WO2018024602A1 - 2,7-diazaspiro[4.4]nonanes - Google Patents

2,7-diazaspiro[4.4]nonanes Download PDF

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WO2018024602A1
WO2018024602A1 PCT/EP2017/069022 EP2017069022W WO2018024602A1 WO 2018024602 A1 WO2018024602 A1 WO 2018024602A1 EP 2017069022 W EP2017069022 W EP 2017069022W WO 2018024602 A1 WO2018024602 A1 WO 2018024602A1
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yl
methyl
diazaspiro
non
trifluoroethyl
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PCT/EP2017/069022
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French (fr)
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Stephan Siegel
Bernard Haendler
Carlo STRESEMANN
Amaury Ernesto FERNANDEZ-MONTALVAN
Antonius Ter Laak
Detlef STÖCKIGT
Hassan Youssef HARB
Dirk Kosemund
Ashley EHEIM
Ursula MÖNNING
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Bayer Aktiengesellschaft
Bayer Pharma Aktiengesellschaft
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention covers 2,7-diazaspiro[4.4]nonane compounds of general formula (I): in which n, X, R2, R3, R4, R5, R6a and R6b are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or diabetes, as a sole agent or in combination with other active ingredients.

Description

2,7-DIAZASPIRO[4.4]NONANES

The present invention covers 2,7-diazaspiro[4.4]nonane compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular cancer, as a sole agent or in combination with other active ingredients.

BACKGROUND

The present invention covers 2,7-diazaspiro[4.4]nonane compounds of general formula (I) which inhibit the interaction between menin and MLL-1 .

The mixed lineage leukemia (MLL) protein complex is the oncogenic driver of a subgroup of leukemias characterized by the fusion of MLL proteins, mainly MLL-1 , to different partners at their N- or C-terminal end. Translocation events leading to the fusion of the N-terminal moiety of MLL proteins with one of more than 80 different partners including AF4, AF9 and ENL have frequently been described (R. Marschalek, Arch. Pharm. 2015, 348:221-228). These fusion proteins interact with various nuclear factors and the resulting complexes will bind to promoters to stimulate aberrant gene expression. The oncogenic function of MLL-fused proteins is critically dependent on the interaction with a protein partner named menin (A . Thiel et al., Bioessays 2012, 34:771-780). This takes place via the MLL N-terminal region which is conserved in all translocations, and where two menin-binding motifs, MBM1 and MBM2, with high and low affinity respectively, have been identified (J. Grembecka et al., J. Biol. Chem. 2010, 285:40690-40698; A. Shi et al., Blood 2012, 120:4461-4469). They interact with a large central cavity of about 5000 A3 found in menin (M.J. Murai et al., J. Biol. Chem., 201 1 , 286:31742-31748). This interaction is necessary for downstream expression of genes essential for leukemia transformation such as several members of the HOX cluster.

Menin is also involved in breast cancer. It directly binds to the estrogen receptor (ER) in a hormone-dependent way to promote MLL recruitment, stimulate H3K4 methylation and control the expression of estrogen target genes (K.M.A. Dreijerink et al., Cancer Res. 2006, 66:4429- 4435; H. Imachi et al., Breast Cancer Res. Treat. 2010, 122:395-407). Silencing of MLL-1 or treatment with a menin inhibitor dramatically reduces proliferation of breast cancer cell lines with a gain-of-function mutation in the p53 tumor suppressor (J. Zhu et al., Nature 2015, 525:206-21 1 ). This is possibly due to the impact of the p53 mutation on the expression of MLL and of MOZ, which leads to increase of global H3K9 acetylation. In line with these results, high menin expression is linked with poor outcome in ER-positive breast cancer patients (H. Imachi et al., Breast Cancer Res. Treat. 2010, 122:395-407). Menin is also implicated in prostate cancer and directly interacts with the androgen receptor (AR) N-terminal domain (R. Malik et al., Nat Medicine, 2015, 21 :344-352). It is essential for AR signalling and acts as a co-regulator of a number of androgen target genes. Inhibition of menin impairs the AR pathway and reduces the proliferation of prostate cancer models, both in vitro and in vivo, probably due to the disruption of the menin-MLL-1 interaction. Also, high menin expression at the RNA and protein levels is associated with reduced survival in prostate cancer patients (R. Malik et al., Nat. Medicine, 2015, 21 :344-352).

Another tumor indication where menin is involved is hepatocellular carcinoma where it is expressed at high levels and regulates the transcription of several genes involved in this disease (B. Xu et al., Proc. Natl. Acad. Sci. USA 2013, 1 10:17480-17485). Finally, a chemical screen with a cell line model of pediatric glioma harboring a mutation in the H3.3 histone at position K27 identified a menin inhibitor as the compound with the strongest anti-proliferative activity (K. Fumato et al., Science 2014, 346:1529-1533).

Menin mutations have been identified in patients with multiple endocrine neoplasia type 1 , leading to the development of tumors in two or more of the body's hormone-producing glands including insulinoma, parathyroid tumor and pituitary tumors (T. Tsukada et al., Cancer Science 2009, 100(2):209-15). Based on the exploration of the menin protein function in endocrine tissues, inhibition of the menin MLL1 interaction is postulated as a therapeutic target for diabetes (X.Wu et al., Curr. Mol. Med. 2008, 8(8):805-1 ). Menin protein negatively regulates pancreatic β-cell proliferation in several preclinical disease models, including pregnancy and obesity (S.K. Agarwal et al., Ann. N Y Acad. Sci. 2004,1014: 189-198). In pregnant mice menin levels are reduced in pancreatic islet β-cells which stimulates β-cell proliferation and insulin production. Moreover, transgenic expression of menin in maternal β-cells prevents islet expansion and leads to hyperglycemia and impaired glucose tolerance, hallmark features of gestational diabetes (S. K. Karnik et al., Science. 2007,318(5851 ):806-9). Furthermore, genetic deletion of the menin gene stimulates beta cell regeneration and reverses established hyperglycemia in diabetic mice by up-regulating multiple proproliferative cell cycle genes (Y. Yang et al., Proc. Natl. Acad. Sci. USA 2010, 107(47): 20358-63).

Altogether these data indicate menin to be an important coactivator for different transcription factors and enzymes involved in chromatin modulation. Its function is deregulated in a number of tumor types, making it an attractive target for cancer treatment as well as other diseases where menin interacts with disease associated transcription factors.

First small molecule inhibitors which inhibit the interaction of menin with fused MLL proteins have recently been described. They obviate the oncogenic function of MLL fusion proteins by impairing the expression of a number of downstream target genes involved in the transformation process, and prevent the proliferation and differentiation of leukemias carrying an MLL translocation. Thienopyrimidines were the first menin inhibitors described and their cellular activity was shown in different MLL-fused leukemia models (A. Shi et al., Blood 2012, 120:4461-4469; J. Grembecka et al., Nat. Chem. Biol. 2012, 8:277-284). Subsequently hydroxy- and aminomethylpiperidine inhibitors were described (S. He et al., J. Med. Chem. 2014, 57:1543-1556). They prevent the interaction between menin and MLL-1 and inhibit the growth of different AML cell lines with fused MLL. New thienopyrimidine derivatives containing an aminopiperidine linker were more recently described (D. Borkin et al., Cancer Cell 2015, 27:589-602; D. Borkin et al., J. Med. Chem. 2016, 59:892-913). They show anti-proliferative activity in AML cell lines with fused MLL and in vivo efficacy in xenograft models.

Inhibitors of the interaction between menin and MLL-1 are described in WO 201 1/029054, US 2014/0275070, US 2014/0371239, WO 2014/164543, WO 2014/200479 and WO 2015/191701.

WO 2005/1 10410 relates to compounds as kinase inhibitors.

EP 1683797 relates to heterocyclic spiro compounds useful for the prevention and/or treatment of disease caused by stress.

However, the state of the art does not describe:

• the 2,7-diazaspiro[4.4]nonane compounds of general formula (I) of the present invention as described and defined herein, i.e. compounds having a 2,7-diazaspiro[4.4]nonane core bearing:

• in its N1-position, a thieno[2,3-d]pyrimidine-4-yl, a pyrrolo[2, 1-f][1 ,2,4]triazine-4-yl or a 2H-pyrazolo[3,4-d]pyrimidine-4-yl moiety and

• in its N2-position, a benzyl or phenethyl moiety

or stereoisomers, tautomers, N-oxides, hydrates, solvates, salts thereof, or mixtures of same, as described and defined herein, and as hereinafter referred to as "compounds of general formula (I)" or "compounds of the present invention",

• or their pharmacological activity.

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.

In particular, the compounds of the present invention have surprisingly been found to effectively inhibit the interaction between menin and MLL-1 for which data are given in biological experimental section and may therefore be used for the treatment or prophylaxis of menin related disorders such as hyperproliferative disorders, conditions and diseases, in particular leukemia, especially acute myeloid leukemia including those harboring an MLL fusion, and breast and prostate cancer, and hepatocellular carcinoma, or diabetes for example.

DESCRIPTION of the INVENTION In accordance with a first aspect, the present invention covers compounds of general formula (I):

Figure imgf000005_0001

(I)

re resents a group selected from

Figure imgf000005_0002

Figure imgf000005_0003

or

wherein * indicates the point of attachment of said group with the rest of the molecule;

R1 represents hydrogen or methyl;

R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;

R3 represents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group

Figure imgf000005_0004

wherein * indicates the point of attachment of said group with the rest of the molecule;

R4 represents hydrogen, hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, C1-C3- alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-Ci-C3-alkyl, -0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-R9,

-C(CH3)2-R9 or 1-R9-cyclopropyl,

wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C4-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy;

R5 represents hydrogen, methyl or chloro; or

R4 and R5 together form an anellated phenyl ring;

R6a, R6b represent, independently from each other, hydrogen or methyl;

R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(CO)-C2-C3-alkenyl, -(S02)-Ci-C3-alkyl or

-(S02)-phenyl,

wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy, or

R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups;

R9 represents cyano, -COOH, -(CO)-0-Ci-C3-alkyl, -(S02)-Ci-C3-alkyl, -NR7R8, -CONR7R8 or -S02NR7R8;

R10 represents Ci-C4-alkyl, Ci-C4-haloalkyl, methoxy-Ci-C3-alkyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl, S-methylsulfonimidoyl-methyl, -CH2-C02R11 or -CH2-CONR12R13;

R11 represents Ci-C4-alkyl;

R12, R13 represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, CrC4-haloalkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl,

-(S02)-Ci-C3-alkyl, -(S02)-phenyl,

wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl,

Ci-C3-alkoxy or Ci-C3-haloalkoxy, or

together with the nitrogen atom to which they are attached form a

4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a C1-C4- alkyl or Ci-C4-haloalkyl group and optionally substituted with an oxo group; R14 represents hydrogen or methyl;

n represents 0 or 1 ;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

DEFINITIONS

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.

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 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.

As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means "1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2".

As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom via a double bond.

Should a composite substituent be composed of more than one parts, e.g. (Ci-C4-alkoxy)-(Ci-C4-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the Ci-C4-alkoxy part can be attached to any carbon atom of the Ci-C4-alkyl part of said (Ci-C4-alkoxy)-(Ci-C4-alkyl)- group. A hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.

The term "ring substituent" means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.

The term "comprising" when used in the specification includes "consisting of.

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. The terms as mentioned in the present text have the following meanings:

The term "halogen atom" means a fluorine, chlorine or bromine atom, particularly a fluorine or chlorine atom.

The term "Ci-C3-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, or 3 carbon atoms, e.g. a methyl, ethyl, propyl or isopropyl. Particularly, said group has 1 or 2 carbon atoms ("Ci-C2-alkyl"), e.g. a methyl or ethyl group.

The term "Ci-C4-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3 or 4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl. Particularly, said group has 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, propyl or isopropyl group, more particularly 1 or 2 carbon atoms ("Ci-C2-alkyl"), e.g. a methyl or ethyl group.

The term "C2-C3-hydroxyalkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 2 or 3 carbon atoms, e.g. a ethyl, propyl or isopropyl, and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a 1-hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl group.

The term "Ci-C3-haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "CrC3-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 Ci-C3-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, hexafluoropropyl, 3,3,3-trifluoropropyl or 1 ,3-difluoropropan-2-yl.

The term "C2-C3-alkenyl" means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2 or 3 carbon atoms. Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-1-yl (or "allyl") or prop-1 -en-1 -yl group. Particularly, said group is vinyl or allyl.

The term "Ci-C3-alkoxy" means a linear or branched, saturated, monovalent group of formula (Ci-C3-alkyl)-0-, in which the term "Ci-C3-alkyl" is as defined supra, e.g. a methoxy, ethoxy, n-propoxy or isopropoxy.

The term "Ci-C3-haloalkoxy" means a linear or branched, saturated, monovalent Ci-C3-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said Ci-C3-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy or trifluoromethoxy.

The term "5-membered heteroaryl" means a monovalent, monocyclic aromatic ring having 5 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).

Said 5-membered heteroaryl group can be, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl.

In general, and unless otherwise mentioned, the heteroaryl 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 thienyl includes thien-2-yl and thien-3-yl.

Particularly, the heteroaryl group is a imidazolyl, triazolyl or oxadiazolyl group.

An oxo substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond.

The term "C1-C3", as used in the present text, e.g. in the context of the definition of "Ci-C3-alkyl", "Ci-C3-haloalkyl", "Ci-C3-alkoxy" or "Ci-C3-haloalkoxy" means an alkyl group having a finite number of carbon atoms of 1 to 3, i.e. 1 , 2 or 3 carbon atoms.

The term "C1-C4", as used in the present text, e.g. in the context of the definition of "Ci-C4-alkyl" or "Ci-C4-haloalkyl" means an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3 or 4 carbon atoms.

Further, as used herein, the term "C2-C4", as used in the present text, e.g. in the context of the definition of "C2-C4-hydroxyalkyl", means a hydroxyalkyl group having a finite number of carbon atoms of 2 to 4, i.e. 2, 3 or 4 carbon atoms.

When a range of values is given, said range encompasses each value and sub-range within said range.

For example:

"C1-C3" encompasses Ci, C2, C3, C1-C3, C1-C2 and C2-C3;

"C1-C4" encompasses Ci, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3 and C3-C4;

"C2-C4" encompasses C2, C3, C4, C2-C4, C2-C3 and C3-C4, ;

As used herein, the term "leaving group" means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-terf-butyl- phenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).

The term "Isotopic variant" of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

The term "Isotopic variant of the compound of general formula (I)" is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

The expression "unnatural proportion" means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1 ), 217-235, 1998.

Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 123l, 124l, 125l, 129l and 1311, respectively.

With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium- containing compounds of general formula (I)"). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3H or 14C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18F or 11C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.

Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D20 can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).

The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound's pharmacokinetic/ pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/1 12363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.

A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.

Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

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.

The compounds of the present invention optionally contain one or more asymmetric centres, 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.

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.

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 purification and the separation of such materials can be accomplished by standard techniques known in the art. 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 crystallisation. 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 derivatisation, optimally chosen to maximise 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 derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

In order to distinguish different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1-30, 1976).

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.

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 oxidised. The present invention includes all such possible N-oxides.

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.

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.

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.

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.

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, 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.

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 aluminium 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, A/-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, A/-methylpiperidine, A/-methyl-glucamine, /V,/V-dimethyl-glucamine, A/-ethyl-glucamine, 1 ,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1 ,3- propanediol, 3-amino-1 ,2-propanediol, 4-amino-1 ,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzy\-N,N,N- trimethylammonium, choline or benzalkonium.

Those skilled in the art will further recognise 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.

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.

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 HCI", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.

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.

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.

Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrugs" here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.

In accordance with a second aspect, the present invention covers compounds of general formula (I):

Figure imgf000015_0001

(I)

in which: X re resents a group selected from:

Figure imgf000016_0001

or

wherein * indicates the point of attachment of said group with the rest of the molecule; represents hydrogen or methyl;

represents hydrogen, fluoro, chloro, hydroxy or methoxy;

re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group

Figure imgf000016_0002

wherein * indicates the point of attachment of said group with the rest of the molecule; R4 represents hydrogen, hydroxy, halogen, cyano, Ci-C3-alkyl, Ci -C3-haloalkyl, C1 -C3- alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-Ci -C3-alkyl, -0-CH2-(CO)-NR7R8, -C H2-R9, -C(CH3)2-R9 or 1-R9-cyclopropyl,

wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano,

Ci-C4-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy;

R5 represents hydrogen, methyl or chloro;

R6a, R6b represent, independently from each other, hydrogen or methyl;

R7, R8 represent, independently from each other, hydrogen, Ci -C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci -C3-alkyl, -(S02)-CrC3-alkyl, -(S02)-phenyl,

wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy, or

R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with an oxo group; R9 represents cyano, -COOH, -(CO)-0-Ci-C3-alkyl, -NR7R8, -CONR7R8 or -S02NR7R8 14 represents hydrogen or methyl;

represents 0 or 1 ;

In accordance with a second embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:

represents a roup selected from

Figure imgf000017_0001

Figure imgf000017_0002

or

wherein * indicates the point of attachment of said group with the rest of the molecule;

R1 represents hydrogen or methyl;

R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;

R3 re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group

Figure imgf000017_0003

wherein * indicates the point of attachment of said group with the rest of the molecule;

R4 represents hydrogen, hydroxy, cyano, Ci-C3-alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-Ci-C3-alkyl,

-0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-S02NH2, -C(CH3)2-CN or 1-cyano-cyclopropyl, wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with cyano, Ci-C4-alkyl or d-Cs-haloalkyl;

R5 represents hydrogen, methyl or chloro; or

R4 and R5 together form an anellated phenyl ring;

R6a, R6b represent, independently from each other, hydrogen or methyl; R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(CO)-CH=CH2, -(S02)-Ci-C3-alkyl or -(S02)- phenyl, or

R7 and R8 together with the nitrogen atom to which they are attached form a 6-membered

nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups;

R9 represents cyano, -COOH, -NR7R8, -CONR7R8, -(S02)-CH3 or -S02NR7R8;

R10 represents C2-C3-alkyl, C2-C3-haloalkyl, methoxy-Ci-C3-alkyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl or -CH2-C02CH3;

R14 represents hydrogen or methyl;

n represents 0 or 1 ;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

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

X re resents a group selected from:

Figure imgf000018_0001

or

wherein * indicates the point of attachment of said group with the rest of the molecule; represents hydrogen or methyl;

represents hydrogen, fluoro, chloro, hydroxy or methoxy; R3 re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group

Figure imgf000019_0001

wherein * indicates the point of attachment of said group with the rest of the molecule;

R4 represents hydrogen, hydroxy, cyano, methoxy, hexafluoropropoxy, -O-phenyl,

imidazolyl, triazolyl, butyl-oxadiazolyl, -NR7R8, -CONH2, -S02NH2, -0-(CO)-CH3,

-0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-S02NH2, -C(CH3)2-CN or 1-cyano-cyclopropyl, wherein said phenyl group is substituted once with cyano and trifluoromethyl; R5 represents hydrogen, methyl or chloro;

R6a, R6b represent, independently from each other, hydrogen or methyl;

R7, R8 represent, independently from each other, hydrogen, methyl, hydroxyethyl,

-(CO)-CH3, -(CO)-CH=CH2, -(S02)-CH3 or -(S02)-phenyl, or

R7 and R8 together with the nitrogen atom to which they are attached form a 6-membered

nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups;

R9 represents cyano, -COOH, tert-butyl-0-C(0)-NH-, -CONH2, -CONHCH3, -CON(CH3)2, -(S02)-CH3 or -S02NH2;

R10 represents ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl,

methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl or -CH2-C02CH3; R14 represents hydrogen;

n represents 0 or 1 ;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In accordance with a fourth embodiment of the first aspect, the present invention covers compounds of general formula (lb),

Figure imgf000020_0001
in which:

R1 represents hydrogen or methyl;

R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;

R3 represents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group

Figure imgf000020_0002

wherein * indicates the point of attachment of said group with the rest of the molecule;

R4 represents hydrogen, hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, C1-C3- alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8,

-S02NR7R8, -0-(CO)-Ci-C3-alkyl, -0-CH2-(CO)-NR7R8, -CH2-R9, -C(CH3)2-R9 or 1-R9-cyclopropyl,

wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C4-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy;

R5 represents hydrogen, methyl or chloro;

R6a, R6b represent, independently from each other, hydrogen or methyl;

R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(S02)-Ci-C3-alkyl or -(S02)-phenyl,

wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy, or

R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with an oxo group; represents cyano, -COOH, -(CO)-0-d-C3-alkyl, -NR7R8, -CONR7R8 or -S02NR7R8; R14 represents hydrogen or methyl;

Z represents difluoromethyl or trifluoromethyl;

n represents 0 or 1 ;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In accordance with a variant of the fourth embodiment of the first aspect, the present invention covers compounds of general formula (lb):

Figure imgf000021_0001

wherein:

R1 represents hydrogen or methyl;

R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;

R3 re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group

Figure imgf000021_0002

wherein * indicates the point of attachment of said group with the rest of the molecule;

R4 represents hydrogen, hydroxy, cyano, methoxy, hexafluoropropoxy, -O-phenyl,

imidazolyl, triazolyl, butyl-oxadiazolyl, -NR7R8, -CONH2, -S02NH2, -0-(CO)-CH3, -0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-S02NH2, -C(CH3)2-CN or 1-cyano-cyclopropyl, wherein said phenyl group is substituted once with cyano and trifluoromethyl; R5 represents hydrogen, methyl or chloro;

R6a, R6b represent, independently from each other, hydrogen or methyl;

R7, R8 represent, independently from each other, hydrogen, methyl, hydroxyethyl,

-(CO)-CH3, -(CO)-CH=CH2, -(S02)-CH3 or -(S02)-phenyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups; R9 represents cyano, -COOH, tert-butyl-0-C(0)-NH-, -CONH2, -CON HCH3, -CON(CH3)2,

Figure imgf000022_0001

R14 represents hydrogen;

Z represents difluoromethyl or trifluoromethyl;

n represents 0 or 1 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In accordance with a fifth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:

X represents a roup selected from:

Figure imgf000022_0002

or

wherein * indicates the point of attachment of said group with the rest of the molecule; represents hydrogen or methyl;

represents hydrogen;

represents hydrogen;

represents hydroxy, cyano, -NH2, -NHCH3-CH2-CH2-OH, -CONH2, -SO2NH2, -CH2-CN, -C(CH3)2-CN, 1-cyano-cyclopropyl, -CHz-CONHz. -Ch -SC^NI-b,

tert-butyl-0-C(0)-NH-CH2- or a group selected from:

Figure imgf000023_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;

R5 represents hydrogen;

R6a represents hydrogen;

n represents 0;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X represents a roup selected from:

Figure imgf000023_0002

or

wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: X re resents a group selected from:

Figure imgf000024_0001

or

wherein * indicates the point of attachment of said group with the rest of the molecule; R 10 represents ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl,

methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl or -CH2-CO2CH3; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X re resents a group selected from:

Figure imgf000024_0002

or

wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: X re resents a group selected from:

Figure imgf000025_0001
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X represents a roup selected from:

Figure imgf000025_0002

or

wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X represents

Figure imgf000025_0003
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X re resents

Figure imgf000026_0001
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X re resents

Figure imgf000026_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X re resents

Figure imgf000026_0003
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X represents

Figure imgf000027_0001
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

X represents

Figure imgf000027_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R1 represents hydrogen or methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R1 represents hydrogen;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R1 represents methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R2 represents hydrogen, fluoro or chloro;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R2 represents hydrogen, hydroxy or methoxy;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R2 represents hydrogen;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R3 re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group

Figure imgf000029_0001

wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R3 represents hydrogen, fluoro, chloro, hydroxy, methyl, cyano or cyanomethyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R3 represents hydrogen, fluoro, chloro, hydroxy, methyl or cyano;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R3 represents hydrogen, fluoro, chloro, hydroxy or methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R3 represents hydrogen, fluoro or chloro;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R3 represents hydrogen, hydroxy or cyano;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R3 represents hydrogen;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R4 represents hydrogen, hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, C1-C3- alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-Ci-C3-alkyl, -0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-R9,

-C(CH3)2-R9 or 1-R9-cyclopropyl,

wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano,

Ci-C4-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R4 represents hydrogen, hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, C1-C3- alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-Ci-C3-alkyl, -0-CH2-(CO)-NR7R8, -CH2-R9, -C(CH3)2-R9 or 1-R9-cyclopropyl,

wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano,

Ci-C4-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R4 represents hydrogen, hydroxy, cyano, Ci-C3-alkoxy, Ci-C3-haloalkoxy, -O-phenyl,

5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-C C3-alkyl,

-0-CH2-(CO)-NR7R8, -CH2-R9, -C(CH3)2-CN or 1 -cyano-cyclopropyl,

wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with cyano, Ci-C4-alkyl or C1-C3- haloalkyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R4 represents hydrogen, hydroxy, cyano, methoxy, hexafluoropropoxy, -O-phenyl,

imidazolyl, triazolyl, butyl-oxadiazolyl, -NR7R8, -CONH2, -S02NH2, -0-(CO)-CH3,

-0-CH2-(CO)-NR7R8, -CH2-R9, -C(CH3)2-CN or 1 -cyano-cyclopropyl,

wherein said phenyl group is substituted once with cyano and trifluoromethyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R4 represents hydrogen, hydroxy, cyano, methoxy, 1 , 1 ,2,3,3,3-hexafluoropropoxy,

2-cyano-4-trifluoromethyl-phenoxy, -NH2, -NHCH3-CH2-CH2-OH, -NHCH3-(CO)-CH3, -NH-(S02)-CH3, -NH-(S02)-C6H5, -CONH2, -S02NH2, -0-(CO)-CH3, -CH2-CN,

-C(CH3)2-CN, 1-cyano-cyclopropyl, -CH2-COOH, -CH2-CONH2, -CH2-CONHCH3, -CH2-CON(CH3)2, -CH2-S02NH2, tert-butyl-0-C(0)-NH-CH2- or a group selected from:

Figure imgf000032_0001

wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R4 represents hydroxy, cyano, -NH2, -NHCH3-CH2-CH2-OH, -CONH2, -S02NH2, -CH2-CN, -C(CH3)2-CN, 1-cyano-cyclopropyl, -CH2-CONH2, -CH2-S02NH2,

tert-butyl-0-C(0)-NH-CH2- or a group selected from:

Figure imgf000032_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R5 represents hydrogen, methyl or chloro; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R5 represents hydrogen or methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R5 represents hydrogen or chloro;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R5 represents hydrogen;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R6a, R6b represent, independently from each other, hydrogen or methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R6a represents hydrogen or methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R6a represents methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R6a represents hydrogen;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R6b represents hydrogen or methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R6b represents methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R6b represents hydrogen;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(CO)-C2-C3-alkenyl, -(S02)-Ci-C3-alkyl or -(S02)-phenyl,

wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy, or

R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(S02)-Ci-C3-alkyl or -(S02)-phenyl,

wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy, or

R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and N R14 and optionally substituted with an oxo group; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(S02)-Ci-C3-alkyl or -(S02)-phenyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and N R14 and optionally substituted with an oxo group; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R7, R8 represent, independently from each other, hydrogen, methyl, hydroxyethyl,

-(CO)-methyl, -(S02)-methyl or -(S02)-phenyl, or

R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and N R14 and optionally substituted with an oxo group; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R7, R8 represent, independently from each other, hydrogen, methyl, hydroxyethyl,

tert-butyl-O-C(O)-, -(CO)-methyl, -(S02)-methyl or -(S02)-phenyl, or

R7 and R8 together with the nitrogen atom to which they are attached form a group selected from:

Figure imgf000036_0001

wherein * indicates the nitrogen atom of -NR7R8; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R9 represents cyano, -COOH, -(CO)-0-Ci-C3-alkyl, -(S02)-Ci-C3-alkyl, -NR7R8, -CONR7R8 or -S02NR7R8; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R9 represents cyano, -COOH, -(CO)-0-Ci-C3-alkyl, -NR7R8, -CONR7R8 or -S02NR7R8; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R9 represents cyano, -COOH, -NR7R8, -CONR7R8 or -S02NR7R8;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R9 represents cyano, -COOH, tert-butyl-0-C(0)-NH-, -CONH2, -CONHCH3, -CON(CH3)2 or -S02NH2;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R10 represents Ci-C4-alkyl, Ci-C4-haloalkyl, methoxy-Ci-C3-alkyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl, S-methylsulfonimidoyl-methyl, -CH2-C02R11 or -CH2-CONR12R13;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R10 represents C2-C3-alkyl, C2-C3-haloalkyl, methoxy-Ci-C3-alkyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl or -CH2-CO2CH3;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R10 represents ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl,

methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl or -CH2-CO2CH3; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R11 represents CrC4-alkyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R11 represents methyl or ethyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R12, R13 represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-haloalkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl,

-(S02)-Ci-C3-alkyl, -(S02)-phenyl,

wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl,

Ci-C3-alkoxy or Ci-C3-haloalkoxy, or together with the nitrogen atom to which they are attached form a

4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a C1-C4- alkyl or Ci-C4-haloalkyl group and optionally substituted with an oxo group; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R14 represents hydrogen or methyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R14 represents hydrogen;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

n represents 0 or 1 ;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

n represents 0;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

n represents 1 ;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

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".

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

The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (V), (VIII) and (XIII). The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.

The compounds according to the invention of general formula (I) can be prepared according to the following schemes 1 , 2, 3 and 4. The schemes and procedures described below illustrate 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 schemes 1 , 2, 3 and 4 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents, R2, R3, R4 or R5 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, reduction or oxidation of functional groups, halogenation, alkylation, acylation, metallation or substitution 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. Specific examples are described in the subsequent paragraphs.

Six routes for the preparation of compounds of general formula (I) are described in schemes 1 , 2, 3, 4, 6 and 7. As outlined in scheme 1 compounds of general formula (lb) can be prepared from starting materials of formula (lla), (Mb) or (lie) by reacting with the spirocyclic amine of the formula (III) containing a suitable protecting group PG.

Figure imgf000041_0001

(Mb) Z=CHF2

(lie) Z=CH3

Figure imgf000041_0002

Scheme 1 : Synthesis of compounds of general formula (lb), in which n, R1, R2, R3, R4, R5, R6a and R6b have the meaning as given for general formula (I), supra, from compounds of formulae (lla), (Mb), (Me), (III) and (VI); PG is a protecting group, e.g. Boc.

An alternative route for the synthesis of the compounds of formula (lb) is shown in scheme 2.

Figure imgf000042_0001

Scheme 2: Synthesis of compounds of general formula (lb), in which n, R1, R2, R3, R4, R5, R6a and R6b have the meaning as given for general formula (I), supra, from compounds of formulae (VI), (III), and (II).

The synthesis of compounds of formula (Ic) starting from commercially available compounds of formula (IX), trifluoroethylation afforded a mixture of alkylated products (X) and (XI) which were separated. The desired compounds of formula (X) were then transferred to the compounds of formula (Ic) using a corresponding synthetic sequence as described in scheme 1.

Figure imgf000043_0001

Scheme 3: Synthesis of compounds of general formula (Ic), in which n, R1, R2, R3, R4, R5, R6a and R6b have the meaning as given for general formula (I), supra, from compounds of formulae (IX), (III), and (VI). An alternative synthetic route toward compounds of formula (Ic) is described in scheme 4.

Figure imgf000044_0001

Scheme 4: Synthesis of compounds of general formula (Ic), in which n, R1, R2, R3, R4, R5, R6a and R6b have the meaning as given for general formula (I), supra, from compounds of formulae (IX), (III), and (VI)

The synthesis of intermediate 120, shown in scheme 5, starts from commercially available ethyl 1 H-pyrrole-2-carboxylate. Friedel Crafts type reaction with trifluoroacetic anhydride afforded 116 and its corresponding isomer. After separation of the isomers 116 was reduced to the corresponding alcohol 117 which was then mesylated and transferred to the intermediate 118 by reaction with sodium borohydride. Intermediate 118 was then transferred to the amino pyrrole 119 and then cyclisized to intermediate I20 using formamidinium acetate.

Figure imgf000045_0001

Scheme 5 : Synthetic approach towards intermediate I20

As outlined in schemes 6 and 7 compounds of general formula (Id) can be prepared from starting material 120 or 121 by reacting with a spirocyclic amine of the formula (III) containing a suitable protecting group PG. After deprotection the amines can be reacted with appropriate aldehydes or ketones to the corresponding compounds of formula (Id).

Figure imgf000046_0001

Scheme 6: Synthesis of compounds of general formula (Id), in which n, R2, R3, R4, R5, R6a and R6b have the meaning as given for general formula (I), supra, from compounds of formulae I20, (III) and (XVII); PG is a protecting group, e.g. Boc.

Figure imgf000047_0001

Figure imgf000047_0002

Figure imgf000047_0003

Scheme 7: Synthesis of compounds of general formula (le), in which n, R1, R2, R3, R4, R5, R6a, R6b, R11, R12 and R13 have the meaning as given for general formula (I), supra, from compounds of formulae 121 , (lid) and (III); PG is a protecting group, e.g. Boc. The compounds are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the Experimental Section.

In accordance with a third aspect, the present invention covers methods of preparing compounds of general formula (lb) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (V):

Figure imgf000048_0001

(V),

in which R1 is as defined for the compound of general formula (I) as defined supra, and Z is methyl, difluoromethyl or trifluoromethyl,

to react with a compound of general formula (VI):

Figure imgf000048_0002

(VI),

in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) as defined supra,

thereby giving a compound of general formula (lb):

Figure imgf000048_0003

(lb), in which n, R1, R2, R3, R4, R5, R6a, R6b and Z are as defined supra.

In accordance with a fourth aspect, the present invention covers methods of preparing compounds of general formula (lb) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (II):

Figure imgf000049_0001

(II),

in which R1 is as defined for the compound of general formula (I) as defined supra, and Z is methyl, difluoromethyl or trifluoromethyl,

to react with a compound of general formula (VIII):

Figure imgf000049_0002

(VIII),

in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) as defined supra,

thereby giving a compound of general formula (lb):

Figure imgf000049_0003

(lb),

in which n, R1, R2, R3, R4, R5, R6a, R6b and Z are as defined supra. In accordance with a fifth aspect, the present invention covers methods of preparing compounds of general formula (Ic) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (XIII):

Figure imgf000050_0001
(XIII),

in which R1 is as defined for the compound of general formula (I) as defined supra,

to react with a compound of general formula (VI):

Figure imgf000050_0002

(VI),

in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) as defined supra,

thereby giving a compound of general formula (Ic):

Figure imgf000050_0003

(Ic),

which n, R1, R2, R3, R4, R5, R6a and R6b are as defined supra. In accordance with a sixth aspect, the present invention covers methods of preparing compounds of general formula (Id) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (XVIII):

Figure imgf000051_0001
(XVIII),

to react with a compound of general formula (VI):

Figure imgf000051_0002

(VI),

in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) as defined supra,

thereby giving a compound of general formula (Id):

Figure imgf000051_0003

(Id),

in which n, R2, R3, R4, R5, R6a and R6b are as defined supra.

The present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein. In accordance with a seventh aspect, the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.

Particularly, the invention covers the intermediate compounds of general formula (V):

Figure imgf000052_0001

(V),

in which R1 is as defined for the compound of general formula (I) as defined supra, and Z is difluoromethyl.

Particularly, the invention covers the intermediate compounds of general formula (VIII):

Figure imgf000052_0002

(VIII),

in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) as defined supra.

Particularly, the invention covers the intermediate compound of formula (XVIII):

Figure imgf000052_0003

(XVIII). In accordance with an eighth aspect, the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.

Particularly, the invention covers the use of intermediate compounds of general formula (V):

Figure imgf000053_0001

(V),

in which R1 is as defined for the compound of general formula (I) as defined supra, and Z is methyl, difluoromethyl or trifluoromethyl, for the preparation of a compound of general formula (I) as defined supra.

Particularly, the invention covers the use of intermediate compounds of general formula (VIII):

Figure imgf000053_0002

(VIII),

in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) as defined supra, for the preparation of a compound of general formula (I) as defined supra.

Particularly, the invention covers the use of intermediate compounds of general formula (XIII):

Figure imgf000054_0001

(XIII),

in which R1 is as defined for the compound of general formula (I) as defined supra, for preparation of a compound of general formula (I) as defined supra.

Particularly, the invention covers the use of intermediate compound of formula (XVIII):

Figure imgf000054_0002

(XVIII),

for the preparation of a compound of general formula (I) as defined supra.

The present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra.

The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (V), (VIII) and (XIII), supra. 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.

Compounds of the present invention can be utilized to inhibit the interaction between menin and MLL-1 and decrease 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.

Hyperproliferative disorders include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid 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 lymphomas, sarcomas, and leukemias.

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.

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.

Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic 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.

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.

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

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

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.

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.

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

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

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

The present invention also provides methods of treating angiogenic disorders including diseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J. Med., 1994, 331 , 1480 ; Peer et al., Lab. Invest., 1995, 72, 638], age-related macular degeneration (AMD) [Lopez et al., Invest. Opththalmol. Vis. Sci., 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of general formula (I) of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, for example by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation, or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.

The present invention also provides methods of treating diabetes.

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.

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.

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.

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

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,

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

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

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

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

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.

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

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.

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. 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.

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 signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling 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.

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.

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

Compounds of the present invention can be utilized to inhibit the interaction between menin and MLL-1. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.

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.

The term "treating" or "treatment" as used in the present text is used conventionally, e.g., 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.

The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of cancer or diabetes. 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 cancer or diabetes.

The pharmaceutical activity of the compounds according to the invention can be explained by their activity as inhibitors of the interaction between menin and MLL-1.

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 diabetes or cancer, particularly acute myeloid leukemia, prostate and breast carcinoma, and hepatocellular carcinoma.

In accordance with a further aspect, the present invention covers the use of a compound of formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of diseases, in particular diabetes or cancer, particularly acute myeloid leukemia, prostate and breast carcinoma, and hepatocellular carcinoma.

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, in a method of treatment or prophylaxis of diseases, in particular diabetes or cancer, particularly acute myeloid leukemia, prostate and breast carcinoma, and hepatocellular carcinoma.

In accordance with a further aspect, the present invention covers the use 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, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular diabetes or cancer disorders, particularly acute myeloid leukemia, prostate and breast carcinoma, and hepatocellular carcinoma.

In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular diabetes or cancer disorders, particularly acute myeloid leukemia, prostate and breast carcinoma, and hepatocellular carcinoma, 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. 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.

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.

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

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.

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.

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.

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,

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

• 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),

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

• isotonicity agents (for example glucose, sodium chloride),

• adsorbents (for example highly-disperse silicas),

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

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

• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl- methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),

• capsule materials (for example gelatine, hydroxypropylmethylcellulose),

· synthetic polymers (for example polylactides, polyglycolides, polyacrylates, 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),

• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

• penetration enhancers,

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

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

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

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

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.

In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer, more specifically acute myeloid leukemia, prostate and breast carcinoma, and hepatocellular carcinoma.

Particularly, the present invention covers a pharmaceutical combination, which comprises: • one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and

• one or more further active ingredients, in particular cancer agents.

The term "combination" in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.

A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a "fixed combination" is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.

A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known cancer agents.

Examples of cancer agents include:

1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of cancer, 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.

The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

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.

EXPERIMENTAL SECTION

The 1H-NMR data of the examples are listed in the form of 1 H-NMR peaklists. For each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δι (intensityi), 62 (int.ensit.y2), ... , δ, (intensity,), ... , δη (intensityn).

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. A 1 H-NMR peaklist is similar to a classical 1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (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 the reproduction of our manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H- 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. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1 % and 4%. 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 %.

Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.

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.

Table 1 : Abbreviations

The following table lists the abbreviations used herein.

Figure imgf000067_0001
Abbreviation Meaning

min minute(s)

M molar

MS mass spectrometry

MsCI methanesulfonyl chloride

NMP 1-methylpyrrolidin-2-one

NMR nuclear magnetic resonance spectroscopy: chemical

shifts (δ) are given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm unless otherwise stated.

PDA Photo Diode Array

Pd/C palladium on activated charcoal

prep. preparative

PTFE polytetrafluoroethylene

PyBOP (benzotriazol-l -yloxy)tripyrrolidinophosphonium

hexafluorophosphate

r.t. or rt or RT room temperature

Rt retention time (as measured either with HPLC or UPLC)

in minutes

sat. saturated

SQD Single-Quadrupole-Detector

T3P 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

UPLC ultra performance liquid chromatography

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.

The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. EXPERIMENTAL SECTION - GENERAL PART

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.

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 or DCM/methanol. 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.

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. Analytical LC-MS methods:

Method 1 : Instrument: Waters Acq uity UPLCMS Single Quad; column: Kinetex 2.6 μηη, 50x2.1 mm; eluent A: water + 0.05 % formic acid (99%); eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0-1.9 1 -99% B, 1 .9-2.1 99% B; flow 1 .3 ml/min; temperature: 60 °C; DAD scan: 200-400 nm. Method 2: Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1 .7 μπι,

50x2.1 mm; eluent A: water + 0.05 % formic acid (99%); eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0-1.7 2-90% B, 1 .7-2.0 90% B; flow 1 .2 ml/min; temperature: 60 °C; DAD scan: 190-400 nm.

Method 3: Instrument: Agilent HPLC 1260; column: Chiralpak IA 3μηι 100x4,6mm; eluent A: acetonitrile + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; isokratic: 90%A+10%B; flow 1 .4 ml/min; temperature: 25 °C; DAD 280 nm.

Method 4: Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEH C18

1.7 μηη, 50x2.1 mm; 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.

Method 5: Instrument: Agilent HPLC 1260; column: Chiralpak AD-H 3μηι 100x4,6 mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; gradient: 20 - 50 % B in 7 min; flow 1 .4 ml/min; temperature: 25 °C; DAD 280 nm.

Method 6: Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IC 5 μηη 100x4.6 mm; eluent A: C02, eluent B: methanol + 0.2 Vol-% aqueous ammonia (32%); isokratic: 39%B; flow 4.0 ml/min; temperature: 37.5°C; BPR: 100 bar; MWD @ 280 nm.

Method 7: Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μηι 100x4,6 mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 7 min; flow 1 .4 ml/min; temperature: 25 °C; DAD 280 nm.

Method 8: Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μηι 100x4,6 mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 7 min; flow 1 .4 ml/min; temperature: 25 °C; DAD 280 nm.

Method 9: Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μηι 100x4,6 mm; eluent A: methanol + 0.1 Vol-% diethylamin (99%); eluent B: ethanol; isokratic: 50%A+50%B; flow 1.4 ml/min; temperature: 25 °C; DAD 280 nm.

Method 10: Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μηι 100x4,6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; gradient: 20 - 50% B in 7 min; flow 1.4 ml/min; temperature: 25 °C; DAD 280 nm.

Method 1 1 : Instrument MS: Waters ZQ; instrument HPLC: Waters UPLC Acquity; column: Acquity BEH C18 (Waters), 50 mm x 2.1 mm, 1.7 μηη; eluent A: water +0, 1 % aqueous ammonia, eluent B: acetonitrile (Sigma-Aldrich); gradient: 0.0 min 99% A - 1.6 min 1 % A -

1.8 min 1 % A - 1.81 min 99% A - 2.0min 99% A; oven: 60 °C; flow: 0.800 ml/min; UV- detection PDA 210-400 nm. Method 12: Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1.7 50x2.1 mm; 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.

Method 13: Column: XBridge BEH C18, 2.5 μηη 2.1 x 50 mm; Waters Acquity Binary pump (Flow 0.8 ml/min); Waters Acquity Autosampler; Waters Acquity SQD; Waters Acquity PDA; run time: 1.30 min; solvents: A) 10 mM ammonium bicarbonate pH 10, B) MeCN; gradient: 2- 98% B in 0.80 min, hold at 98% B to 1 .30 min.

Method 14: Column: XBridge BEH C18, 2.5 μηη 2.1 x 50 mm; Waters Acquity Quaternary pump (Flow 0.8 ml/min); Waters Acquity Autosampler; Waters Acquity QDa; Waters Acquity PDA; run time: 1.35 min; solvents: A) 10 mM ammonium bicarbonate pH 10, B) MeCN; gradient: 2-98% B in 0.80 min, hold at 98% B to 1.35 min.

Method 15: Column: XBridge BEH C18 2.5 μηη 2.1 x 50 mm; Waters Acquity Binary pump (Flow 0.8 ml/min); Waters Acquity Autosampler; Waters Acquity SQD; Waters Acquity PDA; run time: 4.80 min; solvents: A) 10 mM ammonium bicarbonate pH 10, B) MeCN; gradient: 2- 98% B in 4.00 min, hold @ 98% B to 4.70 min.

Method 16: Instrument: Agilent HPLC 1260; column: Chiralpak IA 3μηι 100x4.6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 1-propanol; gradient: 20 - 50% B in 7 min; flow 1 .4 ml/min; temperature: 25 °C; DAD 280 nm.

Method 17: Instrument: Agilent HPLC 1260; column: Chiralpak IC 3μηι 100x4,6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; gradient: 20 - 50% B in 7 min; flow 1.4 ml/min; temperature: 25 °C; DAD 280 nm

Method 18: Instrument: Agilent HPLC 1260; column: cellulose SC 3μ 100x4.6mm; eluent A: methanol + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; isokratic: 50%A+50%B; flow 1 .4 ml/min; temperature: 25 °C; DAD 254 nm

Method 19: Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IG 5μηη 100x4.6mm; eluent A: CO2, eluent B: ethanol + 0.2 Vol-% aqueaous ammonia (32%); isokratic 43%B; flow 4.0 ml/min; temperature: 37.5°C; BPR: 100bar; MWD @ 220nm

Method 20: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μηη, 50x2.1 mm; 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.

Method 21 : Column: CSH C18 1 .7 μηι 2.1 x 50 mm; Waters Acquity Binary pump (Flow 0.8 ml/min); Waters Acquity Autosampler; Waters Acquity QDA; Waters Acquity PDA; run time: 1.40 min; solvents: A) 0.1 % formic acid in water, B) acetonitrile + 0.1 % formic acid; gradient: 2- 95% B with A in 1.20 min, hold @ 95% B, 5% A to 1.40 min, 40 °C

Method 22: Column: CSH C18 1 .7 μηη 2.1 x 50 mm; Waters Acquity Quaternary pump (Flow 0.8 mL/min); Waters Acquity Autosampler; Waters Acquity QDA; Waters Acquity PDA; run time: 1 .40 min; solvents: A) water, B) acetonitrile D) 2% formic acid in water; gradient: 2-95% B with A and 5% D 1 .20 min, hold @ 95% B, 5% D to 1 .40 min, 40 °C.

Method 23: Column: XB C18 2.5 μηη 2.1 x 50 mm; Waters Acquity Quaternary pump (Flow 0.8 mL/min); Waters Acquity Autosampler; Waters Acquity QDA; Waters Acquity PDA; run time: 1.40 min; solvents: B) acetonitrile C) 10 mM ammonium bicarbonate pH10; gradient: 2-98% B with C in 1 .20 min, hold @ 98% B, 2% C to 1 .40 min, 40 °C.

Method 24: Instrument: Agilent HPLC 1260; column: YMC amylose SA 3μηι 100 x 4.6mm; eluent: hexane + 0.1 Vol-% diethylamine (99%)/2-propanol 50:50; flow 1 .4 ml/min; temperature: 25 °C; detection: DAD 280 nm.

Analytical methods preparative HPLC:

Method A: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, Saule: Chiralpak AD-H 5 μηι 250x30 mm; eluent A: hexane + 0.1 Vol-% diethylamin (99%); eluent B: ethanol; gradient: 20 - 50% B in 20 min; flow 40.0 ml/min; UV 280 nm.

Method B: Instrument: Sepiatec: Prep SFC100; column: Chiralpak IC 5 μηη 250x30 mm; eluent A: C02, eluent B: methanol + 0.2 Vol-% aqueous ammonia (32%); isokratic: 39%B; flow 100.0 ml/min temperature: 40°C; BPR: 150 bar; MWD @ 280 nm.

Method C: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, Saule: Chiralpak IA 5μηη 250x30mm; eluent A: acetonitrile + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; isokratic: 90%A+10%B; flow 40.0 ml/min; UV 280 nm.

Method D: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: Chiralpak IA 5 μηη 250x30 mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 20 min; flow 40.0 ml/min; UV 280 nm.

Method E: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: Chiralpak IC 5μηι 250x30mm; eluent A: methanol + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; isokratic: 50%A+50%B; flow 35.0 ml/min; UV 280 nm.

Method F: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: Chiralpak IC 5 μηη 250x30 mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol + 0.1 Vol-% diethylamine (99%); gradient: 20 - 50% B in 15 min; flow 40.0 ml/min; UV 280 nm.

Method G: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: Chiralpak IA 5μηη 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 20 min; flow 40.0 ml/min; UV 280 nm.

Method H: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: Chiralpak IA 5μηη 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol + 0.1 Vol-% diethylamine (99%); isokratic: 50%A+50%B; flow 40.0 ml/min; UV 280 nm.

Method I: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: cellulose SC 5μ 250x30mm; eluent A: methanol + 0.1 Vol-% diethylamine (99%); eluent B: ethanol + 0.1 Vol-% diethylamine (99%); isokratic: 50%A+50%B; flow 30.0 ml/min; UV 254 nm.

Method J: Instrument: Sepiatec: Prep SFC100; column: Chiralpak IG 5μηη 250x30mm; eluent A: C02, eluent B: ethanol +0,2 Vol-% aqueous ammonia (32%); isokratic 43%B; flow 100.0 ml/min temperature: 40°C; BPR: 150bar; MWD @ 220nm.

Method K: Instrument: pump: Labomatic HD-5000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 μηη, 125x30mm; solvent A: water + 0.2 vol-% ammonia (32%), solvent B: acetonitrile; gradient: 0.00-0.50 min 15% B (150 mL/min), 0.50-6.00 min 15-55% B (150 mL/min), 6.00-6.10 min 55- 100% B (150 mL/min), 6.10-8.00 min 100% B (150 mL/min); UV-detection.

Method L: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: YMC Amylose SA 5μηη 250x30mm; Eluent: hexane + 0.1 Vol-% diethylamine (99%)/Ethanol 80:20; flow: 40.0 ml/min; detection: UV 254 nm.

EXPERIMENTAL SECTION - INTERMEDIATES

Intermediate 11

1-(4-formylphenyl)methanesulfonamide

Figure imgf000074_0001

500 mg (2.55 mmol) 1-(4-cyanophenyl)methanesulfonamide (CAS 191868-54-9) and 770 mg (7.26 mmol) sodium hydrogen phosphonite hydrate (CAS 10039-56-2) were dissolved in a mixture of 7.1 ml pyridine and 3.5 ml acetic acid and 3.5 ml water. Raney-nickel (59 mg, 6.4 mmol) was added in one portion and the mixture was stirred at 45 °C for 2 h. The reaction was retreated with an additional equivalent of raney-nickel and stirred for further 15 min at 45°C. The mixture was filtered through a PTFE-filter and the filter cake rinsed with ethyl acetate (10 ml). The filtrate was quenched with water and extracted into ethyl acetate. The organic phase was isolated, dried over a hydrophobic filter paper and evaporated. The residue was purified using prep reversed phase HPLC to yield the desired product as a yellow solid (344 mg, 68 %).

LC-MS (method 2): Rt = 0.38 min; MS (ESIneg): m/z = 198 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 2.073 (2.29), 2.327 (0.79), 2.518 (2.99), 2.523 (2.04), 2.540 (0.69), 2.669 (0.81 ), 4.398 (16.00), 4.413 (1 .71 ), 4.888 (1.47), 6.951 (6.37), 6.984 (0.76), 7.572 (1 .07), 7.581 (6.93), 7.592 (1.34), 7.602 (7.72), 7.627 (0.87), 7.647 (0.95), 7.894 (1 .18), 7.909 (9.38), 7.913 (3.43), 7.925 (2.57), 7.929 (7.83), 8.019 (1 .00), 8.040 (0.87), 8.968 (1 .28), 9.994 (1.52), 10.027 (12.38).

Intermediate I2

4-chloro-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidine

Figure imgf000074_0002

To a suspension of 4 g (25.9 mmol) 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine [CAS 5399-92-8] in 22 ml DMF was added 5.6 ml (39 mmol) 2,2,2-trifluoroethyl trifluoromethanesulfonate and 7.15 g (51.8 mmol) potassium carbonate. The mixture was stirred for 5 min. at 0°C, followed by 17 h at RT. All volatile components were evaporated, water was added and the suspension freeze dried. The residue was purified by silica gel column chromatography to give the desired 4- chloro-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidine (intermediate 12) (1.08g, 15%) and the isomer 4-chloro-1 -(2,2, 2-trifluoroethyl)-1 H-pyrazolo[3,4-d]pyrimidine (1.1 g, 16%).

LC-MS (method 2): Rt = 0.66 min; MS (ESIpos): m/z = 237 [M+H]+

Ή-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.268 (4.69), 2.055 (7.25), 5.074 (4.57), 5.095 (13.00), 5.1 14 (12.98), 5.135 (4.20), 8.319 (12.47), 8.925 (16.00).

Intermediate I3

4-chloro-6-methyl-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidine

Figure imgf000075_0001
To a stirred solution of 4-Chloro-6-methyl-1 H-pyrazolo[3,4-d]pyrimidine (2.0 g, 1 1 .51 mmol) in DMF (9.2 ml) under argon at 0°C was added 2,2,2-trifluoroethyl tnfluoromethanesulfonate (2.5 ml, 17 mmol) followed by potassium carbonate (3.2 g, 23 mmol). The mixture was stirred for 16h at room temperature. The suspension was filtrated through celite and evaporated off. The orange residue was purified by flash chromatography (Biotage Isolera: 100 g KP-Sil 0-60% hexane/ethyl acetate gradient) to give the desired product I3 (1.05 g, 29%) and 4-chloro-6- methyl-1 -(2,2,2-trifluoroethyl)-1 H-pyrazolo[3,4-d]pyrimidine (1.34 g, 40%).

LC-MS (method 2): Rt = 0.74 min; MS (ESIpos): m/z = 251 [M+H]+

Ή-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.267 (0.54), 1.594 (6.29), 2.054 (1.03), 2.687 (3.48), 2.705 (0.45), 2.815 (16.00), 4.962 (0.82), 4.983 (1 .05), 5.005 (0.84), 5.021 (1.12), 5.040 (3.28), 5.061 (3.25), 5.081 (1.05), 8.176 (0.83), 8.233 (3.65).

Intermediate I4

2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one

Figure imgf000075_0002

7 g (31 .2 mmol) 2-amino-5-(2,2,2-trifluoroethyl)thiophene-3-carboxamide was refluxed in a mixture of triethyl orthoacetate (24 ml) and acetic acid (18 ml) for 16 h. After cooling to RT water was added and the mixture was extracted with ethyl acetate (3x). The combined organic extracts were evaporated. The residue was purified by silica gel column chromatography to give the desired intermediate 14 (4.5 g, 44 %).

LC-MS (method 2): Rt = 0.74 min; MS (ESIpos): m/z = 249 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.355 (16.00), 2.518 (0.92), 2.522 (0.60), 3.990 (0.72), 4.018 (2.09), 4.046 (2.00), 4.073 (0.64), 7.333 (3.50).

Intermediate I5

tert-butyl 7-[2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]nonane-2-carboxylate

Figure imgf000076_0001

To a suspension of 200 mg (604 μηηοΙ) 2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin- 4(3H)-one (intermediate I4) in 13 ml acetonitrile was given 137 mg (604 μηηοΙ) tert-butyl 2,7- diazaspiro[4.4]nonane-2-carboxylate [CAS 236406-49-8], 377 mg PyBOP (725 μηιοΙ) [CAS 128625-52-5] and 170 μΙ (1 .2 mmol) triethylamine. The mixture was stirred for 3 h at 80 °C. The residue was filtered and purified by preparative reversed phase HPLC to yield 245 mg (84 %) of the desired product.

LC-MS (method 2): Rt = 1.2 min; MS (ESIpos): m/z = 457 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .389 (12.24), 1 .406 (9.63), 1.866 (0.71 ), 1.886 (1.02), 1.905 (0.74), 1 .986 (0.69), 2.417 (16.00), 2.518 (1.78), 2.523 (1 .25), 3.233 (0.69), 3.259 (2.09), 3.281 (1.47), 3.308 (0.67), 3.374 (1 .30), 3.687 (0.58), 3.847 (0.48), 3.972 (0.67), 4.000 (1.85), 4.028 (1.76), 4.055 (0.56), 7.640 (1.90).

Intermediate I6 tert-butyl 7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]nonane-2-carboxylate

Figure imgf000077_0001

To a solution of 1 g (3.8 mmol) 4-chloro-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidine (intermediate I2) in 15 ml tetrahydrofuran was added 1 .99 ml DIPEA (1 1 .4 mmol), followed by 1.03 g (4.57 mmol) tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate [CAS 236406-49-8]. The reaction mixture was stirred for 17 h at 80 °C in capped microwave vials. The reaction mixture was quenched with sat. ammonium chloride solution and the precipitate filtered through a PTFE-filter. The filtrate was extracted twice with ethyl acetate, the organic layer was isolated, washed with brine, dried over a hydrophobic filter paper and concentrated in vacuo to yield the desired product (1.47 g, 86 %) which was used without further purification.

LC-MS (method 2): Rt = 0.77 min; MS (ESIpos): m/z = 427 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1 .389 (16.00), 1 .408 (13.46), 1 .899 (1.21 ), 1.934 (0.77), 1 .950 (0.61 ), 1.962 (0.83), 1.979 (1 .05), 1 .996 (0.44), 2.076 (0.66), 2.093 (1 .27), 2.1 1 1 (0.72), 2.318 (0.44), 2.323 (0.99), 2.327 (1 .43), 2.331 (1.05), 2.336 (0.50), 2.518 (8.17), 2.523 (5.63), 2.660 (0.44), 2.665 (0.99), 2.669 (1 .43), 2.673 (0.99), 2.678 (0.44), 3.268 (2.70), 3.294 (2.04), 3.385 (1.27), 3.401 (1.16), 3.583 (0.61 ), 3.613 (1.43), 3.648 (0.77), 3.726 (3.70), 3.748 (1 .60), 3.765 (0.77), 3.860 (0.83), 3.878 (1 .60), 3.895 (0.77), 5.319 (0.44), 5.341 (1 .32), 5.359 (1 .93), 5.381 (1.60), 5.403 (0.44), 8.208 (3.20), 8.233 (4.25), 8.734 (2.04), 8.765 (1 .60).

Intermediate I7

tert-butyl 7-[6-methyl-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]nonane-2-carboxylate

Figure imgf000078_0001

To a solution of 1.05 g (3.35 mmol) 4-chloro-6-methyl-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4- d]pyrimidine (intermediate I3) in 13.7 ml tetrahydrofuran was added 1 .75 ml DIPEA (10.1 mmol), followed by 0.91 g (4.0 mmol) tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate [CAS 236406-49-8]. The reaction mixture was stirred for 17 h at 80°C in capped microwave vials. The reaction mixture was quenched with sat. ammonium chloride solution and extracted into ethyl acetate. The organic layer was isolated, washed with brine, dried over a hydrophobic filter paper and concentrated in vacuo to yield the desired product (1.78 g, 102 %) which was used without further purification.

LC-MS (method 2): Rt = 0.78 min; MS (ESIpos): m/z = 441 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1 .389 (16.00), 1 .408 (12.97), 1 .869 (0.68), 1.887 (1 .18), 1 .908 (1.24), 1.926 (0.92), 1.939 (0.90), 1 .957 (0.90), 1.974 (0.40), 2.057 (0.56), 2.074 (1 .10), 2.084 (1.56), 2.093 (0.62), 2.323 (0.44), 2.327 (0.64), 2.331 (0.52), 2.347 (9.40), 2.357 (8.16), 2.518 (1.98), 2.523 (1.36), 2.665 (0.40), 2.669 (0.58), 2.674 (0.76), 3.252 (1 .26), 3.259 (0.98), 3.267 (1.86), 3.287 (1.50), 3.294 (0.78), 3.304 (0.62), 3.367 (1.08), 3.381 (0.94), 3.397 (0.96), 3.562 (0.48), 3.592 (1.22), 3.620 (0.56), 3.630 (0.58), 3.697 (2.79), 3.714 (0.70), 3.732 (1 .24), 3.749 (0.60), 3.833 (0.74), 3.850 (1 .42), 3.867 (0.70), 5.275 (0.34), 5.296 (1 .14), 5.314 (1 .78), 5.336 (1.42), 5.358 (0.40), 8.649 (1 .96), 8.681 (1.30).

Intermediate I8

tert-butyl 7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4.4]nonane- 2-carboxylate

Figure imgf000079_0001

To a suspension of 2.79 g (1 1 .05 mmol) 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine, [CAS 1628317-85-0] in 45 ml tetrahydrofuran was added 5.77 ml DIPEA (33.1 mmol), followed by 3.0 g (13.26 mmol) tert-butyl-2,7-diazaspiro[4.4]nonane-2-carboxylate [CAS 236406-49-8] and the mixture was stirred for 17 h at 80°C in capped microwave vials. The reaction mixture was treated with water and saturated ammonium chloride solution, extracted with ethyl acetate (3x), dried and concentrated in vacuo to yield 5.08 g (94 %) of the desired product.

LC-MS (method 1 ): Rt = 1.27 min; MS (ESIpos): m/z = 443.5 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .172 (0.75), 1.352 (0.48), 1.389 (16.00), 1 .405 (12.65), 1.871 (1.06), 1 .888 (1 .24), 1 .912 (0.89), 1 .930 (0.44), 1.987 (2.22), 2.001 (0.89), 2.518 (1 .32), 2.523 (0.89), 3.242 (0.65), 3.268 (1.89), 3.288 (1.83), 3.372 (1 .84), 3.716 (0.63), 3.860 (0.50), 4.016 (1 .06), 4.035 (0.76), 4.042 (2.48), 4.070 (2.35), 4.098 (0.74), 7.709 (2.38), 8.326 (6.03).

Intermediate I9

4-[27-diazaspiro[4.4]non-2-yl]-2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimid hydrochloride

Figure imgf000079_0002

To a solution of 240 mg (0.5 mmol) tert-butyl-7-[2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate (intermediate I5) in 1.5 ml dichloromethane was added 2.5 ml of a solution of 4M hydrochloride in dioxane. The mixture was stirred for 1 h at RT. All solvent was removed by evaporation to yield 137 mg (63 %) of the desired product which was used without further purification.

LC-MS (method 2): Rt = 0.55 min; MS (ESIpos): m/z = 357 [M+H]+

H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1 .938 (0.53), 1.953 (1.08), 1 .963 (0.99), 1.968 (0.74), 1.979 (1.87), 1 .994 (1 .01 ), 2.01 1 (0.41 ), 2.018 (0.92), 2.033 (1.87), 2.047 (1.25), 2.059 (1.29), 2.073 (0.85), 2.083 (0.51 ), 2.365 (0.78), 2.514 (5.65), 2.521 (16.00), 3.153 (0.62), 3.164 (0.87), 3.176 (1.29), 3.188 (1 .43), 3.200 (0.88), 3.227 (1 .02), 3.239 (1.52), 3.251 (1.40), 3.262 (0.88), 3.274 (0.60), 3.283 (0.76), 3.297 (1 .75), 3.309 (2.70), 3.321 (1.71 ), 3.335 (0.74), 3.428 (0.42), 3.457 (0.58), 3.468 (0.64), 3.489 (0.71 ), 3.498 (0.72), 3.510 (0.67), 3.662 (1.89), 3.666 (1.87), 3.674 (1.92), 3.696 (1 .87), 3.702 (1 .96), 3.708 (1 .91 ), 3.712 (1.91 ), 4.017 (0.62), 4.058 (0.97), 4.080 (2.14), 4.102 (2.03), 4.124 (0.79), 5.758 (3.07), 7.784 (1.06), 9.404 (0.55).

The following intermediate 110 was prepared analogous to intermediate I9 starting from intermediate I7.

Figure imgf000080_0001
InterStructure

Analytical Data

mediate Name

(1 .44), 4.030 (0.47), 4.061 (0.49), 4.091 (0.29), 5.458 (0.22), 5.480 (0.66), 5.506 (1.00), 5.529 (0.82), 5.551 (0.25), 8.273 (0.17), 9.190 (2.14), 9.251 (1.42), 9.397 (0.21 ), 9.615 (0.18).

LC-MS (method 1 ): Rt = 0.30 min; MS (ESIpos): m/z = 341 [M+H]+

Intermediate 111

4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine

trifluoroacetate

Figure imgf000081_0001

To a suspension of 5.09 g (10.4 mmol) tert-butyl7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin- 4-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate (intermediate I8) in 35 ml dichloromethane was added 13.6 ml trifluoroacetic acid at 0°C. The mixture was stirred for 1 h at RT. All volatile ingredients were removed by evaporation to yield 8.92 g (169 %) of the desired product.

LC-MS (method 2): Rt = 0.57 min; MS (ESIpos): m/z = 343 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.351 (0.83), 1.531 (1 .30), 1 .938 (0.99), 1 .957 (1 .57), 1.971 (2.00), 1.990 (3.97), 2.002 (2.05), 2.009 (2.37), 2.019 (3.75), 2.038 (2.34), 2.052 (1 .94), 2.071 (1 .73), 2.083 (1.73), 2.322 (1.17), 2.326 (1.57), 2.331 (1 .09), 2.518 (5.46), 2.522 (3.78), 2.664 (1 .17), 2.668 (1.62), 2.673 (1.12), 3.155 (0.80), 3.171 (1 .57), 3.185 (2.48), 3.200 (3.01 ), 3.214 (1 .54), 3.229 (1.60), 3.243 (2.88), 3.258 (2.34), 3.273 (1 .54), 3.287 (1 .09), 3.296 (1 .30), 3.313 (3.14), 3.328 (4.82), 3.343 (2.88), 3.361 (1.09), 3.777 (0.96), 3.889 (1 .62), 4.029 (1 .86), 4.057 (5.16), 4.084 (4.85), 4.1 1 1 (1 .54), 7.694 (6.04), 8.379 (16.00), 8.927 (1.89).

Intermediate 112 4-[2 -diazaspiro[4.4]non-2-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine hydrochloride

Figure imgf000082_0001

To a solution of 8 g (18.08 mmol) tert-butyl7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]- 2,7-diazaspiro[4.4]nonane-2-carboxylate (intermediate I8) in 160 ml methanol was added 32 ml hydrochloric acid (4M in dioxane) at RT. The mixture was stirred for 16 h at RT. All volatile ingredients were removed by evaporation to yield 7.2 g (105 %) of the desired product which was used whithout further purification.

LC-MS (method 4): Rt = 0.97 min; MS (ESIpos): m/z = 343 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .950 (0.75), 1.964 (0.78), 1 .969 (0.54), 1.983 (1 .52), 2.002 (0.82), 2.01 1 (0.70), 2.030 (1 .42), 2.047 (1 .01 ), 2.062 (0.95), 2.080 (0.68), 2.518 (1.98), 2.522 (1.30), 3.058 (0.69), 3.162 (2.41 ), 3.174 (0.91 ), 3.189 (1.19), 3.204 (0.67), 3.215 (0.57), 3.230 (0.95), 3.244 (0.75), 3.259 (0.48), 3.273 (0.65), 3.291 (1.27), 3.306 (1.89), 3.321 (1.15), 3.339 (0.41 ), 3.564 (16.00), 3.918 (0.75), 4.059 (0.75), 4.086 (1 .97), 4.1 14 (1 .88), 4.142 (0.62), 7.820 (1.02), 8.492 (5.05), 9.495 (0.54).

The following intermediate 113 was prepared analogous to intermediate 111 starting from intermediate I6.

Figure imgf000082_0002
InterStructure

Analytical Data

mediate Name

pyrazolo[3,4-d]pyrimidine 2.327 (3.76), 2.331 (2.61 ), 2.518 (12.75), 2.523 trifluoroacetate (8.73), 2.548 (0.51 ), 2.660 (1 .21 ), 2.665 (2.68),

2.669 (3.76), 2.673 (2.61 ), 3.184 (0.51 ), 3.197

(0.89), 3.214 (1.34), 3.229 (1 .59), 3.243 (1.08),

3.262 (2.29), 3.276 (4.46), 3.290 (2.74), 3.327

(2.29), 3.343 (2.93), 3.357 (2.80), 3.372 (1.66),

3.852 (1 .59), 3.885 (2.93), 3.930 (1.98), 3.948

(4.91 ), 3.985 (3.19), 4.012 (4.46), 4.028 (2.04),

4.134 (2.17), 4.928 (1.02), 4.951 (1.59), 4.974

(1 .59), 4.996 (1.02), 5.265 (0.89), 5.287 (1.47),

5.310 (1 .40), 5.333 (0.76), 5.367 (0.83), 5.389

(0.76), 5.479 (1.59), 5.501 (4.14), 5.522 (4.78),

5.542 (3.12), 5.563 (1.02), 5.758 (16.00), 6.973

(0.51 ), 7.100 (0.57), 7.228 (0.51 ), 8.340 (2.42),

8.418 (0.57), 8.566 (1.15), 8.655 (7.14), 8.699

(0.57), 9.002 (1.15), 9.059 (4.40), 9.130 (5.93).

LC-MS (method 2): Rt = 0.46 min; MS

(ESIpos): m/z = 327 [M+H]+

Intermediate 114

tert-butyl 7-(4-cyanobenzyl)-2,7-diazas iro[4.4]nonane-2-carboxylate

Figure imgf000083_0001
A mixture of tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate, 200 mg (0.884 mmol) and 4- formylbenzonitrile, 1 16 mg (0.884 mmol), in dichloromethane, 5.90 ml, was stirred at room temperature for 30 minutes. To the mixture was added sodium triacetoxyborohydride, 562 mg (2.65 mmol), in portions. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water and stirred at room temperature for 30 minutes. The product was extracted into dichloromethane and the combined organics were dried over sodium sulfate, filtered then concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: heptane-ethyl acetate 1 :1 to 0:1 ) to give the desired product, 190 mg (63 %).

LC-MS (method 13): Rt = 0.89 min., 100%. MS (ESIpos): m/z = 342 [M+H]+.

1H NMR (400 MHz, CDCI3): δ [ppm] = 1.44 (s, 9H), 1 .73-1.84 (m, 4H), 2.37-2.69 (m, 4H), 3.16-

3.43 (m, 4H), 3.64 (s, 2H), 7.43 (d, 2H), 7.59 (d, 2H).

Intermediate 115

4-(2,7-diazaspiro[4.4]non-2-ylmethyl)benzonitrile hydrochloride

Figure imgf000084_0001

To a stirring solution of tert-butyl 7-(4-cyanobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (intermediate 114), 190 mg (0.556 mmol), in methanol, 0.500 ml, was added hydrochloric acid (4 M in 1 ,4-dioxane), 2.50 ml. Stirring continued for 2 hours and the mixture was concentrated under vacuum to give the desired product, 179 mg (102 %). The product was used in the next step without purification.

LC-MS (method 13): Rt = 0.56 min., 89%. MS (ESIpos): m/z = 242 [M+H]+.

Ή NMR (400 MHz, MeOD-d3): δ [ppm] = 2.12-2.34 (m, 4H), 3.35-3.46 (m, 6H), 3.57-3.66 (m, 2H), 4.53-4.54 (m, 2H), 7.85 (d, 2H), 7.78 (d, 2H).

Intermediate 116

ethyl 4-(trifluoroacetyl)-1 H-pyrrole-2-carboxylate

Figure imgf000085_0001

To a stirred solution of ethyl 1 H-pyrrole-2-carboxylate, 100 g (719 mmol), in N,N- dimethylformamide (1000 ml), was added trifluoroacetic anhydride (132 ml, 934 mmol). The mixture was heated to 80 °C for 18 hours. The mixture was allowed to cool to room temperature and then poured in to water and stirred for 15 minutes. The resultant precipitate was collected by filtration under vacuum then dried in a vacuum oven overnight (50 °C) to give the desired product, 82.0 g (49 %), as a 1 :2 mixture of isomers, ethyl 4-(trifluoroacetyl)-1 H- pyrrole-2-carboxylate and ethyl 3-(trifluoroacetyl)-1 H-pyrrole-2-carboxylate. A second crop gave the desired product, 10.4 g (6 %), as a 5:1 mixture of isomers (ethyl 4-(trifluoroacetyl)- 1 /-/-pyrrole-2-carboxylate and ethyl 3-(trifluoroacetyl)-1 H-pyrrole-2-carboxylate). Used in the next step without purification.

Desired isomer: ethyl 4-(trifluoroacetyl)-1 H-pyrrole-2-carboxylate (intermediate 116):

1H NMR (400 MHz, CDCI3): δ [ppm] = 1.38 (t, 3H), 4.38 (q, 2H), 7.42 (s, 1 H), 7.73 (s, 1 H), 9.91 (bs, 1 H); LC-MS (method 13): Rt = 0.76 min., 99%. MS (ESIneg) m/z = 234 [M-H)\ Undesired isomer: ethyl 3-(trifluoroacetyl)-1 H-pyrrole-2-carboxylate:

1H NMR (400 MHz, CDCI3): δ [ppm] = 1.39 (t, 3H), 4.37 (q, 2H), 6.95 (dd, 1 H), 7.14-7.16 (m, 1 H), 10.00 (bs, 1 H).

Intermediate 117

ethyl 4-[2,2,2-trifluoro-1-hydroxyethyl]-1 H-pyrrole-2-carboxylate

Figure imgf000085_0002

To a stirred solution of a 5:1 mixture of ethyl 4-(trifluoroacetyl)-1 /-/-pyrrole-2-carboxylate and ethyl 3-(trifluoroacetyl)-1 H-pyrrole-2-carboxylate (intermediate 116), 10.4 g (44.2 mmol), in methanol (68.0 ml), and tetrahydrofuran (160 ml), was added sodium borohydride, 2.51 g (66.3 mmol) in portions at 0 °C under argon. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water and the product was extracted into ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: heptane- ethyl acetate 85:15 to 60:30) to give the desired product, 5.80 g (55 %). LC-MS (method 13): Rt = 0.65 min., 97%. MS (ESIneg) m/z = 236 [M-H]\

1H NMR (400 MHz, CDCI3): δ [ppm] = 1 .35 (t, 3H), 4.32 (q, 2H), 4.97-5.03 (m, 1 H), 6.99 (s, 1 H), 7.08 (s, 1 H), 9.15 (bs, 1 H).

Intermediate 118

ethyl 4-(2,2,2-trifluoroethyl)-1 H-pyrrole-2-carboxylate

Figure imgf000086_0001

To a stirred solution of ethyl 4-(2,2,2-trifluoro-1-hydroxyethyl)-1 H-pyrrole-2-carboxylate (intermediate 117), 10.7 g (45.1 mmol), and triethylamine, 9.43 ml (67.7 mmol), in dichloromethane, 550 ml, was added methanesulfonyl chloride, 5.24 ml (67.7 mmol). The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organics were dried over magnesium sulfate and concentrated under vacuum keeping below 30 °C. The residue was used directly in the next step without purification.

To a solution of ethyl 4-{2,2,2-trifluoro-1-[(methylsulfonyl)oxy]ethyl}-1 H-pyrrole-2-carboxylate (assumed 45.1 mmol), in ethanol, 535 ml, was added sodium borohydride, 2.56 g (67.7 mmol), in portions at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organics were dried over magnesium sulfate and concentrated under vacuum to give the desired product, 8.60 g (86 %). The product was used in the next step without purification. LC-MS (method 14): Rt = 0.79 min., 75%. MS (ESIneg) m/z = 220 [M-H]-.

1H NMR (400 MHz, CDC ): δ [ppm] = 1 .35 (t, 3H), 3.25 (q, 2H), 4.31 (q, 2H), 6.86 (s, 1 H), 6.90 (s, 1 H), 9.13 (bs, 1 H).

Intermediate 119

ethyl 1 -amino-4-(2,2,2-trifluoroethyl)-1 H-pyrrole-2-carboxylate H 3C F

F

To a vigorously stirred mixture of ethyl 4-(2,2,2-trifluoroethyl)-1 H-pyrrole-2-carboxylate (intermediate 118), 8.60 g (38.9 mmol), ammonium chloride, 12.9 g (241 mmol), aqueous sodium hydroxide (28%), 1 12 ml, Aliquat-336 (methyl tri-n-octylammonium chloride), 437 mg (1 .08 mmol), ammonium hydroxide (28%), 36.0 ml, and tert-butyl methyl ether, 258 ml, was added drop-wise sodium hypochlorite solution (9%), 260 ml. The reaction mixture was then stirred at room temperature for 18 hours. The phases were separated and the aqueous discarded. To the vigorously stirred organic phase was added ammonium chloride, 12.9 g (241 mmol), aqueous sodium hydroxide (28%), 1 12 ml, Aliquat-336 (methyl tri-n-octylammonium chloride), 437 mg (1 .08 mmol), and ammonium hydroxide (28%), 36.0 ml. Sodium hypochlorite solution (9%), 260 ml, was added drop-wise and stirred for a further 18 hours. The reaction mixture was diluted with diethyl ether and the phases separated. The organics were washed with 10% sodium thiosulfate solution, dried over magnesium sulphate and concentrated under vacuum to give the desired product, 7.60 g (79%). The product was used in the next step without purification.

LC-MS (method 15): Rt = 2.07 min., 79%. MS (ESIpos): m/z = 237 [M+H]+.

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1 .34 (t, 3H), 3.18 (q, 2H), 4.28 (q, 2H), 5.54 (s, 2H), 6.77

(d, 1 H), 6.91 (d, 1 H);

Intermediate I20

6-(2,2,2-trif luoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol

Figure imgf000087_0001

A solution of ethyl 1 -amino-4-(2,2,2-trifluoroethyl)-1 H-pyrrole-2-carboxylate (intermediate 119), 1 .14 g (4.83 mmol), formamidinium acetate, 552 mg (5.31 mmol), and N, N- diisopropylethylamine, 32.0 ml, in 1 -butanol, 32.0 ml, was heated to reflux (120 °C) for 18 hours. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: heptane-ethyl acetate 3:2 to 0: 1 ) to give the desired product, 802 mg (77%).

LC-MS (method 13): Rt = 0.56 min., 89%. MS (ESIpos): m/z = 218 [M+H]+. 1H NMR (400 MHz, CDCI3): δ [ppm] = 3.40 (m, 2H), 7.04 (s, 1 H), 7.43 (d, 1 H), 7.55 (s, 1 H), 10.20 (br s, 1 H).

Intermediate 121

tert-Butyl 7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7- diazaspiro[4.4]nonane-2-carboxylate

Figure imgf000088_0001

To a mixture of 6-(2,2,2-trifluoroethyl)pyrrolo[2, 1-f][1 ,2,4]triazin-4-ol (intermediate I20), 700 mg (3.22 mmol), in acetonitrile, 32.0 ml, and triethylamine, 18.3 ml, was added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate, 730 mg (3.22 mmol), and tert-butyl 2,7- diazaspiro[4.4]nonane-2-carboxylate, 1.85 g (3.55 mmol). The mixture was heated to 80 °C for 18 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium hydrogen carbonate solution. The organics were dried over magnesium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: heptane-ethyl acetate 3:7, 0:1 ) to give the desired product, 1.07 g (78%).

LC-MS (method 13): Rt = 0.86 min., 50%. MS (ESIpos): m/z = 426 [M+H]+.

1H NMR (400 MHz, CDCI3): δ [ppm] = 1.46 (s, 9H), 1.80-2.18 (m, 4H), 3.32-3.50 (m, 6H), 3.74- 4.08 (m, 4H), 6.68 (d, 1 H), 7.53 (d, 1 H), 7.83 (s, 1 H).

Intermediate I22

4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine hydrochloride

Figure imgf000089_0001

To a stirred solution of tert-butyl 7-[6-(2,2,2-trifluoroethyl)pyrrolo[2, 1-f][1 ,2,4]triazin-4-yl]-2,7- diazaspiro[4.4]nonane-2-carboxylate (intermediate 121 ), 1.00 g (2.35 mmol), in 1 ,4-dioxane, 2.29 ml, was added hydrochloric acid (4 M in 1 ,4-dioxane), 5.88 ml (23.5 mmol). Stirring continued for 30 minutes. The mixture was combined with a trial reaction using tert-butyl 7-[6- (2,2,2-trifluoroethyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate, 70.0 mg (0.165 mmol), and concentrated under vacuum to give the desired intermediate, 1 .16 g (106% combined yield). Used immediately in the next step without purification.

LC-MS (method 13): Rt = 0.60 min., 49%. MS (ESIpos): m/z = 326 [M+H]+.

Intermediate I23

tert-butyl 4-[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin

diazaspiro[4.4]non-2-yl}methyl)phenyl]piperazine-1-carboxylate

Figure imgf000089_0002
A mixture of 4-(2,7-diazaspiro[4.4]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[2, 1-f][1 ,2,4]triazine hydrochloride (intermediate I22), 72.0 mg (0.166 mmol), and tert-butyl 4-(4- formylphenyl)piperazine-1-carboxylate (CAS 197638-83-8), 40.1 mg (0.138 mmol), in dichloromethane, 1 .40 ml, and triethylamine, 63.0 μΙ_ (0.455 mmol), was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride, 87.8 mg (0.414 mmol), was added in portions. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The product was extracted into dichloromethane and the organics were dried over magnesium sulfate and concentrated under vacuum. The residue was by flash chromatography on silica gel 60 (eluent: ethyl acetate-5% ammonia/methanol 1 :0, 9:1 ) to give the desired product, 84.0 mg (85%).

LC-MS (method 13): Rt = 1.00 min., 96%. MS (ESIpos): m/z = 600 [M+H]+.

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1.47 (s, 9H), 1 .82-2.12 (m, 4H), 2.38-2.78 (m, 4H), 3.07-3.14 (m, 4H), 3.36-3.42 (m, 2H), 3.54-3.57 (m, 6H), 3.62-4.00 (m, 4H), 6.66 (s, 1 H), 6.85 (d, 2H), 7.20 (d, 2H), 7.50 (s, 1 H), 7.81 (s, 1 H).

Intermediate I24

2-amino-5-(2,2-difluoroethyl)thiophene-3-carboxamide

Figure imgf000090_0001

4.94 g (45.7 mmol) 4,4-difluorobutanal was dissolved in 40 ml DMF. Then 3.84 g (45.7 mmol) 2-cyanoacetamide, 1 .47 g (45.7 mmol) sulfur and 8.1 ml triethyl amine were added and the reaction mixture was stirred for 20.5 h at RT. The crude reaction mixture was evaporated and used without further purification.

LC-MS (method 4): Rt = 0.69 min; MS (ESIpos): m/z = 207 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.158 (3.84), 1.177 (8.12), 1 .194 (3.95), 1 .335 (0.26), 2.323 (0.23), 2.327 (0.32), 2.331 (0.22), 2.518 (1.16), 2.523 (0.82), 2.665 (0.23), 2.669 (0.32), 2.673 (0.22), 2.715 (0.18), 2.728 (12.76), 2.888 (16.00), 3.048 (1 .08), 3.058 (1 .07), 3.067 (1.55), 3.085 (1 .64), 3.091 (1 .70), 3.102 (1 .67), 3.137 (0.60), 3.147 (0.57), 3.348 (0.24), 3.585 (3.82), 5.962 (0.23), 5.973 (0.50), 5.983 (0.23), 6.103 (0.46), 6.1 14 (0.99), 6.124 (0.45), 6.245 (0.21 ), 6.255 (0.46), 6.265 (0.21 ), 6.900 (2.85), 7.215 (2.57), 7.950 (2.02).

Intermediate I25

6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-

Figure imgf000091_0001

A mixture of 13.1 g (47.6 mmol) 2-amino-5-(2,2-difluoroethyl)thiophene-3-carboxamide (intermediate I24) in 30 ml acetic acid was treated with 35.6 g (240.5 mmol) (diethoxymethoxy)ethane and heated for 18 h under reflux conditions. The crude reaction mixture was evaporated and the brown residue treated with 50 ml tert-butyl methyl ether. After short stirring a precipitate formed which was filtered and washed 3x with tert-butyl methyl ether. After drying of the solid in vacuum 5.04 g (49 %) of the desired product was obtained.

LC-MS (method 4): Rt = 0.45 min; MS (ESIpos): m/z = 217 [M+H]+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .907 (2.24), 2.518 (2.68), 2.522 (1.72), 3.463 (2.40), 3.471 (2.49), 3.507 (4.78), 3.516 (4.86), 3.552 (2.36), 3.561 (2.34), 6.167 (0.94), 6.178 (2.05), 6.188 (0.92), 6.308 (1 .80), 6.318 (3.87), 6.328 (1 .79), 6.448 (0.87), 6.458 (1.86), 6.468 (0.87), 7.312 (1 1 .63), 8.105 (16.00), 12.505 (0.85).

Intermediate I26

tert-butyl 7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]nonane-2- carboxylate

Figure imgf000091_0002

To a suspension of 1.26 g (5.6 mmol) tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate [CAS 236406-49-8] in 7.5 ml acetonitrile was added 1.2 g (5.6 mmol) 6-(2,2-difluoroethyl)thieno[2,3- d]pyrimidin-4(3H)-one (intermediate I25), 3.47 g PyBOP (6.66 mmol) [CAS 128625-52-5] and 1.55 ml (1 1.1 mmol) triethylamine. The mixture was stirred for 22 h at 80°C. The solvent was removed in vacuum and the residue was treated with water and extracted 3x with ethyl acetate. The combined organic phases were washed with brine and dried over a hydrophibic filter. After removal of the solvent the residue was purified by flash chromatography to give the desired product, 1 .81 g (73%).

LC-MS (method 4): Rt = 1.26 min; MS (ESIpos): m/z = 425 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .154 (3.07), 1.172 (6.35), 1 .190 (3.21 ), 1 .389 (16.00), 1.405 (13.26), 1.867 (1.43), 1.881 (1.44), 1.907 (1.21 ), 1 .987 (13.16), 2.327 (0.53), 2.523 (1 .73), 2.669 (0.52), 3.238 (0.74), 3.266 (2.42), 3.282 (2.16), 3.374 (2.38), 3.471 (1 .06), 3.480 (1 .10), 3.515 (2.09), 3.525 (2.10), 3.560 (1.08), 3.570 (1.02), 3.717 (0.80), 3.857 (0.63), 3.999 (1 .00), 4.017 (2.89), 4.035 (2.84), 4.053 (0.94), 6.188 (0.74), 6.318 (0.74), 6.328 (1 .49), 6.338 (0.68), 6.468 (0.68), 7.604 (2.76), 8.302 (6.23).

Intermediate I27

4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidine hydrochloride

Figure imgf000092_0001
To a stirred solution of 1.81 g (4.26 mmol) tert-butyl 7-[6-(2,2-difluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate (intermediate I26) in 25 ml methanol was added 10 ml hydrochloric acid (4 M in 1 ,4-dioxane). Stirring continued for 16.5 h at RT. After removal of all volatile components in vacuum the desired product was achieved 1 .58 g (99 %), which was used without purification.

LC-MS (method 4): Rt = 0.90 min; MS (ESIpos): m/z = 326 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .825 (0.93), 1.926 (0.42), 1 .945 (1.00), 1.959 (1 .05), 1.978 (2.10), 1 .997 (1 .13), 2.005 (0.99), 2.024 (2.03), 2.042 (1.50), 2.056 (1.43), 2.075 (1.05), 2.154 (0.60), 2.518 (3.67), 2.522 (2.28), 3.076 (0.44), 3.138 (0.49), 3.154 (0.90), 3.162 (0.81 ), 3.168 (1.34), 3.183 (1 .75), 3.198 (0.96), 3.215 (0.85), 3.229 (1.43), 3.243 (1.16), 3.257 (0.82), 3.277 (0.91 ), 3.294 (1 .93), 3.310 (2.84), 3.326 (1 .86), 3.343 (0.82), 3.495 (1.74), 3.504 (2.1 1 ), 3.514 (2.30), 3.523 (2.01 ), 3.549 (4.01 ), 3.554 (1 1.60), 3.563 (16.00), 3.582 (10.52), 3.594 (3.67), 3.604 (3.94), 3.61 1 (3.68), 3.639 (5.02), 3.651 (10.08), 3.901 (1.92), 6.240 (0.54), 6.379 (1 .07), 6.519 (0.51 ), 7.410 (0.42), 7.542 (0.48), 7.544 (0.42), 7.705 (2.50), 7.707 (2.55), 7.729 (0.71 ), 7.969 (0.68), 7.989 (0.62), 8.452 (6.74), 9.453 (0.80). Intermediate 128

2-amino-5-(2,2-difluoroethyl)thiophene-3-carboxamide

Figure imgf000093_0001
Into a 5000-ml 4-necked round-bottom flask, was placed methyl 3-aminothiophene-2- carboxylate (300 g, 1 .91 mol, 1.00 equiv) [CAS 22288-78-4], dichloromethane (3000 ml_), TEA (288 g, 2.85 mol, 1.50 equiv), 4-dimethylaminopyridine (25 g, 204.63 mmol, 0.1 1 equiv), Di- tert-butyl dicarbonate (534 g, 2.45 mol, 1.28 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 2 L of water. The resulting solution was extracted with 500 ml of dichloromethane and the organic layers combined. The resulting mixture was washed with 1x1000 ml of brine. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :50). This resulted in 200 g (41 %) of methyl 3-[[(tert-butoxy)carbonyl]amino]thiophene-2-carboxylate as a white solid.

Intermediate I29

methyl 3-[(tert-butoxycarbonyl)amino]-5-formylthiophene-2-carboxylate

Figure imgf000093_0002

Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed diisopropylamine (280 g, 2.77 mol, 3.60 equiv), tetrahydrofuran (3000 ml). This was followed by the addition of n-BuLi (1000 ml, 3.20 equiv) dropwise with stirring at - 30°C and stirred 30 min at 0°C. To this was added a solution of methyl 3-[[(tert- butoxy)carbonyl]amino]thiophene-2-carboxylate (intermediate I28) (200 g, 777.28 mmol, 1.00 equiv) in tetrahydrofuran (500 ml) dropwise with stirring at -78°C and stirred 1 h. To the mixture was added piperidine-1 -carbaldehyde (532 g, 4.70 mol, 6.00 equiv) dropwise with stirring at - 78°C. The resulting solution was stirred for 1 h at -78°C. The reaction was then quenched by the addition of 2 L of N H4CI (aq). The resulting solution was extracted with 2x2 L of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x500 ml of hydrogen chloride (3 mol/L). The resulting mixture was washed with 2x500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :20). This resulted in 200 g (90%) of methyl 3-[[(tert-butoxy)carbonyl]amino]-5-formylthiophene-2- carboxylate as a light yellow solid.

Intermediate I30

methyl 3-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoro-1-hydroxyethyl)thiophene-2- carboxylate

Figure imgf000094_0001

Into a 3000-ml 4-necked round-bottom flask, was placed methyl 3-[[(tert- butoxy)carbonyl]amino]-5-formylthiophene-2-carboxylate (intermediate I29) (120 g, 420.59 mmol, 1 .00 equiv), tetrahydrofuran (1500 ml), TBAF (31 g, 1 18.56 mmol, 0.28 equiv). This was followed by the addition of trimethyl(trifluoromethyl)silane [CAS 81290-20-21(120 g, 845.07 mmol, 2.00 equiv) dropwise with stirring at 0°C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1 L of water. The resulting solution was extracted with 2x500 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x500 ml of water and 1 x500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 160 g (crude) of desired product as red oil.

Intermediate 131

methyl 3-[(tert-butoxycarbonyl)amino]-5-{2,2,2-trifluoro-1-[(methylsulfonyl)oxy]ethyl}- thiophene-2-carboxylate

Figure imgf000095_0001

Into a 3000-ml 4-necked round-bottom flask, was placed methyl 3-[[(tert- butoxy)carbonyl]amino]-5-(2,2,2-trifluoro-1 -hydroxyethyl)thiophene-2-carboxylate (intermediate I30) (160 g, 450.29 mmol, 1.00 equiv), dichloromethane (1600 ml), triethylamine (67.7 g, 669.04 mmol, 1.50 equiv). This was followed by the addition of methanesulfonyl chloride (61.5 g, 1.20 equiv) dropwise with stirring at OoC. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1 L of water. The resulting solution was extracted with 1x500 ml of dichloromethane and the organic layers combined. The resulting mixture was washed with 1 x500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :10). This resulted in 90 g (46%) of the desired product as a yellow solid.

Intermediate I32

methyl 3-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroethyl)thiophene-2-carboxylate

Figure imgf000095_0002

Into a 2000-ml 4-necked round-bottom flask purged and maintained with an inert atmosphere of hydrogen, was placed methyl 3-[[(tert-butoxy)carbonyl]amino]-5-[2,2,2-trifluoro-1- (methanesulfonyloxy)ethyl]thiophene-2-carboxylate (intermediate 131 ) (90 g, 207.65 mmol, 1.00 equiv), ethyl acetate (900 ml), palladium carbon (40 g). The flask was evacuated and flushed three times with air, followed by flushing with hydrogen. The resulting solution was stirred for 2 days at room temperature. The solids were filtered out and washed with 500 ml of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :20). This resulted in 50 g (71 %) of the desired product as a white solid. 1H-NMR (300 MHz, CDCI3) δ [ppm]: 9.13 (s, 1 H), 7.89 (s, 1 H), 3.88 (s, 3H), 3.56 (q, 2H), 1 ,53 (s, 9H).

Intermediate I33

methyl 3-amino-5-(2,2,2-trifluoroethyl)thiophene-2-carboxylate

Figure imgf000096_0001

Into a 1000-ml 4-necked round-bottom flask, was placed methyl 3-[[(tert- butoxy)carbonyl]amino]-5-(2,2,2-trifluoroethyl)thiophene-2-carboxylate (intermediate I32) (50 g, 147.35 mmol, 1.00 equiv), dichloromethane (500 ml), trifluoroacetic acid (80 ml, 7.30 equiv). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 ml of ethyl acetate. The pH value of the solution was adjusted to 8 with sodium bicarbonate (aq). The resulting solution was extracted with 2x300 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 32 g (91 %) of the desired product as a yellow solid.

Intermediate I34

2-amino-5-[(methylsulfanyl)methyl]thiophene-3-carboxamide

Figure imgf000096_0002

3-(methylsulfanyl)propanal (10.7 g, 103 mmol) [CAS 3268-49-3] was dissolved in DMF (83 ml), 2-cyanoacetamide (8.64 g, 103 mmol), sulfur (3.29 g, 103 mmol) and triethylamine (17 ml) were added. The mixture was stirred for 24 h at RT. All solvents were evaporated and the crude reaction product was used without further purification.

LC-MS (method 8): Rt = 0.70 min; MS (ESIpos): m/z = 202 [M+H]+ The following intermediate was prepared analogous to intermediate 134 starting from the corresponding aldehyde.

Figure imgf000097_0002

Intermediate I36

6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin

Figure imgf000097_0001

Into a 500-ml round-bottom flask, was placed methyl 3-amino-5-(2,2,2-trifluoroethyl)thiophene- 2-carboxylate (intermediate I33) (32 g, 133.77 mmol, 1 .00 equiv), 2-methoxyethan-1 -ol (300 ml), acetic acid; methanimidamide (55.7 g, 535.02 mmol, 4.00 equiv). The resulting solution was stirred for 4 h at 120°C. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 300 ml of water/ice and stirred 30 min. The solids were collected by filtration and washed with 1x100 ml of water. This resulted in 20 g (64% yield) of 6-(2,2,2-trifluoroethyl)-3H,4H-thieno[3,2- d]pyrimidin-4-one as a grey solid.

LC-MS (method 4): Rt = 0.74 min; MS (ESIpos): m/z = 235 [M+H]+

Intermediate I37

6-[(methylsulfanyl)methyl]thieno[2,3-d]pyrimidin-4(3H)-one

Figure imgf000098_0001

2-amino-5-[(methylsulfanyl)methyl]thiophene-3-carboxamide (20.0 g, 98.9 mmol, intermediate 1110) was dissolved in acetic acid (50 ml) and (diethoxymethoxy)ethane (69 ml, 410 mmol) was added. The mixture was refluxed for 4h. After cooling to RT 100 mg hexane/ ethyl acetate (1 :1 ) was added and after stirring for 30 min at 0°C the precipitate was filtered off. The product was washed with 50 ml hexane/ ethyl acetate (1 :1 ) and dried in vacuum to yield the desired product as a beige colored solid (7.3 g, 35% yield).

LC-MS (method 2): Rt = 0.62 min; MS (ESIpos): m/z = 213 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1 .907 (0.58), 2.016 (16.00), 2.048 (0.26), 2.518 (1 .63), 2.522 (1 .06), 3.584 (0.31 ), 3.991 (4.88), 3.993 (5.20), 7.253 (3.28), 8.087 (1 .39), 8.096 (1 .48), 12.490 (0.26).

Intermediate I38

methyl (4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)acetate

Figure imgf000098_0002
A mixture of methyl (5-amino-4-carbamoylthiophen-2-yl)acetate (2.14 g, 9.89 mmol, intermediate 1111 ) in 8.5 ml acetic acid was treated with trimethoxymethane (6.5 ml, 59 mmol) in the microwave at 120 °C for 5 h. The crude reaction mixture was evaporated to dryness. MTBE (30 ml) was added and the resulting mixture was filtered and washed with MTBE. After drying of the solid 2.08 g (85 % purity, 80 % yield) of the desired product was obtained.

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.66 (s, 3H), 4.05 (d, 2H), 7.26 (s, 1 H), 8.09 (s, 1 H), 12.46 (br s, 1 H).

LC-MS (method 1 ): Rt = 0.64 min; MS (ESIpos): m/z = 225 [M+H]+

Intermediate I39

4-chloro-6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidine

Figure imgf000099_0001

Into a 500-ml round-bottom flask, was placed 6-(2,2,2-trifluoroethyl)-3H,4H-thieno[3,2- d]pyrimidin-4-one (intermediate 134) (20 g, 85.40 mmol, 1.00 equiv), methylbenzene (300 ml), DIEA (40 ml, 3.60 equiv), phosphorus oxychloride (40 ml, 2.94 equiv). The resulting solution was stirred for 4 h at 80°C. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :10). This resulted in 1 1 g (51 %) of 4-chloro-6-(2,2,2- trifluoroethyl)thieno[3,2-d]pyrimidine as a light yellow solid.

LC-MS (method 4): Rt = 2.13 min; MS (ESIpos): m/z = 253 [M+H]+

H-NMR (300 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1 H), 7.79 (s, 1 H), 4.37 (q, 2H).

The following intermediate was prepared analogous to intermediate I8 starting from 4-chloro-6- (2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidine by reacting with the corresponding spirocyclic amine.

Figure imgf000099_0002
The following intermediates were prepared analogous to intermediate 126 starting from the corresponding 6-substituted thieno[2,3-d]pyrimidin-4(3H)-ones 137 and 138 by reacting with the corresponding spirocyclic amines.

Figure imgf000100_0001
The following intermediate was prepared analogous to intermediate I8 starting from 7-chloro-2- (2,2,2-trifluoroethyl)-[1 ,3]thiazolo[5,4-d]pyrimidine (CAS # 1935198-98-3) by reacting with the corresponding spirocyclic amine. InterStructure

Analytical Data

mediate Name

N

LC-MS (method 4): Rt = 1.42 min; MS (ESIneg): m/z = 442 [M+H]-

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.39

143 0 CH3 (br d, 10H), 1.84 - 2.08 (m, 5H), 3.21 - 3.31 (m,

3H), 3.35 - 3.41 (m, 2H), 3.65 (br d, 1 H), 3.77 (brs, 1H), 4.04 (d, 1H), 4.18 (brs, 1H), 4.37 (q, tert-butyl 7-[2-(2,2,2- 2H), 8.39 (brd, 1H).

trifluoroethyl)[1,3]thiazolo[5,4- d]pyrimidin-7-yl]-2,7- diazaspiro[4.4]nonane-2- carboxylate

The following intermediates were prepared analogous to intermediate I9 starting from intermediate I40.

Figure imgf000101_0001
Figure imgf000102_0001

d]pyrimidine hydrochloride Intermediate 148

2-amino-5-(2,2-difluoropropyl)thiophene-3-carboxamide

Figure imgf000103_0001
To a solution of 4,4-difluoropentanal (10.0 g) in DMF (85 mL) was sequentially added 2- cyanoacetamide (6.54 g), sulfur (2.49 g) and triethylamine (15 mL) and the mixture was stirred at room temperature for 3 d. The reaction was concentrated to yield the title compound (22.1 g) that was contaminated by some impurities and used without further purification.

LC-MS (method 4): Rt = 0.75 min; MS (ESIpos): m/z = 221 [M+H]+

Intermediate I49

6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidin-4(3H)-one

Figure imgf000103_0002

A mixture of 2-amino-5-(2,2-difluoropropyl)thiophene-3-carboxamide (22.1 g) and (diethoxymethoxy)ethane (70 mL) was treated with acetic acid (56 mL) and stirred at 1 15 °C over night. The mixture was allowed to cool to room temperature and hexane and ethyl acetate (v/v = 1 :1 , 50 mL) was added and the mixture was stirred for 30 min. The resulting prepicated was filtered off and the filter cake was washed with hexane and ethyl acetate (v/v = 1 :1 ) to yield the title compound (9.13 g) as a greyish solid.

LC-MS (method 4): Rt = 0.52 min; MS (ESIpos): m/z = 231 [M+H]+

1H NMR (400 MHz, DMSO-cfe, 22°C) δ ppm 1.55 - 1.74 (m, 3 H), 3.50 - 3.65 (m, 2 H), 7.22 - 7.31 (m, 1 H), 8.06 - 8.15 (m, 1 H), 12.37 - 12.59 (m, 1 H).

Intermediate I50 4-chloro-6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidine

Figure imgf000104_0001

A mixture of 6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidin-4(3H)-one (2.00 g) and phosphoric trichloride (16 ml.) was heated at reflux for 4.5 h. The mixture was allowed to cool to room temperature and concentrated. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted with dichlormethane. The combined organic layers were dried and concentrated to yield the title compound (2.10 g).

LC-MS (method 20): Rt = 1 .14 min; MS (ESIpos): m/z = 249 [M+H]+

1H NMR (400 MHz, DMSO-cfe, 22°C) δ ppm 1.61 - 1.76 (m, 3 H), 3.69 - 3.87 (m, 2 H), 7.45 - 7.58 (m, 1 H), 8.87 - 8.98 (m, 1 H).

Intermediate 151

(rac)-tert-butyl 7-[6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]nonane-2-carboxylate

Figure imgf000104_0002

To a solution of 4-chloro-6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidine (300 mg) and tert-butyl (rac)-2,7-diazaspiro[4.4]nonane-2-carboxylate (328 mg) in DMF (9.0 ml.) was added N,N- diisopropylethylamine (630 μΙ_) and the mixture was stirred for 2 h at 80 °C. The mixture was allowed to cool to room temperature and diluted with water. The mixture was extracted with ethyl acetate and the layers were separated. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the crude title compound (700 mg) that was contaminated by some DMF and used without further purification.

LC-MS (method 4): Rt = 1.28 min; MS (ESIpos): m/z = 439 [M+H]+

1H NMR (400 MHz, DMSO-cfe, 22°C) δ ppm 1.34 - 1.44 (m, 0 H), 1.57 - 1 .72 (m, 3 H), 1 .82 - 2.06 (m, 4 H), 3.22 - 3.31 (m, 2 H), 3.35 - 3.41 (m, 2 H), 3.51 - 3.62 (m, 2 H), 3.64 - 3.95 (m, 4 H), 7.53 - 7.61 (m, 1 H), 8.29 - 8.36 (m, 1 H)

Intermediate I52

(rac)-4-[(27-diazaspiro[4.4]non-2-yl]-6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidine hydrochloride (1 :1 )

Figure imgf000105_0001

To a suspension of tert-butyl (rac)-7-[6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]nonane-2-carboxylate (700 mg) in methanol (4.7 mL) at room temperature was added hydrochloric acid (4 M solution in 1 ,4-dioxane, 1 .4 mL) and the mixture was stirred for 16 h. The reaction mixture was concentrated to yield the title compound (678 mg) that was used without further purification.

LC-MS (method 4): Rt = 0.94 min; MS (ESIpos): m/z = 339 [M+H]+

Intermediate I53

(4-Acetylphenyl)acetonitrile

Figure imgf000105_0002

A solution of (4-bromophenyl)acetonitrile (200 mg, 1 .02 mmol), in 1 ,4-dioxane (5 mL), was degassed with argon for 15 min. Tributyl(1-ethoxyvinyl)stannane (442 mg, 1 .22 mmol) and dichlorobis(triphenylphosphine)palladium(ll) (35.8 mg, 0.0510 mmol) were added and the mixture heated at 90 °C for 6 h. The reaction mixture was cooled to room temperature, filtered through celite, washed through with ethyl acetate and concentrated to give a residue. The residue was dissolved in tetrahydrofuran (10 ml.) and hydrochloric acid (1 M aqueous, 2 ml_, 2 mmol) was added and stirred at room temperature for 1 h. The reaction was poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: ethyl acetate-heptane 2:8 to 25:75) to give the desired product (104 mg, 64%).

1 H NMR (400 MHz, CDCI3): δ [ppm] = 2.61 (s, 3H), 3.82 (s, 2H), 7.44 (d, 2H), 7.97 (d, 2H); UPLC-MS (method 14): Rt = 0.63 min., 95%. MS (ESIneg): m/z = (M-H)- 158.

Intermediate I54

1-(4-Vinylphenyl)cyclopropanecarbonitrile

Figure imgf000106_0001
To a solution of (4-vinylphenyl)acetonitrile, 1.01 g (7.05 mmol), in toluene, 10.1 ml_, was added tetra-n-butylammonium hydroxide, 568 mg (1 .76 mmol), sodium hydroxide, 3.03 g (75.8 mmol), and water, 10.1 ml_. The reaction mixture was stirred at room temperature for 18 hours then diluted with ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: heptane- ethyl acetate; 100:0, 40:1 ) to give the desired product (162 mg, 14%).

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1 .37-1.42 (m, 2H), 1.70-1 .75 (m, 2H), 5.26 (dd, 1 H), 5.74 (dd, 1 H), 6.68 (dd, 1 H), 7.21 -7.26 (m, 2H), 7.36-7.40 (m, 2H);

UPLC-MS (method 13): Rt = 0.89 min., 96.79%. MS (ESIpos): m/z = (2M+H)+ 339. PEAX198-

3.

Intermediate I55

1-(4-Formylphenyl)cyclopropanecarbonitrile

Figure imgf000107_0001

1-(4-Vinylphenyl)cyclopropanecarbonitrile, 162 mg (957 μηιοΙ), was dissolved in a mixture 1 ,4- dioxane, 10 mL, and water, 6.25 mL. Sodium periodate, 410 mg (1.92 mmol), and osmium tetroxide (2.5 wt% in 2-methyl-2-propanol), 488 μί (59.2 μηηοΙ), were added and the reaction mixture stirred at room temperature for 1 .5 hours. Aqueous sodium thiosulfate (10 wt%) was added and the mixture extracted with dichloromethane. The combined organics were dried over sodium sulfate and concentrated under vacuum to give the desired product (169 mg, 103%), which was used without further purification.

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1.51 (d, 1 H), 1 .53 (d, 1 H), 1 .85 (d, 1 H), 1.87 (d, 1 H), 7.43 (d, 2H), 7.87 (d, 2H), 10.00 (s, 1 H); UPLC-MS (method 14): Rt = 0.69 min., 88.5% (does not ionise).

Intemediate I56

Ethyl 4-(trifluoroacetyl)-1 H-pyrrole-2-carboxylate

Figure imgf000107_0002

To a stirring solution of ethyl 1 /-/-pyrrole-2-carboxylate (20.0 g, 144 mmol) in N,N- dimethylformamide (200 mL) was added trifluoroacetic anhydride (26.4 mL, 187 mmol). The reaction mixture was heated to 80 °C overnight. The mixture was cooled to room temperature then poured into water and stirred for 15 min. The precipitate was then collected by filtration under vacuum, then dried in a vacuum oven overnight (50 °C), to give the desired product (20.8 g, 62%, 1 :1 mixture of isomers). Second crop from the filtrate gave (1.32 g, 4%) of desired product which was used in the next step without purification.

Desired isomer ethyl 4-(trifluoroacetyl)-1H-pyrrole-2-carboxylate: 1H NMR (400 MHz, CDCI3): δ [ppm] = 1.38 (t, 3H), 4.38 (q, 2H), 7.42 (s, 1 H), 7.73 (s, 1 H), 9.91 (br s, 1 H); UPLC-MS (method 21 ): Rt = 0.69 min., 74%. MS (ESIneg) m/z = (M-H)- 234. Undesired isomer: 1H NMR (400 MHz, CDCIs): δ [ppm] = 1.39 (t, 3H), 4.37 (q, 2H), 6.95 (dd, 1 H), 7.14-7.16 (m, 1 H), 10.00 (br s, 1 H). Intermediate 157

Ethyl 4-(pentafluoroethyl)-1 H-pyrrole-2-carboxylate

Figure imgf000108_0001
To a stirring solution of ethyl 4-(trifluoroacetyl)-1 /-/-pyrrole-2-carboxylate (1 .32 g, 5.61 mmol), in dichloromethane (19.8 mL) at 0 °C was added drop-wise diethylaminosulfur trifluoride, (1 .63 mL, 12.4 mmol). The reaction was allowed to warm to room temperature over 18 h. The mixture was added drop-wise to ice/water and then diluted with dichloromethane. The organic extracts were washed with sodium carbonate saturated solution then brine. The organics were dried over magnesium sulfate and concentrated under vacuum to give the desired product (1 .19 g, 82%). The product was used in the next step without purification.

1H NMR (400 MHz, CDCI3): δ [ppm] = 1 .37 (t, 3H), 4.34 (q, 2H), 7.06 (s, 1 H), 7.22-7.24 (m, 1 H), 9.46 (br s, 1 H); UPLC-MS (method 22): Rt = 0.82 min., 94%. MS (ESIneg) m/z = (M-H)- 256.

Intermediate I58

Ethyl 1-amino-4-(pentafluoroethyl)-1 H-pyrrole-2-carboxylate

Figure imgf000108_0002

To a vigorously stirred mixture of ethyl 4-(pentafluoroethyl)-1 /-/-pyrrole-2-carboxylate (1 .19 g, 4.63 mmol) ammonium chloride (1 .54 g, 28.7 mmol), ammonium hydroxide solution (4.30 mL, Aliquat-336, 58.0 μί, 0.129 mmol), sodium hydroxide (28% w/w aqueous solution, 13.3 mL) and tert-butyl methyl ether (31 .0 mL) was added drop-wise sodium hypochlorite (14% aqueous solution, 30.9 mL). The reaction mixture was then stirred at room temperature for 1 h. The phases were separated and the organic extracts were washed with sodium thiosulfate (10% aqueous solution), followed by brine. The organic layer was dried over magnesium sulfate and concentrated under vacuum to give the desired product (1 .08 g, 86%) that was used in the next reaction without any purification.

1H NMR (400 MHz, CDCI3): δ [ppm] = 1 .36 (t, 3H), 4.31 (q, 2H), 5.63 (s, 2H), 6.99 (d, 1 H), 7.22 (s, 1 H); UPLC-MS (method 22): Rt = 0.81 min., 80%. MS (ESIpos): m/z = (M+H)+ 273.

Intermediate I59

6-(Pentaf luoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol

Figure imgf000109_0001

A stirring solution of ethyl 1-amino-4-(pentafluoroethyl)-1 /-/-pyrrole-2-carboxylate (1.08 g, 3.97 mmol), and formamidinium acetate (496 mg, 4.76 mmol), in 1 -butanol (25.0 mL) and N,N- diisopropylethylamine (25.0 mL) was heated to 120 °C for 24 hours. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel 60 (eluent: heptane-ethyl acetate 3:2, 0:1 ) to give the desired product (475 mg, 47%).

1H NMR (400 MHz, CDCI3): δ [ppm] = 7.26 (d, 1 H), 7.60 (d, 1 H), 7.70 (s, 1 H), 9.36 (br s, 1 H); UPLC-MS (method 22): Rt = 0.61 min., 98%. MS (ESIneg) m/z = (M-H)- 252.

Intermediate I60

(rac)-ieri- Butyl 7-[6-(pentaf luoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin

diazaspiro[4.4]nonane-2-carboxylate

Figure imgf000109_0002

To a stirring solution of 6-(pentafluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (150 mg, 0.593 mmol) in acetonitrile (2.95 mL) and trimethylamine (1.69 mL) was added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (339 mg, 0.652 mmol), and (rac)-tert- butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (134 mg, 0.593 mmol) at room temperature. The mixture was heated to 80 °C for 18 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was then dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: heptane-ethyl acetate 1 :1 ) to give the desired product (219 mg, 80%).

1H NMR (400 MHz, CDCI3): δ [ppm] = 1.45 (s, 9H), 1 .93-2.19 (m, 4H), 3.32-3.51 (m, 4H), 3.67- 4.1 1 (m, 4H), 6.83-6.99 (m, 1 H), 7.79 (s, 1 H), 7.88 (s, 1 H); UPLC-MS (method 23): Rt = 1 .09 min., 98%. MS (ESIpos): m/z = (M+H)+ 462.

Intermediate 161

(rac)-4-(2,7-Diazaspiro[4.4]non-2-yl)-6-(pentafluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine hydrochloride (1 :3)

Figure imgf000110_0001
To a stirring solution of (rac)-te/t-butyl 7-[6-(pentafluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]- 2,7-diazaspiro[4.4]nonane-2-carboxylate, (219 mg, 0.475 mmol) in 1-4-dioxane (0.46 mL) was added hydrochloric acid (4 M in 1 ,4-dioxane, 1.19 mL, 4.75 mmol) at room temperature and stirring was continued for 1 h. The reaction was concentrated under vacuum to give the desired product as a trihydrochloride salt, 189 mg (100%) that was used directly in the next reaction without purification

1H NMR (400 MHz, DMSO-d6): δ [ppm] = 1 .88-2.05 (m, 4H), 3.10-3.38 (m, 4H), 3.91-4.06 (m, 2H), 7.15 (d, 1 H), 7.93 (d, 1 H), 8.23 (s, 1 H) - 2H obscured by NMR solvent; UPLC-MS (method 23): Rt = 0.73 min., 100%. MS (ESIpos): m/z = (M+H)+ 362.

EXPERIMENTAL SECTION - EXAMPLES Example 1 4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile

Figure imgf000111_0001

To a suspension of 80 mg (158 μηηοΙ) 4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine trifluoroacetate (intermediate 111 ) in 2 ml dichloromethane was added 48 μΙ triethylamine (347 μηηοΙ) followed by 21 mg (158 μηηοΙ) 4-formylbenzonitrile and 62 mg (292 μηηοΙ) sodium triacetoxyborohydride [CAS 56553-60-7] and the mixture was stirred for 17 h at RT. The volatile components were removed by evaporation and the residue was purified by preparative HPLC to yield 36 mg (44 %) of the desired product.

LC-MS (method 12): Rt = 0.77 min; m/z = 458 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .796 (0.46), 1.808 (1.08), 1 .828 (1.71 ), 1.844 (1 .74), 1.863 (0.85), 1 .879 (0.41 ), 2.003 (0.81 ), 2.322 (0.46), 2.327 (0.65), 2.332 (0.54), 2.454 (2.35), 2.477 (3.94), 2.518 (2.23), 2.523 (1 .71 ), 2.539 (3.37), 2.558 (2.12), 2.581 (2.20), 2.601 (0.64), 2.621 (0.74), 2.641 (1 .32), 2.659 (1 .02), 2.664 (1.07), 2.669 (0.85), 2.673 (0.65), 2.678 (0.58), 3.630 (0.65), 3.642 (1 .04), 3.678 (4.07), 3.691 (4.42), 3.726 (1.37), 4.020 (0.75), 4.048 (2.08), 4.076 (2.01 ), 4.103 (0.67), 7.513 (5.18), 7.534 (6.06), 7.690 (4.65), 7.768 (7.51 ), 7.772 (2.39), 7.784 (2.47), 7.789 (6.23), 8.312 (16.00).

The following examples were prepared analogous to the preparation of example 1 starting from intermediate 111 by reacting with the corresponding aldehydes.

Example Structure Analytical Data

Name

H-NMR (400 MHz, DMSO-d6) δ [ppm]:

1.795 (0.39) , 1.807 (1 .01 1 .822 (1.43)

1.827 (1.57) , 1.843 (1 .59 1 .863 (0.78)

2.002 (0.73) , 2.322 (0.62 2.327 (0.92)

2.332 (0.64) , 2.452 (2.13 2.475 (3.38)

2.518 (3.16) , 2.523 (2.27 2.539 (1.01 )

2.558 (1.99) , 2.575 (1 .51 2.619 (0.73)

2.639 (1.29) , 2.654 (0.98 2.660 (0.95)

2.664 (0.92) , 2.669 (1 .03 2.673 (0.90)

3.599 (0.48) , 3.613 (0.87 3.646 (3.64)

Figure imgf000112_0001
3.661 (3.94) , 3.694 (1 .17 3.767 (0.70)

3-({(7-[6-(2,2,2- 4.019 (0.76) , 4.047 (2.07 4.074 (1.99) trifluoroethyl)thieno[2,3-d]pyrimidin-4- 4.102 (0.64) , 7.51 1 (1 .48 7.530 (3.50) yl]-2,7-diazaspiro[4.4]non-2- 7.549 (2.29) , 7.662 (2.18 7.682 (1.90) yl}methyl)benzonitrile 7.693 (4.42) , 7.699 (2.52 7.703 (2.99)

7.706 (1.87) , 7.719 (1 .37 7.722 (2.27)

7.725 (1.43) , 7.751 (3.78 8.312 (16.00)

LC-MS (mel hod 2): Rt = 0.77 min; m/z =

458 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]:

1.788 (0.61 ), 1.800 (1.42), 1.820 (2.19),

1.836 (2.23), 1.855 (1.05) 1.992 (1.01 ),

2.322 (0.97), 2.326 (1.34) 2.331 (0.89),

2.444 (2.67), 2.467 (4.94) 2.518 (4.82),

2.522 (3.36), 2.544 (2.47) 2.559 (2.1 1 ),

2.575 (2.15), 2.595 (0.89) 2.616 (1.01 ) ,

2.635 (1.82), 2.651 (1.42) 2.659 (1.22),

2.664 (1.22), 2.669 (1.58) 2.673 (1.46),

Figure imgf000112_0002
3.369 (0.45), 3.561 (1.01 ) 3.595 (6.16),

[3-({7-[6-(2,2,2- 3.604 (6.12), 3.637 (1.30) 3.757 (1.09), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 4.019 (16.00), 4.045 (2.96), 4.073 (2.79), yl]-2,7-diazaspiro[4.4]non-2- 4.100 (0.93), 7.197 (2.23) 7.215 (3.04), yl}methyl)phenyl]acetonitrile 7.257 (1.94), 7.276 (3.40) 7.303 (5.02) ,

7.313 (3.81 ), 7.332 (4.33) 7.351 (1.50), Example Structure Analytical Data

Name

7.688 (6.40), 8.310 (15.84).

LC-MS (method 2): Rt = 0.77 min; m/z =

472 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]:

1.780 (0.58), 1.793 (1.39), 1.812 (2.27),

1.828 (2.36), 1.847 (1.12), 1.862 (0.55),

F F 1.987 (1.08), 2.322 (0.49), 2.326 (0.66),

2.331 (0.48), 2.413 (2.46), 2.435 (3.51 ),

2.518 (3.12), 2.522 (2.91 ), 2.539 (2.24),

2.554 (2.13), 2.576 (0.74), 2.610 (0.95),

2.629 (1.73), 2.644 (1.35), 2.668 (1.05),

4

3.521 (0.46), 3.547 (0.52), 3.582 (9.24),

3.615 (0.76), 3.743 (1 .07), 3.996 (16.00),

[4-({7-[6-(2,2,2- 4.019 (1.08), 4.046 (2.55), 4.074 (2.48), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 4.102 (0.85), 7.267 (4.30), 7.287 (8.85), yl]-2,7-diazaspiro[4.4]non-2- 7.322 (9.08), 7.343 (4.19), 7.688 (5.94), yl}methyl)phenyl]acetonitrile 8.309 (14.86).

LC-MS (method 2): Rt = 0.76 min; m/z = 472 (M+H)+ separation of example 4 by chiral chromatography afforded 4.1 and its

[4-({7-[6-(2,2,2- enantiomer 4.2.

trifluoroethyl)thieno[2,3-d]pyrimidin-4-

4.1 prep. HPLC (method A)

yl]-2,7-diazaspiro[4.4]non-2- analyt. HPLC (method 5): Rt = 5.17 min yl}methyl)phenyl]acetonitrile (ent-1 )

optical rotation: [a]D 20 = -36.7° +/-0.690 (c = 1.00; chloroform) prep. HPLC (method A)

[4-({7-[6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4- analyt. HPLC (method 5): Rt = 5.64 min

4.2

yl]-2,7-diazaspiro[4.4]non-2- optical rotation: [a]D 20 = 17.0° +/-0.340 (c yl}methyl)phenyl]acetonitrile (ent-2) = 1.00; chloroform) Example Structure Analytical Data

Name

1 H-NMR (400 MHz, DMS0-d6) delta [ppm]: 1 .450 (2.44), 1 .463 (8.31 ), 1 .469 (8.15), 1.482 (3.26), 1 .704 (3.23), 1 .715 (8.60), 1.722 (8.47), 1 .734 (2.74), 1 .755 (0.59), 1.762 (0.62), 1 .773 (0.81 ), 1 .790 (1 .60), 1.810 (2.61 ), 1 .826 (2.74), 1 .845 (1 .34), 1.861 (0.81 ), 1 .986 (1 .24), 2.074 (0.55), 2.323 (1 .37), 2.327 (1 .89), 2.331 (1 .40), 2.414 (2.77), 2.437 (3.94), 2.518 (14.63), 2.523 (10.88), 2.549 (3.03),

5 2.574 (1.01 ), 2.603 (1.14), 2.622 (2.12),

2.637 (1.63), 2.659 (1.21 ), 2.665 (1.56), 2.669 (2.02), 2.673 (1.47), 3.540 (0.65),

Figure imgf000114_0001

3.576 (9.25), 3.61 1 (0.98), 3.740 (1.17),

1 -[4-({7-[6-(2,2,2- 4.021 (1.08), 4.049 (2.90), 4.076 (2.84), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 4.103 (1.01 ), 7.248 (5.57), 7.269 (10.82), yl]-2,7-diazaspiro[4.4]non-2- 7.312 (10.13), 7.332 (5.25), 7.689 (6.97), yl}methyl)phenyl]cyclopropanecarboni

8.309 (16.00).

trile

LC-MS (method 2): Rt = 0.78 min; m/z = 498 (M+H)+ separation of example 5 by chiral chromatography afforded 5.1 and its

1 -[4-({7-[6-(2,2,2- enantiomer 5.2.

trifluoroethyl)thieno[2,3-d]pyrimidin-4-

5.1 prep. HPLC (method B)

yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarboni analyt. HPLC (method 6): Rt = 2.84 min trile (ent-1 )

optical rotation: [a]D 20 = -36.6° +/-0.540 (c = 1.00; chloroform)

1 -[4-({7-[6-(2,2,2- prep. HPLC (method B)

trifluoroethyl)thieno[2,3-d]pyrimidin-4- analyt. HPLC (method 6): Rt = 3.07 min

5.2 yl]-2,7-diazaspiro[4.4]non-2- optical rotation: [a]D 20 = 43.1 ° +/-0.880 (c yl}methyl)phenyl]cyclopropanecarboni

= 1.00; chloroform)

trile (ent-2) Example Structure Analytical Data

Name

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]:

1.791 (0.60), 1.804 (1.54), 1.823 (2.53),

1.840 (2.60), 1.858 (1.30), 1.874 (0.63),

1.996 (1.23), 2.323 (1.40), 2.327 (2.04),

2.331 (1.47), 2.441 (2.88), 2.464 (4.1 1 ),

2.518 (13.75), 2.523 (9.26), 2.551 (3.12),

2.574 (3.02), 2.594 (1.05), 2.619 (1.16),

2.638 (2.14), 2.653 (1.61 ), 2.659 (1.79),

6 2.665 (1.93), 2.669 (2.39), 2.673 (2.07),

3.597 (1.30), 3.631 (5.58), 3.643 (6.04),

3.678 (1.89), 3.761 (1.19), 4.021 (1.02),

4.049 (2.77), 4.077 (2.74), 4.104 (0.98),

Figure imgf000115_0001

7.301 (2.74), 7.367 (7.37), 7.388 (8.14),

4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3- 7.693 (6.32), 7.799 (9.37), 7.820 (8.42), d]pyrimidin-4-yl]-2,7- 7.91 1 (2.81 ), 8.312 (16.00).

diazaspiro[4.4]non-2- yl}methyl)benzamide LC-MS (method 2): Rt = 0.60 min; m/z =

476 (M+H)+ separation of example 6 by chiral chromatography afforded 6.1 and its

4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3- enantiomer 6.2.

d]pyrimidin-4-yl]-2,7-

6.1 prep. HPLC (method D)

diazaspiro[4.4]non-2- analyt. HPLC (method 8): Rt = 5.10 min yl}methyl)benzamide (ent-1 )

optical rotation: [a]D 20 = -36.8° +/-0.320 (c = 1.00; chloroform) prep. HPLC (method D)

4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- analyt. HPLC (method 8): Rt = 5.97 min

6.2

diazaspiro[4.4]non-2- optical rotation: [a]D 20 = 37.8° +/-0.540 (c yl}methyl)benzamide (ent-2) = 1.00; chloroform) Example Structure Analytical Data

Name

1 H-NMR (400 MHz, DMSO-d6) delta

[ppm]: 1 .661 (16.00), 1 .798 (0.35), 1 .817

(0.61 ), 1.833 (0.64), 1 .851 (0.30), 1 .996

(0.27), 2.323 (0.36), 2.327 (0.52), 2.331

(0.39), 2.431 (0.57), 2.454 (0.84), 2.518

(3.91 ), 2.523 (2.60), 2.546 (0.97), 2.568

(0.80), 2.618 (0.26), 2.637 (0.47), 2.652

7 (0.37), 2.659 (0.43), 2.665 (0.47), 2.669

Figure imgf000116_0001

(0.61 ), 2.673 (0.54), 3.593 (2.39), 3.628

2-methyl-2-[4-({7-[6-(2,2,2- (0.22), 3.756 (0.26), 4.022 (0.24), 4.050 trifluoroethyl)thieno[2,3-d]pyrimidin-4- (0.63), 4.078 (0.62), 4.106 (0.22), 7.350 yl]-2,7-diazaspiro[4.4]non-2- (1 .31 ), 7.370 (2.09), 7.438 (2.26), 7.459 yl}methyl)phenyl]propanenitrile (1 .38), 7.693 (1.51 ), 8.31 1 (3.94).

LC-MS (method 2): Rt = 0.80 min; m/z = 500 (M+H)+ separation of example 7 by chiral chromatography afforded 7.1 and its

2-methyl-2-[4-({(5S)-7-[6-(2,2,2- enantiomer 7.2.

trifluoroethyl)thieno[2,3-d]pyrimidin-4-

7.1 prep. HPLC (method E)

yl]-2,7-diazaspiro[4.4]non-2- analyt. HPLC (method 9): Rt = 2.21 min yl}methyl)phenyl]propanenitrile (ent-1 )

optical rotation: [a]D 20 = -36.5° +/-0.530 (c = 1.00; chloroform) prep. HPLC (method E)

2-methyl-2-[4-({(5S)-7-[6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4- analyt. HPLC (method 9): Rt = 5.01 min

7.2

yl]-2,7-diazaspiro[4.4]non-2- optical rotation: [a]D 20 = 25.5° +/-0.290 (c yl}methyl)phenyl]propanenitrile (ent-2)

= 1.00; chloroform)

Figure imgf000117_0001

d]pyrimidine 533 (M+H)+ Example Structure Analytical Data

Name

separation of example 9 by chiral chromatography afforded 9.1 and its

4-{7-[3-chloro-4-(1 H-imidazol-1- enantiomer 9.2.

yl)benzyl]-2,7-diazaspiro[4.4]non-2-

9.1 prep. HPLC (method D)

yl}-6-(2,2,2-trifluoroethyl)thieno[2,3- analyt. HPLC (method 7): Rt = 4.81 min d]pyrimidine (ent-1 )

optical rotation: [a]D 20 = -27.4° +/-0.460 (c = 1.00; chloroform) prep. HPLC (method D)

4-{7-[3-chloro-4-(1 H-imidazol-1- yl)benzyl]-2,7-diazaspiro[4.4]non-2- analyt. HPLC (method 7): Rt = 5.46 min

9.2

yl}-6-(2,2,2-trifluoroethyl)thieno[2,3- optical rotation: [a]D 20 = 30.7° +/-0.590 (c d]pyrimidine (ent-2) = 1.00; chloroform)

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.797 (0.67), 1.810 (1.70), 1.829 (2.77),

F F

1.845 (2.84), 1.864 (1.42), 1.879 (0.75), 1.897 (0.46), 2.000 (1.38), 2.069 (0.75), 2.318 (0.99), 2.323 (1.35), 2.327 (0.99), 2.452 (3.41 ), 2.476 (6.24), 2.518 (5.89), 2.566 (3.09), 2.589 (3.26), 2.610 (1.06), 2.638 (1.21 ), 2.657 (2.77), 2.665 (2.16),

10 2.670 (2.38), 2.694 (0.71 ), 3.609 (1.17),

3.643 (7.27), 3.650 (7.66), 3.683 (1.74), 3.760 (1.35), 4.016 (1.17), 4.042 (3.09), 4.070 (3.02), 4.098 (1.06), 7.477 (7.77), 7.498 (8.87), 7.689 (6.53), 7.779 (10.57), 7.800 (8.90), 8.213 (15.08), 8.307

4-{7-[4-(1 H-1 ,2,4-triazol-1 -yl)benzyl]- (16.00), 9.251 (15.86).

2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine LC-MS (method 2): Rt = 0.67 min; m/z =

500 (M+H)+

4-{7-[4-(1 H-1 ,2,4-triazol-1 -yl)benzyl]- separation of example 10 by chiral

10.1 2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- chromatography afforded 10.1 and its trifluoroethyl)thieno[2,3-d]pyrimidine enantiomer 10.2. Example Structure Analytical Data

Name

(ent-1 ) prep. HPLC (method C)

analyt. HPLC (method 3): Rt = 2.56 min optical rotation: [a]D 20 = 30.8° +/-0.670 (c = 1.00; chloroform) prep. HPLC (method C)

4-{7-[4-(1 H-1 ,2,4-triazol-1 -yl)benzyl]- 2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- analyt. HPLC (method 3): Rt = 3.13 min

10.2

trifluoroethyl)thieno[2,3-d]pyrimidine optical rotation: [a]D 20 = -30.1 ° +/-0.490 (c

(ent-2) = 1.00; chloroform)

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.801 (0.44), 1.813 (1.18), 1.833 (1.96), 1.849 (2.09), 1.867 (0.97), 1.882 (0.47), 2.005 (0.81 ), 2.318 (0.50), 2.322 (1.07),

F F

2.327 (1.49), 2.332 (1.10), 2.336 (0.50), 2.518 (7.56), 2.523 (5.96), 2.526 (4.55), 2.589 (0.60), 2.605 (2.90), 2.627 (2.82), 2.647 (0.76), 2.660 (0.60), 2.664 (1.20), 2.669 (1.83), 2.673 (1.91 ), 2.693 (1.54),

11

2.709 (1.15), 2.730 (0.44), 3.662 (0.78),

CI 3.699 (8.47), 3.736 (1.05), 4.020 (0.94),

4.040 (14.88), 4.076 (2.41 ), 4.103 (0.81 ),

[3-chloro-4-({7-[6-(2,2,2- 7.293 (1.75), 7.297 (1.86), 7.313 (2.12), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 7.317 (2.22), 7.414 (4.76), 7.418 (4.47), yl]-2,7-diazaspiro[4.4]non-2- 7.516 (3.97), 7.535 (3.29), 7.695 (5.75), yl}methyl)phenyl]acetonitrile

8.314 (16.00).

LC-MS (method 4): Rt = 1.40 min; m/z = 506 (M+H)+ Example Structure Analytical Data

Name

H-NMR (400 MHz, DMS0-d6) δ [ppm]:

1.775 (0.45), 1.788 (1.16), 1.807 (1.90),

1.822 (1.96), 1.841 (0.96), 1.858 (0.48),

1.982 (0.85), 2.323 (0.88), 2.327 (1.30),

2.331 (0.91 ), 2.454 (2.18), 2.477 (4.06),

2.518 (5.48), 2.523 (3.57), 2.546 (0.77),

2.565 (2.52), 2.585 (2.30), 2.603 (0.77), 2.631 (0.82), 2.649 (1.50), 2.665 (2.01 ),

12 2.669 (2.07), 2.686 (0.48), 3.574 (0.51 ),

Figure imgf000120_0001
3.604 (0.54), 3.639 (7.63), 3.674 (0.82),

[3-fluoro-4-({7-[6-(2,2,2- 3.740 (0.85), 4.017 (0.94), 4.045 (16.00), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 4.072 (2.44), 4.099 (0.82), 7.151 (4.06), yl]-2,7-diazaspiro[4.4]non-2- 7.174 (5.56), 7.429 (1.53), 7.449 (2.67), yl}methyl)phenyl]acetonitrile 7.468 (1.25), 7.688 (5.59), 8.309 (10.10).

LC-MS (method 4): Rt = 1.30 min; m/z = 490 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]:

1.800 (0.78), 1.819 (1.27), 1.836 (1.33),

1.854 (0.63), 1.998 (0.57), 2.323 (0.70),

2.327 (0.96), 2.331 (0.67), 2.441 (1.43),

2.465 (2.15), 2.518 (3.58), 2.523 (2.51 ),

2.540 (0.81 ), 2.553 (1.19), 2.573 (1.25),

2.594 (0.42), 2.623 (0.52), 2.642 (1.01 ),

2.659 (0.99), 2.665 (1.22), 2.669 (1.16),

13 2.674 (0.85), 2.678 (0.59), 3.552 (0.50),

Figure imgf000120_0002

3.586 (3.13), 3.594 (3.37), 3.627 (0.68),

1-[4-({7-[6-(2,2,2- 3.747 (0.57), 4.022 (0.52), 4.049 (1.38), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 4.077 (1.32), 4.104 (0.46), 4.221 (8.63), yl]-2,7-diazaspiro[4.4]non-2- 6.820 (6.38), 7.279 (0.70), 7.301 (16.00), yl}methyl)phenyl]methanesulfonamide 7.324 (0.62), 7.693 (3.47), 8.311 (10.09).

LC-MS (method 12): Rt = 1.10 min; MS (ESIpos): m/z = 526 [M+H]+ Example Structure Analytical Data

Name

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.956 (0.54), 0.973 (1.17), 0.991 (0.57),

F F 1.775 (0.60), 1.790 (1.58), 1.809 (2.72),

1.825 (2.92), 1.842 (1.34), 1.858 (0.64), 1.905 (0.50), 1.986 (1.21 ), 2.423 (2.65), 2.446 (3.82), 2.518 (8.55), 2.522 (5.90), 2.539 (3.32), 2.559 (2.85), 2.609 (1.04),

14 2.627 (1.95), 2.643 (1 .48), 3.516 (16.00),

3.559 (7.04), 3.563 (7.18), 3.597 (1.14), 3.728 (1.17), 4.018 (1.04), 4.047 (2.75),

[4-({7-[6-(2,2,2- 4.074 (2.68), 4.101 (0.94), 7.172 (5.33), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 7.192 (10.13), 7.233 (9.66), 7.253 (4.93), yl]-2,7-diazaspiro[4.4]non-2- 7.691 (6.81 ), 8.309 (15.70).

yl}methyl)phenyl]acetic acid

LC-MS (method 12): Rt = 0.64 min; MS (ESIpos): m/z = 491 [M+H]+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.774 (1.48), 1.793 (2.31 ), 1.809 (2.36),

F F

1.829 (1.13), 1.968 (1.27), 2.318 (0.45), 2.323 (1.00), 2.327 (1.38), 2.331 (0.95), 2.337 (0.45), 2.518 (4.99), 2.523 (3.43), 2.538 (0.77), 2.559 (1.48), 2.577 (1.70), 2.600 (2.20), 2.622 (4.13), 2.639 (6.54), 2.659 (5.42), 2.665 (3.04), 2.669 (3.1 1 ),

15

2.673 (2.36), 2.686 (1.32), 2.799 (3.93), 2.818 (5.56), 2.836 (2.59), 3.734 (1.27), 4.027 (1.43), 4.054 (4.02), 4.082 (3.84),

4-(2-{7-[6-(2,2,2- 4.1 10 (1.25), 7.432 (7.42), 7.452 (8.58), trifluoroethyl)thieno[2,3-d]pyrimidin-4- 7.684 (6.26), 7.698 (5.51 ), 7.718 (4.54), yl]-2,7-diazaspiro[4.4]non-2- 8.321 (16.00).

yl}ethyl)benzonitrile LC-MS (method 12): Rt = 1 .33 min; MS

(ESIpos): m/z = 472 [M+H]+ Example 16

2-{methyl[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]amino}ethanol

Figure imgf000122_0001
51 mg (134 μηιοΙ) 4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine trifluoroacetate (intermediate 111 ) was solved in 1 ml NMP, 32 mg (180 μηηοΙ) 4-[(2- hydroxyethyl)(methyl)amino]benzaldehyde dissolved in 0.32 ml NMP was added, then 26 mg triethylamine (255 μηηοΙ) in 0.5 ml NMP, followed by the addition of 59 mg (278 μηηοΙ) sodium triacetoxyborohydride dissolved in 1 ml NMP. The mixture was shaken for 2 days at RT. To the reaction mixture was added 0.14 ml sodium hydroxide solution (2M). After filtration the filtrate was purified by preparative HPLC to yield 16 mg (21 %) of the desired product.

LC-MS (method 1 1 ): Rt = 1.22 min; MS (ESIpos): m/z = 506 [M+H]+

According to the preparation of example 16 the following examples 17-39 were prepared starting from the intermediate 111 by reacting with the corresponding aldehydes.

Figure imgf000122_0002
Figure imgf000123_0001

yl}methyl)naphthalen-2-ol Structure

Example Analytical Data

Name

F LC-MS (method 3): Rt = 1.05 min; m/z = 483

21

(M+H)+

2-chloro-4-({7-[6-(2,2,2- trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenol

F

LC-MS (method 3): Rt = 0.88 min; m/z = 560

22 N-[2-chloro-4-({7-[6-(2,2,2- (M+H)+

trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfon

amide

Figure imgf000124_0001

LC-MS (method 3): Rt = 1.01 min; m/z = 622

23 N-[3-chloro-4-({7-[6-(2,2,2- (M+H)+

trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenyl]benzenesulfon

amide

Figure imgf000125_0001

d]pyrimidine

Figure imgf000126_0001

Figure imgf000127_0001

diazaspiro[4.4]non-2- Structure

Example Analytical Data

Name

yl}methyl)benzonitrile

Figure imgf000128_0001
LC-MS (method 3): Rt = 1.16 min; m/z = 514

34

4-{7-[3-(1 H-1 ,2,4-triazol-1- (M+H)+

ylmethyl)benzyl]-2,7- diazaspiro[4.4]non-2-yl}-6- (2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidine

LC-MS (method 3): Rt = 1.42 min; m/z = 519

35

2,6-dimethyl-4-({7-[6-(2,2,2- (M+H)+

trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenyl acetate

Figure imgf000128_0002
LC-MS (method 3): Rt = 1.08 min; m/z = 512

36

(M+H)+

4-({7-[6-(2,2,2- trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)benzenesulfonamide Structure

Example Analytical Data

Name

F

LC-MS (method 3): Rt = 1.14 min; m/z = 532

37 4-[4-({7-[6-(2,2,2- (M+H)+

trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenyl]morpholin-3- one

N

F

LC-MS (method 3): Rt = 1.20 min; m/z = 473

38

(M+H)+

2-amino-5-({7-[6-(2,2,2- trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)benzonitrile

Figure imgf000129_0001

LC-MS (method 3): Rt = 1.46 min; m/z = 557

39

4-{7-[4-(5-butyl-1 ,3,4-oxadiazol- (M+H)+

2-yl)benzyl]-2,7- diazaspiro[4.4]non-2-yl}-6- (2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidine Example 40

[4-({7-[2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4.4]n 2-yl}methyl)phenyl]acetonitrile

Figure imgf000130_0001
To a suspension of 67 mg (153 μηηοΙ) 4-[2,7-diazaspiro[4.4]non-2-yl]-2-methyl-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine hydrochloride (intermediate I9) in 1.9 ml dichloromethane was added 47 μΙ triethylamine (338 μηηοΙ) followed by 22 mg (153 μηηοΙ) (4- formylphenyl)acetonitrile and 60 mg (284 μηηοΙ) sodium triacetoxyborohydride (CAS[56553-60- 7]) and the mixture was stirred for 17 h at RT. The volatile components were removed by evaporation and the residue was purified after filtration by preparative HPLC to yield 72 mg (92 %) of the desired product.

LC-MS (method 1 ): Rt = 0.78 min; m/z = 486 (M+H)+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.785 (0.62), 1.804 (1 .10), 1 .821 (1.16), 1.840 (0.61 ), 1 .974 (0.50), 2.323 (0.36), 2.327 (0.53), 2.331 (0.39), 2.407 (16.00), 2.428 (1.59), 2.518 (3.98), 2.522 (3.1 1 ), 2.544 (1.23), 2.570 (0.39), 2.608 (0.44), 2.627 (0.83), 2.643 (0.65), 2.665 (0.63), 2.669 (0.63), 2.673 (0.43), 3.544 (0.36), 3.577 (3.16), 3.582 (3.27), 3.615 (0.56), 3.725 (0.51 ), 3.976 (0.48), 3.999 (8.41 ), 4.031 (1 .20), 4.059 (0.41 ), 7.268 (1.99), 7.288 (4.32), 7.322 (4.42), 7.343 (2.05), 7.619 (3.07).

Separation of example 40 by chiral chromatography afforded 40.1 and its enantiomer 40.2.

Figure imgf000130_0002
= 1.00; chloroform)

Example 41

4-{7-[4-(morpholin-4-yl)benzyl]-27-diazaspiro[4.4]non-2-yl}-2-(2,2,2-trifluoroethyl)-2H- pyrazolo[3,4-d]pyrimidine

Figure imgf000131_0001

To a suspension of 120 mg (191 μηηοΙ) 4-[2,7-diazaspiro[4.4]non-2-yl]-2-(2,2,2-trifluoroethyl)- 2H-pyrazolo[3,4-d]pyrimidine trifluoroacetate (intermediate 113) in 2.4 ml dichloromethane was added 4-(morpholin-4-yl)benzaldehyde (CAS 1204-86-0) (191 μηιοΙ) followed by 106 μΙ triethylamine (763 μηηοΙ) and 75 mg (353 μηηοΙ) sodium triacetoxyborohydride (CAS[56553-60- 7]) and the mixture was stirred for 17 h at RT. The reaction mixture was concentrated under reduced pressure to dryness and the residue was purified by preparative HPLC to yield 37.5 mg (38%) of the desired product.

LC-MS (method 2): Rt = 0.47 min; MS (ESIpos): m/z = 502 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .769 (1.81 ), 1.788 (3.82), 1 .805 (2.65), 1.828 (2.04), 1.845 (2.10), 1.863 (1 .17), 1 .879 (0.61 ), 1.903 (0.64), 1.916 (1 .08), 1 .933 (2.77), 1.950 (2.59), 1.966 (1.19), 1.980 (0.55), 2.035 (0.50), 2.047 (0.93), 2.065 (2.21 ), 2.083 (2.33), 2.099 (1 .05), 2.1 12 (0.44), 2.336 (0.58), 2.383 (3.56), 2.406 (5.22), 2.467 (3.47), 2.518 (8.31 ), 2.522 (5.74), 2.534 (2.21 ), 2.539 (2.07), 2.552 (3.76), 2.575 (2.68), 2.598 (1 .78), 2.620 (2.07), 2.638 (1 .49), 2.678 (0.61 ), 3.041 (9.41 ), 3.051 (13.32), 3.063 (10.29), 3.478 (9.06), 3.487 (10.46), 3.532 (1 .95), 3.561 (2.86), 3.594 (0.41 ), 3.61 1 (0.93), 3.625 (1 .14), 3.644 (5.77), 3.671 (4.72), 3.687 (2.07), 3.701 (14.95), 3.714 (16.00), 3.725 (14.81 ), 3.747 (2.62), 3.772 (1 .75), 3.796 (1 .46), 3.813 (0.90), 5.313 (1 .17), 5.335 (3.88), 5.356 (5.22), 5.377 (3.93), 5.399 (1.05), 6.846 (5.77), 6.858 (5.86), 6.868 (7.08), 6.880 (5.86), 7.139 (7.78), 7.143 (8.34), 7.160 (7.72), 8.198 (12.04), 8.209 (13.14), 8.707 (7.32), 8.767 (8.42).

The following examples 42-57 were prepared analogous to the preparation of example 41 starting from the corresponding intermediate 113 by reacting with the corresponding aldehydes.

Figure imgf000132_0001
Structure

Example Analytical Data

Name

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.803

(2.16), 1.822 (4.47), 1 .840 (3.15), 1.863 (2.47),

1.879 (2.57), 1 .898 (1.39), 1.91 1 (0.78), 1 .929

(1 .35), 1.940 (1.25), 1 .958 (3.15), 1.976 (3.01 ),

1.992 (1 .42), 2.005 (0.64), 2.058 (0.68), 2.069

(1 .18), 2.088 (2.77), 2.106 (2.71 ), 2.123 (1.29),

2.137 (0.54), 2.323 (1.39), 2.327 (1.96), 2.332

(1 .39), 2.337 (0.58), 2.457 (5.65), 2.480

(10.15), 2.518 (7.17), 2.523 (8.39), 2.540

(1 .39), 2.548 (3.89), 2.570 (3.18), 2.588 (2.50),

2.609 (4.13), 2.632 (3.42), 2.642 (2.71 ), 2.660

(3.18), 2.665 (3.25), 2.669 (3.38), 2.673 (2.84),

2.679 (1 .76), 2.693 (0.61 ), 3.559 (2.37), 3.589

(3.62), 3.607 (0.61 ), 3.625 (1.96), 3.657

(15.63), 3.667 (8.56), 3.681 (4.53), 3.694

43

(4.50), 3.701 (2.91 ), 3.710 (3.08), 3.734 (1.05),

3.753 (4.13), 3.779 (2.77), 3.790 (2.77), 3.807

3-({7-[2-(2,2,2-trifluoroethyl)-2H- (2.47), 3.826 (1.18), 4.133 (2.44), 4.951 (0.74), pyrazolo[3,4-d]pyrimidin-4-yl]- 4.974 (0.71 ), 5.288 (0.78), 5.31 1 (0.91 ), 5.318

2,7-diazaspiro[4.4]non-2- (1 .62), 5.332 (2.00), 5.340 (4.63), 5.354 (4.50), yl}methyl)benzonitrile 5.363 (4.70), 5.376 (4.06), 5.397 (1.25), 7.506

(2.16), 7.518 (2.23), 7.525 (5.18), 7.537 (5.07), 7.544 (3.42), 7.556 (3.25), 7.666 (4.36), 7.685 (3.35), 7.703 (5.34), 7.706 (5.21 ), 7.722 (4.36), 7.725 (4.30), 7.755 (7.68), 7.759 (7.14), 8.204 (14.68), 8.213 (16.00), 8.341 (2.16), 8.418 (0.78), 8.565 (0.95), 8.699 (0.91 ), 8.712 (9.40), 8.780 (9.78).

LC-MS (method 2): Rt = 0.41 min; m/z = 442 (M+H)+

Figure imgf000134_0001
Structure

Example Analytical Data

Name

yl}methyl)phenyl]cyclopropanec (2.76), 2.1 1 1 (1.33), 2.123 (0.62), 2.318 (0.62), arbonitrile 2.323 (1 .33), 2.327 (1.87), 2.331 (1.33), 2.337

(0.62), 2.379 (0.98), 2.382 (0.98), 2.422 (6.10), 2.445 (8.74), 2.518 (8.74), 2.523 (5.48), 2.535 (2.19), 2.540 (2.25), 2.551 (2.55), 2.565 (2.55), 2.577 (4.41 ), 2.600 (3.61 ), 2.620 (2.99), 2.641 (3.02), 2.659 (2.16), 2.665 (2.31 ), 2.669 (2.25), 2.674 (1.69), 3.549 (2.55), 3.578 (16.00), 3.585 (13.93), 3.619 (1.33), 3.632 (1.39), 3.654 (5.13), 3.685 (6.52), 3.709 (1 .48), 3.735 (4.39), 3.760 (3.08), 3.782 (2.46), 3.800 (2.28), 3.818 (1 .16), 5.316 (1.54), 5.339 (5.24), 5.359 (7.35), 5.381 (5.10), 5.403 (1.33), 7.245 (6.25), 7.250 (3.26), 7.256 (6.16), 7.260 (5.10), 7.266 (1 1.85), 7.271 (5.13), 7.277 (10.99), 7.314 (12.80), 7.318 (13.19), 7.334 (7.73), 8.201 (14.34), 8.21 1 (15.76), 8.556 (0.41 ), 8.708 (9.57), 8.771 (10.40).

LC-MS (method 2): Rt = 0.47 min; m/z = 482 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.905 (0.58), 0.923 (1.19), 0.941 (0.58), 1.825 (2.12), 1.843 (4.31 ), 1 .861 (2.84), 1.887 (2.27), 1 .904 (2.23), 1.923 (1.37), 1 .938 (0.72), 1.947 (0.86),

1 ci f / 1.958 (1 .40), 1 .976 (3.13), 1.994 (2.84), 2.009

(1 .37), 2.022 (0.61 ), 2.076 (0.76), 2.084 (8.13), 2.107 (2.73), 2.124 (2.66), 2.141 (1.26), 2.156

46

(0.54), 2.323 (1.58), 2.327 (2.19), 2.331 (1.62), 2.380 (0.54), 2.382 (0.50), 2.405 (0.61 ), 2.423

4-{7-[3-chloro-4-(1 H-imidazol-1- (0.61 ), 2.518 (7.84), 2.523 (5.25), 2.540 (1.04), yl)benzyl]-2,7- 2.570 (4.24), 2.593 (4.06), 2.612 (2.23), 2.622 diazaspiro[4.4]non-2-yl}-2- (2.30), 2.647 (3.56), 2.670 (5.21 ), 2.690 (2.55), (2,2,2-trifluoroethyl)-2H- 2.707 (2.77), 2.721 (1.51 ), 2.729 (1.37), 2.743 pyrazolo[3,4-d]pyrimidine

(0.58), 3.573 (2.34), 3.602 (3.49), 3.617 (0.61 ), Structure

Example Analytical Data

Name

3.635 (1.15), 3.648 (1.29), 3.666 (2.55), 3.681 (14.63), 3.685 (15.96), 3.696 (5.29), 3.713 (4.71 ), 3.726 (3.09), 3.745 (1.01 ), 3.774 (3.92), 3.785 (1.47), 3.801 (3.45), 3.821 (2.41 ), 3.839 (1.15), 5.324 (1.51 ), 5.336 (1.87), 5.346 (4.42), 5.358 (4.71 ), 5.368 (4.53), 5.380 (4.21 ), 5.402 (1.29), 7.086 (10.89), 7.088 (16.00), 7.091 (10.36), 7.422 (12.98), 7.425 (13.45), 7.436 (1.98), 7.440 (1.83), 7.447 (4.17), 7.451 (4.85), 7.456 (4.53), 7.460 (4.42), 7.469 (8.63), 7.479

(8.34) , 7.489 (3.06), 7.500 (2.98), 7.622 (1 1.58), 7.626 (11.18), 7.875 (12.37), 8.208 (13.99), 8.218 (14.35), 8.721 (9.10), 8.794

(9.35) .

LC-MS (method 2): Rt = 0.30 min; m/z = 517 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.905 (0.55), 0.923 (1.15), 0.941 (0.61 ), 1.316 (0.55), 1.334 (1.21 ), 1.351 (0.61 ), 1.800 (2.18), 1.818 (4.55), 1.836 (3.33), 1.858 (2.42), 1.874 (2.48), 1.894 (1.39), 1.907 (0.85), 1.925 (1.09), 1.937 (1.33), 1.955 (3.15), 1.973 (3.09), 1.989 (1.39), γ H 2 N 2.002 (0.67), 2.055 (0.67), 2.067 (1.21 ), 2.084

(16.00), 2.103 (2.67), 2.1 19 (1.27), 2.133 (0.55), 2.318 (1.21 ), 2.323 (2.67), 2.327 (3.70),

47

2.331 (2.61 ), 2.337 (1.21 ), 2.380 (1.15), 2.382 (1.09), 2.405 (0.73), 2.423 (0.67), 2.449 (4.00),

4-({7-[2-(2,2,2-trifluoroethyl)-2H- 2.472 (7.15), 2.518 (15.52), 2.523 (9.45), 2.540 pyrazolo[3,4-d]pyrimidin-4-yl]- (4.42), 2.554 (2.12), 2.570 (3.15), 2.588 (2.55), 2,7-diazaspiro[4.4]non-2- 2.605 (4.36), 2.627 (3.27), 2.639 (2.97), 2.660 yl}methyl)benzamide (3.82), 2.665 (4.12), 2.669 (4.91 ), 2.673 (4.18),

2.678 (2.61 ), 2.693 (0.61 ), 3.559 (2.48), 3.589 (3.64), 3.609 (1.27), 3.624 (1.58), 3.641 (13.09), 3.652 (7.64), 3.672 (6.73), 3.685 Structure

Example Analytical Data

Name

(2.30), 3.697 (5.21 ), 3.716 (1 .52), 3.732 (1.15), 3.748 (4.30), 3.773 (2.79), 3.785 (2.36), 3.805 (2.18), 3.824 (1.15), 4.327 (0.55), 4.344 (0.55), 5.314 (1 .45), 5.337 (5.39), 5.359 (7.88), 5.382 (5.09), 5.404 (1.27), 7.303 (4.06), 7.371 (13.52), 7.391 (14.73), 7.459 (0.85), 7.480 (0.91 ), 7.799 (10.00), 7.803 (10.97), 7.819 (10.18), 7.824 (8.61 ), 7.836 (1.33), 7.856 (1 .03), 7.912 (4.73), 7.990 (0.91 ), 8.007 (0.85), 8.205 (14.30), 8.212 (15.45), 8.551 (0.61 ), 8.708 (8.97), 8.776 (9.82).

LC-MS (method 2): Rt = 0.28 min; m/z = 460 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.762 (0.86), 1.780 (1.84), 1 .798 (1 .29), 1.820 (1.02), 1.837 (1 .06), 1 .855 (0.57), 1.912 (0.53), 1 .930 (1 .35), 1.947 (1.29), 1 .963 (0.59), 2.042 (0.45), 2.061 (1 .04), 2.079 (1.02), 2.084 (0.75), 2.095 (0.49), 2.367 (1.29), 2.376 (1 .06), 2.390 (1.67), 2.399 (1 .59), 2.453 (1.55), 2.518 (4.27), 2.523 (3.33), 2.543 (1.76), 2.566 (1 .45), 2.584 (0.78), 2.600 (0.67), 2.607 (0.67), 2.617 (0.75), 2.632 (0.57), 2.876 (16.00), 2.879 (14.76), 3.350

48

Figure imgf000137_0001
(2.96), 3.435 (3.92), 3.444 (4.86), 3.488 (1.51 ),

3.503 (3.75), 3.518 (3.33), 3.527 (1.37), 3.533

2-{methyl[4-({7-[2-(2,2,2- (1 .22), 3.557 (1.35), 3.613 (0.45), 3.639 (2.29), trifluoroethyl)-2H-pyrazolo[3,4- 3.666 (2.71 ), 3.683 (0.80), 3.699 (0.59), 3.717 d]pyrimidin-4-yl]-2,7- (1 .76), 3.742 (1.06), 3.753 (0.47), 3.771 (0.80), diazaspiro[4.4]non-2- 3.793 (0.73), 3.812 (0.41 ), 4.616 (2.31 ), 4.629 yl}methyl)phenyl]amino}ethanol

(5.29), 4.643 (2.22), 5.313 (0.55), 5.335 (1.80), 5.354 (2.39), 5.376 (1.88), 5.397 (0.51 ), 6.589 (2.88), 6.601 (2.86), 6.610 (3.37), 6.623 (2.67), 7.057 (3.61 ), 7.061 (3.84), 7.079 (3.76), 7.082 (2.88), 8.196 (5.71 ), 8.208 (6.88), 8.707 (3.47), Structure

Example Analytical Data

Name

8.767 (4.16).

LC-MS (method 2): Rt = 0.43 min; m/z = 490 (M+H)+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.923 (1 .00), 0.941 (0.53), 1.783 (2.26), 1 .801 (4.84), 1.818 (3.74), 1 .838 (2.42), 1.854 (2.47), 1.873 (1 .32), 1 .890 (0.63), 1.915 (0.84), 1 .927 (1 .16), 1.945 (2.42), 1 .966 (2.37), 1.983 (1.32), 1.996 (0.68), 2.045 (0.68), 2.057 (1.05), 2.075 (2.1 1 ), 2.084 (3.68), 2.098 (2.00), 2.1 16 (1.21 ), 2.129 (0.63), 2.318 (1.00), 2.323 (2.21 ), 2.327 (3.1 1 ), 2.331 (2.21 ), 2.337 (1 .00), 2.405 (0.79), 2.417 (2.53), 2.423 (1.21 ), 2.439 (4.95), 2.459 (4.00), 2.518 (1 1.37), 2.523 (9.53), 2.540 (2.32), 2.551 (3.26), 2.571 (4.58), 2.594 (2.79), 2.605 (1 .79), 2.622 (3.26), 2.643 (2.42), 2.660 (1 .95), 2.665 (2.74), 2.669 (3.26), 2.674 (2.21 ),

49 2.678 (1.00), 3.461 (0.95), 3.493 (16.00), 3.533

(0.74), 3.557 (2.21 ), 3.587 (3.53), 3.609 (0.53),

3-({7-[2-(2,2,2-trifluoroethyl)-2H- 3.627 (1 .00), 3.640 (1.32), 3.659 (6.89), 3.687 pyrazolo[3,4-d]pyrimidin-4-yl]- (4.84), 3.709 (1.32), 3.734 (3.68), 3.759 (2.63), 2,7-diazaspiro[4.4]non-2- 3.787 (2.42), 3.804 (2.21 ), 3.823 (1.05), 5.316 yl}methyl)phenol (1 .42), 5.339 (4.37), 5.355 (4.89), 5.360 (4.79),

5.377 (4.1 1 ), 5.399 (1.16), 6.587 (2.1 1 ), 6.593 (3.63), 6.608 (2.26), 6.613 (3.84), 6.698 (4.79), 6.702 (5.00), 6.709 (5.79), 6.713 (7.42), 6.737 (3.68), 7.042 (3.00), 7.052 (3.26), 7.062 (5.05), 7.071 (4.74), 7.082 (2.47), 7.091 (2.32), 8.203 (14.21 ), 8.212 (14.47), 8.555 (0.95), 8.712 (8.47), 8.772 (9.16).

LC-MS (method 2): Rt = 0.38 min; m/z = 433 (M+H)+ Structure

Example Analytical Data

Name

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.905 (0.88), 0.923 (1.83), 0.941 (0.88), 1 .514 (0.59), 1.763 (2.06), 1 .781 (4.40), 1.799 (2.79), 1.824 (2.42), 1 .840 (2.57), 1.859 (1.32), 1 .873 (0.59), 1.902 (0.73), 1 .915 (1 .25), 1.932 (3.23), 1.949 (3.01 ), 1 .965 (1.39), 1.978 (0.59), 1 .995 (0.37), 2.031 (0.59), 2.043 (1 .03), 2.061 (2.35), 2.080 (2.35), 2.097 (1.17), 2.1 10 (0.51 ), 2.318 (1 .39), 2.322 (3.16), 2.326 (4.33), 2.331 (3.08), 2.336 (1 .47), 2.376 (2.86), 2.392 (2.50), 2.400 (3.74), 2.404 (2.20), 2.414 (3.67), 2.422 (1.25), 2.440 (0.59), 2.459 (4.04), 2.518 (16.00), 2.522 (1 1.38), 2.539 (3.67), 2.546 (4.48), 2.570

N O H (3.16), 2.577 (2.28), 2.594 (1 .91 ), 2.613 (1.83),

2.627 (1 .39), 2.649 (0.59), 2.659 (1.47), 2.664

50

(3.16), 2.668 (4.40), 2.673 (3.16), 2.678 (1.39), 2.692 (0.37), 3.452 (10.79), 3.460 (1 1.96),

4-({7-[2-(2,2,2-trifluoroethyl)-2H- 3.535 (2.13), 3.564 (3.30), 3.595 (0.51 ), 3.613 pyrazolo[3,4-d]pyrimidin-4-yl]- (1 .10), 3.626 (1.39), 3.642 (6.97), 3.666 (4.92), 2,7-diazaspiro[4.4]non-2- 3.685 (1 .91 ), 3.701 (1.32), 3.724 (3.89), 3.749 yl}methyl)phenol (2.86), 3.775 (2.13), 3.793 (1 .98), 3.812 (1.03),

5.313 (1 .32), 5.335 (4.33), 5.356 (5.94), 5.377 (4.55), 5.399 (1.25), 6.652 (7.78), 6.664 (7.41 ), 6.669 (4.99), 6.673 (8.81 ), 6.681 (3.60), 6.685 (7.49), 7.063 (8.59), 7.067 (9.25), 7.084 (9.03), 7.089 (6.97), 8.196 (12.62), 8.208 (15.63), 8.552 (1 .32), 8.707 (8.07), 8.765 (9.76), 9.247 (0.44).

LC-MS (method 2): Rt = 0.36 min; m/z = 433 (M+H)+

Figure imgf000140_0001
Structure

Example Analytical Data

Name

pyrazolo[3,4-d]pyrimidin-4-yl]- 2.404 (3.64), 2.422 (3.53), 2.440 (1.32), 2.447

2,7-diazaspiro[4.4]non-2- (2.32), 2.457 (2.87), 2.470 (4.19), 2.480 (5.19), yl}methyl)benzenesulfonamide 2.518 (5.85), 2.523 (4.97), 2.526 (4.19), 2.539

(6.95), 2.549 (3.09), 2.569 (2.54), 2.589 (2.98), 2.604 (3.86), 2.626 (2.43), 2.637 (0.99), 2.654 (2.10), 2.660 (1.99), 2.664 (2.54), 2.669 (3.31 ), 2.673 (2.65), 2.685 (2.76), 2.703 (0.44), 3.298 (0.88), 3.304 (1.21 ), 3.314 (0.88), 3.330 (5.19), 3.361 (2.32), 3.371 (0.99), 3.375 (0.55), 3.380 (0.66), 3.387 (0.66), 3.392 (0.44), 3.561 (1.99), 3.591 (3.09), 3.609 (0.44), 3.627 (0.99), 3.640 (1 .21 ), 3.667 (10.59), 3.675 (15.45), 3.699 (5.08), 3.729 (0.88), 3.750 (3.42), 3.774 (2.32), 3.788 (2.10), 3.807 (1.99), 3.825 (0.99), 5.316 (1 .21 ), 5.338 (4.63), 5.359 (6.62), 5.382 (4.30), 5.404 (1.10), 7.306 (13.90), 7.494 (9.93), 7.514 (1 1.37), 7.749 (9.82), 7.754 (10.92), 7.770 (9.05), 7.775 (7.83), 8.203 (15.12), 8.212 (16.00), 8.708 (8.28), 8.775 (8.61 ).

LC-MS (method 2): Rt = 0.30 min; m/z = 496 (M+H)+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (1 .35), 1.81 1 (1.06), 1 .829 (2.26), 1.847 (1.68), 1.864 (1 .42), 1 .884 (1.53), 1.900 (0.73), 1 .915 (0.44), 1.933 (0.55), 1 .945 (0.66), 1.964 (1.42), 1.982 (1 .42), 1 .998 (0.69), 2.074 (0.55), 2.090 (1 .02), 2.1 15 (0.91 ), 2.132 (0.62), 2.337 (0.66),

53 2.518 (8.77), 2.523 (6.25), 2.539 (2.30), 2.581

CI

(2.05), 2.593 (0.80), 2.604 (1 .50), 2.615 (1.57),

[3-chloro-4-({7-[2-(2,2,2- 2.632 (2.01 ), 2.660 (1.02), 2.665 (1.94), 2.670 trifluoroethyl)-2H-pyrazolo[3,4- (3.21 ), 2.673 (2.56), 2.685 (0.99), 2.701 (1.72), d]pyrimidin-4-yl]-2,7- 2.723 (1 .28), 2.741 (0.55), 3.563 (1.17), 3.592 diazaspiro[4.4]non-2- (1 .75), 3.629 (0.58), 3.642 (0.66), 3.659 (1.21 ), yl}methyl)phenyl]acetonitrile 3.671 (1 .53), 3.681 (2.30), 3.697 (7.31 ), 3.712 Structure

Example Analytical Data

Name

(6.21 ), 3.738 (0.62), 3.759 (2.01 ), 3.785 (1.50), 3.794 (1 .39), 3.813 (1.21 ), 3.831 (0.62), 4.042 (16.00), 5.319 (0.77), 5.342 (2.34), 5.360 (2.92), 5.382 (2.30), 5.404 (0.66), 7.289 (1.21 ), 7.306 (2.30), 7.327 (1.35), 7.417 (4.93), 7.517 (2.52), 7.524 (2.45), 7.537 (2.16), 7.545 (2.01 ), 8.205 (7.16), 8.217 (7.42), 8.551 (0.55), 8.716 (4.60), 8.769 (4.82).

LC-MS (method 2): Rt = 0.46 min; m/z = 490 (M+H)+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.785 (1.25), 1.803 (2.55), 1 .820 (2.09), 1.839 (1 .42), 1 .856 (1.55), 1.874 (0.75), 1.891 (0.46), 1.909 (0.54), 1.922 (0.71 ), 1 .940 (1.55), 1.958 (1 .63), 1 .976 (0.79), 2.052 (0.67), 2.071 (1 .21 ), 2.091 (1.21 ), 2.109 (0.67), 2.318 (0.75), 2.323 (1 .75), 2.327 (2.51 ), 2.331 (1.71 ), 2.337 (0.75), 2.461 (2.80), 2.518 (8.36), 2.523 (5.85), 2.531 (2.42), 2.540 (1.09), 2.554 (1.67), 2.570 (1 .55), 2.591 (1.67), 2.612 (2.42), 2.635 (1.96), 2.651

(1 .42) , 2.665 (2.88), 2.669 (3.93), 2.673 (2.76), 3.537 (1.17), 3.567 (1 .88), 3.638 (5.60), 3.654

54

F (8.69), 3.678 (2.76), 3.685 (2.05), 3.707 (0.79),

3.728 (2.17), 3.753 (1 .30), 3.765 (0.67), 3.783

[3-fluoro-4-({7-[2-(2,2,2- (1 .46), 3.801 (1.30), 3.818 (0.63), 3.856 (1 .21 ), trifluoroethyl)-2H-pyrazolo[3,4- 4.046 (16.00), 4.184 (0.46), 5.318 (0.84), 5.328 d]pyrimidin-4-yl]-2,7- (1 .00), 5.340 (2.42), 5.349 (2.67), 5.362 (2.46), diazaspiro[4.4]non-2- 5.372 (2.46), 5.384 (0.88), 5.394 (0.75), 7.151 yl}methyl)phenyl]acetonitrile

(4.43) , 7.178 (4.43), 7.427 (1.09), 7.439 (1 .25), 7.448 (2.17), 7.458 (2.01 ), 7.467 (1.21 ), 7.479 (0.92), 8.198 (7.69), 8.213 (8.81 ), 8.71 1 (4.76), 8.762 (5.39).

LC-MS (method 2): Rt = 0.40 min; m/z = 474 (M+H)+

Figure imgf000143_0001
Structure

Example Analytical Data

Name

amide 3.636 (0.54), 3.654 (0.88), 3.667 (2.35), 3.695

(2.17), 3.714 (0.58), 3.742 (1.59), 3.766 (1.13), 3.782 (0.79), 3.806 (0.68), 3.823 (0.41), 4.222 (10.57), 5.316 (0.53), 5.338 (1.99), 5.359 (2.92), 5.382 (1.89), 5.403 (0.48), 6.818 (4.44), 6.825 (4.74), 7.282 (0.89), 7.305 (16.00), 7.326 (1.08), 8.201 (4.71), 8.212 (4.95), 8.712 (3.21), 8.774 (3.61).

LC-MS (method 2): Rt = 0.32 min; m/z = 510 (M+H)+

1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.132 (1.08), 1.149 (1.08), 1.233 (1.14), 1.763 (1.82), 1.781 (3.83), 1.798 (2.62), 1.816 (1.48), 1.836 (2.15), 1.853 (2.02), 1.873 (1.28), 1.885 (0.81), 1.904 (1.01), 1.915 (1.14), 1.934 (2.69), 1.953 (2.62), 1.969 (1.41), 1.982 (0.61), 2.026 (0.67), 2.037 (1.01), 2.057 (2.08), 2.076 (2.15), 2.093 (1.21), 2.106 (0.54), 2.323 (4.24), 2.327 (4.37), 2.331 (2.96), 2.336 (1.34), 2.464 (3.36), 2.518 (16.00), 2.523 (9.61), 2.540 (1.88), 2.557 (4.91), 2.579 (4.71), 2.599 (2.42), 2.629 (3.70), 2.647 (8.20), 2.661 (8.67), 2.665 (8.67), 2.669

57 (8.54), 2.673 (4.71), 2.678 (3.03), 2.687 (8.61),

2.696 (1.75), 2.712 (1.34), 2.733 (0.54), 2.803 (4.64), 2.822 (6.66), 2.840 (2.96), 3.236 (5.65), 3.498 (2.22), 3.528 (2.96), 3.623 (0.47), 3.639

4-(2-{7-[2-(2,2,2-trifluoroethyl)- (2.69), 3.669 (5.18), 3.699 (2.69), 3.710 (4.03), 2H-pyrazolo[3,4-d]pyrimidin-4- 3.721 (1.68), 3.736 (2.76), 3.752 (0.81), 3.786 yl]-2,7-diazaspiro[4.4]non-2- (1.08), 3.804 (2.55), 3.820 (2.02), 3.835 (1.08), yl}ethyl)benzonitrile

5.330 (1.61), 5.352 (4.71), 5.374 (4.64), 5.397 (1.68), 7.435 (6.99), 7.441 (7.39), 7.456 (8.81), 7.462 (7.93), 7.478 (0.61), 7.498 (0.47), 7.695 (8.47), 7.716 (8.00), 7.722 (8.61), 7.743 (6.79), 8.208 (12.17), 8.226 (14.12), 8.731 (8.47), 8.742 (9.48). Structure

Example Analytical Data

Name

LC-MS (method 2): Rt = 0.44 min; m/z = 456 (M+H)+

According to the preparation of example 41 the following examples 58-60 were prepared starting from the intermediate 110 by reacting with the corresponding aldehydes.

Figure imgf000145_0001
Structure

Example Analytical Data

Name

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.794 (0.76), 1.810 (1.28), 1 .821 (1 .48), 1.837 (1.44), 1.852 (1 .36), 1 .870 (1.44), 1.886 (0.76), 1 .904 (0.52), 1.917 (0.64), 1 .935 (1 .32), 1.953 (1.32), 1.969 (0.64), 2.050 (0.56), 2.068 (1.16), 2.073 (1 .00), 2.083 (3.09), 2.088 (1 .16), 2.106 (0.64), 2.322 (1 .04), 2.326 (1.44), 2.331 (1.44), 2.340 (14.72), 2.347 (16.00), 2.460 (2.57), 2.518 (4.21 ), 2.522 (3.01 ), 2.530 (2.25), 2.539 (1.00),

T N 2.554 (1 .72), 2.569 (1.04), 2.586 (1.32), 2.594

(2.09), 2.618 (1.56), 2.639 (1 .24), 2.649 (1.04), 2.664 (1 .76), 2.668 (1.88), 2.673 (3.09), 3.552

59 (1 .12), 3.582 (1.92), 3.605 (0.52), 3.618 (0.56),

3.636 (1 .16), 3.643 (2.01 ), 3.650 (2.81 ), 3.668

4-({7-[6-methyl-2-(2,2,2- (2.25), 3.679 (4.37), 3.684 (4.05), 3.694 (4.65), trifluoroethyl)-2H-pyrazolo[3,4- 3.725 (2.05), 3.749 (1.28), 3.763 (1.36), 3.780 d]pyrimidin-4-yl]-2,7- (1 .24), 3.799 (0.60), 5.273 (0.72), 5.295 (2.37), diazaspiro[4.4]non-2- 5.316 (3.05), 5.337 (2.13), 5.359 (0.56), 7.514 yl}methyl)benzonitrile

(3.45), 7.519 (4.17), 7.535 (4.53), 7.540 (4.33), 7.765 (4.05), 7.776 (4.69), 7.781 (2.53), 7.785 (3.57), 7.797 (3.73), 8.274 (1 .04), 8.624 (4.57), 8.684 (4.13).

LC-MS (method 2): Rt = 0.39 min; m/z = 456 (M+H)+

Structure

Example Analytical Data

Name

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.904

(0.44), 0.923 (0.92), 0.941 (0.44), 1.788 (0.78),

1.805 (1 .36), 1 .815 (1.53), 1.831 (1.53), 1 .846

(1 .43), 1.864 (1.56), 1 .881 (0.75), 1.902 (0.44),

1.914 (0.71 ), 1 .932 (1.49), 1.950 (1.43), 1 .966

(0.68), 2.048 (0.61 ), 2.066 (1 .22), 2.074 (0.88),

2.084 (4.42), 2.103 (0.65), 2.318 (0.51 ), 2.323

(0.95), 2.327 (1 .43), 2.332 (1.60), 2.340

(15.29), 2.348 (16.00), 2.404 (0.51 ), 2.422

(0.54), 2.436 (1.46), 2.447 (1 .39), 2.459 (2.04),

2.470 (2.55), 2.518 (5.37), 2.523 (3.09), 2.540 (2.41 ), 2.564 (1.56), 2.591 (1 .94), 2.613 (1.70),

60 2.631 (1 .19), 2.653 (1.29), 2.665 (1.22), 2.669

(1 .87), 2.673 (1.36), 3.549 (1 .12), 3.578 (1.90),

3.596 (0.75), 3.603 (0.75), 3.630 (3.30), 3.643

Figure imgf000147_0001

(7.24), 3.666 (2.28), 3.678 (2.31 ), 3.700 (0.75),

4-({7-[6-methyl-2-(2,2,2- 3.723 (1 .90), 3.747 (1.39), 3.759 (1.29), 3.778 trifluoroethyl)-2H-pyrazolo[3,4- (1 .19), 3.796 (0.58), 5.271 (0.71 ), 5.293 (2.65), d]pyrimidin-4-yl]-2,7- 5.315 (3.74), 5.337 (2.34), 5.359 (0.58), 7.304 diazaspiro[4.4]non-2- (2.34), 7.368 (4.1 1 ), 7.372 (4.79), 7.388 (5.06), yl}methyl)benzamide 7.392 (4.59), 7.796 (4.1 1 ), 7.806 (4.55), 7.817

(3.87), 7.826 (3.80), 7.913 (2.45), 8.623 (4.62), 8.687 (4.45).

LC-MS (method 2): Rt = 0.30 min; m/z = 474 (M+H)+

Example 61

2-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4.4]non yl}methyl)phenyl]acetamide

Figure imgf000148_0001

To a solution of 100 mg (212 μηιοΙ) [4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]- 2,7-diazaspiro[4.4]non-2-yl}methyl)phenyl]acetonitrile (example 4) in 1 .0 ml methanol was added under an argon atmosphere 38 mg (636 μηηοΙ) (l E)-N-hydroxyethanimine (CAS 107-29- 9) followed by 30 mg of molecular sieves modified with copper(ll) which has been prepared accordingly to a procedure described in Tetrahedron Letters 52 (201 1 ), 6021-6023. The mixture was stirred for 4 h at 65 °C. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to yield 54 mg (51 %) of the desired product.

LC-MS (method 2): Rt = 0.61 min; MS (ESIpos): m/z = 490 [M+H]+

1 H-NMR (400 MHz, CHLOROFORM-d) delta [ppm]: 1.673 (6.54), 1.877 (0.54), 1 .893 (1.21 ), 1.908 (1.52), 1.920 (1.55), 1 .927 (1 .38), 1 .938 (1.99), 1.955 (1 .49), 1 .971 (0.70), 1 .988 (0.51 ), 2.074 (1.09), 2.519 (0.92), 2.615 (1 .23), 2.638 (1.19), 2.752 (0.81 ), 3.575 (16.00), 3.599 (1 .65), 3.625 (4.93), 3.634 (10.46), 3.649 (4.43), 3.675 (1 .45), 3.712 (1.43), 3.738 (2.44), 3.816 (2.14), 3.841 (1.52), 3.889 (0.98), 5.410 (1 .28), 7.223 (5.19), 7.243 (8.10), 7.317 (6.53), 7.337 (4.42), 7.360 (6.17), 8.420 (1 1.49).

Example 62

4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile

Figure imgf000148_0002

To a mixture of 28 mg (215 μηηοΙ) 4-formylbenzonitrile and 84 mg (398 μηηοΙ) sodium triacetoxyborohydride was added a solution of 80 mg (215 μηηοΙ) 4-[2,7-diazaspiro[4.4]non-2- yl]-6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidine hydrochloride (intermediate I27) and 66 μΙ (473 μηιοΙ) triethylamine in 2 ml dichloromethane. The mixture was stirred for 69 h at RT. The volatile components were removed by evaporation and the residue was purified after filtration by preparative HPLC to yield 46 mg (46 %) of the desired product.

LC-MS (method 12): Rt = 1.22 min; MS (ESIpos): m/z = 440 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.788 (0.45), 1.793 (0.43), 1.805 (1 .18), 1.824 (1 .97), 1.841 (2.02), 1.860 (1.02), 1 .875 (0.45), 1 .997 (0.94), 2.322 (0.55), 2.326 (0.77), 2.332 (0.55), 2.456 (2.52), 2.479 (4.28), 2.518 (3.23), 2.522 (2.22), 2.548 (2.57), 2.570 (2.57), 2.587 (1 .54), 2.606 (0.75), 2.619 (0.83), 2.638 (1 .48), 2.654 (1 .1 1 ), 2.660 (1.03), 2.664 (0.94), 2.669 (0.94), 2.673 (0.85), 3.472 (1.02), 3.482 (1 .08), 3.517 (2.05), 3.527 (2.08), 3.562 (1.09), 3.571 (1 .06), 3.643 (1.22), 3.678 (4.80), 3.691 (5.06), 3.726 (1 .63), 6.178 (0.45), 6.188 (0.91 ), 6.198 (0.42), 6.318 (0.86), 6.328 (1.85), 6.339 (0.85), 6.459 (0.38), 6.469 (0.83), 6.479 (0.38), 7.514 (5.78), 7.535 (6.77), 7.582 (5.40), 7.770 (8.31 ), 7.774 (2.60), 7.786 (2.45), 7.791 (6.85), 8.288 (16.00).

According to the preparation of example 62 the following examples 63-74 were prepared starting from the intermediate I27 by reacting with the corresponding aldehydes.

Figure imgf000149_0001
Structure

Example Analytical Data

Name

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.762 (0.71 ), 1.781 (1.21 ), 1 .798 (1 .28), 1.816 (0.62), 1.967 (0.61 ), 2.366 (1.27), 2.389 (1.77), 2.518 H (3.75), 2.522 (2.50), 2.536 (0.62), 2.567 (0.51 ), 2.585 (0.92), 2.601 (0.70), 2.878 (16.00), 3.320 (2.09), 3.350 (2.51 ), 3.432 (5.38), 3.469 (0.68), 3.479 (0.76), 3.489 (1.31 ), 3.504 (3.08), 3.518

64

Figure imgf000150_0001
(3.44), 3.534 (1.12), 3.558 (0.73), 3.568 (0.71 ),

3.719 (0.54), 4.615 (1.27), 4.629 (2.75), 4.643

2-{[4-({7-[6-(2,2- (1 .24), 6.184 (0.56), 6.314 (0.52), 6.325 (1.1 1 ), difluoroethyl)thieno[2,3- 6.335 (0.53), 6.464 (0.50), 6.594 (3.26), 6.616 d]pyrimidin-4-yl]-2,7- (3.57), 7.055 (3.52), 7.076 (3.20), 7.579 (3.36), diazaspiro[4.4]non-2- 8.281 (7.77).

yl}methyl)phenyl](methyl)amino}

ethanol LC-MS (method 12): Rt = 1 .13 min; MS

(ESIneg): m/z = 486 [M-H]-

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.772 (0.47), 1.790 (1.30), 1 .809 (2.20), 1.824 (2.31 ), 1.843 (1 .10), 1 .859 (0.48), 1.984 (1.04), 2.323 (0.58), 2.327 (0.79), 2.331 (0.55), 2.416 (2.65), 2.439 (3.81 ), 2.518 (4.89), 2.523 (3.54), 2.541 (2.21 ), 2.563 (1.57), 2.582 (0.75), 2.607 (0.88), 2.626 (1 .64), 2.642 (1.23), 2.665 (0.98), 2.669 (0.86), 2.673 (0.58), 3.471 (1 .09), 3.481 (1.17),

65 3.516 (2.16), 3.526 (2.20), 3.547 (0.67), 3.561

Figure imgf000150_0002

(1 .32), 3.582 (8.82), 3.616 (0.68), 3.743 (1.00),

[4-({7-[6-(2,2- 3.997 (15.61 ), 6.176 (0.47), 6.186 (1 .04), 6.197 difluoroethyl)thieno[2,3- (0.46), 6.316 (0.93), 6.327 (2.00), 6.337 (0.93), d]pyrimidin-4-yl]-2,7- 6.457 (0.43), 6.467 (0.92), 6.477 (0.43), 7.269 diazaspiro[4.4]non-2- (4.1 1 ), 7.289 (9.07), 7.324 (9.41 ), 7.344 (4.34), yl}methyl)phenyl]acetonitrile 7.581 (6.01 ), 8.285 (16.00).

LC-MS (method 12): Rt = 1 .18 min; MS (ESIpos): m/z = 454 [M+H]+ Structure

Example Analytical Data

Name

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.752 (0.49), 1.765 (1.20), 1 .783 (2.06), 1.799 (2.18), 1.818 (1 .03), 1 .834 (0.45), 1.967 (0.99), 2.332 (0.64), 2.383 (2.21 ), 2.406 (3.21 ), 2.518 (5.53),

2.522 (4.16), 2.539 (1.29), 2.558 (0.90), 2.577 (1 .61 ), 2.593 (1.18), 2.615 (0.45), 2.673 (0.66), 3.413 (0.86), 3.445 (4.76), 3.455 (4.99), 3.469 (1 .29), 3.478 (1.26), 3.487 (1 .18), 3.514 (2.12),

66 3.523 (2.18), 3.559 (1.20), 3.568 (1.18), 3.725

(0.88), 6.174 (0.49), 6.184 (1 .05), 6.194 (0.47),

4-({7-[6-(2,2- 6.314 (0.94), 6.325 (2.08), 6.335 (0.94), 6.454 difluoroethyl)thieno[2,3- (0.43), 6.465 (0.92), 6.475 (0.45), 6.657 (0.81 ), d]pyrimidin-4-yl]-2,7- 6.664 (7.95), 6.669 (2.46), 6.680 (2.59), 6.685 diazaspiro[4.4]non-2- (8.48), 6.692 (0.96), 7.067 (7.00), 7.088 (6.43), yl}methyl)phenol 7.579 (6.06), 8.282 (16.00), 9.247 (4.28).

LC-MS (method 12): Rt = 1 .04 min; MS (ESIpos): m/z = 431 [M+H]+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.450 (2.14), 1.464 (7.37), 1 .470 (6.97), 1.483 (2.68), 1.704 (2.80), 1 .715 (7.48), 1.722 (7.15), 1 .734 (2.28), 1.772 (0.60), 1 .786 (1 .29), 1.805 (2.14), 1.821 (2.26), 1 .840 (1.1 1 ), 1.855 (0.51 ), 1 .981 (1 .03), 2.416 (2.54), 2.439 (3.68), 2.518 (5.31 ), 2.523 (3.55), 2.540 (2.42), 2.560 (1.62), 2.579 (0.77), 2.598 (0.92), 2.617 (1 .66), 2.632 (1.25),

67 2.654 (0.51 ), 3.472 (1.09), 3.481 (1.14), 3.516

(2.17), 3.526 (2.23), 3.538 (0.91 ), 3.573 (7.55),

1-[4-({7-[6-(2,2- 3.609 (0.83), 3.734 (0.97), 6.177 (0.51 ), 6.187 difluoroethyl)thieno[2,3- (1 .02), 6.197 (0.45), 6.317 (0.92), 6.327 (1.97), d]pyrimidin-4-yl]-2,7- 6.338 (0.92), 6.457 (0.45), 6.468 (0.91 ), 6.478 diazaspiro[4.4]non-2- (0.45), 7.250 (5.29), 7.271 (10.45), 7.312 yl}methyl)phenyl]cyclopropanec

(9.1 1 ), 7.333 (4.55), 7.581 (5.98), 8.285 arbonitrile

(16.00).

LC-MS (method 12): Rt = 1 .27 min; MS

Figure imgf000152_0001
Structure

Example Analytical Data

Name

8.287 (16.00).

LC-MS (method 12): Rt = 0.98 min; MS (ESIpos): m/z = 458 [M+H]+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.793 (0.64), 1.806 (1.57), 1 .825 (2.70), 1.841 (2.82), 1.860 (1 .41 ), 1 .874 (0.67), 1.892 (0.40), 1 .995 (1 .35), 2.074 (0.67), 2.322 (0.64), 2.326 (0.87), 2.332 (0.64), 2.449 (2.98), 2.472 (4.96), 2.522 (3.63), 2.539 (1.77), 2.548 (3.20), 2.570 (3.33), 2.589 (2.14), 2.608 (1.01 ), 2.628 (1.07), 2.647 (2.00), 2.664 (2.10), 2.668 (2.04), 2.684 (0.62), 3.473 (1 .35), 3.482 (1.43), 3.518 (2.66), 3.527

70

Figure imgf000153_0001
(2.72), 3.561 (1.47), 3.571 (1 .47), 3.628 (1.19),

3.663 (7.19), 3.669 (7.34), 3.703 (1.69), 3.751

4-({7-[6-(2,2- (1 .33), 6.178 (0.56), 6.188 (1 .1 1 ), 6.198 (0.54), difluoroethyl)thieno[2,3- 6.318 (1 .07), 6.328 (2.18), 6.339 (1.09), 6.459 d]pyrimidin-4-yl]-2,7- (0.50), 6.468 (1.03), 6.478 (0.54), 7.301 (9.91 ), diazaspiro[4.4]non-2- 7.491 (7.27), 7.512 (8.46), 7.584 (6.63), 7.753 yl}methyl)benzenesulfonamide

(10.26), 7.774 (8.54), 8.288 (16.00).

LC-MS (method 12): Rt = 0.96 min; MS (ESIpos): m/z = 494 [M+H]+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.725 (0.72), 1.742 (3.25), 1 .758 (5.88), 1.776 (5.40), 1.793 (3.75), 1 .81 1 (2.78), 1.829 (1.33), 1 .848 (1 .72), 1.864 (4.52), 1 .881 (5.45), 1.898 (3.25), 1.916 (1 .1 1 ), 1 .972 (1.24), 2.332 (0.81 ), 2.393 (2.69), 2.416 (3.77), 2.518 (7.30), 2.522 (6.10),

71

2-[4-({7-[6-(2,2- 2.540 (2.06), 2.560 (0.90), 2.583 (1.02), 2.603 difluoroethyl)thieno[2,3- (1 .88), 2.618 (1.40), 2.640 (0.54), 2.673 (0.84), d]pyrimidin-4-yl]-2,7- 3.287 (3.93), 3.305 (7.25), 3.323 (6.31 ), 3.428 diazaspiro[4.4]non-2- (4.29), 3.444 (8.16), 3.461 (4.41 ), 3.469 (1.99), yl}methyl)phenoxy]-1-(pyrrolidin- 3.479 (1 .63), 3.504 (9.33), 3.523 (2.82), 3.559

1-yl)ethanone (1 .45), 3.568 (1 .40), 3.732 (1.13), 4.667

Figure imgf000154_0001
Structure

Example Analytical Data

Name

(0.23), 2.632 (0.43), 2.647 (0.32), 2.665 (0.23),

2-[4-({7-[6-(2,2- 2.669 (0.36), 2.673 (0.22), 3.473 (0.27), 3.483 difluoroethyl)thieno[2,3- (0.29), 3.518 (0.54), 3.527 (0.55), 3.563 (0.32), d]pyrimidin-4-yl]-2,7- 3.573 (0.33), 3.592 (2.03), 3.627 (0.20), 3.752 diazaspiro[4.4]non-2- (0.24), 6.188 (0.26), 6.317 (0.24), 6.328 (0.49), yl}methyl)phenyl]-2- 6.338 (0.23), 6.468 (0.23), 7.351 (1.32), 7.372 methylpropanenitrile (2.10), 7.440 (2.51 ), 7.445 (0.69), 7.460 (1.49),

7.586 (1.48), 8.286 (4.18).

LC-MS (method 12): Rt = 1 .30 min; MS (ESIpos): m/z = 482 [M+H]+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.104 (0.79), 1.122 (1.71 ), 1 .140 (0.88), 1.774 (2.20), 1.791 (1 .02), 1 .808 (1.84), 1.825 (2.05), 1 .843 (0.95), 1.858 (0.41 ), 1 .906 (0.59), 1.986 (1.20), 2.322 (0.52), 2.326 (0.73), 2.331 (0.52), 2.442 (1 .47), 2.465 (1.99), 2.518 (3.20), 2.522 (2.25), 2.544 (1 .65), 2.566 (1.62), 2.581 (1.13), 2.601 (0.53), 2.621 (0.63), 2.641 (1 .17), 2.660 (1.04),

74 2.664 (1 .15), 2.668 (1.04), 2.673 (0.76), 2.678

(0.57), 3.469 (1.67), 3.479 (1 .62), 3.494 (0.90),

[4-({7-[6-(2,2- 3.523 (13.79), 3.578 (4.71 ), 3.613 (0.76), 3.708 difluoroethyl)thieno[2,3- (1 .10), 3.742 (0.89), 6.174 (0.43), 6.184 (0.89), d]pyrimidin-4-yl]-2,7- 6.314 (0.83), 6.325 (1.80), 6.335 (0.80), 6.465 diazaspiro[4.4]non-2- (0.79), 7.178 (3.86), 7.198 (7.41 ), 7.240 (7.08), yl}methyl)phenyl]acetic acid 7.261 (3.59), 7.582 (5.07), 8.285 (16.00).

LC-MS (method 12): Rt = 0.63 min; MS (ESIpos): m/z = 473 [M+H]+

Example 75

2-[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]py

yl}methyl)phenyl]-N-methylacetamide

Figure imgf000156_0001

A solution of 25 mg (53 μηιοΙ) [4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]acetic acid (example 74) in 1 ml DMF was treated with

4.3 mg (64 μηηοΙ) methanamine hydrochloride, 40 μΙ (69 μηηοΙ) T3P (50% solution in DMF) and 37 μΙ (212 μηηοΙ) DIPEA. The solution was stirred for 20 h at RT. After additional treatment with

2.4 eq methanamine hydrochloride, 1.3 eq T3P and 8 eq. DIPEA and stirring for another 42 h the reaction mixture was purified after filtration by preparative HPLC to yield 5.1 mg (20 %) of the desired product.

LC-MS (method 12): Rt = 1.03 min; MS (ESIpos): m/z = 486 [M+H]+

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .766 (0.41 ), 1.783 (1.09), 1 .801 (1.95), 1.818 (2.14), 1.835 (1.01 ), 1 .851 (0.45), 1.979 (0.90), 2.331 (1.62), 2.336 (0.75), 2.414 (2.22), 2.437 (3.15), 2.518 (1 1 .57), 2.523 (7.74), 2.548 (15.47), 2.559 (15.36), 2.577 (0.83), 2.600 (0.79), 2.619 (1 .43), 2.635 (1.09), 2.673 (1.62), 2.678 (0.79), 3.339 (16.00), 3.471 (0.94), 3.480 (1 .05), 3.515 (2.07), 3.525 (2.03), 3.547 (6.38), 3.570 (1 .16), 3.581 (0.71 ), 3.736 (0.86), 6.186 (0.86), 6.316 (0.79), 6.326 (1.65), 6.336 (0.79), 6.466 (0.75), 7.162 (3.49), 7.182 (7.96), 7.212 (7.81 ), 7.233 (3.38), 7.583 (5.1 1 ), 7.923 (1.24), 7.934 (1.24), 8.285 (12.85).

According to the preparation of example 75 the following example 76 was prepared starting from example 74 by reacting with the corresponding amine.

Figure imgf000156_0002
Structure

Example Analytical Data

Name

difluoroethyl)thieno[2,3- (16.00), 3.471 (0.45), 3.480 (0.47), 3.516 d]pyrimidin-4-yl]-2,7- (0.97), 3.525 (0.93), 3.552 (3.48), 3.636 (5.43), diazaspiro[4.4]non-2- 6.186 (0.41 ), 6.326 (0.81 ), 7.129 (2.07), 7.150 yl}methyl)phenyl]-N,N- (3.16), 7.221 (3.18), 7.241 (2.01 ), 7.584 (2.37), dimethylacetamide 8.284 (6.16).

LC-MS (method 12): Rt = 1 .10 min; MS (ESIpos): m/z = 500 [M+H]+

Example 77

4-[1-{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4.4]non-^ yl}ethyl]benzamide

Figure imgf000157_0001

A solution of 50 mg (132 μηιοΙ) 4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidine hydrochloride (intermediate 112) and 32 mg (198 μηηοΙ) 4-acetylbenzamide in a mixture of 2 ml methanol was heated to 60°C for 2 h. Then 34 mg (158 μηηοΙ) sodium triacetoxyborohydride was added and the mixture heated for 2 h at 60°C. Then additional 17 mg (264 μηηοΙ) sodium cyanoborohydride was added and the mixture stirred at 60°C for 16h The volatile components were removed by evaporation and the residue was purified after filtration by preparative HPLC to yield 12 mg (17 %) of the desired product as a mixture of diastereomers.

LC-MS (method 4): Rt = 1.12 min; MS (ESIpos): m/z = 490 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .230 (0.33), 1.272 (7.33), 1 .280 (8.00), 1.288 (8.33), 1.297 (7.33), 1 .737 (0.33), 1.758 (0.67), 1.770 (1.67), 1 .787 (2.67), 1 .804 (2.67), 1.818 (1.67), 1.836 (1.00), 1 .973 (1 .33), 2.318 (0.67), 2.345 (2.00), 2.368 (2.33), 2.409 (1 .33), 2.431 (3.33), 2.449 (5.00), 2.473 (2.67), 2.518 (10.67), 2.523 (7.33), 2.539 (1.33), 2.560 (1.33), 2.582 (1 .00), 2.607 (0.67), 2.627 (1 .00), 2.644 (1.00), 2.660 (1.00), 2.692 (0.67), 2.713 (1 .00), 2.728 (1.00), 2.749 (0.33), 3.277 (0.67), 3.296 (1 .00), 3.31 1 (3.00), 3.315 (2.33), 3.326 (4.67), 3.330 (4.67), 3.394 (2.00), 3.397 (2.00), 3.401 (1 .33), 3.406 (1 .00), 3.422 (0.67), 3.427 (0.33), 3.701 (1 .33), 4.016 (1 .00), 4.044 (3.00), 4.071 (2.67), 4.098 (1 .00), 7.277 (2.00), 7.295 (2.00), 7.367 (5.00), 7.379 (5.67), 7.383 (3.67), 7.388 (5.67), 7.399 (5.67), 7.677 (3.33), 7.691 (4.33), 7.773 (5.00), 7.794 (4.67), 7.800 (7.33), 7.821 (6.00), 7.884 (1 .67), 7.908 (2.00), 8.304 (14.33), 8.306 (16.00).

Example 78

4-[1 -{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}ethyl]benzonitrile

Figure imgf000158_0001

A solution of 100 mg (264 μηιοΙ) 4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine hydrochloride (intermediate 112) and 57 mg (396 μηηοΙ) 4- acetylbenzonitrile in a mixture of 2 ml methanol, 1 ml dichloro methane and 0.06 ml acetic acid was heated to 60°C for 2 h. Then 36 mg (581 μηηοΙ) sodium cyanoborohydride was added and the mixture stirred at 60°C for 16h The volatile components were removed by evaporation and the residue was purified after filtration by preparative HPLC to yield 55 mg (42 %) of the desired product as a mixture of diastereomers.

LC-MS (method 12): Rt = 1 .37 min; MS (ESIpos): m/z = 472 [M+H]+

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .265 (5.28), 1 .275 (5.78), 1 .282 (5.93), 1 .291 (5.23), 1 .762 (0.50), 1 .776 (1 .1 1 ), 1 .794 (1 .84), 1 .809 (1 .66), 1 .826 (1 .14), 1 .845 (0.64), 1 .858 (0.41 ), 1 .974 (0.93), 2.337 (0.70), 2.344 (1 .37), 2.367 (1 .58), 2.398 (1 .05), 2.421 (1 .93), 2.433 (0.96), 2.454 (1 .66), 2.467 (2.95), 2.518 (6.34), 2.523 (4.32), 2.572 (0.96), 2.596 (1 .02), 2.619 (0.79), 2.638 (1 .72), 2.678 (0.91 ), 2.699 (0.64), 2.713 (0.55), 3.369 (1 .37), 3.380 (1 .40), 3.385 (1 .52), 3.396 (1 .20), 3.716 (0.82), 4.021 (0.79), 4.049 (2.16), 4.076 (2.07), 4.104 (0.73), 7.518 (3.21 ), 7.530 (3.74), 7.535 (2.54), 7.539 (3.97), 7.550 (4.15), 7.679 (2.60), 7.691 (3.04), 7.749 (2.45), 7.769 (2.16), 7.778 (5.37), 7.799 (4.20), 8.310 (16.00). According to the preparation of example 78 the following example 79 was prepared starting from the intermediate 112 by reacting with the corresponding methyl ketone.

Figure imgf000159_0002

Example 80

4-{7-[4-(morpholin-4-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2-trifluoroethyl)- pyrrolo[2,1 -f][1 ,2,4]triazine

Figure imgf000159_0001
A mixture of 4-(2,7-diazaspiro[4.4]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine hydrochloride (intermediate I22), 72.0 mg (0.166 mmol), and 4-(morpholin-4-yl)benzaldehyde, 26.4 mg (0.138 mmol), in dichloromethane, 1.40 ml, and triethylamine, 63.0 μΙ_ (0.455 mmol), was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride, 87.8 mg (0.414 mmol), was added in portions. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The product was extracted into dichloromethane and the organics were dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: ethyl acetate-5% ammonia/methanol 1 :0, 9:1 ) to give the desired product, 42.9 mg (50 %).

LC-MS (method 13): Rt = 0.85 min., 97%. MS (ESIpos): m/z = 501 [M+H]+.

1H NMR (400 MHz, CDCI3): δ [ppm] = 1.82-2.15 (m, 4H), 2.36-2.82 (m, 4H), 3.14 (dd, 4H), 3.37-3.43 (m, 2H), 3.58 (s, 2H), 3.68-4.55 (m, 8H), 6.66 (s, 1 H), 6.85 (d, 2H), 7.21 (d, 2H), 7.50 (s, 1 H), 7.82 (s, 1 H).

Example 81

4-{7-[4-(piperazin-1 -yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2-trifluoroethyl)- pyrrolo[2,1 -f][1 ,2,4]triazine hydrochloride

Figure imgf000160_0001

To a stirred solution of tert-butyl 4-[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]- 2,7-diazaspiro[4.4]non-2-yl}methyl)phenyl]piperazine-1 -carboxylate, 84.0 mg (0.140 mmol), in 1 ,4-dioxane, 0.816 ml, was added 4 M hydrochloric acid (in 1 ,4-dioxane), 0.350 ml. Stirring continued for 1 hour before being concentrated under vacuum. Dichloromethane was added to the residue and concentrated again under vacuum to give the desired product, 84.0 mg (98 %). LC-MS (method 13): Rt = 0.80 min., 100%. MS (ESIpos): m/z = 500 [M+H]+.

1 H NMR (400 MHz, MeOD): δ [ppm] =2.24-2.42 (m, 4H), 3.34-3.36 (m, 4H), 3.56-3.49 (m, 4H), 5.02-5.71 (m, 6H), 3.82-3.96 (m, 2H), 4.22-4.43 (m, 4H), 7.08-7.1 1 (m, 2H), 7.45-7.59 (m, 3H), 7.99-7.95 (m, 2H).

Example 82

4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile

Figure imgf000161_0001

To a mixture of 6-(2,2,2-trifluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol, 28.3 mg (90.0 μηιοΙ), in acetonitrile, 5.00 ml, and triethylamine, 2.78 ml, was added (benzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate, 46.9 mg (90.0 μηηοΙ), and 4-(2,7- diazaspiro[4.4]non-2-ylmethyl)benzonitrile hydrochloride (intermediate 115), 16.3 mg (75.0 μηηοΙ). The mixture was heated to 80 °C for 18 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium hydrogen carbonate solution. The organics were dried over sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (BIOTAGE ISOLERA, 12 g; SNAP C18 Biotage cartridge) using acetonitrile and water containing 10 mM ammonium bicarbonate pH 10 buffer (20:80 to 75:25 to 100:0) to give the desired product, 3.67 mg (1 1 %).

LC-MS (method 13): Rt = 0.86 min., 98%. MS (ESIpos): m/z = 441 [M+H]+.

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1 .88-2.00 (m, 3H), 2.06-2.16 (m, 1 H), 3.39-3.42 (d, 2H), 3.63-3.84 (m, 5H), 3.96-4.03 (m, 1 H), 6.66 (s, 1 H), 7.43-7.48 (d, 2H), 7.51 (s, 1 H), 7.59-7.61 (d, 2H), 7.82 (s, 1 H).

The following examples were prepared analogous to the preparation of example 1 starting from intermediate 112 by reacting with the corresponding aldehydes. Structure

Example Analytical Data

Name

F F

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.816 (1 .35), 1.834 (2.25), 1 .851 (2.25), 2.008 (1.29), 2.084 (1 .93), 2.322 (2.18), 2.326 (2.83), 2.331 (2.06), 2.522 (14.59), 2.575 (2.06), 2.593

83 (1 .99), 2.664 (3.15), 2.668 (3.73), 2.673 (2.96),

3.696 (3.73), 4.021 (1.22), 4.048 (3.08), 4.076 (3.02), 4.103 (1.09), 7.542 (3.86), 7.561 (5.01 ),

6-(2,2,2-trifluoroethyl)-4-{7-[4- 7.664 (5.59), 7.691 (7.58), 8.313 (16.00).

(trifluoromethyl)benzyl]-2,7- LC-MS (method 2): Rt = 0.82 min; MS diazaspiro[4.4]non-2- (ESIpos): m/z = 501 [M+H]+

yl}thieno[2,3-d]pyrimidine

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.773 (0.47), 1.778 (0.47), 1 .790 (1 .33), 1.810 (2.16), 1.825 (2.28), 1 .844 (1.04), 1.858 (0.49), 1 .982

F F

(0.98), 2.083 (0.75), 2.418 (2.56), 2.441 (3.68), 2.518 (3.70), 2.522 (3.53), 2.527 (3.00), 2.539 (1 .46), 2.550 (2.70), 2.569 (0.81 ), 2.594 (1.00),

N F 2.613 (1 .72), 2.628 (1.32), 2.651 (0.54), 3.528

84 (0.75), 3.561 (4.84), 3.571 (5.09), 3.604 (1.00),

3.736 (0.89), 4.019 (0.91 ), 4.047 (2.51 ), 4.074 (2.42), 4.102 (0.81 ), 7.096 (3.63), 7.101 (1.28),

4-[7-(4-fluorobenzyl)-2,7- 7.1 12 (1 .68), 7.1 18 (7.42), 7.124 (1.67), 7.135 diazaspiro[4.4]non-2-yl]-6- (1 .46), 7.140 (4.42), 7.148 (0.51 ), 7.319 (3.70), (2,2,2-trifluoroethyl)thieno[2,3- 7.334 (4.26), 7.341 (3.79), 7.355 (3.12), 7.689 d]pyrimidine (6.09), 8.310 (16.00).

LC-MS (method 2): Rt = 0.73 min; MS (ESIpos): m/z = 451 [M+H]+ Structure

Example Analytical Data

Name

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]:

1.084 (0.19), 1 .208 (0.32), 1.879 (0.26), 1 .898

(0.45), 1.934 (0.66), 1 .964 (0.72), 1.997 (1.04),

F F

2.050 (1 .51 ), 2.061 (1.77), 2.122 (1.28), 2.134

(1 .64), 2.147 (1.38), 2.300 (0.81 ), 2.304 (1.13),

2.309 (0.79), 2.496 (4.08), 2.500 (2.83), 2.517

(2.09), 2.642 (0.77), 2.646 (1 .06), 2.651 (0.77),

2.971 (0.40), 3.179 (0.53), 3.199 (0.60), 3.209

(0.70), 3.228 (0.68), 3.288 (1 .02), 3.308 (1.23),

3.364 (0.89), 3.377 (0.83), 3.393 (0.60), 3.416 (0.79), 3.430 (0.81 ), 3.445 (0.72), 3.459 (0.66),

85

3.503 (1 .02), 3.840 (1.43), 3.989 (0.89), 4.002

(1 .15), 4.017 (1.94), 4.030 (2.36), 4.045 (1.98),

4.057 (2.19), 4.085 (0.91 ), 4.161 (16.00), 4.165 υ H (14.72), 4.233 (1.09), 4.247 (1.13), 4.264

(1 .87), 4.279 (1.87), 4.306 (1 .91 ), 4.317 (1.91 ),

4-[4-({7-[6-(2,2,2- 4.338 (1 .42), 4.584 (2.68), 6.965 (0.66), 7.072 trifluoroethyl)thieno[2,3- (3.89), 7.091 (4.87), 7.221 (0.72), 7.289 (0.17), d]pyrimidin-4-yl]-2,7- 7.385 (4.40), 7.404 (4.06), 7.518 (0.25), 7.608 diazaspiro[4.4]non-2- (0.72), 7.648 (2.66), 8.324 (3.49), 8.345 (6.70), yl}methyl)phenyl]piperazine-2,6- 10.031 (0.40), 1 1.284 (2.53), 1 1.295 (2.34). dione

LC-MS (method 2): Rt = 0.63 min; MS (ESIpos): m/z = 545 [M+H]+

Structure

Example Analytical Data

Name

Isolated as side product after purification of the reaction mixture towards example 86.

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.232 (0.85), 1 .914 (0.50), 1.952 (0.71 ), 1 .975 (0.78), 2.009 (1.06), 2.030 (0.78), 2.073 (0.78), 2.083 (1 .77), 2.152 (1.70), 2.318 (1.27), 2.322 (2.83), 2.326 (3.96), 2.332 (2.76), 2.336 (1.27), 2.452 (0.71 ), 2.456 (0.78), 2.518 (16.00), 2.522 (10.76), 2.539 (5.10), 2.660 (1.27), 2.664 (2.83), 2.669 (3.96), 2.673 (3.04), 2.678 (1.35), 3.000 (0.50), 3.005 (0.42), 3.198 (0.71 ), 3.228

86 (0.85), 3.249 (0.85), 3.307 (1 .35), 3.327 (1.49),

3.377 (1 .20), 3.392 (1.13), 3.407 (0.99), 3.428 (1 .20), 3.441 (1.20), 3.457 (1 .13), 3.471 (1.13),

Figure imgf000164_0001
3.515 (1.63), 3.608 (1.98), 3.814 (14.37), 4.027

(6.51 ), 4.050 (3.82), 4.070 (3.12), 4.077 (3.19),

{(2-amino-2-oxoethyl)[4-({7-[6- 4.096 (1 .70), 4.186 (0.85), 4.235 (5.81 ), 4.264 (2,2,2-trifluoroethyl)thieno[2,3- (1 .70), 4.289 (1.49), 4.321 (0.92), 6.507 (3.40), d]pyrimidin-4-yl]-2,7- 6.526 (3.68), 6.964 (2.27), 7.092 (2.83), 7.220 diazaspiro[4.4]non-2- (2.62), 7.239 (0.42), 7.340 (3.82), 7.360 (3.82), yl}methyl)phenyl]amino}acetic

7.463 (1 .84), 7.630 (0.57), 7.663 (2.62), 7.914 acid

(1 .91 ), 8.337 (3.96), 8.357 (8.42), 9.81 1 (0.42).

LC-MS (method 2): Rt

(ESIpos): m/z = 563 [M+H]+

Structure

Example Analytical Data

Name

F F

ΙΛΙ-Λ -r 1 H-NMR (400 MHz, DMSO-d6) delta [ppm]:

1.753 (0.1 1 ), 1 .794 (0.57), 1.812 (0.99), 1 .830

(1 .05), 1.847 (0.48), 1 .987 (0.45), 2.083 (0.15),

2.327 (0.14), 2.440 (0.91 ), 2.463 (1.34), 2.523

(0.55), 2.540 (0.90), 2.549 (1 .05), 2.566 (0.90),

2.613 (0.39), 2.632 (0.74), 2.647 (0.55), 2.669

87

Q (0.34), 2.877 (10.83), 3.559 (0.43), 3.592

(2.06), 3.604 (2.22), 3.637 (0.60), 3.753 (0.44),

X 4.019 (0.39), 4.047 (1.04), 4.074 (1.01 ), 4.101

0 ' C H 3 (0.35), 4.438 (5.28), 7.339 (16.00), 7.691

(2.39), 8.310 (5.1 1 ).

4-[7-{4-

[(methylsulfonyl)methyl]benzyl}- LC-MS (method 2): Rt = 0.62 min; MS

2,7-diazaspiro[4.4]non-2-yl]-6- (ESIpos): m/z = 525 [M+H]+

(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidine

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232

(0.73), 1.796 (0.48), 1 .814 (0.79), 1.831 (0.84), 2.084 (0.65), 2.437 (0.87), 2.460 (1.41 ), 2.518 (3.49), 2.522 (2.39), 2.547 (0.84), 2.567 (0.84),

2.629 (0.59), 2.644 (0.45), 2.897 (0.65), 2.912

(1 .91 ), 2.927 (2.02), 2.943 (0.73), 3.360 (1.07),

88 3.375 (2.31 ), 3.389 (2.22), 3.405 (0.82), 3.551

(0.42), 3.584 (1.69), 3.597 (1 .83), 3.630 (0.53),

N-(2-hyd roxyethyl)- 1 -[4-({7-[6- 4.048 (0.84), 4.076 (0.82), 4.296 (5.17), 4.701 (2,2,2-trifluoroethyl)thieno[2,3- (1 .07), 4.715 (2.39), 4.729 (1 .01 ), 7.007 (0.59), d]pyrimidin-4-yl]-2,7- 7.022 (1.27), 7.037 (0.56), 7.308 (16.00), 7.691 diazaspiro[4.4]non-2- (2.14), 8.31 1 (6.75).

yl}methyl)phenyl]methanesulfon

LC-MS (method 2): Rt = 0.65 min; MS amide

(ESIpos): m/z = 570 [M+H]+

Figure imgf000166_0001

diazaspiro[4.4]non-2-

Figure imgf000167_0001

d]pyrimidin-4-yl]-2,7- LC-MS (method 1 ): Rt = 0.65 min; MS Structure

Example Analytical Data

Name

diazaspiro[4.4]non-2- (ESIpos): m/z = 448 [M+H]+

yl}methyl)aniline

H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.808 (0.41 ), 1.813 (0.41 ), 1 .825 (1 .1 1 ), 1.844 (1.88),

F F

1.860 (2.02), 1 .879 (0.93), 1.895 (0.41 ), 2.01 1 (0.82), 2.083 (4.95), 2.322 (0.79), 2.326 (1.1 1 ), 2.332 (0.79), 2.518 (4.22), 2.522 (2.86), 2.577

N F (3.27), 2.590 (1.48), 2.599 (2.38), 2.606 (1.66),

2.627 (0.73), 2.650 (0.59), 2.664 (1.61 ), 2.669

93 (2.20), 2.673 (1.61 ), 2.685 (0.91 ), 3.693 (0.89),

3.736 (4.02), 3.774 (1.13), 4.018 (0.86), 4.046 F (2.43), 4.073 (2.31 ), 4.101 (0.77), 7.499 (0.64),

4-{7-[4-fluoro-2- 7.520 (1 .25), 7.540 (0.73), 7.553 (2.34), 7.559 (trifluoromethyl)benzyl]-2,7- (1 .88), 7.576 (2.31 ), 7.583 (1 .79), 7.687 (5.76), diazaspiro[4.4]non-2-yl}-6- 7.791 (1 .25), 7.806 (1.38), 7.812 (1.27), 7.827 (2,2,2-trifluoroethyl)thieno[2,3- (1 .09), 8.314 (16.00).

d]pyrimidine LC-MS (method 2): Rt = 0.85 min; MS

(ESIpos): m/z = 519 [M+H]+

Separation of example 13 by chiral chromatography (method H) afforded the enantiomers examples 94 and 95.

prep. HPLC (method H)

94 analyt. HPLC (method 17): Rt = 6.91 min

Figure imgf000168_0001

optical rotation: [a]D 20 = 26.2° +/-1.19 (c = 1 .00;

1 -[4-({7-[6-(2,2,2- DMSO)

trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfon amide (ent-1 )

prep. HPLC (method H)

95

Figure imgf000169_0001
analyt. HPLC (method 17): Rt = 7.57 min optical rotation: [a]D 20 = -18.3° +/-1.53 (c =

1 -[4-({7-[6-(2,2,2- 1.00; DMSO)

trifluoroethyl)thieno[2,3- d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfon

amide (ent-2)

Example 96

N-[4-({(5S)-7-[6-(2,2,2-trifluoroethyl)thieno[2 d]py

yl}methyl)phenyl]prop-2-enamide

Figure imgf000169_0002

To a solution of 4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non- 2-yl}methyl)aniline (30.0 mg, 67.0 μηηοΙ) (example 92) in 1 ml acetonitrile was added sodium hydrogen carbonate (5.6 mg, 67.0 μηηοΙ). Then prop-2-enoyl chloride (6.07 mg, 67.0 μηηοΙ) was added and the mixture was stirred at RT for 90 min. Water was added and the solution was extracted 2x with ethyl acetate. After removal of the volatile components by evaporation the residue was purified by preparative HPLC to yield 2 mg (6 %) of the desired product. LC-MS (method 4): Rt = 1 .19 min. MS (ESIpos): m/z = 502 [M+H]+.

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.230 (0.90), 1.775 (0.52), 1 .787 (1.29), 1.806 (2.09), 1 .822 (2.19), 1.841 (1.03), 1.857 (0.49), 1 .987 (1 .08), 2.073 (0.64), 2.322 (0.88), 2.326 (1 .21 ), 2.332 (0.85), 2.415 (2.01 ), 2.438 (2.86), 2.452 (0.41 ), 2.461 (0.59), 2.518 (6.24), 2.522 (5.28), 2.539 (1.65), 2.549 (2.29), 2.595 (0.85), 2.614 (1 .65), 2.630 (1.24), 2.651 (0.49), 2.660 (0.46), 2.664 (0.90), 2.668 (1.21 ), 2.673 (0.88), 3.297 (0.59), 3.496 (0.95), 3.529 (4.64), 3.540 (4.82), 3.573 (1.08), 3.744 (0.90), 4.018 (0.93), 4.047 (2.27), 4.074 (2.22), 4.102 (0.77), 5.718 (3.40), 5.723 (2.96), 5.743 (3.09), 5.748 (3.71 ), 6.21 1 (2.52), 6.216 (2.68), 6.253 (4.12), 6.258 (4.20), 6.385 (3.56), 6.410 (3.61 ), 6.427 (2.40), 6.452 (2.06), 7.239 (6.16), 7.260 (6.78), 7.584 (6.78), 7.605 (5.95), 7.689 (5.87), 8.309 (16.00), 10.100 (4.69).

The following example was prepared analogous to the preparation of example 78 starting from intermediate 112 by reacting with the corresponding methyl ketone.

Structure

Example Analytical Data

Name

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.154 (0.75), 1 .172 (1.53), 1.190 (0.76), 1 .232 (0.51 ), 1.261 (2.91 ), 1 .270 (2.95), 1.277 (4.09), 1.287 (8.64), 1.371 (16.00), 1 .483 (0.48), 1 .768 (0.44), 1.783 (0.88), 1 .802 (0.87), 1.815 (0.58), 1.987 (3.10), 2.322 (0.50), 2.327 (0.71 ), 2.332 (0.57), 2.340 (0.74), 2.364 (0.93), 2.373 (0.87), 2.388 (0.93), 2.415 (0.44), 2.446 (0.48), 2.466

Figure imgf000170_0001

97 (0.51 ), 2.518 (3.53), 2.523 (2.23), 2.540 (0.57),

2.664 (0.54), 2.669 (0.70), 2.673 (0.50), 3.126 tert-butyl {4-[1 -{7-[6-(2,2,2- (6.23), 3.157 (9.94), 3.245 (0.82), 3.262 (0.81 ), trifluoroethyl)thieno[2,3- 3.724 (0.42), 4.017 (0.93), 4.035 (0.92), 4.047 d]pyrimidin-4-yl]-2,7- (0.93), 4.075 (0.90), 7.133 (0.55), 7.152 (0.76), diazaspiro[4.4]non-2- 7.184 (1 .54), 7.205 (2.40), 7.248 (1.47), 7.269 yl}ethyl]benzyl}carbamate (3.35), 7.290 (1.48), 7.675 (0.68), 7.692 (1.47), (mixture of stereoisomers) 8.299 (2.62), 8.307 (4.52).

LC-MS (method 2): Rt = 0.92 min; MS (ESIpos): m/z = 576 [M+H]+ Example 98

N-{4-[(1 -{7-[6-(2,2,2-trifluoroethyl)thien^

yl}ethyl]benzyl}prop-2-enamide

Figure imgf000171_0001

To a stirred solution of tert-butyl {4-[1 -{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}ethyl]benzyl}carbamate (100 mg, 172 μηηοΙ, example 97), in 1 ,4- dioxane, 1 ml, was added 4 M hydrochloric acid (in 1 ,4-dioxane), 1 .0 ml. Stirring continued for 4 h before being concentrated under vacuum to yield crude 1 -{4-[1-{7-[6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2-yl}ethyl]phenyl}methanamine hydrochloride. To a solution of 1-{4-[1-{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}ethyl]phenyl}methanamine hydrochloride (88.0 mg, 172 μηηοΙ) in 2.6 ml acetonitrile was added sodium hydrogen carbonate (28.9 mg, 344 μηηοΙ). Then prop-2-enoyl chloride (15.6 mg, 172 μηηοΙ) was added and the mixture was stirred at RT for 90 min. Water was added and the solution was extracted 2x with ethyl acetate. After removal of the volatile components by evaporation the residue was purified by preparative HPLC to yield 27 mg (28 %) of the desired product as a mixture of stereoisomers.

LC-MS (method 2): Rt = 0.72 min. MS (ESIpos): m/z = 530 [M+H]+.

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.231 (0.99), 1.282 (7.92), 1 .292 (8.23), 1.299 (8.80), 1 .308 (7.36), 1.776 (1.52), 1.791 (2.62), 1 .807 (2.46), 1 .823 (1.63), 1.986 (1 .44), 2.322 (1 .55), 2.327 (2.16), 2.331 (1.59), 2.362 (1 .90), 2.385 (2.12), 2.402 (1.74), 2.425 (2.50), 2.453 (1 .59), 2.518 (10.01 ), 2.522 (6.86), 2.580 (0.68), 2.601 (1.36), 2.617 (2.20), 2.638 (1.55), 2.665 (2.12), 2.669 (2.58), 2.673 (1.90), 2.678 (1 .29), 2.685 (1 .14), 2.701 (0.91 ), 2.722 (0.42), 3.207 (12.82), 3.231 (16.00), 3.300 (2.20), 3.307 (2.62), 3.316 (2.84), 3.749 (1.18), 4.023 (1.18), 4.051 (3.1 1 ), 4.079 (3.00), 4.106 (1.06), 5.501 (0.87), 5.531 (1 .02), 5.548 (1.25), 5.578 (1 .21 ), 5.996 (0.57), 6.103 (2.20), 6.109 (2.20), 6.127 (2.50), 6.133 (2.43), 6.145 (1.48), 6.150 (1 .36), 6.169 (1.40), 6.175 (1 .18), 7.166 (2.01 ), 7.185 (2.27), 7.204 (6.37), 7.225 (7.43), 7.374 (4.13), 7.391 (7.39), 7.412 (4.55), 7.690 (3.79), 7.701 (4.85), 8.306 (1 1.91 ), 8.313 (12.47). Example 99

(rac)-1-[4-({(7-[6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4.4]non yl}methyl)phenyl]methanesulfonamide

Figure imgf000172_0001
To a suspension of (rac)-4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2-difluoropropyl)thieno[2,3- d]pyrimidine hydrochloride (1 :1 ) (70.0 mg) and 1 -(4-formylphenyl)methanesulfonamide (51.7 mg) in dichloromethane (3 mL) at room temperature was sequentially added triethylamine (57 μΙ_) and sodium triacetoxyborohydride (73.2 mg) and the mixture was stirred for 2.5 h. The mixture was concentrated and purified by preparative HPLC (method K) to yield the title compound (55 mg).

LC-MS (method 4): Rt = 1.05 min; MS (ESIpos): m/z = 522 [M+H]+

1H NMR (400 MHz, DMSO-cfe, 22°C) δ ppm 1.56 - 1.73 (m, 3 H), 1.75 - 1.89 (m, 2 H), 1 .91 - 2.07 (m, 2 H), 2.42 - 2.69 (m, 4 H), 3.50 - 3.90 (m, 8 H), 4.18 - 4.26 (m, 2 H), 6.78 - 6.85 (m, 2 H), 7.25 - 7.35 (m, 4 H), 7.51 - 7.59 (m, 1 H), 8.24 - 8.35 (m, 1 H).

Example 100

4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol (ent-1 )

Figure imgf000172_0002
34 mg of 4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol (example 66) were separated by using chiral prep. HPLC (method G) into its enantiomers.

Yield: 13 mg, HPLC (method 16): Rt = 4.12 min Optical rotation: [a]D20 = -24.8° +/-0.420 (c = 1 .00; methanol)

Example 101

4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol (ent-2)

Figure imgf000173_0001

The compound was obtained as second enantiomer of the chiral prep. HPLC (method G) of example 66.

Yield: 15 mg, HPLC (method 16): Rt = 5.08 min

Optical rotation: [a]D20 = 27.7° +/-0.460 (c = 1.00; methanol)

Example 102

1-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide

Figure imgf000173_0002
To a stirred solution of 4-[2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2-trifluoroethyl)thieno[3,2- d]pyrimidine hydrochloride (350 mg, 924 μηηοΙ) (intermediate 144) in 10 ml dichloromethane was added under argon 1 -(4-formylphenyl)methanesulfonamide (198 mg, 93 % purity, 924 μηηοΙ) followed by triethylamine (390 μΙ, 2.8 mmol) and sodium triacetoxyborohydride [CAS 56553-60-7] (362 mg, 1 .71 mmol) and the mixture was stirred for 17 h at RT. The volatile components were removed by evaporation and the residue was purified by preparative HPLC to yield 290 mg (57 %) of the desired product.

LC-MS (method 2): Rt = 0.43 min; m/z = 526 (M+H)+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1 .796 (0.92), 1 .817 (1 .39), 1 .832 (1 .42), 1 .853 (0.76), 1 .907 (0.69), 1 .991 (0.96), 2.006 (0.99), 2.318 (0.59), 2.323 (1 .32), 2.327 (1 .91 ), 2.332 (1 .35), 2.336 (0.59), 2.431 (1 .22), 2.454 (1 .75), 2.518 (6.30), 2.523 (4.95), 2.540 (1 .15), 2.544 (1 .06), 2.560 (2.14), 2.582 (1 .29), 2.641 (0.43), 2.660 (1 .48), 2.665 (2.08), 2.669 (2.44), 2.673 (1 .98), 2.678 (1 .29), 3.595 (5.87), 3.789 (0.63), 4.126 (1 .02), 4.154 (2.90), 4.182 (2.77), 4.220 (10.79), 6.818 (8.25), 7.280 (1 .09), 7.287 (0.63), 7.302 (16.00), 7.304 (15.34), 7.319 (0.53), 7.326 (0.96), 7.380 (6.20), 8.143 (0.53), 8.363 (13.49).

Separation of example 102 by chiral chromatography afforded example 102.1 and its enantiomer example 102.2.

Figure imgf000174_0001

The following examples were prepared analogous to the preparation of example 40 starting from intermediates I44, I45 and I46 by reacting with the corresponding aldehydes.

Figure imgf000175_0001

(ESIpos): m/z = 472 [M+H]+

Figure imgf000176_0001

LC-MS (method 2): Rt = 0.49 min; MS Structure

Example Analytical Data

Name

(ESIpos): m/z = 532 [M+H]+ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.780 (0.55), 1.786 (0.57), 1.798 (1.41 ), 1.813 (1.89),

F F

/N. V_F 1.817 (2.06), 1.834 (2.04), 1.855 (1.18), 1.870

(0.55), 1.988 (1.54), 2.005 (1.57), 2.323 (0.73), γ ¾ H 2 N 2.327 (1.00), 2.332 (0.71 ), 2.425 (2.57), 2.447

(3.40), 2.518 (4.47), 2.523 (3.09), 2.540 (2.04), 2.556 (4.26), 2.579 (2.61 ), 2.632 (0.81 ), 2.652

107

(1.60), 2.669 (2.27), 2.673 (1.68), 2.689 (0.53), 3.637 (11.30), 3.672 (0.65), 3.802 (1.02), 4.125

4-({7-[6-(2,2,2- (1.51 ), 4.153 (4.31 ), 4.181 (4.10), 4.209 (1.30), trifluoroethyl)thieno[3,2- 7.300 (2.46), 7.367 (7.35), 7.380 (9.73), 7.388 d]pyrimidin-4-yl]-2,7- (8.18), 7.799 (9.02), 7.819 (8.05), 7.910 (2.45), diazaspiro[4.4]non-2- 8.364 (16.00).

yl}methyl)benzamide LC-MS (method 4): Rt = 1.04 min; MS

(ESIpos): m/z = 476 [M+H]+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.787 (0.62), 1.806 (0.88), 1.828 (0.85), 1.846 (0.60), 1.982 (0.68), 2.023 (16.00), 2.413 (0.52), 2.435 (0.71 ), 2.518 (2.12), 2.522 (1.69),

108 2.539 (1.26), 2.630 (0.55), 2.664 (0.42), 2.669

(0.47), 3.584 (2.22), 3.738 (0.57), 3.998 (8.09),

(4-{[7-{6- 4.009 (4.96), 7.270 (1.89), 7.290 (3.90), 7.324 [(methylsulfanyl)methyl]thieno[2, (3.51 ), 7.345 (1.71 ), 7.512 (3.35), 8.269 (7.43).

3-d]pyrimidin-4-yl}-2,7- LC-MS (method 4): Rt = 0.63 min; MS diazaspiro[4.4]non-2- (ESIpos): m/z = 450 [M+H]+

yl]methyl}phenyl)acetonitrile

Figure imgf000178_0001

yl)acetate Structure

Example Analytical Data

Name

0 C H 3 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .74 - 1.88 (m, 2H), 1 .98 (br s, 2H), 2.42 (d, 1 H), 2.52 - 2.66 (m, 2H), 3.53 - 3.92 (m, 9H), 4.00 (s,

111

2H), 4.05 (s, 2H), 7.25 - 7.30 (m, 2H), 7.30 - 7.36 (m, 2H), 7.53 (s, 1 H), 8.27 (s, 1 H).

LC-MS (method 4): Rt = 1 .15 min; MS methyl (4-{7-[4- (ESIpos): m/z =462 [M+H]+

(cyanomethyl)benzyl]-2,7- diazaspiro[4.4]non-2- yl}thieno[2,3-d]pyrimidin-6- yl)acetate

0 C H 3

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .66 N N (s, 6H), 1.76 - 1.88 (m, 2H), 1 .98 (br s, 2H),

2.44 (d, 1 H), 2.53 - 2.64 (m, 2H), 3.54 - 3.91

112 (m, 9H), 4.05 (s, 2H), 7.34 - 7.39 (m, 2H), 7.43

- 7.47 (m, 2H), 7.54 (s, 1 H), 8.27 (s, 1 H). methyl (4-{7-[4-(2-cyanopropan- LC-MS (method 1 ): Rt = 0.81 min; MS 2-yl)benzyl]-2,7- (ESIpos): m/z = 490 [M+H]+ diazaspiro[4.4]non-2- yl}thieno[2,3-d]pyrimidin-6- yl)acetate

The following example was prepared analogous to the preparation of example 40 starting from intermediate I47.

Figure imgf000179_0001
Structure

Example Analytical Data

Name H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .76 -

N 1.86 (m, 2H), 1 .88 - 2.1 1 (m, 2H), 2.38 - 2.48

(m, 1 H), 2.52 - 2.61 (m, 2H), 2.62 - 2.71 (m,

113 1 H), 3.54 - 3.79 (m, 4H), 3.95 - 4.18 (m, 2H),

4.22 (s, 2H), 4.30 - 4.46 (m, 2H), 6.82 (s, 2H),

1 -[4-({7-[2-(2,2,2- 7.30 (br d, 4H), 8.38 (d, 1 H).

trifluoroethyl)[1 ,3]thiazolo[5,4-

LC-MS (method 4): Rt = 1 .12 min; MS d]pyrimidin-7-yl]-2,7- (ESIpos): m/z = 527 [M+H]+

diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfon

amide

Separation of example 113 by chiral

1 -[4-({7-[2-(2,2,2- chromatography afforded example 113.1 and trifluoroethyl)[1 ,3]thiazolo[5,4- its enantiomer example 113.2.

d]pyrimidin-7-yl]-2,7-

113.1 prep. HPLC (method L)

diazaspiro[4.4]non-2- analyt. HPLC (method 24): Rt = 2.89 min yl}methyl)phenyl]methanesulfon

amide (enantiomer 1 ) optical rotation: [a]D 20 = +25.2° (c = 1.00;

DMSO)

1 -[4-({7-[2-(2,2,2- trifluoroethyl)[1 ,3]thiazolo[5,4- prep. HPLC (method L)

d]pyrimidin-7-yl]-2,7-

113.2 analyt. HPLC (method 24): Rt = 3.96 min

diazaspiro[4.4]non-2- optical rotation: [a]D 20 = -22° (c = 1 .00; DMSO) yl}methyl)phenyl]methanesulfon

amide (enantiomer 2)

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .76 - 1.85 (m, 2H), 1 .86 - 2.10 (m, 2H), 2.34 - 2.46 (m, 1 H), 2.53 - 2.59 (m, 2H), 2.67 (br dd, 1 H),

114 3.58 (s, 2H), 3.60 - 3.77 (m, 2H), 3.94 - 4.18

(m, 4H), 4.29 - 4.46 (m, 2H), 7.28 (br d, 2H), 7.30 - 7.37 (m, 2H), 8.38 (s, 1 H).

LC-MS (method 4): Rt = 1 .32 min; MS Structure

Example Analytical Data

Name

[4-({7-[2-(2,2,2- (ESIpos): m/z =473 [M+H]+ trifluoroethyl)[1 ,3]thiazolo[5,4- d]pyrimidin-7-yl]-2,7- diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile

Separation of example 114 by chiral

[4-({7-[2-(2,2,2- chromatography afforded example 114.1 and trifluoroethyl)[1 ,3]thiazolo[5,4- its enantiomer example 114.2.

d]pyrimidin-7-yl]-2,7-

114.1

prep. HPLC (method I)

diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile analyt. HPLC (method 18): Rt = 1.88 min

(enantiomer 1 )

optical rotation: [a]D 20 = -24° (c = 1 .00; DMSO)

[4-({7-[2-(2,2,2- prep. HPLC (method I)

trifluoroethyl)[1 ,3]thiazolo[5,4- d]pyrimidin-7-yl]-2,7- analyt. HPLC (method 18): Rt = 3.18 min

114.2

diazaspiro[4.4]non-2- optical rotation: [a]D 20 = +29.8° (c = 1.00; yl}methyl)phenyl]acetonitrile DMSO)

(enantiomer 2)

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .66 (s, 6H), 1 .76 - 1.86 (m, 2H), 1 .87 - 2.1 1 (m, 2H), 2.36 - 2.47 (m, 1 H), 2.53 - 2.70 (m, 3H), 3.54 - 3.78 (m, 4H), 3.94 - 4.19 (m, 2H), 4.29 -

115

Figure imgf000181_0001
4.46 (m, 2H), 7.32 - 7.40 (m, 2H), 7.40 - 7.48

(m, 2H), 8.37 (s, 1 H).

2-methyl-2-[4-({7-[2-(2,2,2- trifluoroethyl)[1 ,3]thiazolo[5,4- LC-MS (method 4): Rt = 1 .44 min; MS d]pyrimidin-7-yl]-2,7- (ESIpos): m/z = 501 [M+H]+

diazaspiro[4.4]non-2- yl}methyl)phenyl]propanenitrile

2-methyl-2-[4-({7-[2-(2,2,2- Separation of example 115 by chiral

115.1 trifluoroethyl)[1 ,3]thiazolo[5,4- chromatography afforded example 115.1 and d]pyrimidin-7-yl]-2,7- its enantiomer example 115.2. Structure

Example Analytical Data

Name

diazaspiro[4.4]non-2- prep. HPLC (method I)

yl}methyl)phenyl]propanenitrile analyt. HPLC (method 18): Rt = 1.77 min

(enantiomer 1 )

optical rotation: [a]D 20 = -27° (c = 1 .00; DMSO)

2-methyl-2-[4-({7-[2-(2,2,2- trifluoroethyl)[1 ,3]thiazolo[5,4- prep. HPLC (method I)

d]pyrimidin-7-yl]-2,7-

115.2 analyt. HPLC (method 18): Rt = 4.70 min

diazaspiro[4.4]non-2- optical rotation: [a]D 20 = +26° (c = 1.00; DMSO) yl}methyl)phenyl]propanenitrile

(enantiomer 2)

The following example was prepared analogous to the preparation of example 61 starting from example 104.

Figure imgf000182_0001
The following examples were prepared analogous to the preparation of example 80 starting from intermediate 122 by reacting with the corresponding aldehydes.

Figure imgf000183_0001
Figure imgf000184_0001

yl}methyl)phenyl]amino}ethanol

Figure imgf000185_0001

yl}methyl)benzenesulfonamide

Figure imgf000186_0001

f][1 ,2,4]triazine

Example 123

(rac)-2-[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]acetamide

Figure imgf000186_0002

To a mixture of 4-(2,7-diazaspiro[4.4]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine trihydrochloride (50.0 mg, 0.1 15 mmol) and 2-(4-formylphenyl)acetamide (18.8 mg, 0.115 mmol) in dichloromethane (1.2 ml.) and acetonitrile (2.40 ml.) was added triethylamine (48.0 μΙ_, 0.345 mmol), and stirred at room temperature for 1 h. Sodium triacetoxyborohydride (73.1 mg, 0.345 mmol), was added in three portions over 30 minutes and the reaction mixture stirred at room temperature for 18 hours. Further trimethylamine (48.0 μΙ_, 0.345 mmol) and sodium triacetoxyborohydride (73.1 mg, 0.345 mmol), were added and the reaction stirred at room temperature for 24 h. Further sodium triacetoxyborohydride (146 mg, 0.690 mmol) was added in three portions over three hours. The reaction was stirred for 2 h at room temperature, quenched with water and stirred for 30 minutes. The mixture was extracted with dichloromethane, the combined organic layers dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash chromatography on silica gel 60 (eluent: ethyl acetate-6% ammonia/methanol 1 :0 to 92:8) then by flash chromatography on silica gel 60 (eluent: dichloromethane-12% ammonia/methanol 39:1 to 19:1 ). The residue was triturated with heptanes to give the desired product (16.8 mg, 31 %).

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1 .79-2.19 (m, 4H), 2.38-2.85 (m, 4H), 3.34-3.48 (m, 2H), 3.56-4.08 (m, 8H), 5.34 (br s, 2H), 6.66 (s, 1 H), 7.22 (d, 2H), 7.31 (d, 2H), 7.51 (s, 1 H), 7.82 (s, 1 H);

UPLC-MS (method 15): Rt = 1.99 min., 98%. MS (ESIpos): m/z = (M+H)+ 473.

Example 124

1-[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarbonitrile

Figure imgf000187_0001

A mixture of 1 -(4-formylphenyl)cyclopropanecarbonitrile (47.3 mg, 276 μηηοΙ), and 4-(2,7- diazaspiro[4.4]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazine trihydrochloride (100 mg, 230 μηηοΙ), in dichloromethane (2.40 ml.) and trimethylamine (96.0 μΙ_), was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride, 146 mg (690 μηηοΙ) was added in portions. The reaction mixture was stirred at room temperature for 18 h, then sodium triacetoxyborohydride (146 mg, 690 μηηοΙ) and trimethylamine (96.0 μΙ_) were added and stirring continued for 4 hours. Sodium borohydride (26.1 mg, 690 μηηοΙ), was added under argon and the reaction mixture stirred at room temperature for 1 hour. The reaction was quenched by the addition of methanol then water and extracted with dichloromethane. The combined organics were dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 60 (eluent: ethyl acetate-12% ammonia/methanol; 99:1 , 95:5) to give the desired product (23.1 mg, 21 %).

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1.37 (d, 1 H), 1 .39 (d, 1 H), 1 .69 (d, 1 H), 1.71 (d, 1 H), 1.78-2.20 (m, 4H), 2.36-2.83 (m, 4H), 3.32-3-50 (m, 2H), 3.54-4.09 (m, 6H), 6.66 (s, 1 H), 7.22 (d, 2H), 7.29 (d, 2H), 7.51 (s, 1 H), 7.82 (s, 1 H);

UPLC-MS (method 15): Rt = 2.72 min., 97.59%.

Example 125

(rac)-[4-({7-[6-(2,2,2-trif luoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non- 2-yl}methyl)phenyl]acetonitrile

Figure imgf000188_0001

A mixture of 4-(2,7-diazaspiro[4.4]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine trihydrochloride (70.1 mg, 161 μηηοΙ), and (4-formylphenyl)acetonitrile (23.4 mg, 161 μηηοΙ) were stirred in titanium(IV) isopropoxide (2 mL) for 1 h at room temperature, then warmed to 50 °C for 5 minutes. The reaction was cooled to room temperature, methanol (2 mL) was added followed by sodium borohydride (12.2 mg, 322 μηηοΙ) and stirred for 1.5 h. Water and dichloromethane were added and the suspension filtered through celite. The organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified twice by flash chromatography on silica gel 60 (eluent: ethyl acetate-12% ammonia/methanol 1 :0 to 95:5; then dichloromethane-12% ammonia/methanol 1 :0 to 97:3) then by reverse phase chromatography (Biotage Isolera, 12 g; SNAP C18 Biotage cartridge) using acetonitrile and water containing 10 mM ammonium bicarbonate pH 10 buffer (20:80 to 100:0) to give the desired product (6.37 mg, 9%).

1H NMR (400 MHz, CDCI3): δ [ppm] = 1 .78-2.21 (m, 4H), 2.36-2.84 (m, 4H), 3.34-3.48 (m, 2H), 3.55-4.09 (m, 8H), 6.66 (s, 1 H), 7.26 (d, 2H), 7.33 (d, 2H), 7.51 (s, 1 H), 7.82 (s, 1 H);

UPLC-MS (method 15): Rt = 2.48 min., 98%. MS (ESIpos): m/z = (M+H)+ 455.

Example 126

{4-[1-7-[6-(2,2,2-Trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}ethyl]phenyl}acetonitrile,

Figure imgf000189_0001

To a mixture of 4-(2,7-diazaspiro[4.4]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine trihydrochloride (60.0 mg, 138 μηηοΙ), and (4-acetylphenyl)acetonitrile (22.0 mg, 138 μηηοΙ) in titanium isopropoxide (407 μΙ_, 1 .38 mmol) was added trimethylamine (58.0 μΙ_, 0.414 mmol), and the mixture stirred at room temperature for 30 min. The reaction mixture was heated at 50 °C for 5 min and stirred for a further 30 min at room temperature. Methanol (0.4 ml.) and sodium borohydride (10.4 mg, 0.276 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of water, dichloromethane was added and the mixture was filtered through celite. The organic phase was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash chromatography on silica gel 60 (eluent: ethyl acetate-12% ammonia/methanol 1 :0 to 97:3), then by flash chromatography on silica gel 60 (eluent: dichloromethane-12% ammonia/methanol 1 :0 to 97:3), to give the desired produc (12.1 mg, 19%) as a mixture of diastereoisomers.

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1 .25-1.39 (m, 3H), 1.75-2.16 (m, 4H), 2.32-2.95 (m, 4H), 3.19-3.29 (m, 1 H), 3.36-3.47 (m, 2H), 3.59-4.05 (m, 6H), 6.66 (s, 1 H), 7.20-7.36 (m, 4H), 7.50 (s, 1 H), 7.82 (s, 1 H); UPLC3-MS (Long Acidic 20-70%): Rt = 1 .17 min., 95%. MS (ESIpos): m/z = (M+H)+ 469.

The following example was prepared analogous to the preparation of example 41 starting from intermediate 113 by reacting with the corresponding aldehyde.

Figure imgf000190_0001

Example 128

(4-{[7-(6-{[methylsulfinyl]methyl}thieno[2,3-d]pyrimidin-4-yl)-2 -diazaspiro[4.4]non yl]methyl}phenyl)acetonitrile

Figure imgf000191_0001

To a stirred mixture of 0.6 ml dichloromethane and 75μΙ methanol was added scandium(lll)triflate (13.1 mg, 26.7 μηηοΙ) and then hydrogen peroxide (140 μΙ, 30 % in water, 1.3 mmol) and the mixture was stirred for 5 min. Then (4-{[7-{6- [(methylsulfanyl)methyl]thieno[2,3-d]pyrimidin-4-yl}-2,7-diazaspiro[4.4]non-2-yl]methyl}phenyl)- acetonitrile (60.0 mg, 133 μηηοΙ) dissolved in a mixture of 0.6 ml dichloromethane and 75μΙ methanol was added and stirring continued for 2.5 h at RT. After addition of DMSO the reaction mixture was purified by preparative reversed phase HPLC to yield 16mg (25%) of (4- {[7-(6-{[methylsulfinyl]methyl}thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]non-2-yl]methyl}- phenyl)acetonitrile as a mixture of stereoisomers. Furthermore 3 mg (4 %) of (4-{[7-{6- [(methylsulfonyl)methyl]thieno[2,3-d]pyrimidin-4-yl}-2,7-diazaspiro[4.4]non-2-yl]methyl}phenyl)- acetonitrile (example 129) were isolated.

LC-MS (method 2): Rt = 0.42 min; m/z = 466 (M+H)+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.793 (1 .25), 1.81 1 (2.15), 1.828 (2.44), 1.845 (1 .12), 1.860 (0.51 ), 1.900 (13.63), 1 .986 (1 .03), 2.083 (0.61 ), 2.326 (0.55), 2.41 1 (1.80), 2.434 (2.54), 2.518 (3.20), 2.523 (3.35), 2.61 1 (0.78), 2.630 (1 .50), 2.646 (1 .19), 2.665 (0.74), 2.668 (0.97), 2.673 (0.54), 3.580 (8.44), 3.614 (0.63), 3.651 (0.54), 3.670 (0.62), 3.693 (0.72), 3.701 (0.75), 3.729 (0.85), 3.731 (0.87), 3.739 (0.90), 3.743 (0.92), 3.750 (0.89), 3.762 (0.88), 3.765 (0.88), 3.778 (0.85), 3.781 (0.83), 3.793 (0.77), 3.824 (0.65), 3.832 (0.56), 3.835 (0.52), 3.996 (15.21 ), 4.248 (1.56), 4.282 (2.13), 4.444 (2.29), 4.478 (1.70), 7.268 (4.02), 7.288 (8.48), 7.322 (8.47), 7.342 (3.88), 7.603 (6.34), 8.299 (16.00).

Example 129

(4-{[7-{6-[(methylsulfonyl)methyl]thieno[2,3-d]pyrimidin-4-yl}-2 -diazaspiro[4.4]non yl]methyl}phenyl)acetonitrile

Figure imgf000192_0001

Preparation see example 128.

LC-MS (method 2): Rt = 0.46 min; m/z = 482 (M+H)+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.231 (0.68), 1.800 (1 .30), 1 .815 (2.36), 1.832 (2.50), 1 .847 (1.24), 1.863 (0.56), 1.899 (2.30), 1 .986 (1 .14), 2.083 (0.60), 2.322 (0.68), 2.327 (0.92), 2.331 (0.72), 2.414 (2.02), 2.437 (2.86), 2.522 (5.57), 2.552 (2.52), 2.617 (0.88), 2.636

(1 .66) , 2.651 (1.32), 2.664 (1.08), 2.669 (1 .28), 2.673 (1 .24), 3.003 (16.00), 3.549 (0.52), 3.583

(7.67) , 3.617 (0.74), 3.745 (1.06), 3.995 (13.42), 4.200 (0.48), 4.843 (4.89), 7.269 (3.80), 7.289 (7.81 ), 7.324 (7.85), 7.344 (3.86), 7.716 (5.79), 8.316 (10.87), 8.330 (0.46).

The following example was prepared analogous to the preparation of example 128 starting from example 109.

Figure imgf000192_0002
Structure

Example Analytical Data

Name

3-d]pyrimidin-4-yl)-2,7- diazaspiro[4.4]non-2- yl]methyl}phenyl)methanesulfon

amide

Example 131

1-(4-{[7-{6-[(methylsulfonyl)methyl]thieno[2,^

yl]methyl}phenyl)methanesulfonamide

Figure imgf000193_0001

A stirred solution of 1-(4-{[7-{6-[(methylsulfanyl)methyl]thieno[2,3-d]pyrimidin-4-yl}-2,7- diazaspiro[4.4]non-2-yl]methyl}phenyl)methanesulfonamide (42.0 mg, 83.4 μηηοΙ) in 3ml dichloromethane was added m-chloroperoxybenzoic acid (37.4 mg, 77 % purity, 167 μηηοΙ) and the mixture was stirred for 90 min at RT. After addition of water the organic solvents were evaporated and the crude reaction mixture was purified by preparative HPLC to yield 0.3 mg (1 %) of the desired product.

LC-MS (method 2): Rt = 0.39 min; m/z = 536 (M+H)+

1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.850 (1 .07), 1.232 (3.20), 1.820 (1 .60), 1.836 (1 .60), 2.005 (1 .07), 2.322 (3.20), 2.326 (4.27), 2.331 (3.20), 2.439 (1 .60), 2.522 (16.00), 2.539 (3.73), 2.665 (4.27), 2.669 (5.33), 2.673 (3.73), 3.001 (12.27), 3.204 (0.53), 3.256 (1.07), 3.278 (2.13), 3.294 (1 .60), 3.315 (4.80), 3.447 (2.13), 3.500 (1 .07), 3.593 (3.73), 4.221 (8.53), 4.843 (3.20), 6.820 (6.93), 7.299 (14.93), 7.717 (4.27), 8.316 (6.93). Example 132

(rac)-[4-({7-[6-(Pentafluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile

Figure imgf000194_0001

A mixture of (rac)-4-(2,7-diazaspiro[4.4]non-2-yl)-6-(pentafluoroethyl)pyrrolo[2, 1 - f][1 ,2,4]triazine hydrochloride (1 :3) (60.0 mg, 0.127 mmol, intermediate 161 ) and (4- formylphenyl)acetonitrile (15.4 mg, 0.106 mmol), in dichloromethane (520 μΙ_) and trimethylamine (49.0 μΙ_, 0.351 mmol), was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (67.5 mg, 0.319 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with water and stirred at room temperature for 30 min, then extracted with dichloromethane. The organic extracts were washed with water and dried over sodium sulfate, filtered then concentrated under vacuum. The residue was purified by column chromatography on silica gel 60 (eluent: ethyl acetate) to give the desired product (47.0 mg, 74%).

1 H NMR (400 MHz, CDCI3): δ [ppm] = 1 .83-2.17 (m, 4H), 2.42-2.81 (m, 4H), 6.32 (s, 2H), 3.66- 4.06 (m, 6H), 6.88 (s, 1 H), 7.26 (d, 2H), 7.31 (d, 2H), 7.77 (s, 1 H), 7.88 (s, 1 H); UPLC-MS (method 23): Rt = 1 .06 min., 97%. MS (ESIpos): m/z = (M+H)+ 491 . EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS

Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein

• the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and

• the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:

In vitro assay 1 : Menin / MLL-1 peptide binding assay

The ability of the compounds described in the present invention to disrupt the interaction between Menin (full length) and MLL-1 (a. a. 4-15) was used as quantitative measure of their menin-binding affinities. To this end a TR-FRET assay which detects the binding of a biotinylated MLL-1 -derived synthetic peptide (purchased from e.g. Biosyntan (Berlin, Germany)) of sequence Btn-PEG2- PEG2-S-Nva-RWRFPARPGTT-Amide to recombinant, full length, N-terminally His-tagged Menin. The protein was produced in-house via E. coli expression, followed by subsequent Ni- Sepharose affinity- and Superdex S200-size exclusion chromatography purification steps.

Typically, 1 1 different concentrations of each compound (0.1 nM, 0.33 nM, 1 .1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μΜ, 0.51 μΜ, 1 .7 μΜ, 5.9 μΜ and 20 μΜ) were tested in duplicate within the same microtiter plate. To this end, 100-fold concentrated compound solutions (in DMSO) were previously prepared with a Precision Pippeting System (BioTek) by serial dilution (1 :3.4) of 2 mM stocks in clear, low-volume 384-well microtiter source plates (Greiner Bio-One).

Subsequently, 50 nl of compounds were transferred into black, low-volume test plates from the same supplier using a Hummingbird capillary based liquid handling instrument (Digilab). Tests were started by the addition of 2 μΙ of 2.5-fold concentrated Menin solution (5 nM = 2 nM final concentration in the 5 μΙ assay volume) in aqueous assay buffer [50 mM Tris/HCI pH 7.5, 50 mM sodium chloride (NaCI), 0.1 % bovine serum albumin (BSA) and 1 mM dithiothreitol (DTT)] to the compounds in the test plate with a Multidrop dispenser (Thermo-Fisher). Test plates were then incubated 10' at 22°C, in order to allow pre-equilibration of putative compound- Menin complexes. Subsequently, 3 μΙ of a 1 .67-fold concentrated solution containing MLL-1 peptide (83.5 nM = 50 nM final concentration) and TR-FRET detection reagents [83.5 nM Streptavidin XL-665 = 50 nM final concentration and 3.33 nM anti-6XHis-Tb cryptate = 2 nM final concentration (both from Cisbio), were dispensed into the plates.

The mixture was further incubated in the dark for 0.5-4 hours at 22°C. Finally the inhibition of the formation of menin / MLL-1 complexes was assessed by measurement of the resonance energy transfer from the anti-6XHis-Tb cryptate to the Streptavidin XL-665 present in the reaction. To this end, the fluorescence emissions at 622 nm and 665 nm after excitation at 337 nm were measured in a TR-FRET reader, e.g. a Rubystar or Pherastar (both from BMG Lab Technologies) or a Viewlux (Perkin-Elmer) and the ratio of the emissions at 665 nm and at 622 nm was taken as indicator for the amount of complexes in equilibrium.

The data were normalised using two sets of control wells (16 each). The first accounted for 100% menin / MLL-1 binding (0 % inhibition), and contained all reaction components but DMSO instead of inhibitors. The second represented 0% menin / MLL-1 binding (100% inhibition), and included all assay components except Menin. I C50 values were calculated by fitting the normalized inhibition data to a 4-parameter logistic equation using the Screener analysis software (Genedata).

The suitability of the compounds of the present invention for the treatment of different cancer forms can be demonstrated in the following cell line in vitro models:

Leukemia models:

In vitro assay 2: MV4-11 cell proliferation assay

In accordance with the invention, the ability of the substances to inhibit cell proliferation was determined. Cell viability was determined by means of the alamarBlue® reagent (Invitrogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength 590 nm. The MV4-1 1 cells (American Type Culture Collection ATCC, Catalogue No.: CRL-9591 ) were sown at a concentration of 6000 cells/well in 100 μΙ of growth medium (Iscove's Modified Dulbecco's Medium +10% FCS) on 96-well microtiter plates. After overnight incubation at 37°C, the fluorescence values were determined (CO values). Then the plates were treated with various substance dilutions (e.g. 1 E-5 M, 3E-6 M, 1 E-6 M, 3E-7 M, 1 E-7 M, 3E-8 M, 1 E-8 M, 3E-9 M) and incubated at 37 °C over 96 hours. Subsequently, the fluorescence values were determined (CI values). For the data analysis, the CO values were subtracted from the CI values and the results were compared between cells which had been treated with various dilutions of the substance or only with buffer solution. The I C50 values (substance concentration needed for 50% inhibition of cell proliferation) were calculated therefrom.

In vitro assay 3: MOLM-13 cell proliferation assay

In accordance with the invention, the ability of the substances to inhibit cell proliferation was determined. Cell viability was determined by means of the alamarBlue® reagent (Invitrogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength 590 nm. The MOLM-13 cells (The Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Catalogue No.: ACC 554) were sown at a concentration of 4000 cells/well in 100 μΙ of growth medium (RPMI 1640 Medium with stable Glutamine + 10% FCS) on 96-well microtiter plates. After overnight incubation at 37°C, the fluorescence values were determined (CO values). Then the plates were treated with various substance dilutions (e.g. 1 E-5 M, 3E-6 M, 1 E-6 M, 3E-7 M, 1 E-7 M, 3E-8 M, 1 E-8 M, 3E-9 M) and incubated at 37 °C over 96 hours. Subsequently, the fluorescence values were determined (CI values). For the data analysis, the CO values were subtracted from the CI values and the results were compared between cells which had been treated with various dilutions of the substance or only with buffer solution. The I C50 values (substance concentration needed for 50% inhibition of cell proliferation) were calculated therefrom.

Prostate cancer models:

In vitro assay 4: LAPC-4 cell proliferation assay

In accordance with the invention, the ability of the substances to inhibit cell proliferation was determined. Cell viability was determined by CellTiter-Glo® staining (Promega) in a Victor X3 Multilabel Reader (Perkin Elmer) by measurement of luminescence. The LAPC-4 cells (American Type Culture Collection ATCC, Catalogue No.: CRL-13009) were sown at a concentration of 1000 cells/well in 30 μΙ of growth medium (RPMI 1640 without phenol red, 2 mM L-glutamine, 10% FCS, 1 nM R1881 ) on 384-well microtiter plates and incubated overnight at 37 °C. Then the cells were treated with inhibitor substance at various concentrations(e.g. 1 E-5 M, 3E-6 M, 1 E-6 M, 3E-7 M, 1 E-7 M, 3E-8 M, 1 E-8 M, 3E-9 M). Following incubation at 37 °C for 168 hours, cell number was determined. CI value was defined as the signal measured at day 7 for cells treated only with 0.1 % DMSO. CO value was defined as the signal measured at day 0. For the data analysis, the CO values were subtracted from the CI values and the results were compared between cells which had been treated with various dilutions of the substance or only with buffer solution. The I C50 values (substance concentration needed for 50% inhibition of cell proliferation) were calculated therefrom. In vitro assay 5: LNCaP cell proliferation assay

In accordance with the invention, the ability of the substances to inhibit cell proliferation was determined. Cell viability was determined by CellTiter-Glo® staining (Promega) in a Victor X3 Multilabel Reader (Perkin Elmer) by measurement of luminescence. The LNCaP cells (American Type Culture Collection ATCC, Catalogue No.: CRL-1740) were sown at a concentration of 1000 cells/well in 30 μΙ of growth medium (RPMI 160 medium with stable glutamine and Pen/Strep + 10% FCS) in 384-well microtiter plates and incubated overnight at 37 °C.Then the plates were treated at day 0 with various inhibitor substance dilutions (e.g. 1 E- 5 M, 3E-6 M, 1 E-6 M, 3E-7 M, 1 E-7 M, 3E-8 M, 1 E-8 M, 3E-9 M) and incubated at 37 °C over 144 hours. Subsequently, the luminescence values were determined. CI value was defined as the signal measured at day 6 for cells treated only with 0.1 % DMSO. CO was defined as the signal measured at day 0. For the data analysis, the CO values were subtracted from the CI values and the results were compared between cells which had been treated with various dilutions of the substance or only with buffer solution. The I C50 values (substance concentration needed for 50% inhibition of cell proliferation) were calculated therefrom.

Breast cancer models:

In vitro assay 6: MCF7 cell proliferation assay

In accordance with the invention, the ability of the substances to inhibit cell proliferation was determined. Cell viability was determined by CellTiter-Glo® staining (Promega) in a Victor X3 Multilabel Reader (Perkin Elmer) by measurement of luminescence. The MCF7 cells (American Type Culture Collection ATCC, Catalogue No.: HTB-22) were sown at a concentration of 120 cells/well in 30 μΙ of growth medium (RPMI 1640 medium with stable glutamine + 10% FCS + 10 pM E2) in 384-well microtiter plates and incubated overnight at 37 °C. Then the plates were treated at day 0 with various inhibitor substance dilutions (e.g. 1 E-5 M, 3E-6 M, 1 E-6 M, 3E-7 M, 1 E-7 M, 3E-8 M, 1 E-8 M, 3E-9 M) and incubated at 37 °C for 96 hours. Cell number was determined at day 0 and day 4. CI was defined as the signal measured at day 4 for cells treated only with 0.1 % DMSO. CO was defined as the signal measured at day 0. For the data analysis, the CO values were subtracted from the CI values and the results were compared between cells which had been treated with various dilutions of the substance or only with buffer solution. The IC50 values (substance concentration needed for 50% inhibition of cell proliferation) were calculated therefrom.

In vitro assay 7: MDA-MB-468 cell proliferation assay

In accordance with the invention, the ability of the substances to inhibit cell proliferation was determined. Cell viability was determined by CellTiter-Glo® staining (Promega) in a Victor X3 Multilabel Reader (Perkin Elmer) by measurement of luminescence. The MDA-MB-468 cells (American Type Culture Collection ATCC, Catalogue No.: HTB-132) were sown at a concentration of 500 cells/well in 30 μΙ of growth medium (RPMI 1640 medium with stable glutamine + 10% FCS) in 384-well microtiter plates and incubated overnight at 37 °C. Then the plates were treated at day 0 with various inhibitor substance dilutions (e.g. 1 E-5 M, 3E-6 M, 1 E-6 M, 3E-7 M, 1 E-7 M, 3E-8 M, 1 E-8 M, 3E-9 M) and incubated at 37 °C for 96 hours. Cell number was determined at day 0 and day 4. CI was defined as the signal measured at day 4 for cells treated only with 0.1 % DMSO. CO was defined as the signal measured at day 0. For the data analysis, the CO values were subtracted from the CI values and the results were compared between cells which had been treated with various dilutions of the substance or only with buffer solution. The I C50 values (substance concentration needed for 50% inhibition of cell proliferation) were calculated therefrom.

Results: Binding assay

Table 2 shows the results of the inhibition in the menin/MLL-1 HTRF assay.

Table 2:

Figure imgf000199_0001
Example ICso [menin/MLL-1)] (nmol/l)

10.0 30

10.1 30

10.2 140

1 1 .0 150

12.0 70

13.0 4

14.0 360

15.0 320

16.0 10

17.0 130

18.0 500

19.0 50

20.0 880

21 .0 120

22.0 150

23.0 420

24.0 280

25.0 250

26.0 20

27.0 1 10

28.0 80

29.0 80

30.0 90

31 .0 100

32.0 310

33.0 200

34.0 270

35.0 390

36.0 60

37.0 140

38.0 30

39.0 390

40.0 60

40.1 1410

40.2 60

41 .0 450 Example ICso [menin/MLL-1)] (nmol/l)

42.0 3590

43.0 7230

44.0 1680

45.0 650

46.0 2330

47.0 1900

48.0 840

49.0 2520

50.0 1 150

51 .0 4340

52.0 1520

53.0 2710

54.0 2050

55.0 1080

56.0 150

57.0 >20000

58.0 21 10

59.0 9600

60.0 9900

61 .0 70

62.0 80

63.0 10

64.0 20

65.0 20

66.0 20

67.0 30

68.0 40

69.0 40

70.0 70

71 .0 80

72.0 170

73.0 30

74.0 1440

75.0 120

76.0 220

77.0 750 Example ICso [menin/MLL-1)] (nmol/l)

78.0 1120

79.0 470

80.0 400

81.0 1980

82.0 1140

83.0 380

84.0 110

85.0 50

86.0 170

87.0 20

88.0 10

89.0 10

90.0 20

91.0 20

92.0 20

93.0 16700

94.0 10

95.0 30

96.0 10

97.0 6410

98.0 3390

99.0 40

100.0 90

101.0 30

102.0 10

102.1 40

102.2 20

103.0 700

104.0 60

105.0 830

106.0 300

107.0 160

108.0 40

109.0 10

110.0 150

111.0 290 Example ICso [menin/MLL-1)] (nmol/l)

112.0 230

113.0 60

113.1 40

113.2 150

114.0 150

114.1 500

114.2 120

115.0 340

115.1 1300

115.2 260

116.0 150

117.0 80

117.1 90

117.2 340

118.0 340

119.0 370

120.0 940

121.0 1250

122.0 610

123.0 1070

124.0 500

125.0 170

126.0 17000

127.0 >20000

128.0 990

129.0 210

130.0 830

131.0 60

132.0 3260 Results:Proliferation assays

Table 3 shows the results of the inhibition in proliferation assays performed in leukemia cell lines.

Table 3:

Figure imgf000204_0001
Example ICso [MV4-1 1 ] (nmol/l) ICso [MOLM-13] (nmol/l)

21.0 >1250

22 >1250

26.0 500

27.0 1270

28.0 630

29.0 850

30.0 360

31.0 570

33.0 >1250

36.0 1630

37.0 >1250 >5000

38.0 >5000

40.0 600

40.1 >5000

40.2 220 1450

56.0 >1250

61.0 410

62.0 450

63.0 50 1560

64.0 140 2630

65.0 60 1600

66.0 250

67.0 140 2170

68.0 310 >7000

69.0 320

70.0 720 >7000

71.0 260

72.0 >1250

73.0 140 2290

75.0 290

76.0 760

82.0 >5000

83.0 2700 2870

84.0 1830 2030

85.0 1970 6980

86.0 >3000 2590 Example ICso [MV4-11] (nmol/l) ICso [MOLM-13] (nmol/l)

87.0 80 1440

88.0 40 2860

89.0 130 1020

90.0 530 5760

91.0 990 >9000

92.0 120 370

94.0 110 620

95.0 320

96.0 30 150

99.0 110 1120

100.0 1000 >9000

101.0 520 7900

102.0 310 1720

102.1 1170

102.2 680 5990

>9000

103.0 >3000 5120

104.0 370

105.0 >3000 6060

106.0 780 3220

107.0 >3000 8990

108.0 100 1580

109.0 90 1190

110.0 >3000 >9000

111.0 >3000 >9000

112.0 >3000 >9000

113.0 430 4690

113.1 290

113.2 1510

114.0 >3000 2160

114.1 >3000 6620

114.2 1220 2740

115.0 >3000 8700

115.2 >3000 7880

116.0 1910 >9000

>3000 Example ICso [MV4-11] (nmol/l) ICso [MOLM-13] (nmol/l)

117.0 1380 4050

117.1 1280 2820

117.2 >3000 >9000

118.0 >3000 8730

119.0 >3000 5560

120.0 >3000 >9000

121.0 >3000 >9000

123.0 >3000 >9000

124.0 >3000 5840

125.0 1290

128.0 >3000 >9000

129.0 2700 3970

130.0 >3000 >9000

Table 4 shows the results of the inhibition in proliferation assays performed in prostate and breast cancer cell lines (IC50 is the concentration for 50% of maximal inhibition of cell proliferation). Table 4:

Figure imgf000208_0001
Example ICso [LAPC-4] ICso [LNCaP] ICso [MCF7] ICso [MDA-MB- (nmol/l) n(mol/l) (nmol/l) 468] (nmol/l)

62.0 7430 2530 5480

63.0 >10000 >10000 >10000

64.0 >10000 >10000 >10000

65.0 >10000 4740 8450

66.0 >10000 >10000 >10000

67.0 >10000 4080 9800

68.0 >10000 7410 >10000

69.0 >10000 >10000 >10000

70.0 >10000 7020 >10000

71.0 >10000 >10000 >10000

73.0 >10000 6400 9530

75.0 >10000 >10000 >10000

88.0 >10000 >10000

90.0 >7250 4820 >5550 >6500

91.0 >10000 >7400 7730 >10000

92.0 >10000 >10000

94.0 >10000 >10000 >10000

96.0 1900 2710

102.0 >10000 >10000 >10000

102.2 >10000 >10000 >10000 >10000

109.0 >10000 >10000

1 16.0 >10000 >10000 >10000

125.0 8670 6320 2520

Claims

1. A compound of general formula (I):
Figure imgf000210_0001
(I)
in which:
X represents a roup selected from:
Figure imgf000210_0002
Figure imgf000210_0003
or
wherein * indicates the point of attachment of said group with the rest of the molecule;
R1 represents hydrogen or methyl;
R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;
R3 represents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group
Figure imgf000210_0004
wherein * indicates the point of attachment of said group with the rest of the molecule; R4 represents hydrogen, hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, C1-C3- alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-Ci-C3-alkyl, -0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-R9, -C(CH3)2-R9 or 1-R9-cyclopropyl,
wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C4-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy; R5 represents hydrogen, methyl or chloro; or
R4 and R5 together form an anellated phenyl ring;
R6a, R6b represent, independently from each other, hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(CO)-C2-C3-alkenyl, -(S02)-CrC3-alkyl or
-(S02)-phenyl,
wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy, or
R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups;
R9 represents cyano, -COOH, -(CO)-0-Ci-C3-alkyl, -(S02)-Ci-C3-alkyl, -NR7R8, -CONR7R8 or -S02NR7R8;
R10 represents Ci-C4-alkyl, Ci-C4-haloalkyl, methoxy-Ci-C3-alkyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl, S-methylsulfonimidoyl-methyl, -CH2-C02R11 or -CH2-CONR12R13;
R11 represents Ci-C4-alkyl;
R12, R13 represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-haloalkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl,
-(S02)-Ci-C3-alkyl, -(S02)-phenyl,
wherein said phenyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl,
Ci-C3-alkoxy or Ci-C3-haloalkoxy, or
together with the nitrogen atom to which they are attached form a
4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a C1-C4- alkyl or Ci-C4-haloalkyl group and optionally substituted with an oxo group; R14 represents hydrogen or methyl;
n represents 0 or 1 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
2. The compound according to claim 1 , wherein:
X re resents a group selected from:
Figure imgf000212_0001
or
wherein * indicates the point of attachment of said group with the rest of the molecule; R1 represents hydrogen or methyl;
R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;
R3 re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group
Figure imgf000212_0002
wherein * indicates the point of attachment of said group with the rest of the molecule;
R4 represents hydrogen, hydroxy, cyano, Ci-C3-alkoxy, Ci-C3-haloalkoxy, -O-phenyl, 5-membered heteroaryl, -NR7R8, -CONR7R8, -S02NR7R8, -0-(CO)-C C3-alkyl,
-0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-S02NH2, -C(CH3)2-CN or 1-cyano-cyclopropyl, wherein said phenyl or 5-membered heteroaryl group is optionally substituted, one or more times, independently from each other, with cyano, Ci-C4-alkyl or d-Cs-haloalkyl;
R5 represents hydrogen, methyl or chloro; or
R4 and R5 together form an anellated phenyl ring;
R6a, R6b represent, independently from each other, hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen, Ci-C3-alkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C3-alkyl, -(CO)-CH=CH2, -(S02)-Ci-C3-alkyl or -(S02)- phenyl, or
R7 and R8 together with the nitrogen atom to which they are attached form a 6-membered
nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups;
R9 represents cyano, -COOH, -NR7R8, -CONR7R8, -(S02)-CH3 or -S02NR7R8;
R10 represents C2-C3-alkyl, C2-C3-haloalkyl, methoxy-CrC3-alkyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl or -CH2-CO2CH3;
R14 represents hydrogen or methyl;
n represents 0 or 1 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
3. The compound according to claim 1 or 2, wherein:
X re resents a group selected from:
Figure imgf000213_0001
or
wherein * indicates the point of attachment of said group with the rest of the molecule; R1 represents hydrogen or methyl;
R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy;
R3 re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group
Figure imgf000213_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; represents hydrogen, hydroxy, cyano, methoxy, hexafluoropropoxy, -O-phenyl, imidazolyl, triazolyl, butyl-oxadiazolyl, -NR7R8, -CONH2, -S02NH2, -0-(CO)-CH3, -0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-S02NH2, -C(CH3)2-CN or 1-cyano-cyclopropyl, wherein said phenyl group is substituted once with cyano and trifluoromethyl; R5 represents hydrogen, methyl or chloro;
R6a, R6b represent, independently from each other, hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen, methyl, hydroxyethyl,
-(CO)-CH3, -(CO)-CH=CH2, -(S02)-CH3 or -(S02)-phenyl, or
R7 and R8 together with the nitrogen atom to which they are attached form a 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups;
R9 represents cyano, -COOH, tert-butyl-0-C(0)-NH-, -CONH2, -CONHCH3, -CON(CH3)2, -(S02)-CH3 or -S02NH2;
R10 represents ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl,
methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl or -CH2-C02CH3;
R14 represents hydrogen;
n represents 0 or 1 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
4. The compound according to claim 1 of general formula (lb):
Figure imgf000214_0001
wherein:
R1 represents hydrogen or methyl;
R2 represents hydrogen, fluoro, chloro, hydroxy or methoxy; R3 re resents hydrogen, fluoro, chloro, hydroxy, methyl, cyano, cyanomethyl or a group
Figure imgf000215_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R4 represents hydrogen, hydroxy, cyano, methoxy, hexafluoropropoxy, -O-phenyl,
imidazolyl, triazolyl, butyl-oxadiazolyl, -NR7R8, -CONH2, -SO2NH2, -0-(CO)-CH3,
-0-CH2-(CO)-NR7R8, -CH2-R9, -CH(CH3)-S02NH2, -C(CH3)2-CN or 1-cyano-cyclopropyl, wherein said phenyl group is substituted once with cyano and trifluoromethyl; R5 represents hydrogen, methyl or chloro;
R6a, R6b represent, independently from each other, hydrogen or methyl;
R7, R8 represent, independently from each other, hydrogen, methyl, hydroxyethyl,
-(CO)-CH3, -(CO)-CH=CH2, -(S02)-CH3 or -(S02)-phenyl, or
R7 and R8 together with the nitrogen atom to which they are attached form a 6-membered
nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR14 and optionally substituted with hydroxy or one or two oxo groups;
R9 represents cyano, -COOH, tert-butyl-0-C(0)-NH-, -CONH2, -CONHCH3, -CON(CH3)2, -(S02)-CH3 or -S02NH2;
R14 represents hydrogen;
Z represents difluoromethyl or trifluoromethyl;
n represents 0 or 1 ;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
5. The compound according to claim 1 , 2, 3 or 4 which is selected from the group consisting of: 4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
3-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
[3-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile [4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[^ yl}methyl)phenyl]acetonitrile
[4-({(5S)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4 ]non-2- yl}methyl)phenyl]acetonitrile
[4-({(5R)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2- yl}methyl)phenyl]acetonitrile
1-[4-({(5S)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarbonitrile
1-[4-({(5R)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarbonitrile
1- [4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarbonitrile
4-({(5R)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzamide
4-({(5S)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzamide
4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzamide
2- methyl-2-[4-({(5S)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]propanenitrile
2-methyl-2-[4-({(5R)-7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]propanenitrile
2-methyl-2-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro yl}methyl)phenyl]propanenitrile
2-fluoro-4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4 ]non yl}methyl)benzonitrile
4-{(5S)-7-[3-chloro-4-(1 H-imidazol-1 -yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
4-{(5R)-7-[3-chloro-4-(1 H-imidazol-1-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
4-{7-[3-chloro-4-(1 H-imidazol-1 -yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine 4-{(5S)-7-[4-(1 H-1 ,2,4-triazoM -yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
4-{(5R)-7-[4-(1 H-1 ,2,4-triazol-1-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
4-{7-[4-(1 H-1 ,2,4-triazol-1-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
[3-chloro-4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile
[3-fluoro-4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2 yl}methyl)phenyl]acetonitrile
1- [4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetic acid
4-(2-{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin^-yl]-2J-diazaspiro[4.4]non-2- yl}ethyl)benzonitrile
2- {methyl[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]amino}ethanol
2- methoxy-5-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4.4]non-2- yl}methyl)phenol
4-chloro-2-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol
3- ({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol
1-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)naphthalen-2-ol
2-chloro-4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol
N-[2-chloro^-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
N-[3-chloro^-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]benzenesulfonamide 4-{7-[4-(1 ,1 ,2,3,3,3-hexafluoropropoxy)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
2- [4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenoxy]-5-(trifluoromethyl)benzonitrile
4-{7-[4-(morpholin-4-yl)benzyl]-2J-diazaspiro[4 ]non-2-yl}-6-(2,2,2-trifluoroethyl)thieno[2,3- d]pyrimidine
N-methyl-N-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]n yl}methyl)phenyl]acetamide
1-(pyrrolidin-1 -yl)-2-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenoxy]ethanone
1- (morpholin-4-yl)-2-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenoxy]ethanone
tert-butyl [4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzyl]carbamate
4-{7-[2-chloro-4-(morpholin-4-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
3- fluoro-4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4 ]non yl}methyl)benzonitrile
3- methoxy-4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2- yl}methyl)benzonitrile
4- {7-[3-(1 H-1 ,2,4-triazol-1-ylmethyl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
2,6-dimethyl-4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4 ]n yl}methyl)phenyl acetate
4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzenesulfonamide
4-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]morpholin-3-one
2- amino-5-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-^^ yl}methyl)benzonitrile
4-{7-[4-(5-butyl-1 ,3,4-oxadiazol-2-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine [4-({(5S)-7-[2-methyl-6-(2,2,2-trifluoro
2-yl}methyl)phenyl]acetonitrile
[4-({(5 R)-7-[2-methy l-6-(2 ,2 ,2-trif I u oroe%
2- yl}methyl)phenyl]acetonitrile
[4-({7-[2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4.^ yl}methyl)phenyl]acetonitrile
4-{7-[4-(morpholin-4-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-2-(2,2,2-trifluoroethyl)-2H- pyrazolo[3,4-d]pyrimidine
4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
3- ({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
4- {7-[4-(1 H-1 ,2,4-triazol-1-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-2-(2,2,2-trifluoroethyl)-2H- pyrazolo[3,4-d]pyrimidine
1-[4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarbonitrile
4-{7-[3-chloro-4-(1 H-imidazol-1-yl)benzyl]-2J-diazaspiro[4 ]non-2-yl}-2-(2,2,2-trifluoroethyl)- 2H-pyrazolo[3,4-d]pyrimidine
4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzamide
2- {methyl[4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]amino}ethanol
3- ({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol
4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenol
1- (pyrrolidin-1 -yl)-2-[4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenoxy]ethanone
4- ({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzenesulfonamide
[3-chloro-4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]n
2- yl}methyl)phenyl]acetonitrile [3-fluoro-4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2J-diazasp
2-yl}methyl)phenyl]acetonitrile
2-methyl-2-[4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]propanenitrile
1-[4-({7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
4-(2-{7-[2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2- yl}ethyl)benzonitrile
[4-({7-[6-methyl-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]acetonitrile
4-({7-[6-methyl-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non 2-yl}methyl)benzonitrile
4-({7-[6-methyl-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non 2-yl}methyl)benzamide
2-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetamide
4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
6-(2,2-difluoroethyl)-4-{7-[4-(morpholin-4-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}thieno[2,3- d]pyrimidine
2-{[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl](methyl)amino}ethanol
[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile
4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4 ]non-2-yl}methyl)p
1-[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarbonitrile
6-(2,2-difluoroethyl)-4-{7-[4-(1 H-1 ,2,4-triazol-1-yl)benzyl]-2,7-diazaspiro[4.4]non-2- yl}thieno[2,3-d]pyrimidine
4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzamide
4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzenesulfonamide 2- [4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenoxy]-1-(pyrrolidin-1 -yl)ethanone
3- ({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
2-[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]-2-methylpropanenitrile
[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetic acid
2-[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]-N-methylacetamide
2-[4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]-N,N-dimethylacetamide
4- [1 -{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}ethyl]benzamide
4-[1 -{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}ethyl]benzonitrile
{4-[1-{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}ethyl]phenyl}acetonitrile
4-{7-[4-(morpholin-4-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2-trifluoroethyl)pyrrolo[2,1 - f][1 ,2,4]triazine
4-{7-[4-(piperazin-1-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2-trifluoroethyl)pyrrolo[2,1 - f][1 ,2,4]triazine hydrochloride
4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f|[1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
6-(2,2,2-trifluoroethyl)-4-{7-[4-(trifluoromethyl)benzyl]-2J-diazaspiro[4 ]non-2-yl}thieno[2,3- d]pyrimidine
4-[7-(4-fluorobenzyl)-2J-diazaspiro[4 ]non-2-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine
4-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]piperazine-2,6-dione
{(2-amino-2-oxoethyl)[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]amino}acetic acid
4-[7-{4-[(methylsulfonyl)methyl]benzyl}-2,7-diazaspiro[4.4]non-2-yl]-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine N-(2-hydroxyethyl)-1 -[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J^ diazaspiro[4.4]non-2-yl}methyl)phenyl]methanesulfonamide
1- [4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]ethanesulfonamide
N,N-dimethyl-1 -[4-({7-[6-(2,2,2-trifluoroethy^
2- yl}methyl)phenyl]methanesulfonamide
1-[2-fluoro-4-({7-[6-(2,2,2-trifluoroethy
yl}methyl)phenyl]methanesulfonamide
4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)aniline
4-{7-[4-fluoro-2-(trifluoromethyl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)thieno[2,3-d]pyrimidine
1-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
1-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
N-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]prop-2-enamide
tert-butyl {4-[1-{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2- yl}ethyl]benzyl}carbamate
N-{4-[(1 R)-1 -{7-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-27-diazaspiro[4.4]non-2- yl}ethyl]benzyl}prop-2-enamide
1-[4-({7-[6-(2,2-difluoropropyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2-yl}methyl)p
4-({7-[6-(2,2-difluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2-yl}methyl)p
1-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
1-[4-({(5S)-7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
1-[4-({(5R)-7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2J-diazaspiro[4 ]non-2- yl}methyl)phenyl]methanesulfonamide 4-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzonitrile
[4-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile
[3-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile
1-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]piperidin-4-ol
4-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzamide
(4-{[7-{6-[(methylsulfanyl)methyl]thieno[2,3-d]pyrimidin-4-yl}-2,7-diazaspiro[4.4]non-2- yl]methyl}phenyl)acetonitrile
1-(4-{[7-{6-[(methylsulfanyl)methyl]thieno[2,3-d]pyrimidin-4-yl}-2J-diazaspiro[4 ]non-2- yl]methyl}phenyl)methanesulfonamide
methyl (4-{7-[4-(sulfamoylmethyl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}thieno[2,3-d]pyrimidin-6- yl)acetate
methyl (4-{7-[4-(cyanomethyl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}thieno[2,3-d]pyrimidin-6- yl)acetate
methyl (4-{7-[4-(2-cyanopropan-2-yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}thieno[2,3-d]pyrimidin- 6-yl)acetate
1-[4-({7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
1-[4-({(5S)-7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2J-diazaspiro[4 ]non yl}methyl)phenyl]methanesulfonamide
1-[4-({(5R)-7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
[4-({7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile
[4-({(5S)-7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2J-diazaspiro[4 ]non yl}methyl)phenyl]acetonitrile
[4-({(5R)-7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazo^
yl}methyl)phenyl]acetonitrile 2-methyl-2-[4-({7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]propanenitrile
2-methyl-2-[4-({(5S)-7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]propanenitrile
2-methyl-2-[4-({(5R)-7-[2-(2,2,2-trifluoroethyl)[1 ,3]thiazolo[5,4-d]pyrimidin-7-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]propanenitrile
2-[4-({7-[6-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetamide
1-[4-({(5S)-7-[6-(2,2,2-trifluoroethyl)pyrrolo[2 -^[1 ,2,4]triazin-4-yl]-27-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
1-[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
1- [4-({(5R)-7-[6-(2,2,2-trifluoroethyl)pyrrolo[2 -f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]methanesulfonamide
N,N-dimethyl-1 -[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]-2,7- diazaspiro[4.4]non-2-yl}methyl)phenyl]methanesulfonamide
2- {methyl[4-({7-[6-(2,2,2-trifluoroethyl)pyrro^
yl}methyl)phenyl]amino}ethanol
4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-1][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzamide
4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-1][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)benzenesulfonamide
4-{7-[4-(4-methylpiperazin-1 -yl)benzyl]-2,7-diazaspiro[4.4]non-2-yl}-6-(2,2,2- trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine
2-[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetamide
1-[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]cyclopropanecarbonitrile
[4-({7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile
{4-[1-{7-[6-(2,2,2-trifluoroethyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}ethyl]phenyl}acetonitrile 4-|7-(3,5-dimethoxy-4-methylbenzyl)-27-diazaspiro[4 ]non-2-yl]-2-(2,2,2-trifluoroethyl)-2H- pyrazolo[3,4-d]pyrimidine
(4-{[7-(6-{[methylsulfinyl]methyl}thieno[2,3-d]pyrimidin-4-yl)-2J-diazaspiro
yl]methyl}phenyl)acetonitrile
(4-{[7-{6-[(methylsulfonyl)methyl]thieno[2,3-d]pyrim^
yl]methyl}phenyl)acetonitrile
1-(4-{[7-(6-{[methylsulfinyl]methyl}thieno[2,3-d]pyrimidin-4-yl)-2J-diazasp
yl]methyl}phenyl)methanesulfonamide
1-(4-{[7-{6-[(methylsulfonyl)methyl]thieno[2,3-d]pyrim^
yl]methyl}phenyl)methanesulfonamide
[4-({7-[6-(pentafluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]-2,7-diazaspiro[4.4]non-2- yl}methyl)phenyl]acetonitrile
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
6. A method of preparing a compound of general formula (lb) according to any one of claims 1 to 5, said method comprising the step of allowing an intermediate compound of general formula (V):
Figure imgf000225_0001
(V),
in which R1 is as defined for the compound of general formula (I) according to any claims 1 to 5, and Z is methyl, difluoromethyl or trifluoromethyl,
to react with a compound of general formula (VI):
Figure imgf000225_0002
(VI),
in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5,
thereby giving a compound of general formula (lb):
Figure imgf000226_0001
(lb),
in which n, R1, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5 and Z is methyl, difluoromethyl or trifluoromethyl.
7. A method of preparing a compound of general formula (lb) according to any one of claims 1 to 5, said method comprising the step of allowing an intermediate compound of general formula (II):
Figure imgf000226_0002
(II),
in which R1 is as defined for the compound of general formula (I) according to any claims 1 to 5, and Z is methyl, difluoromethyl or trifluoromethyl,
to react with a compound of general formula (VIII):
Figure imgf000226_0003
(VIII), in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5,
thereby giving a compound of general formula (lb):
Figure imgf000227_0001
(lb),
in which n, R1, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5 and Z is methyl, difluoromethyl or trifluoromethyl.
8. A method of preparing a compound of general formula (Ic) according to any one of claims 1 to 5, said method comprising the step of allowing an intermediate compound of general formula (XIII):
Figure imgf000227_0002
(XIII),
in which R1 is as defined for the compound of general formula (I) according to any claims 1 to 5,
to react with a compound of general formula (VI):
Figure imgf000227_0003
(VI),
in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5,
thereby giving a compound of general formula (lc):
Figure imgf000228_0001
(lc),
in which n, R1, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5.
9. A method of preparing a compound of general formula (Id) according to any one of claims 1 to 5, said method comprising the step of allowing an intermediate compound of formula (XVIII):
Figure imgf000228_0002
(XVIII),
to react with a compound of general formula (VI):
Figure imgf000228_0003
(VI), in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5,
thereby giving a compound of general formula (Id):
Figure imgf000229_0001
(Id),
in which n, R2, R3, R4, R5, R6a and R6b are as defined for the compound of general formula (I) according to any one of claims 1 to 5.
10. A compound of general formula (I) according to any one of claims 1 to 5 for use in the treatment or prophylaxis of a disease.
1 1 . A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 5 and one or more pharmaceutically acceptable excipients.
12. A pharmaceutical combination comprising:
• one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 5, and
• one or more further active ingredients, in particular cancer agents.
13. Use of a compound of general formula (I) according to any one of claims 1 to 5 for the treatment or prophylaxis of a disease.
14. Use of a compound of general formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment or prophylaxis of a disease.
15. Use according to claim 10, 13 or 14, wherein the disease is diabetes or cancer, such as acute myeloid leukemia, prostate carcinoma, breast carcinoma, hepatocellular carcinoma, for example.
16. A compound of general formula (V) or (XVIII):
Figure imgf000230_0001
in which R1 is as defined for the compound of general formula (I) according to any claims 1 to 5.
17. Use of a compound of general formula (V), (XIII) or (XVIII):
Figure imgf000230_0002
(V) (XIII) (XVIII), in which R1 is as defined for the compound of general formula (I) according to any one claims 1 to 5 and Z is methyl, difluoromethyl or trifluoromethyl,
for the preparation of a compound of general formula (I) according to any one of claims 1 to 5
18. A compound of general formula (XIX) or (XX):
Figure imgf000231_0001
(XIX) (XX),
in which R1 is as defined for the compound of general formula (I) according to any claims 1 to 5.
19. Use of a compound of general formula (XIX) or (XX):
Figure imgf000231_0002
(XIX) (XX),
in which R1 is as defined for the compound of general formula (I) according to any one of claims 1 to 5 for the preparation of a compound of general formula (I) according to any one of claims 1 to 5.
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US10246464B2 (en) 2014-09-09 2019-04-02 The Regents Of The University Of Michigan Thienopyrimidine and thienopyridine compounds and methods of use thereof
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