WO 2017/207387 Al 07 December 2017 (07.12.2017) W !P O PCT

Home , Pamidronic acid

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/207387 Al 07 December 2017 (07.12.2017) W !P O PCT

(51) International Patent Classification: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, C07D 487/10 (2006.01) A61P 35/02 (2006.01) UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, C07D 495/04 (2006.01) A61K 31/519 (2006.01) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, C07D 513/06 (2006.01) EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (21) International Application Number: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, PCT/EP20 17/062540 KM, ML, MR, NE, SN, TD, TG). (22) International Filing Date: 24 May 2017 (24.05.2017) Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a (25) Filing Language: English patent (Rule 4.1 7(H)) (26) Publication Langi English Published: (30) Priority Data: — with international search report (Art. 21(3)) 16172216.0 31 May 2016 (3 1.05.2016) 16205809.3 2 1 December 2016 (21 .12.2016) (71) Applicant: BAYER PHARMA AKTIENGESEL- LSCHAFT [DE/DE]; Mullerstr. 178, 13353 Berlin (DE). (72) Inventors: SIEGEL, Stephan; Aschaffenburger Str. 6, 10779 Berlin (DE). HAENDLER, Bernard; Am Biber- bau 8, 13465 Berlin (DE). STRESEMANN, Carlo; Sven-Hedin-StraBe 18, 14163 Berlin (DE). FERNAN¬ DEZ-MONTALVAN, Amaury, Ernesto; Kopenhagener Str. 42, 10437 Berlin (DE). TER LAAK, Antonius; Hed- wigstrasse 11, 12159 Berlin (DE). STOCKIGT, Detlef; Clara-Zetkin-Strasse 27, 14471 Potsdam (DE).

(74) Agent: BIP PATENTS; Alfred-Nobel-Str. 10, 40789 Mon- heim am Rhein NRW (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH,

(54) Title: SPIRO CONDENSED AZETIDINE DERIVATIVES AS INHIBITORS OF THE MENIN-MMLl INTERACTION (57) Abstract: The present invention covers diazaspiroalkylmethyl-indole compounds x \ of general formula (I) in which R , X and Y are as defined herein, methods of preparing N- said compounds, intermediate compounds useful for preparing said compounds, phar 00 maceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or o prophylaxis of diseases, in particular of cancer, as a sole agent or in combination with ( other active ingredients. Y o (I) PI O CONDENSED AZETIDINE DERIVATIVES A S INHIBITORS OF THE MENIN-MML1 INTERACTION

The present invention covers diazaspiroalkylmethyl-indole 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 diazaspiroalkylmethyl-indole 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, 201 5, 2 1:344-352). It is essential for A R signalling and acts as a co-regulator of a number of androgen target genes. Inhibition of menin impairs the A R 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, 2 1:344-352).

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 201 3 , 110:17480-17485). 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).

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.

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, US 2016/9505781 , US 2016/9505782, WO 2014/164543, WO 2014/200479, WO 2015/191701 , WO 2016/195776 and WO 2016/197027.

WO 1999/065494 relates to conformationally constrained compounds as inhibitors of prenyl- protein transferase. 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.

WO 2008/033447 relates to azetidine and azetidone derivatives useful in treating pain and disorders of lipid metabolism.

WO 2008/033456 relates to spiro-condensed azetidine derivatives useful in treating pain, diabetes and disorders of lipid metabolism.

However, the state of the art does not describe:

· the diazaspiroalkylmethyl-indole compounds of general formula (I) of the present invention as described and defined herein, i.e. compounds having a diazaspiroalkyl core bearing:

• in its N -position, a thieno[2,3-d]pyrimidine-4-yl, a thieno[3,2-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, an indolylmethyl 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, for example. DESCRIPTION of the INVENTION

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

(I) in which:

X re resents a group selected from:

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

Y represents a group

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

R represents hydrogen or methyl;

2 R represents hydrogen, Ci-C 4-hydroxyalkyl, -CN, -CONH2 or -C0 2R ; R3 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl, C2-C4-hydroxyalkyl, -C2-C4-alkylen-

6 7 9 5 NR R , -CO2R or -Ci-C 2-alkylen-R ;

R4 represents hydrogen, hydroxy, halogen, methyl or methoxy;

R5 represents -CO2R , -CON R6R7, 4- to 6-membered heterocycloalkyl optionally substituted with -CO2R , phenyl or 5-membered heteroaryl, 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 and said 5-membered heteroaryl is optionally substituted with Ci-C4-alkyl;

R6 and R7 are the same or different and represent, independently from each other, hydrogen,

Ci-C4-alkyl, C3-C6 -cycloalkyl, Ci-C4-haloalkyl 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;

R8 represents hydrogen or Ci-C4-alkyl;

R9 represents hydrogen or Ci-C4-alkyl;

R 0 represents Ci-C4-alkyl, Ci-C4-haloalkyl,-methoxy-Ci-C3-alkyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl, S-methylsulfonimidoyl-methyl, -CH2-CO2R

2 13 or -CH2-CONR R ;

R represents hydrogen or Ci-C4-alkyl;

R 2 , R 3 represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6 -cycloalkyl,

Ci-C 4-haloalkyl, C2-C3-hydroxyalkyl, tert-butyl-O-C(O)-, -(CO)-Ci-C 3-alkyl,

-(S0 2)-Ci-C 3-alkyl, -(S0 2)-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.

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".

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 -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 ie/f-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 "Ci -C4-hydroxyalkyl" 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 ie/f-butyl, and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxy propyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2- methyl-propyl, 1-hydroxy-2-methyl-propyl group.

The term "Ci -C4-haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci -C4-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-C4-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.

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

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

Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example.

The term "C2-C4-alkylene" means a linear, saturated, bivalent hydrocarbon group having 2 , 3 or

4 carbon atoms, e.g. an ethylene, propylene or butylene group. Particularly, said group has 2 or 3 carbon atoms ("C2-C3-alkylene"), e.g. an ethylene or propylene group, more particularly 2 carbon atoms ("C2-alkylene"), e.g. an ethylene group.

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 pyrazolyl group. 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-C4" encompasses C i , 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-ie/f-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), H (tritium), C, C, 4 C, 5 N, 70 , 0 , 2P, 33P, S, 4S, 5S, 6S, F, 6CI, 2Br, 2 l, 24 l, 25 l, 29 l and 1, 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 H or 4 C, 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 F or C 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 C-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 D2O 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, 11-30, 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, /V-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, /V-methylpiperidine, /V-methyl-glucamine, Λ/,/V-dimethyl-glucamine, /V-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(/>butyl)ammonium, /V-benzyl-/V,/V,/V- 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 embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:

X re resents a group selected from:

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

Y represents a group

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

R represents hydrogen or methyl;

2 R represents hydrogen, Ci-C3-hydroxyalkyl, -CN, -CONH 2 or -CC>2R ;

R3 represents hydrogen, methyl, Ci-C3-haloalkyl, C2-C3-hydroxyalkyl, -CH2-CH2-NR 6R7, -

9 C0 2R or 5 -Ci-C 2-alkylen-R ;

R4 represents hydrogen, methyl or methoxy; R5 represents -CO2R , -CONH2, phenyl, pyrazolyl, methylpyrazolyl or 4- to 6-membered heterocycloalkyl;

R6 and R7 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl 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;

R8 represents hydrogen or methyl;

R9 represents hydrogen or methyl;

R 0 represents ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, methoxyethyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl,

5 -methylsulfonimidoyl-methyl, -CH2-CO2CH3 or -CH 2-CONH 2; 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 represents a roup selected from:

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

Y re resents a group selected from:

- 17 - R 0 represents ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, methoxyethyl, methylsulfanylmethyl, methylsulfinylmethyl, methylsulfonylmethyl,

S-methylsulfonimidoyl-methyl, -CH2-CO2CH3 or -CH2-CONH2; 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 (la),

(la) in which:

Y re resents a group selected from: - 19 - wherein: * indicates the point of attachment of said group with the rest of the molecule;

R represents hydrogen or methyl;

R8 represents hydrogen or methyl; x represents 1 or 2 ; y represents 1 or 2 ,

wherein at least one of x and y represent 2 ; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a fifth embodiment of the first aspect, the present invention covers compounds of general formula (Id),

in which:

Y re resents a group selected from: - 22 - wherein: * indicates the point of attachment of said group with the rest of the molecule;

R represents hydrogen or methyl;

R8 represents hydrogen or methyl; x represents 1 or 2 ; y represents 1 or 2 ,

wherein at least one of x and y represent 2 ; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a second aspect, the present invention covers compounds of general formula (I):

(I) in which:

X represents a roup selected from:

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

Y represents a group

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

R represents hydrogen or methyl;

2 9 R represents hydrogen, -CN, -CONH2 or -C0 2R ; 3 6 7 9 R represents hydrogen, Ci-C 4-alkyl, C2-C4-hydroxyalkyl, -C2-C4-alkylen-N R R , -CO2R or 5 -Ci-C 2-alkylen-R ;

R4 represents hydrogen, hydroxy, halogen, methyl or methoxy;

5 9 6 7 R represents -C0 2R , -CON R R or 5-membered heteroaryl, wherein said 5-membered

heteroaryl is optionally substituted with Ci-C 4-alkyl;

R6 and R7 are the same or different and represent, independently from each other, hydrogen,

Ci-C 4-alkyl, C3-C6 -cycloalkyl, Ci-C 4-haloalkyl 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

a a one additional heteroatom selected from O , S , NH, NR in which R represents a Ci-C 4-

alkyl or Ci-C 4-haloalkyl group;

8 R represents hydrogen or Ci-C 4-alkyl;

9 R represents hydrogen or Ci-C 4-alkyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

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

X represents a roup selected from:

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

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

R represents hydrogen or methyl;

2 9 R represents hydrogen, -CN, -CONH 2 or -CO2R ;

3 6 7 9 R represents hydrogen, methyl, C2-C3-hydroxyalkyl, -CH2-CH2-NR R , -C0 2R or 5 -CH2-R ;

R4 represents hydrogen, methyl or methoxy;

5 9 R represents -C0 2R , -CONH 2, pyrazolyl or methylpyrazolyl;

R6 and R7 are the same or different and represent, independently from each other, hydrogen,

Ci -C4 -alkyl 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;

R8 represents hydrogen or methyl;

R9 represents hydrogen or methyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

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

X represents a roup selected from:

wherein * indicates the point of attachment of said group with the rest of the molecule; Y represents a group selected from wherein: * indicates the point of attachment of said group with the rest of the molecule;

R represents hydrogen or methyl;

R8 represents hydrogen; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

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

(la) in which:

Y re resents a group selected from: wherein: * indicates the point of attachment of said group with the rest of the molecule;

R represents hydrogen or methyl;

R8 represents hydrogen or methyl; x represents 1 or 2 ; y represents 1 or 2 ,

wherein at least one of x and y represent 2 ; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In accordance with a fifth embodiment of the second aspect, the present invention covers compounds of general formula (Id),

in which:

Y re resents a group selected from: x represents 1 or 2 ; y represents 1 or 2 ,

wherein at least one of x and y represent 2 ; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

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

represents a group selected from

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

Y represents a group

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

R represents hydrogen or methyl;

R2 represents hydrogen, -CN or -CON ;

3 5 R represents hydrogen, Ci-C4-alkyl, C2-C4 -hydroxyalkyl or -C -R ; R4 represents hydrogen, hydroxy, halogen, methyl or methoxy;

R5 represents -CONR 6R7 or 5-membered heteroaryl;

R6 and R7 are the same or different and represent, independently from each other, hydrogen,

one additional heteroatom selected from O, S, NH, NRa in which Ra represents a C1-C4- alkyl or Ci-C4-haloalkyl group; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

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

X represents a roup selected from:

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

Y represents a group

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

R represents hydrogen or methyl;

R2 represents hydrogen, -CN or -CON ;

R3 represents hydrogen, methyl or -CH2-CON H2;

R4 represents hydrogen or methyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a third embodiment of the third aspect, the present invention covers compounds of general formula (I), supra, in which:

X represents a roup selected from:

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

represents a group selected from:

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

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

In accordance with a fourth embodiment of the third aspect, the present invention covers compounds of general formula (la), represents a group selected from

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

R represents hydrogen or methyl; x represents 1 or 2 ; y represents 1 or 2 ,

wherein at least one of x and y represent 2 ; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of either the first, the second or the third aspect, the present invention covers compounds of formula (I), supra, in which: X represents a roup selected from:

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.