure to afford the title compound (394 mg, 94%).

[1147] LC-MS (Method 2): Rt= 0.86 min; MS (ESIpos): m / z = 453 [M+H]+

[1148] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.482 (1.79), 0.503 (1.77), 0.677 (0.70), 0.700 (5.87), 0.708 (9.95), 1.145 (0.41), 1.154 (4.20), 1.172 (9.42), 1.190 (4.81), 1.219 (0.40), 1.234 (0.71), 1.237 (0.65), 1.361 (11.54), 1.378 (11.49), 1.955 (0.70), 1.988 (14.39), 2.318 (0.48), 2.361 (3.30), 2.395 (3.50), 2.518 (4.80), 2.523 (3.25), 2.660 (0.52), 2.686 (10.36), 2.781 (0.71), 2.942 (1.19), 3.197 (3.98), 3.232 (4.08), 3.354 (5.79), 3.457 (1.17), 3.470 (1.07), 3.487 (0.91), 3.565 (0.57), 3.599 (0.43), 3.636 (0.47), 3.677 (0.44), 3.700 (0.44), 3.999 (1.25), 4.017 (3.56), 4.034 (3.44), 4.052 (1.12), 4.428 (3.20), 4.451 (3.05), 5.672 (0.65), 5.688 (2.12), 5.705 (2.10), 5.722 (0.62), 7.394 (1.91), 7.413 (4.05), 7.433 (2.30), 7.614 (3.49), 7.617 (3.74), 7.634 (3.08), 7.637 (2.91), 7.860 (15.44), 7.861 (16.00), 7.902 (3.12), 7.905 (3.14), 7.922 (3.00), 8.792 (15.66), 8.794 (15.23).

[1149] Intermediate 135

[1150] (15R)-2-Chloro-15-methyl-ll-(trifluoromethyl)-7H,9H,15H,16H-spiro[6,17-(azeno)pyrido[3,4- g][l,6,10]benzoxadiazacyclotridecine-8,l'-cyclopropane]

[1151] General procedure G used.

[1152] 2- { [ 1 -( { 2- [( 1 R)- 1 - Aminoethyl] -6-(trifluoromethyl)phenoxy } methyl)cyclopropyl] methyl } -6- chloropyrido[3,4-d]pyrimidin-4-ol (394 mg, 870 μmol), BOP (500 mg, 1.13 mmol), DBU (520 pl, 3.5 mmol), DIPEA (230 pl, 1.3 mmol), and DMF (5.0 mL) afforded the title compound (250 mg, 63% yield).

[1153] LC-MS (Method 2): Rt= 1.48 min; MS (ESIpos): m / z = 435 [M+H]+

[1154] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.511 (0.40), 0.693 (0.76), 0.712 (1.13), 0.731 (0.65), 1.153 (4.65), 1.171 (8.73), 1.189 (4.40), 1.594 (2.40), 1.612 (2.43), 1.986 (16.00), 2.518 (0.67), 2.523 (0.44),

[1155] 2.589 (0.72), 3.164 (0.55), 3.207 (0.47), 3.822 (0.67), 3.848 (0.69), 3.998 (1.20), 4.016 (3.71), 4.034

[1156] (3.71), 4.052 (1.20), 4.633 (0.66), 4.660 (0.60), 6.221 (0.59), 7.232 (0.40), 7.252 (0.87), 7.271 (0.47),

[1157] 7.520 (0.78), 7.525 (0.84), 7.540 (0.72), 7.544 (0.70), 7.744 (0.66), 7.748 (0.67), 7.763 (0.63), 7.767

[1158] (0.59), 8.295 (2.46), 8.297 (2.51), 8.809 (2.80), 8.811 (2.76), 9.214 (0.66), 9.231 (0.64).

[1159] Intermediate 136 tert-butyl { ( 1 R)- 1 - [2-(2- { 1 - [(4-carbamoyl-6-chloropyridin-3-yl)carbamoyl] cyclopropyl } ethoxy)-3- (trifluoromethyl)phenyl] ethyl } carbamate

[1160]

[1161] General procedure C used.

[1162] 1 - { 2- [2 - { ( 1 R) - 1 - [(Tert-butoxycarbonyl)amino]ethyl } -6-(trifluoromethyl)phenoxy]ethyl } cyclopropane- 1-carboxylic acid (600 mg, 1.44 mmol), 5-amino-2-chloropyridine-4-carboxamide (296 mg, 1.72 mmol), TCFH (807 mg, 2.87 mmol), NMI (230 pl, 2.9 mmol), and DMA (15 mL) afforded the title compound (540 mg, 66% yield).

[1163] LC-MS (Method 2): Rt= 1.34 min; MS (ESIpos): m / z = 571 [M+H]+

[1164] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.935 (0.75), 0.996 (1.08), 1.010 (0.53), 1.027 (0.69), 1.048 (0.68), 1.099 (4.04), 1.105 (0.57), 1.152 (4.58), 1.170 (9.34), 1.187 (8.49), 1.203 (4.33), 1.232 (14.20), 1.331 (0.40), 1.386 (0.97), 1.906 (11.02), 1.985 (16.00), 2.030 (0.47), 2.168 (0.48), 2.185 (0.71), 2.201

[1165] (0.43), 2.214 (0.40), 2.244 (0.51), 3.959 (0.58), 3.980 (0.59), 3.997 (1.48), 4.015 (3.63), 4.032 (3.49), 4.051 (1.17), 4.427 (0.47), 4.448 (0.43), 4.953 (0.55), 7.277 (0.58), 7.296 (1.26), 7.316 (0.75), 7.496 (1.98), 7.516 (1.69), 7.641 (0.87), 7.660 (0.74), 7.887 (3.25), 8.200 (1.11), 8.616 (0.97), 9.487 (5.19), 11.784 (1.25).

[1166] Intermediate 137 tert-butyl { ( 1 R) - 1 - [2 - { 2 - [ 1 -(6-chloro-4-hydroxypyrido [3 ,4-d] pyrimidin-2-yl)cyclopropyl] ethoxy } -3 - (trifluoromethyl)phenyl] ethyl } carbamate General procedure D used.

[1167] Tert-butyl {(lR)-l-[2-(2-{ l-[(4-carbamoyl-6-chloropyridin-3-yl)carbamoyl]cyclopropyl}ethoxy)-3- (trifluoromethyl)phenyl] ethyl} carbamate (540 mg, 946 μmol), NaOMe (390 pl, 21 % purity, 1.0 mmol), and EtOH (30 mL) afforded the title compound (460 mg, 88% yield).

[1168] LC-MS (Method 2): Rt= 1.15 min; MS (ESIpos): m / z = 553 [M+H]+

[1169] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.944 (0.44), 0.954 (0.40), 1.153 (9.51), 1.155 (8.71), 1.170 (9.78), 1.178 (1.90), 1.188 (4.73), 1.281 (0.52), 1.295 (0.41), 1.906 (6.84), 1.986 (16.00), 2.030 (0.43), 2.039 (0.63), 2.214 (0.96), 3.997 (1.20), 4.015 (3.54), 4.033 (3.43), 4.051 (1.12), 7.274 (0.67), 7.466 (0.42), 7.479 (0.84), 7.495 (0.63), 7.609 (0.43), 7.882 (1.09), 8.771 (2.18), 11.974 (0.43), 12.378 (0.55).

[1170] Intermediate 138

[1171] 2- [ 1 -(2- { 2- [( 1 R)- 1 -aminoethyl] -6-(trifluoromethyl)phenoxy } ethyl)cyclopropyl] -6-chloropyrido[3 ,4- d]pyrimidin-4-ol — hydrogen chloride (1 / 1)

[1172] General procedure F used.

[1173] T ert-butyl { ( 1 R) - 1 - [2 - { 2 - [ 1 -(6-chloro-4-hydroxypyrido [3 ,4-d] pyrimidin-2-yl)cyclopropyl] ethoxy } -3- (trifluoromethyl)phenyl] ethyl} carbamate (460 mg, 832 μmol), HC1 in 1,4-dioxane (2.1 ml, 4.0 M, 8.3 mmol), and EtOH (10 mL) afforded the title compound (410 mg, quantitative yield).

[1174] LC-MS (Method 2): Rt= 0.83 min; MS (ESIpos): m / z = 453 [M+H]+

[1175] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.000 (0.43), 1.026 (7.34), 1.044 (16.00), 1.062 (6.70), 1.472 (0.56), 1.488 (0.56), 3.403 (2.64), 3.420 (7.06), 3.437 (7.42), 3.455 (2.52), 7.906 (0.76), 7.908 (0.75), 8.873 (0.71), 8.875 (0.71).

[1176] Intermediate 139

[1177] (15R)-2-chloro-15-methyl-ll-(trifluoromethyl)-8H,9H,15H,16H-spiro[6,17-(azeno)pyrido[3,4- g][l,6,10]benzoxadiazacyclotridecine-7,l'-cyclopropane]

[1178] General procedure G used

[1179] 2- [ 1 -(2- { 2- [( 1 R)- 1 - Aminoethyl] -6-(trifluoromethyl)phenoxy } ethyl)cyclopropyl] -6-chloropyrido[3 ,4- d]pyrimidin-4-ol - hydrogen chloride (1 / 1) (410 mg, 838 μmol), BOP (741 mg, 1.68 mmol), DBU (500 pl, 3.4 mmol), DIPEA (360 pl, 2.1 mmol), and DMF (20 mL) afforded the title compound (210 mg, 58% yield).

[1180] LC-MS (Method 2): Rt= 1.55 min; MS (ESIpos): m / z = 435 [M+H]+

[1181] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.901 (1.26), 1.152 (4.08), 1.170 (7.73), 1.188 (4.28), 1.555 (2.09), 1.572 (2.07), 1.986 (16.00), 3.997 (1.11), 4.015 (3.39), 4.033 (3.40), 4.050 (1.10), 7.273 (0.68), 7.526 (0.60), 7.530 (0.64), 7.546 (0.55), 7.550 (0.52), 7.761 (0.51), 7.765 (0.52), 7.781 (0.49), 7.784

[1182] (0.46), 8.316 (1.90), 8.318 (1.91), 8.720 (2.24), 8.722 (2.31), 9.279 (0.55), 9.295 (0.52).

[1183] Intermediate 140 tert-butyl {(lR)-l-[2-({(ls,3S)-3-[(4-carbamoyl-6-chloropyridin-3-yl)carbamoyl]cyclobutyl}oxy)-3- (trifluoromethyl)phenyl] ethyl } carbamate

[1184] General procedure C used.

[1185] (lS,3s)-3-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenoxy]cyclobutane-l- carboxylic acid (300 mg, 744 μmol), 5-amino-2-chloropyridine-4-carboxamide (153 mg, 892 μmol), TCFH (417 mg, 1.49 mmol), NMI (120 pl, 1.5 mmol), and DMA (3.0 mL) afforded the title compound (440 mg, 90% yield).

[1186] LC-MS (Method 2): Rt= 1.28 min; MS (ESIpos): m / z = 558 [M+H]+

[1187] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (4.72), 1.172 (10.12), 1.190 (5.20), 1.233 (0.64), 1.261 (1.21), 1.277 (1.23), 1.295 (0.47), 1.318 (0.52), 1.356 (4.87), 1.906 (2.38), 1.988 (16.00), 2.322 (0.49), 2.327 (0.70), 2.331 (0.52), 2.518 (2.44), 2.523 (1.48), 2.659 (0.42), 2.665 (0.67), 2.669 (0.85), 2.673 (0.62), 3.999 (1.23), 4.017 (3.73), 4.035 (3.68), 4.053 (1.17), 7.313 (0.64), 7.523 (0.70), 7.539 (0.64), 7.543 (0.60), 7.686 (0.52), 7.704 (0.46), 7.790 (2.05), 8.105 (0.55), 8.484 (0.49), 9.269 (1.20), 10.945 (0.67).

[1188] Intermediate 141 tert-butyl {(lR)-l-[2-{[(ls,3S)-3-(6-chloro-4-hydroxypyrido[3,4-d]pyrimidin-2-yl)cyclobutyl]oxy}-3-

[1189] (trifluoromethyl)phenyl] ethyl } carbamate

[1190] General procedure D used.

[1191] Tert-butyl {(lR)-l-[2-({(ls,3S)-3-[(4-carbamoyl-6-chloropyridin-3-yl)carbamoyl]cyclobutyl}-oxy)-3- (trifluoromethyl)phenyl]ethyl}carbamate (505 mg, 907 μmol), NaOMe (370 pl, 21 % purity, 1000 μmol), and EtOH (12 mL) was used. The material was used immediately in the next step without purification.

[1192] LC-MS (Method 1): Rt= 1.38 min; MS (ESIpos): m / z = 539.8 [M+H]+ Intermediate 142

[1193] 2-[(lS,3s)-3-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenoxy}cyclobutyl]-6-chloropyrido[3,4- d]pyrimidin-4-ol

[1194] Tert-butyl {(lR)-l-[2-{ [(ls,3S)-3-(6-chloro-4-hydroxypyrido[3,4-d]pyrimidin-2-yl)cyclobutyl]-oxy}-3- (trifluoromethyl)phenyl]ethyl}carbamate (489 mg, 907 μmol) and HC1 in 1,4-dioxane (2.3 ml, 4.0 M, 9.1 mmol) were combined and stirred at room temperature for 18 hours. The mixture was basified with sat. aq. NaHCO3sol. and extracted into EtOAc (3x). The combined org. phases were filtered through hydrophobic filter paper and concentrated under reduced pressure to afford the title compound (452 mg, quantitative yield).

[1195] LC-MS (Method 2): Rt= 0.75 min; MS (ESIpos): m / z = 440.4 [M+H]+.

[1196] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (0.98), 1.171 (2.11), 1.189 (1.21), 1.216 (1.21), 1.218

[1197] (1.15), 1.234 (2.47), 1.236 (2.55), 1.252 (1.11), 1.254 (1.32), 1.288 (3.81), 1.305 (3.71), 1.351 (0.47),

[1198] 1.839 (2.04), 1.903 (16.00), 1.987 (3.00), 2.031 (0.47), 2.518 (0.83), 2.523 (0.51), 2.669 (0.46), 2.673

[1199] (0.41), 2.689 (0.46), 2.702 (0.60), 2.710 (0.67), 2.725 (0.87), 2.735 (0.77), 2.747 (0.85), 2.777 (0.63), 2.796 (0.45), 2.946 (0.43), 2.952 (0.42), 2.971 (0.56), 3.348 (0.53), 3.977 (0.89), 3.995 (0.96), 3.998 (1.26), 4.015 (1.41), 4.034 (0.73), 4.344 (0.75), 4.361 (0.79), 4.373 (0.63), 7.312 (0.53), 7.331 (0.97), 7.351 (0.53), 7.527 (0.86), 7.530 (1.04), 7.546 (0.76), 7.550 (0.77), 7.887 (0.80), 7.906 (1.21), 7.908 (1.24), 7.931 (3.44), 7.932 (3.32), 7.935 (1.32), 7.937 (1.08), 8.772 (0.49), 8.774 (0.49), 8.917 (3.37), 8.919 (3.27), 8.939 (0.70), 8.941 (0.67).

[1200] Intermediate 143 tert-butyl {(lR)-l-[2-({(2R)-5-[(4-carbamoyl-6-chloropyridin-3-yl)amino]-5-oxopentan-2-yl}oxy)-3-

[1201] (trifluoromethyl)phenyl] ethyl } carbamate

[1202]

[1203] General procedure C used.

[1204] (4R)-4-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenoxy]pentanoic acid (430 mg, 1.06 mmol), 5-amino-2-chloropyridine-4-carboxamide (218 mg, 1.27 mmol), TCFH (744 mg, 2.65 mmol), NMI (210 pl, 2.7 mmol), and DMA (12 mL) afforded the title compound (740 mg, quantitative yield).

[1205] LC-MS (Method 2): Rt= 1.29 min; MS (ESIpos): m / z = 559.3 [M+H]+.

[1206] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.135 (0.66), 1.149 (0.75), 1.239 (0.59), 1.255 (0.64), 1.333 (3.03), 1.907 (0.94), 1.955 (8.33), 2.685 (16.00), 2.781 (7.87), 2.941 (12.92), 7.276 (0.48), 7.519 (0.42), 7.780 (0.59).

[1207] Intermediate 144 tert-butyl {(lR)-l-[2-{[(2R)-4-(6-chloro-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-2-yl)butan-2- yl]oxy } -3-(trifluoromethyl)phenyl]ethyl } carbamate

[1208] General procedure D used. Tert-butyl {(lR)-l-[2-({(2R)-5-[(4-carbamoyl-6-chloropyridin-3-yl)amino]-5-oxopentan-2-yl}oxy)-3- (trifluoromethyl)phenyl] ethyl} carbamate (700 mg, 1.25 mmol), NaOEt (510 pl, 21 % purity, 1.4 mmol), and EtOH (60 mL) afforded the title compound (540 mg, 77% yield).

[1209] LC-MS (Method 2): Rt= 1.06 min; MS (ESIpos): m / z = 541.3 [M+H]+.

[1210] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.153 (3.94), 1.158 (3.86), 1.171 (4.94), 1.189 (2.17), 1.199 (3.54), 1.216 (3.78), 1.315 (16.00), 1.955 (0.88), 1.986 (3.26), 2.113 (0.64), 2.131 (0.88), 2.147 (0.71), 2.165 (0.54), 2.179 (0.72), 2.198 (0.85), 2.215 (0.61), 2.518 (1.33), 2.523 (0.86), 2.685 (10.79), 2.781

[1211] (0.84), 2.833 (0.58), 2.854 (1.24), 2.872 (1.26), 2.894 (0.72), 2.941 (1.28), 4.016 (0.69), 4.034 (0.68),

[1212] 4.544 (0.60), 4.560 (0.57), 4.978 (0.47), 4.997 (0.64), 5.014 (0.45), 7.254 (1.02), 7.274 (2.15), 7.293

[1213] (1.22), 7.443 (0.84), 7.463 (0.82), 7.512 (1.95), 7.516 (2.12), 7.531 (1.78), 7.535 (1.72), 7.678 (1.18),

[1214] 7.696 (0.98), 7.929 (2.94), 8.821 (6.85).

[1215] Intermediate 145

[1216] 2-[(3R)-3-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenoxy]butyl]-6-chloropyrido[3,4-d]pyrimidin-

[1217] 4(3H)-one — hydrogen chloride (1 / 1)

[1218] General procedure F used.

[1219] Tert-butyl {(lR)-l-[2-{[(2R)-4-(6-chloro-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-2-yl)butan-2- yl]oxy}-3-(trifluoromethyl)phenyl]ethyl}carbamate (540 mg, 998 μmol), HC1 in 1,4-dioxane (5.0 ml, 4.0 M, 20 mmol), and 1,4-dioxane (5.0 mL) afforded the title compound (520 mg, quantitative yield).

[1220] LC-MS (Method 2): Rt= 0.80 min; MS (ESIpos): m / z = 441.1 [M+H]+.

[1221] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.100 (11.48), 1.156 (6.31), 1.171 (6.45), 1.501 (7.15), 1.518 (7.22), 1.954 (0.81), 2.082 (16.00), 2.089 (0.67), 2.106 (0.77), 2.125 (1.06), 2.141 (0.83), 2.160 (0.40),

[1222] 2.188 (0.79), 2.205 (0.99), 2.223 (0.77), 2.240 (0.50), 2.518 (1.82), 2.522 (1.11), 2.684 (9.60), 2.779

[1223] (0.68), 2.839 (1.45), 2.857 (2.48), 2.878 (1.30), 2.940 (0.94), 3.071 (3.75), 3.563 (1.35), 4.128 (6.78),

[1224] 4.371 (0.74), 4.386 (1.40), 4.401 (1.35), 4.416 (0.69), 4.667 (0.79), 4.682 (0.99), 4.698 (0.76), 5.759 (0.80), 7.413 (1.25), 7.433 (2.56), 7.452 (1.41), 7.695 (2.27), 7.698 (2.45), 7.715 (2.08), 7.718 (2.00), 7.950 (8.64), 7.952 (8.53), 8.027 (1.99), 8.045 (1.87), 8.651 (2.84), 8.860 (8.26), 8.862 (7.95).

[1225] Intermediate 146 tert-butyl {(lR)-l-[2-({(2S)-5-[(4-carbamoyl-6-chloropyridin-3-yl)amino]-5-oxopentan-2-yl}oxy)-3-

[1226] (trifluoromethyl)phenyl] ethyl } carbamate

[1227] General procedure C used.

[1228] (4S)-4-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenoxy]pentanoic acid (900 mg, 2.22 mmol), 5-amino-2-chloropyridine-4-carboxamide (457 mg, 2.66 mmol), TCFH (1.56 g, 5.55 mmol), NMI (440 pl, 5.5 mmol), and DMF (26 mL) afforded the title compound (1.06 g, 79% yield).

[1229] LC-MS (Method 2): Rt= 1.29 min; MS (ESIpos): m / z = 559 [M+H]+

[1230] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.111 (1.71), 1.125 (1.82), 1.154 (3.98), 1.171 (8.71), 1.189

[1231] (4.71), 1.216 (2.13), 1.233 (2.22), 1.342 (9.23), 1.362 (0.91), 1.369 (1.22), 1.905 (1.70), 1.978 (0.70),

[1232] 1.986 (16.00), 2.518 (0.96), 2.523 (0.66), 2.563 (1.47), 2.582 (0.73), 3.998 (1.13), 4.016 (3.45), 4.034

[1233] (3.38), 4.052 (1.08), 7.247 (0.44), 7.266 (0.93), 7.286 (0.54), 7.480 (0.50), 7.501 (0.51), 7.514 (1.12),

[1234] 7.518 (1.19), 7.533 (0.96), 7.537 (0.94), 7.651 (0.81), 7.670 (0.73), 7.780 (3.45), 8.087 (0.84), 8.477 (0.76), 9.269 (3.88), 10.961 (1.59).

[1235] Intermediate 147 tert-butyl {(lR)-l-[2-{[(2S)-4-(7-chloro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-2-yl)butan-2- yl]oxy } -3-(trifluoromethyl)phenyl]ethyl [carbamate

[1236] General procedure D used.

[1237] Tert-butyl {(lR)-l-[2-({(2S)-5-[(4-carbamoyl-6-chloropyridin-3-yl)amino]-5-oxopentan-2-yl}oxy)-3- (trifluoromethyl)phenyl] ethyl} carbamate (1.09 g, 1.95 mmol), NaOEt (800 μl, 21 % purity, 2.1 mmol), and EtOH (110 mL) afforded the title compound (855 mg, 77% yield).

[1238] LC-MS (Method 2): Rt= 1.09 min; MS (ESIpos): m / z = 541 [M+H]+

[1239] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.135 (2.78), 1.153 (4.33), 1.171 (4.20), 1.189 (4.41), 1.204 (2.98), 1.243 (16.00), 1.369 (0.96), 1.986 (6.04), 2.143 (0.48), 2.157 (0.56), 2.176 (0.62), 2.192 (0.56),

[1240] 2.518 (0.97), 2.523 (0.61), 2.788 (0.66), 2.804 (0.75), 2.825 (0.77), 2.846 (0.67), 2.864 (0.49), 3.998

[1241] (0.43), 4.015 (1.28), 4.034 (1.25), 4.052 (0.40), 4.653 (0.48), 4.668 (0.46), 4.933 (0.42), 4.950 (0.57),

[1242] 7.243 (0.55), 7.263 (1.17), 7.282 (0.71), 7.443 (0.76), 7.463 (0.74), 7.514 (1.53), 7.531 (1.24), 7.534

[1243] (1.25), 7.629 (1.27), 7.648 (1.17), 7.924 (3.23), 8.815 (2.56), 12.698 (0.43).

[1244] Intermediate 148

[1245] 2-[(3S)-3-{2-[(lR)-l-aminoethyl]-6-(trifluoromethyl)phenoxy}butyl]-7-chloropyrido[4,3-d]pyrimidin-

[1246] 4(3H)-one — hydrogen chloride (1 / 1)

[1247] General procedure F used.

[1248] Tert-butyl {(lR)-l-[2-{[(2S)-4-(7-chloro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-2-yl)butan-2- yl]oxy}-3-(trifluoromethyl)phenyl]ethyl}carbamate (844 mg, 1.56 mmol), HC1 in 1,4-dioxane (7.8 ml, 4.0 M, 31 mmol), and 1,4-dioxane (7.8 mL) afforded the title compound (715 mg, 91% yield).

[1249] LC-MS (Method 2): Rt= 0.84 min; MS (ESIpos): m / z = 441 [M+H]+1H-NMR (400 MHz, DMS0-d6) • [ppm]: 1.105 (0.73), 1.173 (12.33), 1.189 (12.43), 1.501 (10.51), 1.518 (10.66), 2.087 (0.87), 2.103 (1.45), 2.121 (2.07), 2.138 (1.63), 2.156 (0.71), 2.167 (0.64), 2.186 (1.51), 2.202 (1.87), 2.221 (1.41), 2.238 (0.80), 2.518 (3.28), 2.523 (2.04), 2.820 (3.26), 2.839 (5.84), 2.858 (2.86), 3.162 (14.26), 3.563 (9.63), 3.599 (0.84), 4.305 (2.12), 4.398 (1.60), 4.413 (2.69), 4.429 (2.59), 4.444 (1.32), 4.675 (1.37), 4.689 (1.72), 4.704 (1.30), 5.759 (1.30), 7.414 (1.68), 7.433 (3.55), 7.453 (1.97), 7.708 (3.56), 7.727 (3.03), 7.950 (9.64), 7.951 (12.00), 7.955 (6.16), 7.995 (2.34), 8.015 (1.88), 8.492 (1.27), 8.578 (3.09), 8.816 (16.00), 8.818 (12.38).

[1250] Intermediate 149 tert-butyl { ( 1 R)- 1 - [2- { 4- [(4-carbamoyl-6-chloropyridin-3-yl)amino] -4-oxobutoxy } -5-fluoro-3- (trifluoromethyl)phenyl] ethyl } carbamate

[1251] General procedure C used.

[1252] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -4-fluoro-6-(trifluoromethyl)phenoxy]butanoic acid (2.12 g, 5.18 mmol), 5-amino-2-chloropyridine-4-carboxamide (1.07 g, 6.21 mmol), TCFH (2.91 g, 10.4 mmol), NMI (830 pl, 10 mmol), and DMA (30 mL) afforded the title compound (2.43 g, 78% yield).

[1253] LC-MS (Method 2): Rt= 1.29 min; MS (ESIpos): m / z = 563 [M+H]+

[1254] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.150 (4.52), 1.168 (9.64), 1.186 (5.03), 1.252 (3.82), 1.269 (4.00), 1.331 (16.00), 1.983 (14.32), 2.078 (0.90), 2.081 (0.91), 2.094 (1.33), 2.382 (2.26), 2.518 (0.78), 2.523 (0.53), 2.589 (1.40), 2.607 (2.48), 2.625 (1.25), 2.922 (2.02), 3.338 (0.48), 3.350 (0.84), 3.366 (2.20), 3.417 (2.14), 3.421 (1.89), 3.427 (1.00), 3.433 (0.73), 3.438 (0.58), 3.442 (0.43), 3.872 (0.80), 3.894 (0.83), 3.995 (1.12), 4.013 (3.21), 4.030 (3.11), 4.048 (0.99), 4.162 (0.58), 4.181 (0.53), 4.914 (0.45), 4.933 (0.61), 4.950 (0.41), 7.433 (1.09), 7.440 (1.47), 7.453 (1.16), 7.461 (1.41), 7.507 (0.89), 7.514 (0.86), 7.533 (1.51), 7.554 (0.84), 7.780 (3.89), 8.083 (1.39), 8.482 (1.13), 9.162 (0.40), 9.260 (2.38), 10.976 (1.40). Intermediate 150 tert-butyl [( 1 R)- 1 - { 2- [3 -(6-chloro-4-hydroxypyrido[3 ,4-d]pyrimidin-2-yl)propoxy] -5-fluoro-3- (trifluoromethyl)phenyl } ethyl] carbamate

[1255] General procedure D used.

[1256] Tert-butyl { ( 1 R)- 1 - [2- { 4- [(4-carbamoyl-6-chloropyridin-3-yl)ammo] -4-oxobutoxy } -5-fluoro-3-

[1257] (trifluoromethyl)phenyl] ethyl] carbamate (2.18 g, 3.87 mmol), NaOMe (1.6 ml, 21 % purity, 4.3 mmol), and EtOH (75 mL) afforded the title compound (1.98 g, 94% yield).

[1258] LC-MS (Method 2): Rt= 1.03 min; MS (ESIpos): m / z = 545 [M+H]+

[1259] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.119 (0.40), 1.236 (4.17), 1.249 (16.00), 1.405 (0.53), 2.251 (0.59), 2.268 (0.94), 2.283 (0.88), 2.299 (0.50), 2.318 (0.40), 2.518 (2.27), 2.523 (1.63), 2.862 (0.60),

[1260] 2.881 (1.38), 2.900 (1.05), 2.921 (0.44), 3.308 (0.40), 3.314 (0.89), 3.316 (1.02), 3.321 (1.00), 3.325

[1261] (0.75), 3.385 (1.13), 3.388 (1.10), 3.391 (0.92), 3.396 (0.66), 3.404 (0.50), 3.906 (0.61), 3.927 (0.66),

[1262] 4.237 (0.42), 4.919 (0.50), 7.430 (0.67), 7.438 (0.97), 7.451 (0.75), 7.459 (0.95), 7.487 (0.66), 7.494

[1263] (0.60), 7.515 (1.14), 7.535 (0.68), 7.931 (2.32), 8.835 (3.70).

[1264] Intermediate 151

[1265] 2-(3 - { 2- [( 1 R)- 1 -aminoethyl] -4-fluoro-6-(trifluoromethyl)phenoxy }propyl)-6-chloropyrido[3 ,4- d]pyrimidin-4-ol

[1266] General procedure E used. Tert-butyl [(lR)-l-{2-[3-(6-chloro-4-hydroxypyrido[3,4-d]pyrimidin-2-yl)propoxy]-5-fluoro-3- (trifluoromethyl)phenyl}ethyl]carbamate (1.98 g, 3.63 mmol), TFA (2.8 ml, 36 mmol), andDCM (40 mL) afforded the title compound (1.67 g, quantitative yield).

[1267] LC-MS (Method 2): Rt= 0.81 min; MS (ESIpos): m / z = 445 [M+H]+

[1268] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.969 (0.47), 0.987 (1.04), 1.004 (0.51), 1.239 (15.93), 1.256 (16.00), 2.205 (0.93), 2.222 (3.01), 2.239 (4.71), 2.256 (3.21), 2.273 (1.09), 2.518 (3.50), 2.523 (2.23),

[1269] 2.839 (4.42), 2.858 (7.17), 2.876 (3.80), 3.884 (1.33), 3.899 (2.53), 3.906 (2.08), 3.922 (3.17), 3.937

[1270] (1.53), 3.996 (1.48), 4.012 (3.09), 4.027 (1.86), 4.034 (2.36), 4.049 (1.08), 4.375 (0.92), 4.387 (2.47),

[1271] 4.391 (2.57), 4.404 (2.47), 4.408 (2.48), 4.420 (0.87), 5.753 (4.18), 7.402 (3.15), 7.410 (3.51), 7.422 (3.26), 7.430 (3.36), 7.721 (2.80), 7.730 (2.84), 7.745 (2.83), 7.754 (2.67), 7.942 (14.07), 7.943 (13.88),

[1272] 8.854 (13.65), 8.855 (13.70).

[1273] Intermediate 152

[1274] (15R)-2-chloro-13-fluoro-4,15-dimethyl-l l-(trifluoromethyl)-8,9,15,16-tetrahydro-7H-6,17-

[1275] (azeno)pyrido[3,4-g][l,6,10]benzoxadiazacyclotridecine

[1276] (15R)-2-Chloro-13-fluoro-15-methyl-ll-(trifluoromethyl)-8,9,15,16-tetrahydro-7H-6,17-

[1277] (azeno)pyrido[3,4-g][l,6,10]benzoxadiazacyclotridecine (200 mg, 469 μmol) was dissolved in DMSO (4.0 mL) was placed under argon, then DBU (140 pl, 940 μmol) and nitromethane (130 pl, 2.3 mmol) were added and stirred at 60 °C for 18 hours. Purification by flash column chromatography (hexane / EtOAc) afforded the title compound (192 mg, 88% yield).

[1278] LC-MS (Method 2): Rt= 1.55 min; MS (ESIpos): m / z = 441 [M+H]+

[1279] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.121 (0.98), 1.152 (1.92), 1.171 (3.74), 1.189 (1.99), 1.539 (5.95), 1.557 (6.04), 1.986 (7.12), 2.075 (0.45), 2.322 (0.42), 2.327 (0.62), 2.332 (0.60), 2.368 (0.55), 2.518 (1.40), 2.523 (0.91), 2.669 (0.49), 2.701 (16.00), 2.791 (0.44), 2.831 (0.70), 2.838 (0.70), 2.858

[1280] (0.76), 2.928 (0.59), 2.935 (0.83), 2.943 (0.75), 2.950 (0.67), 2.989 (0.43), 3.356 (1.07), 3.580 (0.60),

[1281] 3.591 (0.59), 3.604 (0.60), 3.998 (0.53), 4.015 (1.61), 4.033 (1.62), 4.051 (0.53), 4.674 (0.76), 4.900

[1282] (0.42), 4.908 (0.50), 4.925 (0.79), 4.944 (0.46), 5.758 (0.77), 5.992 (0.56), 6.008 (0.80), 6.024 (0.54),

[1283] 7.419 (1.39), 7.427 (1.75), 7.440 (1.43), 7.448 (1.65), 7.535 (1.25), 7.544 (1.21), 7.558 (1.29), 7.566

[1284] (1.13), 8.114 (4.84), 9.138 (1.62), 9.154 (1.55).

[1285] Intermediate 153 tert-butyl { ( 1 R) - 1 - [2 - { 4 - [ (5 -bromo-3 -carbamoylpyridin-2-yl)amino] -4-oxobutoxy } -3 - (trifluoromethyl)phenyl] ethyl } carbamate

[1286]

[1287] General procedure C used.

[1288] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy]butanoic acid (400 mg, 1.02 mmol), 2-amino-5-bromopyridine-3-carboxamide (265 mg, 1.23 mmol), TCFH (717 mg, 2.55 mmol), NMI (200 pl, 2.6 mmol), and DMA (6.5 mL) afforded the title compound (600 mg, quantitative yield).

[1289] LC-MS (Method 2): Rt= 1.26 min; MS (ESIpos): m / z = 589 [M+H]+

[1290] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.083 (0.51), 1.171 (0.44), 1.258 (1.25), 1.278 (0.77), 1.346 (2.63), 1.903 (2.60), 1.955 (9.10), 1.986 (0.65), 2.685 (16.00), 2.781 (8.60), 2.941 (13.75), 8.544 (0.76), 8.550 (0.78).

[1291] Intermediate 154 tert-butyl [( 1 R)- 1 - { 2- [3 -(6-bromo-4-oxo-3 ,4-dihydropyrido[2,3-d]pyrimidin-2-yl)propoxy] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[1292] General procedure D used. T ert-butyl { ( 1 R) - 1 - [2 - { 4 - [ (5 -bromo-3 -carbamoylpyridin-2-yl)amino] -4-oxobutoxy } -3-

[1293] (trifluoromethyl)phenyl] ethyl} carbamate (600 mg, 1.02 mmol), NaOEt (76.2 mg, 1.12 mmol), EtOH (19 mL) afforded the title compound (580 mg, quantitative yield). The obtained material was used without further purification.

[1294] LC-MS (Method 2): Rt= 1.00 min; MS (ESIpos): m / z = 571.3 [M+H]+.

[1295] Intermediate 155

[1296] 2-(3 - { 2- [( 1 R)- 1 -aminoethyl] -6-(trifluoromethyl)phenoxy }propyl)-6-bromopyrido[2,3-d]pyrimidin- 4(3H)-one

[1297] General procedure E used.

[1298] Tert-butyl [(lR)-l-{2-[3-(6-bromo-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)propoxy]-3-

[1299] (trifluoromethyl)phenyl} ethyl] carbamate (580 mg, 1.02 mmol), TFA (780 pl, 10 mmol), and DCM (70 mL) afforded the title compound (600 mg, quantitative yield). The obtained material was used without further purification.

[1300] LC-MS (Method 2): Rt= 0.73 min; MS (ESIpos): m / z = 471.4 [M+H]+.

[1301] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.850 (1.45), 1.232 (16.00), 1.248 (9.43), 1.881 (0.47), 1.955 (0.46), 1.987 (0.48), 2.084 (0.86), 2.217 (1.28), 2.235 (1.98), 2.251 (1.52), 2.518 (6.24), 2.522 (4.18),

[1302] 2.685 (2.62), 2.800 (1.47), 2.818 (2.19), 2.837 (1.30), 2.941 (0.43), 3.914 (1.07), 3.936 (1.38), 3.951

[1303] (0.67), 4.024 (0.64), 4.041 (1.38), 4.062 (1.10), 4.078 (0.44), 4.454 (1.73), 4.470 (1.67), 4.487 (0.53),

[1304] 7.291 (1.02), 7.311 (2.21), 7.330 (1.27), 7.506 (1.98), 7.525 (1.61), 7.866 (1.70), 7.883 (1.56), 8.133

[1305] (0.61), 8.139 (0.80), 8.491 (2.91), 8.497 (2.88), 8.507 (1.16), 8.889 (2.30), 8.895 (2.16). Intermediate 156

[1306] (15R)-2-bromo-15-methyl-ll-(trifluoromethyl)-8,9,15,16-tetrahydro-7H-6,17-(azeno)pyrido[2,3- g] [ 1 ,6, 10]benzoxadiazacyclotridecine

[1307] General procedure G used.

[1308] Trifluoroacetic acid — 2-(3 - { 2- [( 1 R)- 1 -aminoethyl] -6-(trifluoromethyl)phenoxy }propyl)-6- bromopyrido[2,3-d]pyrimidin-4(3H)-one (1 / 1) (600 mg, 1.03 mmol), BOP (589 mg, 1.33 mmol), DBU (610 pl, 4.1 mmol), DIPEA (710 pl, 4.1 mmol), and DMF (10 mL) afforded the title compound (250 mg, 54% yield).

[1309] LC-MS (Method 2): Rt= 1.27 min; MS (ESIpos): m / z = 453 [M+H]+

[1310] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.083 (0.55), 1.230 (0.94), 1.258 (1.44), 1.510 (0.72), 1.527 (0.92), 1.540 (3.23), 1.559 (3.15), 1.573 (0.61), 1.600 (1.81), 1.610 (1.99), 1.622 (2.13), 1.645 (1.81), 1.660 (1.49), 1.673 (1.19), 1.885 (0.46), 1.899 (1.21), 1.914 (1.99), 1.928 (1.27), 1.943 (0.51), 2.394 (0.41), 2.523 (1.16), 2.621 (2.00), 2.646 (1.80), 2.686 (3.80), 2.728 (13.62), 2.888 (16.00), 2.927 (0.50), 2.932 (0.46), 2.941 (0.46), 3.230 (0.85), 3.245 (1.60), 3.249 (1.59), 3.385 (0.56), 3.459 (1.47), 3.474 (2.53), 3.488 (1.40), 3.538 (1.99), 3.561 (2.11), 4.943 (0.44), 5.758 (1.12), 6.081 (0.57), 7.239 (0.48), 7.258 (1.01), 7.277 (0.56), 7.517 (0.89), 7.521 (0.92), 7.537 (0.80), 7.541 (0.76), 7.747 (0.89), 7.762 (0.74), 7.950 (2.24), 8.134 (0.61), 8.139 (0.59), 8.975 (1.60), 8.981 (2.28), 9.007 (2.12), 9.013 (1.58), 9.253 (0.48), 9.268 (0.47), 9.480 (0.63), 10.853 (0.44).

[1311] Intermediate 157 tert-butyl { (1R)- 1 -[2- { 4-[(5-bromo-3-carbamoylpyridin-2-yl)amino] -3-methyl-4-oxobutoxy } -3- (trifluoromethyl)phenyl] ethyl } carbamate

[1312]

[1313] General procedure C used.

[1314] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy] -2-methylbutanoic acid (2.50 g, 70 % purity, 4.32 mmol), 2-amino-5-bromopyridine-3-carboxamide (1.12 g, 5.18 mmol), TCFH (2.42 g, 8.63 mmol), NMI (690 pl, 8.6 mmol), and DMA (28 mL) afforded the title compound (260 mg, 10% yield).

[1315] LC-MS (Method 2): Rt= 1.25 min; MS (ESIneg): m / z = 602 [M]

[1316] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.062 (6.11), 1.079 (6.26), 1.099 (0.76), 1.117 (0.67), 1.154 (4.72), 1.171 (9.76), 1.180 (2.26), 1.189 (7.17), 1.196 (2.24), 1.207 (2.32), 1.233 (2.16), 1.250 (3.39), 1.266 (2.39), 1.334 (7.42), 1.351 (3.64), 1.412 (1.75), 1.719 (0.43), 1.735 (0.61), 1.753 (0.73), 1.769 (0.59), 1.819 (0.41), 1.836 (0.52), 1.851 (0.51), 1.986 (16.00), 2.000 (0.58), 2.017 (0.53), 2.154 (0.40), 2.171 (0.43), 2.465 (0.56), 2.522 (1.32), 2.822 (1.24), 2.842 (0.69), 3.029 (2.04), 3.043 (0.86), 3.766 (0.64), 3.784 (1.29), 3.802 (1.47), 3.819 (0.78), 3.825 (0.74), 3.843 (0.65), 3.868 (0.49), 3.998 (1.29),

[1317] 4.016 (3.79), 4.034 (3.71), 4.052 (1.21), 5.449 (1.29), 5.452 (1.24), 5.477 (1.26), 5.480 (1.36), 5.926

[1318] (1.39), 5.928 (1.41), 5.970 (1.36), 5.972 (1.35), 6.803 (0.81), 6.895 (0.83), 6.923 (0.88), 6.939 (0.80),

[1319] 6.967 (0.74), 7.294 (1.31), 7.314 (2.69), 7.333 (1.91), 7.517 (1.25), 7.536 (1.34), 7.592 (1.23), 7.608

[1320] (1.02), 7.677 (0.98), 7.698 (0.79), 7.903 (1.14), 7.920 (0.96), 8.100 (0.55), 8.134 (0.59), 8.139 (0.61),

[1321] 8.216 (1.14), 8.229 (0.55), 8.235 (0.47), 8.548 (1.91), 8.553 (2.03), 11.054 (0.62).

[1322] Intermediate 158 tert-butyl [( 1 R)- 1 - { 2- [3 -(6-bromo-4-oxo-3 ,4-dihydropyrido[2,3-d]pyrimidin-2-yl)butoxy] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[1323]

[1324] General procedure D used.

[1325] Tert-butyl { (1R)- 1 -[2- { 4-[(5-bromo-3-carbamoylpyridin-2-yl)amino] -3-methyl-4-oxobutoxy } -3- (trifluoromethyl)phenyl] ethyl} carbamate (260 mg, 50 % purity, 215 μmol), NaOMe (88 pl, 21 % purity, 240 μmol), and EtOH (15 mL) afforded the title compound (120 mg, 95% yield).

[1326] LC-MS (Method 2): Rt= 1.00 min; MS (ESIpos): m / z = 584 [M]+

[1327] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (5.26), 1.162 (3.99), 1.171 (10.22), 1.180 (2.27), 1.189

[1328] (5.26), 1.198 (2.15), 1.246 (3.45), 1.337 (1.24), 1.346 (1.42), 1.354 (1.39), 1.363 (1.29), 1.383 (1.01),

[1329] 1.987 (16.00), 2.518 (1.04), 2.522 (0.64), 3.998 (1.21), 4.016 (3.60), 4.034 (3.49), 4.052 (1.10), 7.288

[1330] (0.58), 7.489 (0.40), 7.500 (0.57), 7.516 (0.46), 8.548 (0.65), 8.981 (0.44), 8.987 (0.43).

[1331] Intermediate 159

[1332] 2-(4- { 2-[(lR)- 1 -aminoethyl] -6-(trifluoromethyl)phenoxy }butan-2-yl)-6-bromopyrido[2,3-d]pyrimidin-

[1333] 4(3H)-one — hydrogen chloride (1 / 1)

[1334] General procedure F used.

[1335] Tert-butyl [( 1R)- 1 - { 2-[3-(6-bromo-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)butoxy] -3-

[1336] (trifluoromethyl)phenyl}ethyl]carbamate (120 mg, 205 μmol), HC1 in 1,4-dioxane (510 pl, 4.0 M, 2.0 mmol), and EtOH (4.0 mL) afforded the title compound (110 mg, quantitative yield).

[1337] LC-MS (Method 1): Rt= 0.85 min; MS (ESIpos): m / z = 484 [M]+1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.033 (7.39), 1.050 (16.00), 1.068 (8.40), 1.345 (1.11), 1.348 (1.18), 1.363 (1.16), 1.365 (1.15), 1.479 (0.75), 1.490 (0.92), 1.496 (0.89), 1.506 (0.79), 2.518 (0.60), 3.409 (2.71), 3.426 (7.00), 3.444 (8.25), 3.461 (2.39), 4.154 (1.70), 7.442 (0.51), 7.673 (0.45), 8.541 (0.56), 8.587 (0.96), 8.590 (1.03), 8.593 (0.92), 8.597 (0.81), 9.002 (1.32), 9.008 (1.28).

[1338] Intermediate 160

[1339] (7RS,15R)-2-bromo-7,15-dimethyl-ll-(trifluoromethyl)-8,9,15,16-tetrahydro-7H-6,17-

[1340] (azeno)pyrido[2,3-g][l,6,10]benzoxadiazacyclotridecine

[1341] General procedure G used.

[1342] 2-[(2RS)-4- { 2-[(lR)- 1 -Aminoethyl] -6-(trifluoromethyl)phenoxy }butan-2-yl] -6-bromopyrido[2,3- d]pyrimidin-4(3H)-one — hydrogen chloride (1 / 1) (110 mg, 211 μmol), BOP (186 mg, 422 μmol), DBU (130 pl, 840 μmol), DIPEA (92 pl, 530 μmol), and DMF (5.0 mL) afforded the title compound (50.0 mg, 50% yield).

[1343] LC-MS (Method 2): Rt= 1.37 min; MS (ESIpos): m / z = 466 [M+H]+

[1344] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (4.15), 1.171 (8.61), 1.189 (4.37), 1.241 (5.57), 1.259

[1345] (5.86), 1.300 (6.39), 1.318 (6.50), 1.550 (8.32), 1.568 (8.60), 1.906 (0.43), 1.923 (0.41), 1.941 (0.44),

[1346] 1.987 (16.00), 2.104 (0.42), 2.117 (0.55), 2.125 (0.56), 2.139 (0.52), 2.146 (0.45), 2.396 (0.87), 2.432

[1347] (1.16), 2.522 (3.77), 2.895 (0.46), 2.902 (0.55), 2.913 (0.57), 2.922 (0.71), 2.942 (0.52), 3.068 (0.46),

[1348] 3.076 (0.49), 3.086 (0.67), 3.094 (0.66), 3.103 (0.49), 3.862 (0.48), 3.998 (1.25), 4.016 (3.68), 4.034 (3.61), 4.052 (1.18), 4.865 (0.52), 4.889 (1.02), 4.910 (0.93), 5.986 (0.48), 6.003 (0.66), 6.020 (0.46), 6.242 (0.84), 6.260 (1.26), 6.278 (0.80), 7.250 (1.49), 7.270 (3.20), 7.289 (1.79), 7.515 (2.98), 7.519 (3.25), 7.535 (2.71), 7.539 (2.63), 7.743 (1.30), 7.760 (1.22), 7.782 (1.56), 7.799 (1.42), 8.971 (2.60), 8.977 (6.80), 8.980 (9.09), 8.983 (9.37), 8.990 (2.96), 9.141 (1.25), 9.157 (1.22), 9.186 (1.54), 9.203 (1.52).

[1349] Intermediate 161 tert-butyl { ( 1 R) - 1 - [2 - { 4 - [ (5 -bromo-3 -carbamoyl-6-methylpyridin-2-yl)amino] -4-oxobutoxy } -3 - (trifluoromethyl)phenyl] ethyl } carbamate

[1350] General procedure C used. 4-[2-{(lR)-l-[(Tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)phenoxy]butanoic acid (200 mg, 511 μmol), 2-amino-5-bromo-6-methylpyridine-3-carboxamide (141 mg, 613 μmol), TCFH (430 mg, 1.53 mmol), NMI (120 pl, 1.5 mmol), and DMA (2.0 mL) afforded the title compound 190 mg, 62% yield).

[1351] LC-MS (Method 2): Rt= 1.31 min; MS (ESIpos): m / z = 603 [M+H]+1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (0.84), 1.173 (1.02), 1.191 (1.26), 1.209 (0.99), 1.250

[1352] (16.00), 1.275 (3.03), 1.326 (1.87), 1.340 (4.23), 1.354 (7.54), 1.427 (0.52), 1.479 (0.45), 1.907 (2.04), 1.979 (0.59), 1.998 (0.69), 2.014 (0.57), 2.031 (0.44), 2.247 (0.63), 2.263 (1.01), 2.280 (0.99), 2.295 (0.57), 2.404 (0.91), 2.421 (0.97), 2.430 (0.48), 2.443 (1.10), 2.461 (0.63), 2.518 (1.42), 2.523 (1.00), 2.708 (11.81), 2.945 (0.84), 2.962 (1.51), 2.979 (0.73), 3.801 (0.47), 3.864 (0.42), 3.975 (0.67), 3.982 (0.55), 3.997 (0.75), 4.250 (0.43), 4.937 (0.59), 4.953 (0.80), 4.973 (0.57), 5.758 (1.58), 7.306 (0.95),

[1353] 7.325 (2.10), 7.344 (1.26), 7.534 (2.70), 7.554 (2.51), 7.700 (1.41), 7.719 (1.24), 8.213 (0.44), 8.592 (2.54).

[1354] Intermediate 162 tert-butyl [( 1 R)- 1 - { 2- [3 -(6-bromo-7 -methyl-4-oxo-3 ,4-dihydropyrido[2,3-d]pyrimidin-2-yl)propoxy] -3- (trifluoromethyl)phenyl } ethyl] carbamate

[1355] General procedure D used.

[1356] Tert-butyl { (1R)- 1 - [2- { 4-[(5-bromo-3-carbamoyl-6-methylpyridin-2-yl)amino] -4-oxobutoxy } -3-

[1357] (trifluoromethyl)phenyl] ethyl} carbamate (190 mg, 315 μmol), NaOEt (23.6 mg, 346 μmol), and EtOH (5.4 mL) afforded the title compound (280 mg, quantitative yield).

[1358] LC-MS (Method 2): Rt= 1.03 min; MS (ESIpos): m / z = 587 [M+H]+

[1359] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.078 (0.68), 1.109 (0.68), 1.154 (0.60), 1.172 (1.04), 1.190 (0.80), 1.238 (3.30), 1.259 (13.21), 1.320 (0.64), 1.355 (6.09), 1.469 (0.50), 1.907 (16.00), 1.956 (4.15), 1.987 (1.54), 2.031 (0.56), 2.254 (0.67), 2.273 (1.00), 2.288 (0.81), 2.323 (1.06), 2.327 (1.28), 2.331 (0.85), 2.423 (0.46), 2.518 (4.28), 2.523 (2.82), 2.564 (1.00), 2.575 (1.01), 2.625 (1.87), 2.664 (4.30), 2.674 (1.56), 2.684 (8.82), 2.686 (12.84), 2.729 (3.19), 2.767 (1.70), 2.781 (3.95), 2.829 (2.55), 2.865 (0.50), 2.884 (1.10), 2.903 (1.02), 2.924 (0.46), 2.941 (6.03), 2.980 (3.25), 3.391 (0.47), 3.925 (0.55), 3.946 (0.58), 3.961 (0.43), 4.915 (0.46), 5.759 (1.53), 7.298 (0.78), 7.318 (1.58), 7.337 (0.96), 7.527 (1.93), 7.545 (1.81), 7.673 (0.76), 7.693 (0.92), 8.489 (1.77), 12.622 (0.79).

[1360] Intermediate 163

[1361] 2-(3 - { 2- [( 1 R)- 1 -aminoethyl] -6-(trifluoromethyl)phenoxy }propyl)-6-bromo-7 -methylpyrido[2,3- d]pyrimidin-4(3H)-one

[1362] General procedure E used. Tert-butyl [( 1 R)- 1 - { 2- [3 -(6-bromo-7 -methyl-4-oxo-3 ,4-dihydropyrido[2,3-d]pyrimidin-2-yl)propoxy] -3- (trifluoromethyl)phenyl} ethyl] carbamate (185 mg, 316 μmol), TFA (240 pl, 3.2 mmol), and DCM (2.7 mL) afforded the title compound (155 mg, quantitative yield).

[1363] LC-MS (Method 2): Rt= 0.81 min; MS (ESIpos): m / z = 484 [M+H]+.

[1364] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.797 (0.68), 0.814 (0.75), 0.821 (0.78), 0.904 (0.81), 0.922 (0.44), 1.035 (0.61), 1.052 (1.22), 1.070 (0.75), 1.243 (5.93), 1.259 (5.97), 1.902 (0.71), 2.230 (1.10), 2.247 (1.61), 2.264 (1.13), 2.282 (0.41), 2.518 (3.02), 2.523 (2.07), 2.690 (16.00), 2.834 (1.04), 2.846 (1.41), 2.866 (2.08), 2.883 (1.15), 2.976 (1.32), 3.428 (2.87), 3.445 (2.27), 3.837 (4.60), 3.902 (0.41), 3.920 (5.38), 3.941 (1.08), 3.956 (0.49), 4.028 (0.49), 4.043 (1.06), 4.059 (0.60), 4.066 (0.79), 4.410 (0.40), 4.426 (1.30), 4.443 (1.28), 5.759 (4.40), 6.945 (0.87), 6.966 (0.89), 7.298 (0.76), 7.318 (1.66), 7.338 (0.93), 7.507 (1.37), 7.511 (1.42), 7.526 (1.21), 7.530 (1.12), 7.870 (1.32), 7.887 (1.24), 8.190 (0.91), 8.211 (0.81), 8.499 (6.35).

[1365] Intermediate 164

[1366] (15R)-2-bromo-3,15-dimethyl-l l-(trifluoromethyl)-8,9,15,16-tetrahydro-7H-6,17-(azeno)pyrido[2,3- g] [ 1 ,6, 10]benzoxadiazacyclotridecine

[1367] General procedure G used.

[1368] 2-(3-{2-[(lR)-l-Aminoethyl]-6-(trifluoromethyl)phenoxy}propyl)-6-bromo-7-methylpyrido[2,3- d]pyrimidin-4(3H)-one (208 mg, 429 μmol), BOP (246 mg, 557 μmol), DBU (260 pl, 1.7 mmol), DIPEA (300 pl, 1.7 mmol), and DMF (7.4 mL) afforded the title compound (113 mg, 56% yield).

[1369] LC-MS (Method 2): Rt= 1.31 min; MS (ESIpos): m / z = 468 [M+H]+

[1370] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.154 (1.56), 1.172 (3.32), 1.189 (1.64), 1.230 (0.43), 1.530 (4.44), 1.548 (4.34), 1.907 (0.68), 1.987 (5.72), 2.323 (0.44), 2.327 (0.62), 2.331 (0.46), 2.386 (0.45), 2.518 (1.80), 2.523 (1.19), 2.670 (14.20), 2.704 (1.06), 2.727 (12.84), 2.729 (12.25), 2.768 (0.55), 2.786 (0.57), 2.794 (0.72), 2.814 (0.49), 2.888 (16.00), 2.899 (0.75), 2.906 (0.60), 2.913 (0.48), 3.542 (0.52), 3.567 (0.48), 3.999 (0.46), 4.016 (1.29), 4.034 (1.22), 4.939 (0.59), 5.759 (8.46), 6.049 (0.52), 6.066 (0.76), 6.084 (0.52), 7.235 (0.64), 7.255 (1.37), 7.274 (0.76), 7.513 (1.24), 7.517 (1.34), 7.533 (1.12), 7.537 (1.10), 7.736 (1.10), 7.740 (1.11), 7.756 (1.06), 7.950 (2.00), 8.959 (4.74), 9.176 (0.64), 9.194

[1371] (0.55).

[1372] Intermediate 165 tert-butyl { (1R)- 1 - [2- { 4-[(5-bromo-3-carbamoyl-6-methoxypyridin-2-yl)amino] -4-oxobutoxy } -3- (trifluoromethyl)phenyl] ethyl } carbamate

[1373] General procedure C used.

[1374] 4- [2- { ( 1 R)- 1 - [(Tert -butoxycarbonyl) amino] ethyl } -6-(trifluoromethyl)phenoxy]butanoic acid (500 mg, 1.28 mmol), 2-amino-5-bromo-6-methoxypyridine-3-carboxamide (377 mg, 1.53 mmol), TCFH (1.08 g, 3.83 mmol), NMI (310 pl, 3.8 mmol), and DMA (8.3 mL) afforded the title compound (740 mg, 94% yield).

[1375] LC-MS (Method 2): Rt= 1.36 min; MS (ESIpos): m / z = 619.6 [M+H]+.

[1376] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 0.797 (0.68), 0.814 (0.75), 0.821 (0.78), 0.904 (0.81), 0.922 (0.44), 1.035 (0.61), 1.052 (1.22), 1.070 (0.75), 1.243 (5.93), 1.259 (5.97), 1.902 (0.71), 2.230 (1.10), 2.247 (1.61), 2.264 (1.13), 2.282 (0.41), 2.518 (3.02), 2.523 (2.07), 2.690 (16.00), 2.834 (1.04), 2.846 (1.41), 2.866 (2.08), 2.883 (1.15), 2.976 (1.32), 3.428 (2.87), 3.445 (2.27), 3.837 (4.60), 3.902 (0.41), 3.920 (5.38), 3.941 (1.08), 3.956 (0.49), 4.028 (0.49), 4.043 (1.06), 4.059 (0.60), 4.066 (0.79), 4.410 (0.40), 4.426 (1.30), 4.443 (1.28), 5.759 (4.40), 6.945 (0.87), 6.966 (0.89), 7.298 (0.76), 7.318 (1.66), 7.338 (0.93), 7.507 (1.37), 7.511 (1.42), 7.526 (1.21), 7.530 (1.12), 7.870 (1.32), 7.887 (1.24), 8.190 (0.91), 8.211 (0.81), 8.499 (6.35).

[1377] Intermediate 166 tert-butyl [( 1 R)- 1 - { 2- [3 -(6-bromo-7 -methoxy-4-oxo-3 ,4-dihydropyrido[2,3-d]pyrimidin-2-yl)propoxy] -

[1378] 3-(trifluoromethyl)phenyl}ethyl]carbamate

[1379] General procedure D used.

[1380] T ert-butyl { ( 1 R) - 1 - [2 - { 4 - [ (5 -bromo-3 -carbamoyl-6-methoxypyridin-2-yl)amino] -4-oxobutoxy } -3-

[1381] (trifluoromethyl)phenyl] ethyl} carbamate (740 mg, 1.19 mmol), NaOEt (89.4 mg, 1.31 mmol), and EtOH (18 mL) afforded the title compound (730 mg, quantitative yield).

[1382] LC-MS (Method 2): Rt= 1.14 min; MS (ESIpos): m / z = 601.6 [M+H]+.

[1383] 1H-NMR (400 MHz, DMSO-d6) • [ppm]: 1.052 (0.72), 1.069 (0.55), 1.097 (0.49), 1.171 (0.78), 1.189 (0.56), 1.261 (11.00), 1.322 (1.09), 1.354 (1.51), 1.907 (2.52), 1.955 (3.38), 1.987 (1.36), 2.268 (0.66), 2...

Claims

CLAIMS1. A compound of general formula (I)in whichX represents C-R3or N;Y represents C-R3or N; wherein X and Y are both independently from each other C-R3or one of X and Y is N and the other one of X and Y is C-R3;R1represents C1-6-alkyl or C3-6-cycloalkyl wherein in both one carbon atom can be replaced by an oxygen or N-CH3, N-CH2-CH3, N-CH2-CH2-CH3,N-CH(CH3)2, or N-C(O)-CH3, except for the carbon atoms in the C3-6- cycloalkyl residue that are directly attached to the aromatic bicyclus and wherein epoxides and aziridines are excluded; or-Cl, -Br;C1 -3alkyl substituted with at least one or more -F; or-N(R7)2, wherein both R7can be selected independently from each other and wherein only one R7can be C3-6cycloalkyl as defined below for R7; orare independently from each other -H,-CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); oror wherein each ring carbon atom can optionally be substituted with1 or 2 -CHi, -F or -OH, or a mixture thereof; or; orRdrepresents -CH3, -CH2-CH3, -CH(CH3) orR2represents -H; C1-4 alkyl optionally substituted with -F and / or -OH wherein -F and -OHare not bound to the same carbon atom; ; -O-C1-4optionally substituted with -F; -CN or halogen;R3represents -H, -F, -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, -O-CH3orR4represents -H, -Cl, -F, -CH3, -CH2-CH3, -NH2, wherein the residues containing a carbon atom can optionally be substituted with one or more -F;R5represents -CH3, -CH2F, -CHF2, -CH2-CH3or -C« CH;R6represents -H, -CH3, -CH2-CH3, -CH(CH3)2or , -C(O)-CH3,-C(O)-OC(CH3)3, optionally substituted with -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;R7represents-H;C1-3alkyl optionally substituted with 1 or more -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom; or C3-6cycloalkyl, in which one carbon atom can be optionally replaced by an oxygen atom, wherein epoxides and residues that generate -N-C-O- motifs are excluded; orA moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or - O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;R8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2,R9represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F, under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;Rl° represents -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F;L represents, whereinX’ is selected from -C(Ra)(Ra)-, -O-, -C(O)-, -N(R8)-, -S-, -S(O)- or -S(O)2-;Y’ is selected from -C(Ra)(Ra)-, -C(O)-;Z’ is selected from -C(Ra)(Ra)-, -O-, -N(R8)-;Rais selected independently from each other from -H, -F, -CH3,-CHF2or -CF3with the condition that a maximum of four Raare not -H; orRais when two Rathat are bound to the same or to two neighboring atom(s) form a 3 to 5 membered ring, wherein the 3 to 5 membered ring can be substituted with 1 or more -F and wherein L can comprise only one 3 to 5 membered ring; wherein X’, Y’ and Z’ are selected in the way that L does not contain more than one - sulfur atom or -C(O)- and none of the following structures are present -O-O-, -O-N-, -N- N-, -O-CH2-N-, -N-CH2-N-, -O-CH2-O-, -C(O)-S-, -C(O)-NH-S-, -O-S(O)2-; or, wherein the double bond between X’ ’ andX’ ’ can be in E or Z configuration andX” represents -CRaa;Y” represents -C(Rab)(Rab);Z”represents -O-, -N(R6)- or -CH2-;Raarepresents -H, -CH3;Rabrepresents independently from each other -H, -F, -CH3, -CHF2,-CF3or , or in which both Rabtogether with the carbon atom they are attached to form a three membered ring, wherein when Z” is -O- or -N(R6)- residue Rabis not -F;R11and R12independently from each other represent Ci-4-alkyl, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH2(CH3)2, or -N(R8)(R8); orR11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13), S(O)2and in which each remaining carbon atom in the 4 to 6 membered heterocycloalkyl residue can optionally be substituted by 1 or 2 -CH3, or by 1 -CH2-CH3; or a 5 to 6 membered heterocycloalkenyl;R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2,-C(O)-CH3, -C(O)-OC(CH3)3, -S(O)2-CH3,T represents O or N(R6);U represents CH2, O, S or N(R6);V represents C=O or S(O)2;W represents CH2, O or N(R13); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. Compound according to claim 1 , characterized in thatX represents C-R3or N;Y represents C-R3or N; wherein X and Y are both independently from each other C-R3or one of X and Y is N and the other one of X and Y is C-R3;R1represents -Cl, -Br; or-OH, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH(CH3)2,C1-3alkyl substituted with at least one or more -F; or-N(R7)2, wherein both R7can be selected independently from each other and wherein only one R7can be C3-6cycloalkyl as defined below for R7; orare independently from each other -H, -CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); oror , or , wherein each ring carbon atom can optionally be substituted with 1 or 2 -CH3, -F or -OH, or a mixture thereof; oror ; orOwherein Rdrepresents -CH3, -CH2-CH3, -CH(CH3)2orR2represents H; C1-4alkyl optionally substituted with -F and / or -OH wherein -F and -OHare not bound to the same carbon atom; ; -O-C1-4optionally substituted with -F; -CN or halogen;R3represents -H, -F, -CH3, -CF2H, -CH2-CH3, -CH(CH3)2, or ;R4represents -H, -Cl, -F, -CH3, -NH2, wherein the residues containing a carbon atom can optionally be substituted with one or more -F;R5represents -CH3, -CH2F, -CHF2, -CH2-CH3or -C« CH;R6represents -H, -CH3, -CH2-CH3, -CH(CH3)2, , -C(O)-CH3,-C(O)-OC(CH3)3;R7represents a moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or -O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;R8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, ;R9represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F, under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;R10represents -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F;L represents, whereinX’ is selected from -C(Ra)(Ra)-, -O-, -C(O)-, -N(R8)-, -S-, -S(O)- or -S(O)2-;Y’ is selected from -C(Ra)(Ra)-, -C(O)-;Z’ is selected from -C(Ra)(Ra)-, -O-, -N(R8)-;Rais selected independently from each other from -H, -F, -CH3, -CHF2or -CF3with the condition that a maximum of four Raare not -H; orRais when two Rathat are bound to the same or to two neighboring atom(s) form a 3 to 6 membered ring, wherein the 3 to 6 membered ring can be substituted with 1 or more -F and wherein L can comprise only one 3 to 6 membered ring; wherein X’, Y’ and Z’ are selected in the way that L does not contain more than one sulfur atom or -C(O)- and none of the following structures are present -O-O-, -O-N-, -N- N-, -O-CH2-N-, -N-CH2-N-, -O-CH2-O- or-C(O)-S-, -C(O)-NH-S-, -O-S(O)2-; or, wherein the double bond between X’ ’ andX’ ’ can be in E or Z configuration andX” represents -CRaa;Y” represents -C(Rab)(Rab);Z”represents -O-, -N(R6)- or -CH2-;Raarepresents -H, -CH3;Rabrepresents independently from each other -H, -F, -CH3, -CHF2,-CF3or or in which both Rabtogether with the carbon atom they are attached to form a three membered ring, wherein when Z” is -O- or -N(R6)- residue Rabis not -F;R11and R12independently from each other represent Ci 4-alkyl; orR11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13), S(O)2and in which each remaining carbon atom in the 4 to 6 membered heterocycloalkyl residue can optionally be substituted by 1 or 2 -CH3; or a 5 membered heterocycloalkenyl;R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2,-C(O)-CH3, -C(O)-OC(CH3)3, -S(O)2-CH3, ;T represents O or N(R6);U represents CH2, O, S or N(R6);V represents C=O, S(O)2;W represents O or N(R13); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. Compound according to claims 1 or 2, characterized in thatX represents C-R3or N;Y represents C-R3or N; wherein X and Y are both independently from each other C-R3or one of X and Y is N and the other one of X and Y is C-R3;-N(R7)2, wherein both R7can be selected independently from each other and whereinonly one R7can be C3-6cycloalkyl as defined below for R7; orare independently from each other -H,-CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); or, wherein each ring carbon atom can optionally be substituted with 1 or2 -CH3, -F or -OH, or a mixture thereof; or, wherein Rdrepresents -CH3;R2represents -H; C1-4 alkyl optionally substituted with -F and / or -OH wherein -F and -OHare not bound to the same carbon atom; ; -O-C1-4optionally substituted with -F; -CN or halogen;R3represents -H, -F, -CH3, -CF2H, -CH2-CH3, or ;R4represents -H, -Cl, -F, -CH3, wherein the residues containing a carbon atom can optionally be substituted with one or more -F;R5represents -CH3, -CHF2or -C• CH;R7represents a moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or -O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;R8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2,L represents, whereinX’ is selected from -C(Ra)(Ra)-, -O-, -C(O)-, -N(R8)-, -S-, -S(O)- or -S(O)2-;Y’ is selected from -C(Ra)(Ra)-, -C(O)-;Z’ is selected from -C(Ra)(Ra)-, -O-, -N(R8)-;Rais selected independently from each other from -H, -F, -CH3, -CHF2or -CF3with the condition that a maximum of four Raare not -H; orRais when two Rathat are bound to the same or to two neighboring atom(s) form a 3 to 4 membered ring, wherein the 3 to 4 membered ring can be substituted with 1 or more -F and wherein L can comprise only one 3 to 4 membered ring;wherein X’, Y’ and Z’ are selected in the way that E does not contain more than one - sulfur atom or -C(O)- and none of the following structures are present -O-O-, -O-N-, -N- N-, -O-CH2-N-, -N-CH2-N-, -O-CH2-O-, -C(O)-S-, -C(O)-NH-S-, -O-S(O)2-, -O-C(O)-; or, wherein the double bond between X’ ’ andX’ ’ can be in E or Z configuration andX” represents -CRaa;Y” represents -C(Rab)(Rab);Z''represents -O-, -N(R6)- or -CH2-;Raarepresents -H, -CH3;Rabrepresents independently from each other -H, -F, -CH3, -CHF2,-CF3 or , or in which both Rabtogether with the carbon atom they are attached to form a three membered ring, wherein when Z” is -O- or -N(R6)- residue Rabis not -F;R11and R12independently from each other represent C1-3-alkyl; orR11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O or N(R13);R13represents -H, -CH3, -CH2CH3, -CH(CH3)2, -C(O)-CH3,T represents O;U represents CH2, O or N-CH3;V represents C=O, S(O)2;W represents O or N(R13); or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. Compound according to claim 1 in whichR1represents C1-6-alkyl or C3-6-cycloalkyl wherein in both one carbon atom can be replaced by an oxygen or N-CH3, N-CH2-CH3, N-CH2-CH2-CH3,N-CH(CH3)2, or N-C(O)-CH3, except for the carbon atoms in the C3-6- cycloalkyl residue that are directly attached to the aromatic bicycle and wherein epoxides and aziridines are excluded; or- Cl, -Br; or-OH, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH(CH3)2, , preferably-O-CH3, -O-CH2-CH3, -O-CH(CH3)2,C1-3alkyl substituted with at least one or more F.

5. Compound according to claim 1 in whichR1represents -N(R7)2, wherein both R7can be selected independently from each other and wherein only one R7can be C3-6cycloalkyl as defined below for R7; orare independently from each other -H, -CH3and / or one Rbtogether with one Rcforms a bridge with 1 or 2 carbon atom(s); oror ; oror or wherein each ring carbon atom can optionally be substituted with1 or 2 -CH3, -F or -OH or a mixture thereof; orR6represents -H, -CH3, -CH2-CH3, -CH(CH3)2, , -C(O)-CH3or-C(O)-O(CH3)3, optionally substituted with -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;R7representsC1-3alkyl optionally substituted with 1 or more -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom; or C3-6cycloalkyl, in which one carbon atom can be optionally replaced by an oxygen atom, wherein epoxides and residues that generate -N-C-O- motifs are excluded; or a moiety in which both R7together with the nitrogen atom they are attached to form a 4 to 6 membered ring, wherein the ring is optionally substituted with one or more -F or - O-CH3, under the condition that the substituents are not bound to a ring carbon atom directly next to the ring nitrogen atom;R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(O)-CH3,-C(O)-O(CH3)3, -S(O)2-CH3,, preferably -H, -CH3, -CH2CH3,-CH(CH3)2, -C(O)-CH3,represents CH2, O, S or N(R6); represents C=O or S(O)2;W represents CH2, O or N(R13), preferably O or N(R13).

6. Compound according to claim 1 in whichR1representsR13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(O)-CH3,-C(O)-O(CH3)3, -S(O)2-CH3, , preferably -H, -CH3, -CH2CH3,-CH(CH3)2, -C(O)-CH3,W represents CH2, O or N(R13), preferably O or N(R13).

7. Compound according to claim 1 in whichR1represents; andR8represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2,R11and R12independently from each other represent C1-4-alkyl, -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -O-CH2(CH3)2, or -N(R8)(R8), preferably C1-3- alkyl; orR11and R12together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13), S(O)2and in which each remaining carbon atom in the 4 to 6 membered heterocycloalkyl residue can optionally be substituted by 1 or 2 -CH3, or by 1 -CH2-CH3, preferably together with the phosphor atom they are attached to form a 4 to 6 membered heterocycloalkyl in which the carbon atom opposite to the phosphor atom of a 6 membered ring can be replaced by O, N(R13); or a 5 to 6 membered heterocycloalkenyl;R13represents -H, -CH3, -CH2CH3, -CH2-CH2-CH3, -CH(CH3)2,-C(O)-CH3, -C(O)-O(CH3)3, -S(O)2-CH3, , preferably -H,-CH3, -CH2CH3, -CH(CH3)2, -C(O)-CH3,8. Compound according to claim 1 in whichR1representsR9represents -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F, under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;R10represents -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, , optionally substituted with -F;V represents C=O or S(O)2and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof and mixtures of same.

9. Compound according to claim 1 in whichR1represents Rdrepresents -CH3, -CH2-CH3, -CH(CH3)2or, preferably -CH3;R6represents -H, -CH3, -CH2-CH3, -CH(CH3)2, , -C(O)-CH3or-C(O)-O(CH3)3optionally substituted with -F under the condition that -F is not bound to a carbon atom that is directly next to a nitrogen atom;T represents O or N(R6) and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

10. Compound according to claims 1 to 9 in whichX represents C-R3;Y represents C-R3; andR3represents -H, -F, -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, -O-CH3orpreferably -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

11. Compound according to claims 1 to 9 in whichX represents N;Y represents C-R3; andR3represents -H, -F, -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, -O-CH3or, preferably -CH3, -CF3, -CF2H, -CH2-CH3, -CH(CH3)2, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

12. A compound of general formula (I) according to any one of claims 1 to 11 for use in the treatment or prophylaxis of a disease.

13. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 11 and one or more pharmaceutically acceptable excipients.

14. Use of a compound of general formula (I) according to any one of claims 1 to 11 for the treatment or prophylaxis of a disease.

15. Use of a compound of general formula (I) according to any one of claims 1 to 11 for the preparation of a medicament.

16. Use according to claim 12, 14 or 15, wherein the disease is a hyperproliferative or genetic disorder, such as cancer, for example.

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