WO2017207534A1 - Substituted heteroarylbenzimidazole compounds - Google Patents

Abstract

The present invention covers substituted heteroarylbenzimidazole compounds of general formula (I) : in which R¹, R², R³, R⁴, R⁵, R^6a and R^6b 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 hyperproliferative and/or inflammatory disorders disorders, as a sole agent or in combination with other active ingredients.

Description

SUBSTITUTED HETEROARYLBENZIMIDAZOLE COMPOUNDS

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

BACKGROUND The present invention covers heteroarylbenzimidazole compounds of general formula (I) which inhibit Tank-binding kinase 1 (TBK1 ) and/or ΙκΒ kinase epsilon (ΙΚΚε).

Tank-binding kinase 1 (TBK1 ) and ΙκΒ kinase epsilon (ΙΚΚε) are two non-canonical ΙκΒ kinases (IKKs). They play crucial roles in interferon regulatory factor (IRF) and nuclear factor kappaB (N F-KB) signaling cascades. TBK1 and ΙΚΚε share 49% identity and 65% similarity with each other and the kinase domains are 27% identical to IKKa and ΙΚΚβ (Shen RR & Hahn WC (201 1 ) Emerging roles for the non-canonical IKKs in cancer. Oncogene 30(6):631 -641 ). Both ΙΚΚε and TBK1 are comprised of an N-terminal kinase domain, an ubiquitin-like domain, a C- terminal LZ and a HLH motif (Larabi A, et al. (2013) Crystal structure and mechanism of activation of TANK-binding kinase 1 . Cell reports 3(3):734-746). Despite their similarity in structure, TBK1 and ΙΚΚε exhibit differential expression patterns. TBK1 , like IKKa and ΙΚΚβ, is ubiquitously expressed. In contrast, ΙΚΚε expression is restricted to particular tissue compartments, with highest levels detected in lymphoid tissues, peripheral blood lymphocytes and the pancreas. Various epithelial-derived cell lines also exhibit ΙΚΚε expression (reviewed in Shen RR & Hahn WC (201 1 ) Emerging roles for the non-canonical IKKs in cancer. Oncogene 30(6):631 -641 ).

TBK1 was originally identified as an IKK-related Serine/Threonine kinase which, in complex with ΙΚΚε, induces the transcription of IFN-I genes as part of the anti-viral innate immune response. Within this pathway, TBK1 resides downstream of Toll-like receptors and has as natural substrates the transcription factors IRF3 and IRF7 which, upon phosphorylation by TBK1 , translocate to the nucleus and trigger IFN-I gene transcription (Han KJ, et al. (2004) Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. The Journal of biological chemistry 279(15):15652-15661 ).

Although TBK1 and ΙΚΚε are not a part of the classical ΙΚΚα/β/γ signaling complex, these kinases were originally characterized as activators of N F-κΒ and target multiple N F-KB members and effectors. Both IKK-related kinases phosphorylate ΙκΒα at one of the two-serine residues typically targeted on ΙκΒα (Shen RR & Hahn WC (201 1 ) Emerging roles for the non- canonical IKKs in cancer. Oncogene 30(6):631 -641 ).

TBK1 and ΙΚΚε have been linked to the pathophysiology of several diseases and represent promising potential targets for drug development as is demonstrated by several drug finding projects, both from academia and from the pharmaceutical industry as reviewed recently by Yu and colleagues (Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (201 1 - 2014). Expert opinion on therapeutic paienis:1 -12).

Recent literature data have provided clear and robust evidence for a role of TBK1 and ΙΚΚε in cancer biology.

ΙΚΚε was found to be amplified in breast cancer lines and breast carcinomas. Subsequent experiments identified ΙΚΚε as a breast cancer oncogene (Boehm JS, et ai. (2007) Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129(6):1065-1079). Work by other groups further confirmed the role of ΙΚΚε (and TBK1 ) in breast cancer (e.g. Barbie TU, et ai. (2014) Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth. The Journal of clinical investigation 124(12):541 1 -5423, Jiang Z, Liu JC, Chung PE, Egan SE, & Zacksenhaus E (2014) Targeting HER2(+) breast cancer: the TBK1/IKKepsilon axis. Oncoscience 1 (2):180-182) and demonstrated a role in glioma (Guan H, et ai. (201 1 ) IKBKE is over-expressed in glioma and contributes to resistance of glioma cells to apoptosis via activating NF-kappaB. The Journal of pathology 223(3):436-445).

TBK1 is up-regulated under hypoxic conditions and was shown to behave as a pro-angiogenic factor (Korherr C, et al. (2006) Identification of proangiogenic genes and pathways by high- throughput functional genomics: TBK1 and the IRF3 pathway. Proceedings of the National Academy of Sciences of the United States of America 103(1 1 ):4240-4245). Moreover, TBK1 over-expression in HUVEC cells induces the secretion of pro-angiogenic factors via the activation of IRF3 (Korherr C, et al. (2006) Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway. Proceedings of the National Academy of Sciences of the United States of America 103(1 1 ):4240-4245). In addition, TBK1 has been identified as a key factor linking innate immune signaling to tumor cell survival via the small GTPase and Ras effector RalB (Chien Y, et al. (2006) RalB GTPase- mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127(1 ): 157-170).

Apparently, Ras-transformed cancer cells are addicted to TBK1 -induced survival signals, and TBK1 kinase inhibition may therefore constitute a tumor cell-specific approach to cancer treatment. In line with this, TBK1 was shown to be essential for cell lines with activated KRas. This links RalB mediated activation of TBK1 to the generation of specific NF-KB-regulated survival signals downstream of oncogenic KRas (Barbie DA, et al. (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269):108-1 12). Moreover, it was shown that an autocrine circuit between KRAs via ΤΒΚ1/ΙΚΚε to CCL5 and IL-6 secretion could be responsible for an autostimulatory growth stimulus of tumor cells. This was shown for lung adenocarcinomas, especially for non-small cell lung cancers (NSCLC) (Zhu Z, et al. (2014) Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer discovery 4(4):452 -465).

Besides its role in cancer, TBK1 has been proposed as a target for the treatment of autoimmune diseases, inflammation and other diseases. TBK1 is involved in regulating rheumatoid synovitis and also acts as a key regulator in neuroinflammation, microvascular inflammation and gastritis. Additional potential indications include obesity and type 2 diabetes. TBK1 signaling has also been shown to be involved in mediating normal tension glaucoma, familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia diseases. In the field of cancer, there are an increasing number of reports demonstrating that TBK1 mediates cell apoptosis and proliferation in cancer cell lines, especially those that depend on oncogenic KRAS expression. Additionally, it was shown that TBK1 plays a key role in maintaining drug resistance in prostate cancer (PCa) cells by interaction with mammalian target of rapamycin and inhibiting its function, which can induce cell-cycle arrest in PCa cells. Also, several reports have suggested that TBK1 is involved in breast cancer regulation, especially in human HER2- positive breast cancer cells. TBK1 silencing decreased the expression of epithelial markers and increased the expression of mesenchymal markers in ERa (estrogen receptor)-positive breast cancer cells. Furthermore, TBK1 plays a significant role in radiation-induced epithelial— mesenchymal transition. Additionally, TBK1 -dependent mechanism for NF-κΒ signaling pathway contributes to autophagy addiction in K-Ras-driven non-small-cell lung cancer cells (reviewed in Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (201 1 - 2014). Expert opinion on therapeutic patents: 1 -12).

Prior art

Various inhibitors of TBK1 and / or ΙΚΚε derived from chemotypes different from the compounds of the present invention have been described in patent applications and scientific publications as listed below:

WO 2010127754 discloses 3-([1 ,2,3]-triazol-4-yl-pyrrolo[2.3-b]pyridine derivatives as inhibitors of PDK1 , ΙΚΚε and TBK 1.

WO 201 1046970 discloses amino-pyrimidine compounds as inhibitors of TBK1 and/or ΙΚΚε. WO 2012010826 discloses pyrimidine compounds as inhibitors of TBK1 and/or ΙΚΚε. WO 2012104007 discloses 7-azaindole derivatives as inhibitors or PDK1 , ΙΚΚε,ΤΒΚ 1 and TGF-beta..

WO 2012161877 discloses pyridine and pyrazine derivatives as inhibitors of TBK1 and ΙΚΚε.

WO 2012161879 discloses thiazole derivatives as inhibitors of TBK1 and ΙΚΚε.

E. G. Mclver et al., Bioorg. Med. Chem. Lett. 2012, 22, 7169-7173, disclose pyrimidine derivatives as inhibitors of TBK1 and ΙΚΚε.

T. Wang et al., Bioorg. Med. Chem. Lett. 2012, 22, 2063-2069, disclose azabenzimidazole derivatives as inhibitors of TBK1 and ΙΚΚε.

CN 103251600 discloses a 2-amino-4-(3'-cyano-4'-pyyrolidyl)phenyl pyrimidine compound inter alia as inhibitor of TBK-1 .

WO 2013024282 discloses an inhibitor of one or both of TBK1 and ΙΚΚε, or a down-regulator of the expression of one or both TBK1 and ΙΚΚε, for use in a method of treating a cancer that is dependent on the PI3kinase pathway, and cites multiple further patent applications and scientific publications disclosing further inhibitors of TBK1 and ΙΚΚε.

WO 2013034238 discloses benzonitrile derivatives as inhibitors of TBK1 and ΙΚΚε.

WO 2013075785 discloses 3-cyanaryl-1 H-pyrazolo[2.3-b]pyridine derivatives as inhibitors of TBK1 and ΙΚΚε.

WO 20131 17285 discloses furo-[3,2b] and thieno-[3.2-b]pyridine derivatives as inhibitors of TBK1 and ΙΚΚε.

WO 2014004863 discloses heteroaromatic compounds as inhibitors of TBK1 and/or ΙΚΚε.

J. W. Johannes et al., Bioorg. Med. Chem. Lett. 2014, 24, 1 138-1 143, disclose 6-aryl- azabenzimidazole derivatives as inhibitors of TBK1 and ΙΚΚε.

US 20150344473 discloses fused heteroaromatic compounds of TBK1 and ΙΚΚε.

The subject is also addressed by a recent review article, see T. Yu, Y. Yang, D. Q. Yin, S. Hong, Y.-J. Son, J.-H. Kim and J. Y, Cho, TBK1 inhibitors: a review of patent literature (201 1 - 2014), Expert Opin. Then Patents 2015, 25(1 1 ), 1385-1396.

A number of published patent applications disclose chemical structures showing a certain structural similarity to the compounds of the present invention which however address different mechanisms of biological activity and/or different technical fields:

WO 1998056376 discloses heteroaryl compounds for the modulation of protein tyrosine kinase related signal transduction.

WO 2002076438 discloses ligands of the Flt-1 receptor. WO 2004058762 discloses inhibitors of Mitogen Activated Protein Kinase-activated Protein Kinase-2 (MK-2).

WO 2004085425 discloses fused azole derivatives as Kinase inhibitors.

WO 2005020921 discloses c-Kit modulators and method of use.

US 2005038023 discloses pyrazole compounds as Protein Kinase inhibitors.

WO 2006099379 discloses benzazole derivatives as beta-Secretase inhibitors.

WO 2007084390 discloses organic compounds as HDAC inhibitors.

WO 2007089512 discloses heterocyclic compounds as activators of Glucokinase.

WO 2007100646 discloses multicyclic compounds as modulators of various protein kinase receptor enzymes, such as Tie-2 and Aurora kinase.

WO 2008057280 discloses multicyclic compounds as modulators of various protein kinase receptors, such as Tie-2 and Aurora kinase.

WO 2010034797 discloses 1 H-benzimidazole-5-carboxamides as anti-inflammatory agents.

WO 20101 15736 discloses heterocyclic compounds as inhibitors of dihydroorotate dehydrogenase.

WO 201 1 161 159 discloses heterocyclic compounds as Kinase inhibitors.

WO 2012068546 discloses heterocycle amines as inhibitors of IRAK-1 and IRAK-4.

WO 2015031564 discloses substituted 1 H-benzo[d]imidazole series compounds as lysine specific demethylase (LSD-1 ) inhibitors.

However, the state of the art does not describe the substituted heteroarylbenzimidazole compounds of general formula (I) of the present invention as described and defined herein.

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 TBK1 and/or ΙΚΚε and may therefore be used for the treatment or prophylaxis of hyperproliferative and/or inflammatory disorders, such as cancer, for example. DESCRIPTION of the INVENTION

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

(I).

in which : represents a group selected from

pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R⁷ group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R⁸ group, represents a group selected from

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

in which "^*" represents the point of attachment to the rest of the molecule,

or

R¹ represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R⁹ group;

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;

R⁴ represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy; represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl; represents a hydrogen atom, a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-haloalkyl, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom; represents a hydrogen atom, a halogen atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom; represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3-

C6-cycloalkyl and (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-,

said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl group; represents a halogen atom or a group selected from d-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-hydroxyalkyl, (Ci-C₃-alkoxy)-(Ci-C₃-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, C4-C8-cycloalkenyl, (Cs-Cs-cycloalkyl)- (Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7- membered heterocycloalkenyl, phenyl, heteroaryl, -CN, -C(=0)R¹⁴, -C(=0)-OR¹⁴, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a, -N(R¹⁷)-C(=0)-R¹⁴, -N(R¹⁷)-S(=0)₂-R¹⁴, -N(R¹⁷)-C(=0)-N(R¹²)R^12a, -N(R¹⁷)-C(=0)-OR¹⁴, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)-(Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH₂)x-phenyl, -0-(CH₂)x-heteroaryl, -0-C(=0)-R¹⁴ -0-C(=0)-N(R¹²)R^12a, d-Ce-alkylsulfanyl, Ci-C₆-haloalkylsulfanyl, -S(=0)₂-R¹⁴, -S(=0)₂-N(R¹²)R^12a and -S(=0)(=NR¹⁸)R¹⁴; and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(0-CH₂-0)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -(S-(CH₂)₂)-, -(0-(CH₂)₃)-, -((CH₂)₃)-, -((CH₂)₄)-, -(0-CH=CH)-, -(S-CH=CH); represents a hydrogen atom or a group selected from methyl, ethyl, methoxy and ethoxy; represents a hydrogen atom or a Ci-C3-alkyl group; represents a hydrogen atom or a group selected from Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C₄-haloalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, C3-C6-cycloalkyl and benzyl,

or

and R^12a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C₃-alkyl, -C(=0)R¹⁹, C(=0)OR¹⁹ and S(=0)₂R¹⁹; represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, Cs- Ce-cycloalkyl, (C3-C₆-cycloalkyl)-(Ci-C3-alkyl)-, C₂-C₆-alkenyl, C₂-C₆-alkynyl, 4- to 7- membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; represents a group selected from Ci-C₄-alkyl and benzyl; and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, C3-C6-cycloalkyl and benzyl,

or

and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxy, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)- (Ci-C₃-alkyl)-; R¹⁶ represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl; represents a hydrogen atom or a group selected from -CN, -C(=0)OR Ci-C4-alkyl and benzyl; represents a Ci-C3-alkyl group; represents an integer selected from 1 , 2, 3 and 4, 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 or sulphur 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".

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

If within the present text any item is referred to as "supra" within the description it is referred to any of the respective disclosures made within the specification in any of the preceding pages, or above on the same page.

If within the present text any item is referred to as "infra" within the description it is referred to any of the respective disclosures made within the specification in any of the subsequent pages, or below on the same page.

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, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.

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

The term "Ci-C6-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ie f-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl,

1 .2- dimethylpropyl, neo-pentyl, 1 ,1 -dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 -dimethylbutyl, 2,2-dimethylbutyl,

3.3- dimethylbutyl, 2,3-dimethylbutyl, 1 ,2-dimethylbutyl or 1 ,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or ie f-butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group.

The term "C2-C6-alkylene" means a linear or branched, saturated, divalent hydrocarbon chain (or "tether") having 2, 3, 4, 5 or 6 carbon atoms, e.g. -CH2-CH2- ("ethylene" or "C2-alkylene"), -CH2-CH2-CH2-, -C(H)(CH₃)-CH₂- or -C(CH₃)₂-) ("propylene" or "C₃-alkylene"), or, for example -CH₂-C(H)(CH₃)-CH₂-, -CH₂-C(CH₃)₂-), -CH2-CH2-CH2-CH2- ("butylene" or "C₄-alkylene"), "Cs-alkylene", e.g. -CH2-CH2-CH2-CH2-CH2- ("n-pentylene"), or "-C₆-alkylene-", e.g. -CH2-CH2-CH2-CH2-CH2-CH2- ("n-hexylene") or -C(CH₃)2-C(CH₃)2- group. Particularly, said alkylene is a -C(CH3)2-C(CH3)2- group.

The term "Ci-C6-hydroxyalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl" is defined supra, and in which 1 , 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl,

1 .2- dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1 -hydroxypropan-2-yl,

2- hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl,

3- hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group.

The term "Ci-C6-alkylsulfanyl" means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-S-, in which the term "Ci-C6-alkyl" is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, ie f-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, hexylsulfanyl group.

The term "Ci-C6-haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl" is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom, to give rise to a "Ci-C6-fluoroalkyl" group, particularly a "Ci-C4-fluoroalkyl" group, more particularly, a "Ci-C3-fluoroalkyl" group. Said Ci-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2 ,2 ,2-trif luoroethy I , pentafluoroethyl, 3,3,3-trifluoropropyl or

1 .3- difluoropropan-2-yl.

The term "Ci-C6-alkoxy" means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-0-, in which the term "Ci-C6-alkyl" is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ie f-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.

The term "Ci-C6-haloalkoxy" means a linear or branched, saturated, monovalent Ci-C6-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, to give rise to a "Ci-C6-fluoroalkoxy" group, particularly a "Ci-C4-fluoroalkoxy" group, more particularly, a "Ci-C3-fluoroalkoxy" group. Said Ci-C6-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

The term "Ci-C6-haloalkylsulfanyl" means a linear or branched, saturated, monovalent C1-C6- alkylsulfanyl 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 to give rise to a "Ci-C6-fluoroalkylsulfanyl" group, particularly a "Ci-C4-fluoroalkylsulfanyl" group, more particularly, a "Ci-C3-fluoroalkylsulfanyl" group. Said Ci-C6-haloalkylsulfanyl group is, for example, fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 2,2,2-trifluoroethylsulfanyl or pentafluoroethylsulfanyl.

The term "C2-C6-alkenyl" means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkenyl"). Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-1 -yl (or "allyl"), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1 -enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1 -en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, 1 -methylprop-2-enyl,

2- methylprop-1 -enyl, 1 -methylprop-1 -enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1 -methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1 -methylbut-2-enyl,

3- methylbut-1 -enyl, 2-methylbut-1 -enyl, 1 -methylbut-1 -enyl, 1 ,1 -dimethylprop-2-enyl,

1 - ethylprop-1 -enyl, 1 -propylvinyl, 1 -isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl,

2- methylpent-4-enyl, 1 -methylpent-4-enyl, 4-methylpent-3-enyl, 3-methylpent-3-enyl, 2-methylpent-3-enyl, 1 -methylpent-3-enyl, 4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, 1 -methylpent-2-enyl, 4-methylpent-1 -enyl, 3-methylpent-1 -enyl, 2-methylpent-1 -enyl, 1 -methylpent-1 -enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl,

1 - ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1 -ethyl but-2-enyl, 3-ethylbut-1 -enyl,

2- ethylbut-1 -enyl, 1 -ethylbut-1 -enyl, 2-propylprop-2-enyl, 1 -propylprop-2-enyl,

2- isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, 2-propylprop-1 -enyl, 1 -propylprop-1 -enyl, 2-isopropylprop-1 -enyl, 1 -isopropylprop-1 -enyl, 3,3-dimethylprop-1 -enyl or

1 -(1 ,1 -dimethylethyl)ethenyl group. Particularly, said group is vinyl or allyl.

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

3- methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methyl- pent-4-ynyl, 2-methylpent-3-ynyl, 1 -methylpent-3-ynyl, 4-methylpent-2-ynyl, 1 -methyl- pent-2-ynyl, 4-methylpent-1 -ynyl, 3-methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl, 1 -propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1 ,1 -dimethylbut-3-ynyl, 1 ,1 -dimethylbut-2-ynyl or 3,3-dimethylbut-1 -ynyl group. Particularly, said alkynyl group is ethynyl, prop-1 -ynyl or prop-2-ynyl.

The term "Cs-Cs-cycloalkyl" means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("Cs-Cs-cycloalkyl"). Particularly, said group is monocyclic and has 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl"). Said Cs-Cs-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl.

The term "C4-C8-cycloalkenyl" means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C4-C6-cycloalkenyl"). Said C4-C8-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.

The term "Cs-Cs-cycloalkoxy" means a saturated, monovalent, mono- or bicyclic group of formula (C3-C8-cycloalkyl)-0-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term "Cs-Cs-cycloalkyl" is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.

The term "spirocycloalkyl" means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10 or 1 1 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom. Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.

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

Said heterocycloalkyi 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 ,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, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, for example.

Particularly, "4- to 6-membered heterocycloalkyi" means a 4- to 6-membered heterocycloalkyi as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, "5- or 6-membered heterocycloalkyi" means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O. The term "5- to 7-membered heterocycloalkenyl" means a monocyclic, unsaturated, non- aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.

Said heterocycloalkenyl group is, for example, 4/-/-pyranyl, 2/-/-pyranyl, 2,5-dihydro-1 /-/-pyrrolyl, [1 ,3]dioxolyl, 4/-/-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothio- phenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4H-[1 ,4]thiazinyl.

The term "heterospirocycloalkyi" means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 1 1 ring atoms in total, in which the two rings share one common ring carbon atom, which "heterospirocycloalkyi" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.

Said heterospirocycloalkyi group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro[4.6]-.

The term "fused heterocycloalkyl" means a bicyclic, saturated heterocycle with 6, 7, 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, which "fused heterocycloalkyl" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said fused 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 fused heterocycloalkyl group is, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thiazabicyclo[4.3.0]- nonyl or azabicyclo[4.4.0]decyl.

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

Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1 ]heptyl, thiazabicyclo[2.2.1 ]heptyl, diazabicyclo[2.2.1 ]heptyl, azabicyclo- [2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi- cyclo[3.2.1 ]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1 ]octyl, azabicyclo[3.3.1 ]nonyl, diazabicyclo[3.3.1 ]nonyl, oxazabicyclo[3.3.1 ]nonyl, thiazabicyclo[3.3.1 ]- nonyl, azabicyclo[4.2.1 ]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiaza- bicyclo[4.2.1 ]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or azabicyclo[4.2.2]decyl.

The term "heteroaryl" means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).

Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10- membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

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

Particularly, the heteroaryl group is a a 5- or 6-membered heteroaryl group.

The term "heteroaryloxy" means a monovalent, monocyclic, bicyclic or tricyclic aromatic group of the formula (heteroaryl)-O-, in which the term "heterorayl is as defined supra, e.g. thienyloxy, thiazolyloxy, pyridinyloxy, pyrimidinyloxy, benzofuranyloxy, for example.

The term "phenyloxy" means a group of the formula (phenyl)-O.

The term "Ο-ι-Οβ", as used in the present text, e.g. in the context of the definition of "Ci-C6-alkyl", "Ci-C6-haloalkyl", "Ci-C6-hydroxyalkyl", "Ci-C6-alkoxy" or "Ci-C6-haloalkoxy" means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms. Further, as used herein, the term "C3-C8", as used in the present text, e.g. in the context of the definition of "Cs-Cs-cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.

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

For example:

"C1-C6" encompasses Ci , C2, C3, C₄, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;

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

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

"C2-C6" encompasses C2, C3, C₄, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;

"C3-C10" encompasses C3, C₄, C5, C6, C7, Ce, Cg, C10, C3-C10, C3-Cg, C3-C8, C3-C7,

C3-C6, C3-C5, C3-C4, C4-C10, C₄-Cg, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-Cg, Cs-Ce, C5-C7, C5-C6, C6-C10, C6-Cg, C6-Ce, C6-C7, C7-C10, C7-Cg, C7-C8, Ce-Cio, Ce-Cg and

"C3-C8" encompasses C3, C₄, C5, C6, C7, Ce, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Ce, C5-C7, C5-C6, C6-Ce, C6-C7 and C7-C8;

"C₃-C₆" encompasses C₃, C₄, C₅, C₆, C₃-C₆, C3-C5, C3-C4, C₄-C₆, C₄-C₅, and C₅-C₆; "C4-C8" encompasses C₄, C5, C6, C7, Ce, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Ce, C5-C7, C5-C6, C6-Ce, C6-C7 and C7-C8;

"C4-C7" encompasses C₄, C₅, C₆, C₇, C₄-C₇, C₄-C₆, C₄-C₅, C5-C7, C₅-C₆ and C₆-C₇;

"C4-C6" encompasses C₄, C5, C6, C4-C6, C4-C5 and C5-C6;

"C5-C10" encompasses C5, C6, C7, Ce, Cg, C10, C5-C10, Cs-Cg, C5-C8, C5-C7, C5-C6, C6-C10, C6- Cg, C6-Ce, C6-C7, C7-C10, C7-Cg, C7-C8, Ce-Cio, Ce-Cg and Cg-Cio!

"C6-C10" encompasses C6, C7, C8, Cg, C10, C6-C10, C6-Cg, C6-Ce, C6-C7, C7-C10, C7-Cg, C7-C8, Ce-Cio, Ce-Cg and Cg-Cio-

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.

As used herein, the term "protective group" is a protective group attached to an oxygen or nitrogen atom in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g. by chemical modification of the respective hydroxy or amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for hydroxy and amino groups are descibed for example in P.G.M. Wuts in Greene's Protective Groups in Organic Synthesis, 5^th edition, Wiley 2014; more specifically, protective groups for amino groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl, acetyl or tetrahydropyranoyl, or carbamate based groups, such as ie f.-butoxycarbonyl (Boc). Protective groups for hydroxy groups can be selected from acyl groups such as benzoyl, acetyl, pivaloyl or tetrahydropyranoyl, or can include silicon, as in e.g. tert-butyldimethylsilyl, tert- butyldiphenylsilyl, triethylsilyl or triisopropylsilyl.

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 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.

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.

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, it is possible for the compounds of the present invention to exist as tautomers. For example, any compound of the present invention can exist, as shown below, as a tautomer 1 , or tautomer 2 or tautomer 3, in which "^*" represents the point of attachment to the rest of the molecule, or even a mixture in any amount of the three tautomers, namely :

tautomer 1 tautomer 2 tautomer 3

The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

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 stoichiometrv 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.

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

or

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;

R⁴ represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl;

R⁵ represents a hydrogen atom;

R_6i represents a hydrogen atom, a halogen atom or a group selected from Ci-C3-alkyl and trifluoromethyl, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁶ represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,

said C3-C4-cycloalkyl and said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;

R⁸ represents a halogen atom or a group selected from d-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, C₃-C₄-cycloalkyl, (C₃-C₄-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C₃-alkyl)-, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)- and Ci-C4-alkylsulfanyl, or

R⁷ and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(O-CH2-O)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -((CH₂)₃)-, -((CH₂)₄)-;

R⁹ represents a hydrogen atom or a group selected from methoxy and ethoxy;

R¹⁰ represents a hydrogen atom or a methyl or ethyl group;

R¹¹ represents a hydrogen atom or a group selected from Ci-C₄-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a and phenyl,

said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C₄-alkyl, Ci-C₄-fluoroalkyl and benzyl,

or

R¹² and R^12a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group, said group being optionally substituted once with a methyl group;

R¹³ represents a group selected from Ci-C₄-alkyl, Ci-C₄-fluoroalkyl, C3-C6-cycloalkyl and (C₃-C₆-cycloalkyl)-(Ci-C₂-alkyl)-;

R¹⁴ represents a group selected from Ci-C₄-alkyl and benzyl;

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,

or

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl and C1-C3- fluoroalkyl;

R¹⁶ represents a group selected from Ci-C₄-alkyl, Ci-C₄-fluoroalkyl and C3-C6-cycloalkyl, 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:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

or

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule; R³ represents a hydrogen atom, a fluorine atom, a chlorine atom, or a group selected from methyl, ethyl, methoxy and ethoxy;

R⁴ represents a hydrogen atom, or a group selected from methyl and trifluoromethyl;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a Ci-C2-alkyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl ,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group;

R⁸ represents a fluorine, atom, a chlorine atom, or a group selected from Ci-C6-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-, -N(R¹²)R^12a,

Ci-C4-alkoxy, Ci-C4-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-;

R⁹ represents a hydrogen atom or a methoxy group;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶,

-S(=0)₂N(R¹⁵)R^15a and 2-chlorophenyl;

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C₂-fluoroalkyl, methyl and ethyl;

R¹³ represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)-(methyl)-;

R¹⁴ represents a Ci-C4-alkyl group;

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,

or

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a methyl group;

R¹⁶ represents a group selected from methyl, ethyl and trifluoromethyl, 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 compounds of general formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents a represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group; R⁸ represents a fluorine atom or a group selected from Ci-C3-alkyl, (Ci-C2-alkoxy)-(Ci-C2- alkyl)-, -N(R¹²)R^12a, Ci-C₃-alkoxy and (cyclopropyl)-(methoxy)-;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C₃-fluoroalkyl, -C(=0)R¹³ and -C(=0)OR¹⁴, R¹² and R^12a, independently from each other, represent a group selected from methyl and ethyl;

R¹³ represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;

R¹⁴ represents a tert-butyl group,

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 compounds of general formula (I), supra, in which:

R¹ represents a group selected from

in which "*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "*" represents the point of attachment to the rest of the molecule;

represents a hydrogen atom;

represents a hydrogen atom;

represents a hydrogen atom; R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group;

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule; R³ represents a hydrogen atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group;

R⁸ represents a group selected from methyl and methoxy;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group

in which "*" represents the point of attachment to the rest of the molecule;

represents a group

in which "*" represents the point of attachment to the rest of the molecule; R³ represents a hydrogen atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "*" represents the point of attachment to the rest of the molecule,

the ring of said group being optionally substituted, identically or differently, with two R⁸ groups;

represents a group

in which "*" represents the point of attachment to the rest of the molecule; R³ represents a hydrogen atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being optionally substituted, identically or differently, with two R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups

R^6a and R^6b is different from a hydrogen atom;

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule, the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a fluorine atom, a chlorine atom or a methyl group;

R^6b represents a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group;

R⁸ represents a group selected from methyl and methoxy;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from a group selected from 2,2,2-trifluoroethyl and cyclopropyl;

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

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

R¹ represents a group selected from

in which "*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "*" represents the point of attachment to the rest of the molecule;

R³ represents represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents a represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group;

R⁸ represents a fluorine atom or a group selected from Ci-C3-alkyl, (Ci-C2-alkoxy)-(Ci-C2- alkyl)-, -N(R¹²)R^12a, Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-;

R¹⁰ represents a hydrogen atom or a methyl group; R¹¹ represents a group selected from Ci-C₃-fluoroalkyl, -C(=0)R¹³ and -C(=0)OR¹⁴,

R¹² and R^12a, independently from each other, represent a group selected from methyl and ethyl;

R¹³ represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;

R¹⁴ represents a tert-butyl group,

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

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

represents a hydrogen atom or a fluorine atom;

represents a hydrogen atom;

represents a hydrogen atom;

represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom; R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

represents a hydrogen atom or a fluorine atom; R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;

R⁸ represents a group selected from methyl, methoxy, (methoxy)-(methyl)- and (cyclopropyl)-(methoxy)-;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from C2-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being optionally substituted, identically or differently, with two R⁸ groups;

represents a group

in which "*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups

R^6a and R^6b is different from a hydrogen atom;

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;

R¹⁰ represents a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "*" represents the point of attachment to the rest of the molecule, the ring of said group being optionally substituted, identically or differently, with one or two R⁸ groups;

R² represents a group

in which "*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R¹³ represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;

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

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being optionally substituted, identically or differently, with two R⁸ groups;

represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups

R^6a and R^6b is different from a hydrogen atom;

R⁸ represents a group selected from methyl, (methoxy)-(methyl)- and (cyclopropyl)- (methoxy)-;

R¹⁰ represents a methyl group;

R¹¹ represents a group -C(=0)R¹³;

R¹³ represents a group selected from 2,2,2-trifluoroethyl and cyclopropyl;

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

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a fluorine atom, a chlorine atom or a methyl group;

R^6b represents a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;

R⁸ represents a group selected from methyl, methoxy, (methoxy)-(methyl)- and (cyclopropyl)-(methoxy)-;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from 2,2-difluoroethyl, 2,2,2-trifluoroethyl and -C(=0)R¹³;

R¹³ represents a group selected from a group selected from 2,2,2-trifluoroethyl and cyclopropyl;

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. Further embodiments of the first aspect of the present invention

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

R¹ represents a group selected from

pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R⁷ group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R⁸ group,

or

R¹ represents a group selected from

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

in which "^*" represents the point of attachment to the rest of the molecule,

or

R¹ represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R⁹ 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:

R¹ represents a group selected from

pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R⁷ group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R⁸ 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:

R¹ represents a group selected from

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

in which "^*" represents the point of attachment to 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 a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R⁹ 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:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

or

R¹ represents a group selected from

in which "^*" represents the point of attachment to 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 a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ 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:

R¹ represents a group selected from

in which "^*" represents the point of attachment to 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 a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

represents a group selected from

in which "^*" represents the point of attachment to 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 a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ 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:

R¹ represents a group selected from

in which "^*" represents the point of attachment to 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 a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted with one further R⁸ group,

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted with one further R⁸ group,

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups,

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being optionally substituted with one R⁸ group,

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups, 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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

the ring of said group being, besides R⁷, optionally substituted with one further R⁸ group,

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups,

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

the ring of said group being optionally substituted, identically or differently, with one or two R⁸ groups,

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

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 compounds of formula (I), supra, in which: R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

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 compounds of formula (I), supra, in which:

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted with one further R⁸ group,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "*" represents the point of attachment to the rest of the molecule;

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "*" represents the point of attachment to the rest of the molecule;

and

represents a (C3-C4-cycloalkyl)-(methyl)- group, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

and

R⁷ represents a hydrogen atom or a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

and

R⁷ represents a hydrogen atom or a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group, 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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

and

R⁷ represents a hydrogen atom or a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

and

R⁷ represents a group selected from (cyclopropyl)-(methyl)- and (cyclobutyl)-(methyl)-, said (cyclopropyl)-(methyl)- and (cyclobutyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 compounds of formula (I), supra, in which: R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

and

R⁷ represents a group selected from (cyclopropyl)-(methyl)- and (cyclobutyl)-(methyl)-, 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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being optionally substituted with one R⁸ group,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

the ring of said group being optionally substituted, identically or differently, with one or two R⁸ groups,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

and in which R⁸ is selected from methyl, (methoxy)-(methyl)- and (cyclopropyl)- (methoxy)-;

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule; and in which R⁸ is selected from methyl and (cyclopropyl)-(methoxy)-;

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

said group being optionally substituted, identically or differently, with one or two R⁸ groups,

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 compounds of formula (I), supra, in which:

R¹ represents a group

in which "^*" represents the point of attachment to 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:

R² represents a group selected from

in which "^*" represents the point of attachment to 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:

R² represents a group selected from

in which "^*" represents the point of attachment to 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:

R² represents a group selected from

in which "^*" represents the point of attachment to 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:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to 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:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "*" represents the point of attachment to the rest of the molecule,

and in which R¹¹ represents a Ci-C2-fluoroalkyl group;

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 compounds of formula (I), supra, in which: R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule, 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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule, and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "*" represents the point of attachment to the rest of the molecule,

and in which R¹¹ represents a Ci-C2-fluoroalkyl group;

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which: R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R¹¹ represents a Ci-C2-fluoroalkyl group;

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule, and 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 compounds of formula (I), supra, in which:

in which "^*" represents the point of attachment to the rest of the molecule, and 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 compounds of formula (I), supra, in which:

R² represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule, and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule, and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group C H ₃

in which "^*" represents the point of attachment to the rest of the molecule,

and 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule, and 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 a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy,

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 a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy,

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 a hydrogen atom, a fluorine atom, a chlorine atom, or a group selected from methyl, ethyl, methoxy and ethoxy,

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 a hydrogen atom, a fluorine atom, or a group selected from methyl and methoxy,

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 compounds of formula (I), supra, in which:

R³ represents a hydrogen atom or a fluorine atom,

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 compounds of formula (I), supra, in which:

R³ represents a hydrogen atom,

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 compounds of formula (I), supra, in which:

R³ represents a fluorine atom,

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 a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-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 a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl, 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 a hydrogen atom, or a group selected from methyl 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 a hydrogen atom or a methyl group,

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 compounds of formula (I), supra, in which:

R⁴ represents a hydrogen atom,

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 a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl,

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 a hydrogen atom or a fluorine atom or a chlorine atom a group selected from methyl, trifluoromethyl and cyclopropyl,

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 compounds of formula (I), supra, in which:

R⁵ represents a hydrogen atom,

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:

R^6a represents a hydrogen atom, a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-haloalkyl, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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:

R^6a represents a hydrogen atom, a halogen atom or a group selected from Ci-C3-alkyl and trifluoromethyl, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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:

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a Ci-C2-alkyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6a represents a fluorine atom, a chlorine atom or a methyl group,

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 compounds of formula (I), supra, in which:

R^6a represents a fluorine atom, a chlorine atom or a methyl group, with the proviso that R^6b represents a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6a represents a hydrogen atom, with the proviso that the group R^6b is different from a hydrogen atom, 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 compounds of formula (I), supra, in which:

R^6a represents a fluorine atom or a chlorine atom,

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 compounds of formula (I), supra, in which:

R^6a represents a chlorine atom,

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 compounds of formula (I), supra, in which:

R^6a represents a fluorine atom,

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 compounds of formula (I), supra, in which:

R^6a represents a methyl 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:

R^6b represents a hydrogen atom, a halogen atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom, 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:

R^6b represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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:

R^6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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:

R^6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups

R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6b represents a hydrogen atom, with the proviso that the group R^6a is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6b represents a fluorine atom,

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 compounds of formula (I), supra, in which:

R^6b represents a chlorine atom,

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: R^6a represents a hydrogen atom, a halogen atom or a group selected from

Ci-C4-alkyl and Ci-C4-haloalkyl, and in which

R^6b represents a hydrogen atom, a halogen atom or a methyl group,

with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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:

R^6a represents a hydrogen atom, a halogen atom or a group selected from

Ci-C3-alkyl and trifluoromethyl, and in which

R^6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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:

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a

Ci-C2-alkyl group, and in which

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom,

with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and in which

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3- Ce-cycloalkyl and (C₃-C₆-cycloalkyl)-(Ci-C₃-alkyl)-,

said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl 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 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,

said C3-C4-cycloalkyl and said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl 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 represents a group selected from C2-C4-alkyl, C2-C4-fluoroalkyl and (C3-C4-cycloalkyl)- (methyl)-,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl 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 represents a group selected from C2-C4-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,

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 compounds of formula (I), supra, in which:

R⁷ represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group,

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 compounds of formula (I), supra, in which:

R⁷ represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C₂-C₄-fluoroalkyl,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 compounds of formula (I), supra, in which: R⁷ represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl,

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 compounds of formula (I), supra, in which:

R⁷ represents a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 compounds of formula (I), supra, in which:

R⁷ represents a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl, 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 represents a group selected from C2-C4-fluoroalkyl and (cyclopropyl)-(methyl)-,

said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl 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 represents a group selected from C2-C4-fluoroalkyl and (cyclopropyl)-(methyl)-,

said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom, 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 represents a group selected from C2-C4-fluoroalkyl and (cyclobutyl)-(methyl)-,

said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl 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 represents a group selected from C2-C4-fluoroalkyl and (cyclobutyl)-(methyl)-,

said (cyclobutyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 represents a group selected from C2-C3-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl 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 represents a group selected from C2-C3-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 represents a group selected from C2-C3-fluoroalkyl and (cyclopropyl)-(methyl)-,

said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl 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 represents a group selected from C2-C3-fluoroalkyl and (cyclopropyl)-(methyl)-,

said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 represents a group selected from C2-C3-fluoroalkyl and (cyclobutyl)-(methyl)-,

said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl 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 represents a group selected from C2-C3-fluoroalkyl and (cyclobutyl)-(methyl)-, said (cyclobutyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl 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 represents a (cyclopropyl)-(methyl)- group,

said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl 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 represents a (cyclobutyl)-(methyl)- group,

said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl 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 represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl 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 represents a (cyclopropyl)-(methyl)- group,

said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl 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 represents a (cyclobutyl)-(methyl)- group,

said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, , identically or differently, with a fluorine atom or a methyl group,

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 compounds of formula (I), supra, in which:

R⁷ represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 compounds of formula (I), supra, in which: R⁷ represents a (cyclopropyl)-(methyl)- group,

said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 compounds of formula (I), supra, in which:

R⁷ represents a (cyclobutyl)-(methyl)- group,

said (cyclobutyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,

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 compounds of formula (I), supra, in which:

R⁷ represents a (C3-C4-cycloalkyl)-(methyl)- group,

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 compounds of formula (I), supra, in which:

R⁷ represents a (cyclobutyl)-(methyl)- group,

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 compounds of formula (I), supra, in which:

R⁷ represents a (cyclopropyl)-(methyl)- 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:

R⁸ represents a halogen atom or a group selected from d-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-hydroxyalkyl, (Ci-C₃-alkoxy)-(Ci-C₃-alkyl)-,

C2-C6-alkenyl, C2-C6-alkynyl, C₃-C8-cycloalkyl, C4-C8-cycloalkenyl, (C₃-C8-cycloalkyl)- (Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7- membered heterocycloalkenyl, phenyl, heteroaryl, -CN, -C(=0)R¹⁴, -C(=0)-OR¹⁴, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a, -N(R¹⁷)-C(=0)-R¹⁴, -N(R¹⁷)-S(=0)₂-R¹⁴, -N(R¹⁷)-C(=0)- N(R¹²)R^12a, -N(R¹⁷)-C(=0)-OR¹⁴, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C₃-C₈-cycloalkoxy-,

(C3-C8-cycloalkyl)-(Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH₂)_x-phenyl, -0-(CH₂)x-heteroaryl, -0-C(=0)-R¹⁴, -0-C(=0)-N(R¹²)R^12a, Ci-C₆-alkylsulfanyl, Ci-C₆- haloalkylsulfanyl, -S(=0)₂-R¹⁴, -S(=0)₂-N(R¹²)R^12a and -S(=0)(=NR¹⁸)R¹⁴;

or

R⁷ and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(O-CH2-O)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -(S-(CH₂)₂)-, -(0-(CH₂)₃)-, -((CH₂)₃)-, -((CH₂)₄)-, -(0-CH=CH)-, -(S-CH=CH),

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:

R⁸ represents a halogen atom or a group selected from Ci-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-hydroxyalkyl, (Ci-C₃-alkoxy)-(Ci-C₃-alkyl)-,

C₂-C6-alkenyl, C₂-C6-alkynyl, C₃-C8-cycloalkyl, C₄-C8-cycloalkenyl, (C₃-C8-cycloalkyl)- (Ci-C₃-alkyl)-, (phenyl)-Ci-C₃-alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7- membered heterocycloalkenyl, phenyl, heteroaryl, -CN, -C(=0)R¹⁴, -C(=0)-OR¹⁴, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a, -N(R¹⁷)-C(=0)-R¹⁴, -N(R¹⁷)-S(=0)₂-R¹⁴, -N(R¹⁷)-C(=0)- N(R¹²)R^12a, -N(R¹⁷)-C(=0)-OR¹⁴, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C₃-C₈-cycloalkoxy-,

(C₃-C8-cycloalkyl)-(Ci-C₃-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH₂)_x-phenyl, -0-(CH₂)_x-heteroaryl, -0-C(=0)-R¹⁴, -0-C(=0)-N(R¹²)R^12a, Ci-C₆-alkylsulfanyl, d-Ce-haloalkylsulfanyl, -S(=0)₂-R¹⁴, -S(=0)₂-N(R¹²)R^12a and -S(=0)(=NR¹⁸)R¹⁴;

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 and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(O-CH2-O)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -(S-(CH₂)₂)-, -(0-(CH₂)₃)-, -((CH₂)₃)-, -((CH₂)₄)-, -(0-CH=CH)-, -(S-CH=CH);

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:

R⁸ represents a halogen atom or a group selected from d-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, C₃-C₄-cycloalkyl, (C₃-C₄-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C₃-alkyl)-, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a,

Ci-C6-alkoxy, Ci-C₄-fluoroalkoxy, (C₃-C₄-cycloalkyl)-(methoxy)- and Ci-C₄-alkylsulfanyl, or

R⁷ and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(0-CH₂-0)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -((CH₂)₃)-, -((CH₂)₄)-,

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:

R⁸ represents a halogen atom or a group selected from Ci-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, C₃-C₄-cycloalkyl, (C₃-C₄-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C₃-alkyl)-, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a, Ci-C6-alkoxy, Ci-C₄-fluoroalkoxy, (C₃-C₄-cycloalkyl)-(methoxy)- and Ci-C₄-alkylsulfanyl, 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 and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(O-CH2-O)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -((CH₂)₃)-, -((CH₂)₄)-,

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:

R⁸ represents a halogen atom or a group selected from Ci-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-, -N(R¹²)R^12a, Ci-Ce-alkoxy, Ci-C₄-fluoroalkoxy, (C₃-C₄-cycloalkyl)-(methoxy)- and Ci-C₄-alkylsulfanyl,

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:

R⁸ represents a group selected from

Ci-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-, -N(R¹²)R^12a, Ci-Ce-alkoxy, Ci-C₄-fluroalkoxy, (C₃-C₄-cycloalkyl)-(methoxy)- and Ci-C₄-alkylsulfanyl,

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:

R⁸ represents a group selected from

Ci-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-, -N(R¹²)R^12a, Ci-Ce-alkoxy, Ci-C₄-fluoroalkoxy and (C₃-C₄-cycloalkyl)-(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:

R⁸ represents a fluorine, atom, a chlorine atom, or a group selected from

d-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-,

-N(R¹²)R^12a, Ci-C₄-alkoxy, Ci-C₄-fluoroalkoxy and (C₃-C₄-cycloalkyl)-(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:

R⁸ represents a group selected from

Ci-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-, -N(R¹²)R^12a, Ci-C₄-alkoxy, Ci-C₄-fluoroalkoxy and (C₃-C₄-cycloalkyl)-(methoxy)-, 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 compounds of formula (I), supra, in which:

R⁸ represents a fluorine atom or a group selected from Ci-C₃-alkyl, (Ci-C₂-alkoxy)-(Ci-C₂- alkyl)-, -N(R¹²)R^12a, Ci-C₃-alkoxy and (cyclopropyl)-(methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from Ci-C₃-alkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, -N(R¹²)R^12a, Ci-C₃-alkoxy and (cyclopropyl)-(methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from Ci-C3-alkyl, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from Ci-C3-alkyl, Ci-C3-alkoxy and (cyclopropyl)- (methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from Ci-C3-alkyl and Ci-C3-alkoxy,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, N-azetidinyl, N-pyrrolidinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-, 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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl, methoxy, (methoxy)-(methyl)- and (cyclopropyl)-(methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl, methoxy and (cyclopropyl)-(methoxy)-, 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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl and 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:

R⁸ represents a group selected from

d-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-, 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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl, trifluoromethyl and (methoxy)-(methyl)-, 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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl and trifluoromethyl,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methyl and (methoxy)-(methyl)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a methyl group,

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 compounds of formula (I), supra, in which:

R⁸ represents a (methoxy)-(methyl)- group,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from dimethylamino and diethylamino,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-, 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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methoxy, ethoxy and iso-propoxy,

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 compounds of formula (I), supra, in which:

R⁸ represents a group selected from methoxy and (cyclopropyl)-(methoxy)-,

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 compounds of formula (I), supra, in which:

R⁸ represents a methoxy group,

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 compounds of formula (I), supra, in which:

R⁸ represents a (cyclopropyl)-(methoxy)- 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:

R⁹ represents a hydrogen atom or a group selected from methyl, ethyl, methoxy and ethoxy,

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 a hydrogen atom or a group selected from methoxy and ethoxy,

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 a hydrogen atom or a methoxy group,

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 compounds of formula (I), supra, in which:

R⁹ represents a methoxy 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:

R¹⁰ represents a hydrogen atom or a Ci-C3-alkyl 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:

R¹⁰ represents a hydrogen atom or a methyl or an ethyl 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:

R¹⁰ represents a hydrogen atom or a methyl 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:

R¹⁰ represents a hydrogen atom,

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 compounds of formula (I), supra, in which:

R¹⁰ represents a methyl 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:

R¹¹ represents a hydrogen atom or a group selected from Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C₄-haloalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶,

-S(=0)₂N(R¹⁵)R^15a, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and 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:

R¹¹ represents a hydrogen atom or a group selected from Ci-C₄-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a and phenyl,

said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and 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:

R¹¹ represents a hydrogen atom or a group selected from Ci-C₄-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴ and phenyl,

said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and 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:

R¹¹ represents a group selected from Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a and phenyl,

said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and 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:

R¹¹ represents a hydrogen atom or a group selected from Ci-C₄-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a and 2-chlorophenyl,

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 a group selected from Ci-C₄-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a and 2-chlorophenyl,

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 a group selected from Ci-C3-alkyl, C3-C₄-cycloalkyl, Ci-C₃-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a and 2-chlorophenyl,

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 a group selected from Ci-C3-alkyl, C3-C4-cycloalkyl, d-Cs-fluoroalkyl, -C(=0)R¹³ and -C(=0)OR¹⁴,

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 a hydrogen atom or a group selected from Ci-C₃-fluoroalkyl, -C(=0)R¹³ and -C(=0)OR¹⁴,

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 compounds of formula (I), supra, in which:

R¹¹ represents a group selected from Ci-C₃-fluoroalkyl, -C(=0)R¹³ and -C(=0)OR¹⁴, 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 compounds of formula (I), supra, in which:

R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³,

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 compounds of formula (I), supra, in which:

R¹¹ represents a -C(=0)R¹³ group,

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 compounds of formula (I), supra, in which:

R¹¹ represents a Ci-C3-fluoroalkyl group,

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 compounds of formula (I), supra, in which:

R¹¹ represents a C2-C3-fluoroalkyl group,

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 compounds of formula (I), supra, in which: R¹¹ represents a -C(=0)OR¹⁴ group,

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 compounds of formula (I), supra, in which:

R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-,

or in which

R¹¹ represents a C2-C3-fluoroalkyl group,

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 compounds of formula (I), supra, in which: R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a group selected from 2,2,2- trifluoroethyl and cyclopropyl,

or in which R¹¹ represents a C2-C3-fluoroalkyl group,

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 compounds of formula (I), supra, in which:

R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-,

or in which

R¹¹ represents a group selected from 2,2-difluoroethyl and 2,2,2-trifluoroethyl,

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 compounds of formula (I), supra, in which:

R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a group selected from 2,2,2- trifluoroethyl and cyclopropyl,

or in which

R¹¹ represents a group selected from 2,2-difluoroethyl and 2,2,2-trifluoroethyl,

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 compounds of formula (I), supra, in which:

R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-,

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 compounds of formula (I), supra, in which: R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a group selected from 2,2,2- trifluoroethyl and cyclopropyl,

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 compounds of formula (I), supra, in which:

R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a 2,2,2-trifluoroethyl group, 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 compounds of formula (I), supra, in which:

R¹¹ represents a -C(=0)R¹³ group, in which R¹³ represents a cyclopropyl group,

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 compounds of formula (I), supra, in which:

R¹¹ represents a group selected from 2,2-difluoroethyl and 2,2,2-trifluoroethyl,

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 compounds of formula (I), supra, in which:

R¹¹ represents a 2,2-difluoroethyl group,

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 compounds of formula (I), supra, in which:

R¹¹ represents a 2,2,2-trifluoroethyl 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:

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,

or

R¹² and R^12a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, d-Cs-alkyl, -C(=0)R¹⁹, C(=0)OR¹⁹ and S(=0)₂R¹⁹,

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 and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,

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 and R^12a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C₃-alkyl, -C(=0)R¹⁹, C(=0)OR¹⁹ and S(=0)₂R¹⁹,

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 and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl and benzyl,

or

R¹² and R^12a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group, said group being optionally substituted once with a methyl 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:

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl and benzyl,

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 and R^12a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group, said group being optionally substituted once with a methyl 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:

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl,

or R¹² and R^12a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group, said group being optionally substituted once with a methyl 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:

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl,

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 compounds of formula (I), supra, in which:

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C2-fluoroalkyl, methyl and ethyl,

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 compounds of formula (I), supra, in which:

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,

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 compounds of formula (I), supra, in which:

R¹² and R^12a, independently from each other, represent a group selected from methyl and ethyl,

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 compounds of formula (I), supra, in which:

R¹² and R^12a each represent a methyl group,

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 compounds of formula (I), supra, in which:

R¹² and R^12a each represent an ethyl 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:

R¹³ represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, C3-C₆-cycloalkyl, (C3-C₆-cycloalkyl)-(Ci-C3-alkyl)-, C₂-C₆-alkenyl, C₂-C₆-alkynyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, 5- to 6- membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and 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:

R¹³ represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl and (C₃-C₆-cycloalkyl)-(Ci-C2-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:

R¹³ represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)-(methyl)-,

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 compounds of formula (I), supra, in which:

R¹³ represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-,

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 compounds of formula (I), supra, in which:

R¹³ represents a Ci-C2-fluoroalkyl group,

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 compounds of formula (I), supra, in which:

R¹³ represents a C3-C4-cycloalkyl group,

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 compounds of formula (I), supra, in which:

R¹³ represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-, 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 compounds of formula (I), supra, in which:

R¹³ represents a group selected from 2,2,2-trifluoroethyl and cyclopropyl,

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 compounds of formula (I), supra, in which:

R¹³ represents a 2,2,2-trifluoroethyl group,

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 compounds of formula (I), supra, in which:

R¹³ represents a cyclopropyl 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 a group selected from Ci-C4-alkyl and benzyl,

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 a benzyl 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 a Ci-C4-alkyl 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 a tert-butyl 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:

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,

or

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxy, -CN, d-Cs-alkyl, Ci-C₃-haloalkyl, Ci-C₃-alkoxy, Ci-C₃-haloalkoxy and

(Ci-C₃-alkoxy)-(Ci-C₃-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: R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,

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:

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxy, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C₃-alkoxy)-(Ci-C₃-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:

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,

or

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl and C1-C3- fluoroalkyl,

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:

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,

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:

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl and C1-C3- fluoroalkyl,

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 compounds of formula (I), supra, in which:

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,

or

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a methyl group, 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 compounds of formula (I), supra, in which:

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,

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 compounds of formula (I), supra, in which:

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a methyl 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:

R¹⁶ represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, (C3-C6- cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and 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:

R¹⁶ represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, and C3-C6-cycloalkyl, 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:

R¹⁶ represents a group selected from Ci-C2-alkyl, Ci-C2-fluoroalkyl, and cyclopropyl, 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:

R¹⁶ represents a group selected from methyl, ethyl 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:

R¹⁷ represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl, 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:

R¹⁸ represents a hydrogen atom or a group selected from -CN, -C(=0)OR¹⁴, Ci-C4-alkyl and benzyl,

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:

R¹⁹ represents a Ci-C3-alkyl 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:

x represents an integer selected from 1 , 2 and 3.

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

x represents an integer selected from 1 and 2. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

x represents an integer 1 .

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

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R⁴ represents a hydrogen atom and R⁵ represents a hydrogen atom,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom and R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R³ represents a hydrogen atom, R⁴ represents a hydrogen atom and R⁵ represents a hydrogen atom,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R³ represents a hydrogen atom or a fluorine atom, R⁴ represents a hydrogen atom and R⁵ represents a hydrogen atom,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule, and in which R³ represents a hydrogen atom, R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom and R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³, 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R³ represents a hydrogen atom or a fluorine atom, R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom and R¹¹ represents a group selected from C1-C3- fluoroalkyl and -C(=0)R¹³,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom, R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom,

with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom, 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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom, R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, and R¹¹ represents a group selected from C1-C3- fluoroalkyl and -C(=0)R¹³,

with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R³ represents a hydrogen atom, R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom, R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R³ represents a hydrogen atom or a fluorine atom, R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom, R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom,

with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R³ represents a hydrogen atom, R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom, R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, and R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³,

with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 compounds of formula (I), supra, in which:

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule,

and in which R³ represents a hydrogen atom or a fluorine atom, R⁴ represents a hydrogen atom, R⁵ represents a hydrogen atom, R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, and R¹¹ represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³,

with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom,

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 further 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 (XXI). The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra. General Syntheses of compounds of formula (I)

The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (I), and intermediates useful for their synthesis.

In addition to the routes described below, also other routes may be used to synthesise the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, modification of any of the substituents, such as R¹, R², R³, R⁴, R⁵, R^6a or R^6b, or of substituents contained therein, such as R⁷ and R⁸ in R¹, and R¹¹ in R², can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, alkylation, acylation, sulfonylation, metallation, metal catalysed coupling reactions, exemplified by but not limited to Suzuki, Sonogashira, Negishi and Ullmann couplings, ester saponifications, amide coupling reactions, formation and cleavage of ethers, reductive aminations, hydrogenolyses e.g. of halogen atoms bonded to aromatic rings, and/or substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example P.G.M. Wuts in Greene's Protective Groups in Organic Synthesis, 5^th edition, Wiley 2014).

Compounds of formula (I), and the intermediates used in their synthesis, may be chiral, e.g. in case of R¹⁰ being different from hydrogen, and may then be formed as mixtures of stereoisomers. Said mixtures of stereoisomers can be separated by methods well known the person skilled in the art, such as preparative chromatography, such as high pressure liquid chromatography (HPLC) or superfluid chromatography (SFC) using chiral stationary phases, which are commercially available in considerable variety. If compounds of formula (I), or intermediates used in their synthesis, are sufficiently basic or acidic, stereoisomeric mixtures, in particular mixtures of enantiomers, can be resolved using chiral, enantiomerically pure acids, such as tartaric acid and 2,3-bis(benzoyloxy)butanedioic acid, or chiral, enantiomerically pure amines, such as 1 -phenylethylamine or strychnine, respectively, via the formation of diastereomeric salts which can be separated.

The general synthesis strategy to compounds of the general formula (I) is outlined in Scheme 1 . As starting materials, diaminobenzene derivatives of formula (II), in which R³, R^6a and R^6b are as defined for the compounds of general formula (I) and X represents a group selected from a boronic acid, a boronic acid ester, a -CN group, a -C(=0)-0-R^E group, in which R^E represents a Ci-C3-alkyl group, and a R¹ group which is as defined for the compounds of general formula (I), and aminopyridine derivatives of formula (III), in which R⁴ and R⁵ are as defined for the compounds of general formula (I), and in which Y represents a group selected from -CH2-O-PG¹, in which PG¹ represents a protective group suitable for alcohols, as defined supra, such as tert-butyl dimethylsilyl, a R² group, which is as defined for the compounds of general formula (I), and a G¹ group, in which R¹⁰ is as defined for the compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R² in general formula (I), can be employed.

In a first key step, said aminopyridines of formula (III) can be reacted with di-1 H-imidazol-1 - ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in a solvent such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide or dioxane, followed by the addition of diaminobenzene derivatives of formula (II), to give thioureas of formulae (IV) and (IVa) as regioisomeric mixtures. Said thioureas of formulae (IV) and (IVa) can be, in a second key step, further converted into benzimidazole derivatives of formula (V) by reaction with a carbodiimide, such as N,N'-dipropan-2-ylcarbodiimide or 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide, or a salt thereof, in an aliphatic chlorinated hydrocarbon, such as dichloromethane and chloroform, as a solvent. Noteworthily, regioisomeric mixtures of thioureas of formulae (IV) and (IVa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery.

( V )

Scheme 1 : General synthesis strategy for the preparation of the compounds of the present invention.

Dependent of the nature of the X and Y groups, compounds of formula (V) can either already constitute compounds of the general formula (I), or various synthetic intermediates thereof. More detailed synthesis routes to compounds of general formula (I) are given below, as outlined in the Schemes 2a, 2b, 2c, 2d, 2e, 2f, 3a, 3b, 3c, 4 and 5.

Schemes 2a and 2d outline an approach to compounds of general formula (I), in which R¹ can be introduced in a late step by means of the well-known Suzuki coupling, from nitroaniline derivatives of formula (VI), diaminobenzene derivatives of formula (VII), aminopyridine derivatives of formula (VIII), and piperazine derivatives of formula (IX).

Scheme 2a: Synthesis of intermediates of formulae (XI) and (XII) from starting materials of formulae (VI), (VII), (VIII) and (IX).

Diaminobenzene derivatives of formula (VII), in which R³, R^6a and R^6b are as defined for compounds of general formula (I), and in which LG¹ represents a leaving group, preferably chloride, bromide or iodide, can be converted, using methods well known to the person skilled in the art, e.g. by reacting with a suitable boron reagent, such as 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi-1 ,3,2-dioxaborolane, in the presence of a palladium catalyst, such as bis(diphenylphosphino)ferrocene-palladium(l l)dichloride dichloromethane adduct or, preferably, dichlorobis(tricyclohexylphosphine)palladium(ll) , to give boronic acid derivatives of formula (XI). Said boronic acid derivatives of formula (XI) may be a boronic acid (R^B = -H) or an ester of the boronic acid, e.g. its isopropyl ester (R^B = Ci-C4-alkyl, e.g. -CH(CH3)2), or an ester derived from a diol such as pinacol in which the boronic acid intermediate forms a cyclic boronic ester, such as a 4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (R^B-R^B = C2-C6-alkylene, e.g. -C(CH3)2-C(CH3)2-). Many boronic acids and their esters are commercially available and well- known to the person skilled in the art; see e.g. D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991 -8 and references cited therein. Alternatively, and in an analogous fashion as described supra for the conversion of compounds of formula (VII) into boronic acid derivatives of formula (XI), nitroaniline derivatives of formula (VI), in which R³, R^6a and R^6b are as defined for the compounds of general formula (I), and in which LG¹ represents a leaving group, preferably chloride, bromide or iodide, can be converted into boronic acid derivatives of formula (X). Subsequently, said boronic acid derivatives of formula (X) can be reduced to the corresponding diamines of formula (XI) by methods well known to the person skilled in the art, e.g. by palladium catalysed hydrogenolysis.

Further, aminopyridines of formula (VIII), in which R⁴, R⁵ and R¹⁰ are as defined for compounds of general formula (I), and in which LG² represents a leaving group, preferably chloride or bromide, can be reacted with piperazine derivatives of formula (IX), in which R¹¹ is as defined for compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R² in general formula (I), to give intermediates of formula (XII). The aminopyridines of formula (VIII) may be employed as free bases or as salts; furthermore, their amino group can optionally be protected by a protective group which is removed on later stage. Suitable groups for protection of amines, e.g. the phthalimido group, and methods for their introduction and removal, are well known to the person skilled in the art, see e.g. P.G.M. Wuts in Greene's Protective Groups in Organic Synthesis, 5^th edition, Wiley 2014.

The reader is further referred to the fact that the definition of R¹¹ for compounds of general formula (I) includes some protective groups, such as ie f-butoxycarbonyl, which may be cleaved off (to give R¹¹ = hydrogen) and replaced by another R¹¹ group at a later stage.

Starting materials of formulae (VI), (VII) (VIII) and (IX) are well known to the person skilled in the art and are commercially available in considerable variety, or can be prepared by well- known synthesis methods. With respect to said aminopyridine derivaties of formula (VIII), special reference is being made to protected aminopyridine derivatives of formula (XV), which are useful in particular for the preparation of compounds of general formula (I) and advanced intermediates thereof, in which R¹⁰ is different from a hydrogen atom. They can be prepared according to Scheme 2b from aminopyridines of formula (XIII), in which R⁴, R⁵ and R¹⁰ are as described for the compounds of general formula (I) with the proviso that R¹⁰ is different from a hydrogen atom, by reaction with benzene-1 ,2-dicarbonyl dichloride (also known as phthaloyl chloride) in the presence of a base, e.g. an aliphatic tertiary amine such as triethylamine, in an aliphatic halogenated hydrocarbon, such as dichloromethane, as a solvent, to give phthalimide derivatives of formula (XIV). Said phthalimide derivatives can subsequently be reacted with reagents suitable for the introduction of LG², such as /V-halo succinimides, e.g. /V-bromo succinimide, and a radical starter, such as 2,2'-(£)-diazene-1 ,2-diylbis(2-methylpropanenitrile) (also known as AIBN), to give compounds of formula (XV), in which R⁴, R⁵ and R¹⁰ are as described for the compounds of general formula (I) with the proviso that R¹⁰ is different from hydrogen, and in which LG² represents a leaving group, preferably chloride or bromide.

Scheme 2b: Synthesis of protected aminopyridine intermediates of formula (XV).

Diamines of formula (XIa), in which R^A represents a Ci-C4-alkyl group, thus constituting a sub- compartment of formula (XI), can be advantageously approached using the modified approach shown below in Scheme 2c. 2-Bromo-5-nitrophenol derivatives of formula (XVI), in which R^6a and R^6b are as defined for the compounds of general formula (I), can be reacted with 1 ,1 , 1 -tri- (Ci-C3-alkyl)methylhydrazinium salts such as 1 ,1 , 1 -trimethylhydrazinium iodide in the presence of a suitable base, such as an alkali alkoxide, such as sodium 2-methylbutan-2-olate, to give a 2-amino-6-bromo-3-nitrophenol derivative of formula (XVII), which in turn can be reacted with a compound of formula R^A-LG³, in which R^A represents a Ci-C4-alkyl group, and LG³ represents a leaving group, preferably bromide or iodide, in the presence of a base such as sodium carbonate in a solvent such as acetonitrile or Ν,Ν-dimethylformamide, to yield a phenyl ether compound of formula (XVIII). Said aryl ether compounds of formula (XVIII) can be converted into the corresponding boronic acid derivatives of formula (XIX), which may be a boronic acid (R^B = -H) or an ester of the boronic acid, e.g. its isopropyl ester (R^B = Ci-C4-alkyl, e.g. -CH(CH3)2), or an ester derived from a diol such as pinacol in which the boronic acid intermediate forms a cyclic boronic ester, such as a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (R^B-R^B = C2-C6-alkylene, e.g. -C(CH3)2-C(CH3)2-), in an analogous fashion as described supra for the conversion of compounds of formulae (VI) and (VII) into boronic acid derivatives of formulae (X) and (XI). Subsequently, boronic acid derivatives of formula (XIX) can be reduced to the corresponding diamines of formula (XIa), in which R^A represents a Ci-C4-alkyl group, by methods well known to the person skilled in the art, e.g. by palladium catalysed hydrogenolysis.

Said 2-Bromo-5-nitrophenol derivatives of formula (XVI) are well known to the person skilled in the art and are commercially available in certain cases.

( XIX ) ( Xla )

Scheme 2c: Synthesis of intermediates of formula (Xla) from 2-bromo-5-nitrophenol derivatives of formula (XVI).

As outlined in Scheme 2d, infra, compounds of formula (Xlla), formula (Xlla) being equivalent to formula (XII) in Scheme 2a, can be reacted with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in a solvent such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide or dioxane, preferably dichloromethane, followed by the addition of diaminobenzene derivatives of formula (XI), to give thioureas of formulae (XX) and (XXa) as regioisomeric mixtures. Said thiourea derivatives can be further converted into benzimidazole derivatives of formula (XXI) by reaction with a carbodiimide of formula R^D1-N=C=N-R^D2 (or a salt thereof), in which R^D1 and R^D2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N- dimethylamino group, preferably R^D1 being ethyl and R^D2 being 3-N,N-dimethylaminopropyl, or both R^D1 and R^D2 being isopropyl, in a halogenated aliphatic hydrocarbon comprising 1 , 2 or 3 carbon atoms and 1 , 2, 3, 4, 5 or 6 halogen atoms, preferably chlorine atoms, as a solvent, particularly preferred solvents being dichloromethane and chloroform. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XX) and (XXa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery. In a final step, the resulting benzimidazole derivatives of formula (XXI) can be reacted with compounds of formula (XXII), in which R¹ is as defined for compounds of general formula (I), and in which LG⁴ represents a leaving group, preferably chloride, bromide or iodide, in a Suzuki coupling to give compounds of general formula (I). Specific examples are described in the Experimental Section.

R¹— LG⁴ ( XXII )

Scheme 2d: Conversion of intermediates of formulae (XI) and (Xlla) into compounds of general formula (I).

Said Suzuki coupling reaction can be catalysed by palladium catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PP i3)₄], tris(dibenzylideneacetone)di- palladium(O) [Pd2(dba)3], or by Pd(ll) catalysts such as dichlorobis(triphenylphosphine)- palladium(ll) [Pd(PP i3)2Cl2], dichlorobis(tricyclohexylphosphine)palladium(ll), and palladium(ll) acetate in combination with triphenylphosphine, or by [1 ,1 - bis(diphenylphosphino)ferrocene]palladium dichloride, in free form [Pd(dppf)C ] or as dichloromethane adduct [Pd(dppf)C x CH2CI2]. Preferred is the use of [1 ,1 - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct [Pd(dppf)C x CH2CI2] as a catalyst.

The reaction can preferably be carried out in a mixture of a solvent such as 1 ,2- dimethoxyethane, dioxane, DMF, THF, or n-propanol with water and in the presence of a base such as aqueous potassium carbonate, aqueous sodium carbonate, aqueous sodium bicarbonate or potassium phosphate.

The reaction can be performed at temperatures ranging from room temperature (i.e. 20°C) to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven, (review: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991 -8 and references cited therein).

The reaction can preferably be completed after 1 to 36 hours of reaction time.

Compounds of formula (XXII) are well known to the person skilled in the art and are commercially available in considerable variety, or can be prepared by well-known synthesis methods.

In a somewhat related approach, certain R¹ groups such as 1 ,2,4-oxadiazol-5-yl and 1 ,2,4- triazol-5-yl can be formed from acyclic precursor groups.

As shown in Scheme 2e, aminopyridine derivatives of formula (XXIV), in which R⁴, R⁵ and R¹⁰ are as defined for compounds of general formula (I), and in which PG¹ represents a protective group suitable for alcohols, as defined supra, such as tert-butyl dimethylsilyl, can be reacted with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in dichloromethane as a solvent, followed by the addition of esters of 3,4- diaminobenzoic acid of formula (XXIII), in which R³, R^6a and R^6b are as defined for compounds of general formula (I), and in which R^E represents a Ci-C3-alkyl group, to give thiourea derivatives of formulae (XXV) and (XXVa) as regioisomeric mixtures. Said thiourea derivatives can be further converted into benzimidazole derivatives of formula (XXVI) by reaction with a carbodiimide, such as N,N'-dipropan-2-ylcarbodiimide or 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide, or a salt thereof, in an aliphatic chlorinated hydrocarbon such as dichloromethane or chloroform as a solvent. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XXV) and (XXVa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery.

Scheme 2e: Synthesis of intermediates of formulae (XXVIII) from starting materials of formulae (XXIII) and (XXIV).

The moiety -OPG¹ present in formula (XXVI) is then converted into a group LG⁵, which is a leaving group as defined supra, preferably chloride, giving rise to compounds of formula (XXVII), by first cleaving off said protective group PG¹ by a method known to the person skilled in the art, e.g. by treatment with tetra-n-butylammonium fluoride in case said PG¹ is tert-butyl dimethylsilyl, followed by treatment e.g. with a halogenating agent such as thionyl chloride (SOC ), phosphoroxychloride (POCI3), or phosphorus trichloride (PCI3), or with a sulfonyl chloride such as methylsulfonyl chloride. In a similar fashion as discussed in context of Scheme 2a, supra, said compounds of formula (XXVII) can be reacted with piperazine derivatives of formula (IX), in which R¹¹ is as defined for compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R² in general formula (I), to give intermediates of formula (XXVIII).

Starting materials of formulae (XXIII) and (XXIV) are well known to the person skilled in the art and can be purchased commercially in certain cases, or can be prepared by known methods. As shown in Scheme 2f, the further elaboration of compounds of formula (XXVMIa), which is equivalent to formula (XXVIII) in Scheme 2e, commences with the hydrolytic cleavage of the carboxylic ester moiety present in formulae (XXVIII) and (XXVMIa), using methodology well known to the person skilled in the art, such as by treatment with an aqueous alkali hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a solvent such as methanol, ethanol or tetrahydrofuran, or a mixture thereof, at elevated temperature, preferably between 40°C and 80 °C, to give carboxylic acids of formula (XXIX). Said carboxylic acids of formula (XXIX) can be subsequently reacted with compounds of formula (XXX), in which R⁸ is as defined for compounds of general formula (I), and in which Q represents -O- or -N(R⁷)-, in which, in turn, R⁷ is as defined for compounds of general formula (I), in the presence of a suitable coupling agent, such as benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and a base, such as Ν,Ν'-diisopropyethylamine, to give intermediates of formula (XXXI). Cyclisation to compounds of formula (la), constituting a sub- compartment of general formula (I), can be accomplished by heating said compounds of formula (XXXI) in a mixture of an aliphatic alcohol of the formula Ci-C4-alkyl-OH, such as n- propanol, and water, in the presence of an alkali acetate, such as sodium acetate or potassium acetate. Optionally, a carboxamide based solvent such as Ν,Ν-dimethylformamide, N,N- dimethylacetamide or N-methylpyrrolidin-2-one can be added as a co-solvent to enhance solubility of the reactants.

Compounds of formula (XXX) are well known to the person skilled in the art, and can be prepared using known methods.

In a similar fashion, R¹ = 1 ,2,4-oxadiazol-3-yl can be elaborated from a cyano group.

Scheme 2f: Conversion of intermediates of formula (XVIa) into compounds of formula (la).

In an alternative approach, the benzimidazole core in formula (I) can be constructed on late stage. This synthesis route proceeds via diamines of formula (XXXIV), the synthesis of which is outlined in Scheme 3a, and which can be prepared by a Suzuki coupling, as discussed supra, from compounds of formula (VII), in which R³, R^6a and R^6b are as defined for the compounds of general formula (I), and in which LG¹ represents a leaving group, preferably chloride, bromide or iodide (see Scheme 2a), and compounds of formula (XXXII), in which R¹ is as defined for compounds of general formula (I), and R^B represents hydrogen, a Ci-C4-alkyl group such as isopropyl, or R^B-R^B together form a C2-C6-alkylene group, such as a -C(CH3)2-C(CH3)2- group, giving rise e.g. to a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane. Said Suzuki coupling reaction can be catalysed by palladium catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PP i3)₄], tris(dibenzylideneacetone)di- palladium(O) [Pd2(dba)3], or by Pd(ll) catalysts such as dichlorobis(triphenylphosphine)- palladium(ll), [Pd(PPh3)2Cl2], dichlorobis(tricyclohexylphosphine)palladium(ll), and palladium(ll) acetate in combination with triphenylphosphine, or by [1 ,1 - bis(diphenylphosphino)ferrocene]palladium dichloride, in free form [Pd(dppf)C ] or as dichloromethane adduct [Pd(dppf)C x CH2CI2]. Alternatively, diamines of formula (XXXIV) can be prepared from nitroaniline derivatives of formula (XXXIII) by methods well known to the person skilled in the art, such as catalytic hydrogenolysis, e.g. by reacting an ethanolic solution of compounds of formula (XXXIM) with an atmosphere of hydrogen in the presence of palladium on carbon. Said nitroaniline derivatives of formula (XXXIII) can also be prepared by a Suzuki coupling as discussed supra, either employing boronic acid derivatives of formula (XXXII) and nitroaniline derivatives of formula (VI), or employing boronic acid derivatives of formula (X) and compounds of formula (XXII). In said compounds of formulae (VI), (X) and (XXII), R¹' R³, R^6a and R^6b are as defined for compounds of general formula (I), LG¹ and LG⁴ represent, independently from each other, a leaving group, preferably chloride, bromide or iodide, and R^B represents hydrogen, a Ci-C₄-alkyl group such as isopropyl, or R^B-R^B together form a C2-C6-alkylene group, such as a

-C(CH3)2-C(CH3)2- group, giving rise e.g. to a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane. The availability of compounds of formulae (VI), (VII), (X) and (XXII) is described supra; boronic acid derivatives of formula (XXXII) are well known to the person skilled in the art and are commercially available in considerable variety.

Diaminobenzene derivatives of formula (XXXIVa), constituting a sub-compartment of formula (XXXIV), can be prepared in one step from diaminobenzoate derivatives of formula (XXIII), in which R³, R^6a and R^6b are as defined for the compounds of general formula (I), and in which R^E represents Ci-C3-alkyl, by reaction with a compound of formula (XXX), as defined in the context of Scheme 2f, in a solvent such as dioxane in the presence of a base such as cesium carbonate. Diaminobenzoate derivatives of formula (XXIII) are known to the person skilled in the art, and can be prepared by known methods and can be purchased commercially in certain cases.

( XXXIVa )

Scheme 3a: Synthesis of intermediates of formulae (XXXIV) and (XXXIVa).

Within said synthesis routes to diamines of formula (XXXIV), R groups such as R⁷ or R⁸ groups, which constitute substituents of heteroaromatic R¹ groups, can be modified as outlined in the initial paragraphs of this chapter.

As shown below in Scheme 3b, diamines of formula (XXXIVb), in which R¹, R^6a and R^6b are as defined for the compounds of general formula (I), and in which R^A represents a Ci-C4-alkyl group, said diamines constituting a further sub-compartment of formula (XXXIV), can be prepared advantageously in certain cases from aryl ether derivatives of formula (XVIII), in which R^6a and R^6b are as defined for the compounds of general formula (I), and in which R^A represents a Ci-C4-alkyl group (see also Scheme 2c), by means of Suzuki coupling as discussed supra, by reacting with boronic acid derivatives of formula (XXXII) resulting in intermediates of formula (XXXV), followed by reduction of the nitro group, e.g. by palladium catalysed hydrogenolysis, to give diamines of formula (XXXIVb).

( XVIII ) ( XXXV ) ( XXXIVb )

Scheme 3b: Synthesis of intermediates of formula (XXIIb).

The further transformation of said diamine intermediates of formula (XXXIV) can be, as outlined in Scheme 3c, accomplished by reacting aminopyridines of formula (Xlla) (see Scheme 2d), in which R², R⁴ and R⁵ are as defined for compounds of general formula (I), with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in a solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide or dioxane, followed by the addition of diaminobenzene derivatives of formula (XXXIV), to give thioureas of formulae (XXXVI) and (XXXVIa) as regioisomeric mixture. Said thiourea derivatives can be further converted into compounds of general formula (I) by reaction with a carbodiimide of formula R^D1-N=C=N-R^D2 (or a salt thereof), in which R^D1 and R^D2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N- dimethylamino group, preferably R^D1 being ethyl and R^D2 being 3-N,N-dimethylaminopropyl, or both R^D1 and R^D2 being isopropyl, in a halogenated aliphatic hydrocarbon comprising 1 , 2 or 3 carbon atoms and 1 , 2, 3, 4, 5 or 6 halogen atoms, preferably chlorine atoms, as a solvent, particularly preferred solvents being dichloromethane and chloroform. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XXXVI) and (XXXVIa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery. Specific examples are described in the Experimental Section.

Scheme 3c: Synthesis of compounds of general formula (I) from diamine intermediates of formula (XXXIV).

A third approach proceeds via late-stage elaboration of the R² moiety by attaching its piperazine pharmacophore, using nucleophilic substitution. As shown in Scheme 4, aminopyridine derivatives of formula (XXIV) (see also Scheme 2e), in which R⁴, R⁵ and R¹⁰ are as defined for compounds of general formula (I), and in which PG¹ represents a protective group suitable for alcohols, as defined supra, such as tert-butyl dimethylsilyl, can be reacted with with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, a solvent such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide or dioxane, followed by the addition of diamine intermediates of formula (XXXIV) (see also Scheme 3a), in which R¹, R³, R^6a and R^6b are as defined for compounds of general formula (I), to give thiourea derivatives of formulae (XXXVII) and (XXXVIIa) as regioisomeric mixtures. Said thiourea derivatives can be further converted into benzimidazole derivatives of formula (XXXVIII) by reaction with a carbodiimide, such as N,N'-dipropan-2- ylcarbodiimide or 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide, or a salt thereof, in an aliphatic chlorinated hydrocarbon such as dichloromethane or chloroform as a solvent. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XXXVII) and (XXXVIIa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery. The moiety -OPG¹ present in formula (XXXVIII) can then be converted into a group LG⁶, which is a leaving group as defined supra, preferably chloride or (methylsulfonyl)oxy, giving rise to compounds of formula (XXXIX), by first cleaving off said protective group PG¹ by a method known to the person skilled in the art, e.g. by treatment with tetra-n-butylammonium fluoride in case said PG¹ is tert-butyl dimethylsilyl, followed by treatment e.g. with a halogenating agent such as thionyl chloride (SOC ), phosphoroxychloride (POC ), or phosphorus trichloride (PCI3), or with a sulfonyl chloride such as methylsulfonyl chloride. In a similar fashion as discussed in context of Schemes 2a and 2e, supra, said compounds of formula (XXXIX) can be reacted with piperazine derivatives of formula (IX), in which R¹¹ is as defined for compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R² in general formula (I), to give compounds of formula (lb), which is equivalent to general formula

(")^■

Scheme 4: Synthesis of compounds of general formula (I) from diamine intermediates of formula (XXXIV) and aminopyridine derivatives of formula (XXIV).

The reader is referred to the fact that the definition of R¹¹ for compounds of general formula (I) includes some protective groups, such as tert-butoxycarbonyl, which may be cleaved off (to give R¹¹ = hydrogen) and replaced by another R¹¹ group at a later stage, thus particularly qualifying this sequence of steps for late-stage diversification of R¹¹, by e.g. acidic cleavage of said tert-butoxycarbonyl group, followed by reaction of the resulting free NH group with reagents (RG) suitable for the introduction of further R¹¹ groups, such as R¹³-C(=0)OH, R¹³- C(=0)-LG⁷, R¹⁴0-C(=0)-LG⁷, R^15a(R¹⁵)N-C(=0)-LG⁷, R^15a(R¹⁵)N-S(=0)₂-LG⁷, R¹⁶-S(=0)₂-LG⁷ and R^11a-LG⁸, in which R¹³, R¹⁴, R¹⁵, R^15a and R¹⁶ are as defined for the compounds of general formula (I), R^11a represents a group selected from Ci-C4-alkyl, C3-C6-cycloalkyl and C1-C4- haloalkyl, particularly Ci-C3-fluoroalkyl, LG⁷ represents a leaving group as defined supra, preferably chloride, and in which LG⁸ represents a leaving group as defined supra, preferably bromide, iodide, (methylsulfonyl)oxy or (trifluoromethylsulfonyl)oxy, using methods well known to the person skilled in the art.

This sequence is also outlined in Scheme 5, according to which tert-butoxycarbonyl derivatives of formula (lc), in which R¹, R³, R⁴, R⁵, R^6a, R^6b and R¹⁰ are as defined for the compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R² in general formula (I), rendering formula (lc) yet another sub-set of general formula (I), can be converted into the corresponding monosubstituted piperazines of formula (Id), constituting yet another sub-set of general formula (I), by treatment with a strong acid, preferably hydrochloric acid or trifluoroacetic acid. Said monosubstituted piperazines of formula (Id) can be formed as free bases or as salts, and can be reacted with one reagent selected from the group (RG) consisting of R¹³-C(=0)OH, R¹³-C(=0)-LG⁷, R¹⁴0-C(=0)-LG⁷, R^15a(R¹⁵)N-C(=0)-LG⁷, R^15a(R¹⁵)N-S(=0)₂-LG⁷, R¹⁶-S(=0)₂-LG⁷ and R^11a-LG⁸, in which R¹³, R¹⁴, R¹⁵, R^15a and R¹⁶ are as defined for the compounds of general formula (I), R^11a represents a group selected from Ci-C4-alkyl, C3-C6-cycloalkyl and Ci-C4-haloalkyl, particularly C1-C3- fluoroalkyl, LG⁷ represents a leaving group as defined supra, preferably chloride, and in which LG⁸ represents a leaving group as defined supra, preferably bromide, iodide, (methylsulfonyl)oxy or (trifluoromethylsulfonyl)oxy, as described in the preceding paragraph. Said reagents are all well known to the person skilled in the art and are commercially available in considerable variety.

Scheme 5: Synthesis of compounds of general formula (I) from compounds of formula (Ic) via monosubstituted piperazine derivatives of formula (Id).

Particularly, said free NH group in said compounds of formula (Id) can be subjected to a peptide coupling by reaction with a carboxylic acid of formula R¹³-C(=0)OH, in which R¹³ is as defined for compounds of general formula (I), in the presence of a peptide coupling reagent, selected from HATU (0-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate), or T3P (2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide), all of them being well known to the person skilled in the art and all of them being commercially available, in the presence of a base such as a tertiary aliphatic amine of the formula N(Ci-C₄- alkyl)3, or sodium bicarbonate, in an appropriate solvent such as Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide or N-methyl pyrrolidin-2-one. Specific examples are described in the Experimental Section.

Particularly furthermore, said free NH group can be subjected to a fluoroalkylation reaction with a reagent of formula R^11a-LG⁸, in which R^11a represents Ci-C3-fluoroalkyl and in which LG⁸ represents a (trifluoromethylsulfonyl)oxy group, in the presence of a base such as a tertiary aliphatic amine of the formula N(Ci-C4-alkyl)3, in an appropriate solvent such as N,N- dimethylformamide, Ν,Ν-dimethylacetamide or N-methyl pyrrolidin-2-one. Specific examples are described in the Experimental Section.

In accordance with a second aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra.

In one embodiment of the invention, said methods comprise the step of allowing an intermediate compound of general formula (XXI) :

(XXI) ,

in which R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra, and in which R^B, which can be different or identical, represent a hydrogen atom or a Ci-C4-alkyl group, or both R^B groups together form a C2-C6-alkylene group,

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

R— LG

(XXII) ,

in which R¹ is as defined for the compound of general formula (I) as defined supra, and in which LG⁴ represents a leaving group,

in the presence of a palladium catalyst,

thereby giving a compound of general formula (I) :

(I).

in which R¹, R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra.

another embodiment of the invention, said methods comprise the steps of

allowing an intermediate compound of general formula (XI la) :

(Xlla),

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

to react with a reagent selected from thiophosgene and di-1 H-imidazol-1 - ylmethanethione, in the presence of a catalytic amount of 1 H-imidazole, followed by the addition of an intermediate compound of general formula (XXXIV) :

(XXXIV),

in which R¹, R³, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra,

thereby giving a regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa) :

(XXXVI) (XXXVIa), in which R¹, R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra, followed by

allowing said regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa):

(XXXVI) (XXXVIa),

in which R¹, R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra,

to react with a carbodiimide of formula R^D1-N=C=N-R^D2 (or a salt thereof), in which R^D1 and R^D2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N-dimethylamino group,

thereby giving a compound of general formula (I) :

(I).

in which R¹, R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra.

In accordance with a third aspect, the present invention covers further methods of preparing compounds of general formula (I) as defined supra.

In one embodiment of the invention, said methods comprise the step of allowing an intermediate compound of general formula (XXI) :

(XXI) ,

in which R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra, and in which R^B, which can be different or identical, represent a hydrogen atom or a Ci-C4-alkyl group, or both R^B groups together form a C2-C6-alkylene group,

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

R— LG

(XXII) ,

in which R¹ is as defined for the compound of general formula (I) as defined supra, and in which LG⁴ represents a leaving group,

in the presence of a palladium catalyst,

thereby giving a compound of general formula (I) :

(I),

in which R¹ , R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra, then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids. In another embodiment of the invention, said methods comprise the steps of

i. allowing an intermediate compound of general formula (Xlla) :

(Xlla),

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

to react with a reagent selected from thiophosgene and di-1 H-imidazol-1 - ylmethanethione, in the presence of a catalytic amount of 1 H-imidazole, followed by the addition of an intermediate compound of general formula (XXXIV) :

(XXXIV),

in which R¹, R³, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra,

thereby giving a regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa) :

(XXXVI) (XXXVIa),

in which R¹, R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra, followed by ii. allowing said regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa):

(XXXVI) (XXXVIa),

in which R¹ , R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra,

to react with a carbodiimide of formula R^D1-N=C=N-R^D2 (or a salt thereof), in which R^D1 and R^D2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N-dimethylamino group,

thereby giving a compound of general formula (I) :

in which R¹ , R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra,

then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.

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 fourth aspect, the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.

In one embodiment, the invention covers the intermediate compounds of general formula (XXI):

(XXI),

in which R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra, and in which R^B, which can be different or identical, represent a hydrogen atom or a Ci-C4-alkyl group, or both R^B groups together form a C2-C6-alkylene group.

In another embodiment, the invention covers the intermediate compounds of general formula (Xllb):

(Xllb),

in which R², R⁴, R⁵ and R¹⁰ are as defined for the compound of general formula (I) as defined supra, and in which R¹¹ represents a hydrogen atom or a group selected from Ci-C4-alkyl, C3-C6-cycloalkyl and Ci-C4-haloalkyl.

In another embodiment, the invention covers the intermediate compounds of general formula (XXXIV):

(XXXIV),

in which R¹ , R³, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra.

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

In one embodiment, the invention covers the use of intermediate compounds of general formula (XXI):

(XXI),

in which R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) as defined supra, and in which R^B, which can be different or identical, represent a hydrogen atom or a Ci-C4-alkyl group, or both R^B groups together form a C2-C6-alkylene group, for the preparation of a compound of general formula (I) as defined supra.

In another embodiment, the invention covers the use of intermediate compounds of general formula (XI la):

(Xlla), in which R², R⁴ and R⁵ 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.

In another embodiment, the invention covers the use of intermediate compounds of general formula (XXXIV):

(XXXIV),

in which R¹, R³, R^6a and R^6b 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.

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 (XXI), 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 general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit TBK1 kinase and/or ΙΚΚε kinase and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably hyperproliferative and/or inflammatory disorders in humans and animals.

Compounds of the present invention can be utilized to inhibit the activity of TBK1 and/or ΙΚΚε kinases. 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 hyperproliferative and/or inflammatory disorders.

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 leukaemias.

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.

In yet another aspect, the present invention provides methods of treating or preventing a disease or condition associated with inflammation, a metabolic disorder, infection or an immune disease or condition by administering to a subject having such a condition or disease, a therapeutically effective amount of a compound or composition of the invention. In one group of embodiments, diseases or conditions, including chronic diseases, of humans or other species can be treated or prevented by inhibition of IRF-3 phosphorylation through inhibition of TBK1 kinase and/or ΙΚΚε kinase. These diseases or conditions include (1 ) inflammatory or allergic diseases such as systemic anaphylaxis and hypersensitivity responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis and urticaria, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, hypersensitivity lung diseases and the like, and (9) autoimmune diseases, such as arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, glomerulonephritis and the like, (10) graft rejection (including allograft rejection and graft-v-host disease), (1 1 ) other diseases in which undesired inflammatory responses are to be inhibited, e.g., atherosclerosis, myositis, neurological disorders such as stroke, ischemic reperfusion injury, traumatic brain injury and closed-head injuries, neurodegenerative diseases (e.g., Parkinson's disease), multiple sclerosis, Alzheimer's disease, encephalitis, meningitis, osteoporosis, gout, hepatitis, nephritis, gall bladder disease, sepsis, sarcoidosis, conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis and Behcet's syndrome; (12) metabolic disorders that are sensitive to inhibition of TNF or IL-1 signaling, such as obesity, type II diabetes, Syndrome X, insulin resistance, hyperglycemia, hyperuricemia, hyperinsulinemia, cachexia, hypercholesterolemia, hyperhpidemia, dyslipidemia, mixed dyslipidemia and hypertriglyceridemia, eating disorders, such as anorexia nervosa and bulimia, (13) infectious diseases, e.g., bacteremia and septic shock; (14) cardiovascular disorders, such as acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis and vascular stenosis; and (15) immune diseases or conditions.

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 hyperproliferative and/or inflammatory disorders, particularly cancer.

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:

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

• provide for the administration of lesser amounts of the administered chemotherapeutic agents, • 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,

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

• provide for a higher response rate among treated patients,

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

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

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

The pharmaceutical activity of the compounds according to the invention can be explained by their activity as inhibitors of TBK1 and/or ΙΚΚε kinase.

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

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 hyperproliferative and/or inflammatory disorders, particularly cancer.

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 hyperproliferative and/or inflammatory disorders, particularly cancer.

In accordance with a further aspect, the present invention covers 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 hyperproliferative and/or inflammatory disorders, particularly cancer.

In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular hyperproliferative and/or inflammatory disorders, particularly cancer, 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 a compound inhibiting TBK1 kinase and/or ΙΚΚε kinase, for the treatment of a hyperproliferative and/or inflammatory disease, such as cancer.

In accordance with a further aspect, the present invention covers a method for controlling the activity of TBK1 kinase and/or ΙΚΚε kinase in humans and animals by administering an effective amount of at least one compound of the general formula (I), as defined supra, or of a medicament comprising the same.

In accordance with a further aspect, the present invention covers a method for controlling the activity of IRF-3 phosphorylation in humans and animals by administering an effective amount of at least one compound of the general formula (I), as defined supra, or of a medicament comprising the same.

In accordance with a further aspect, the present invention covers a method for controlling a hyperproliferative and/or inflammatory disease, such as cancer, in humans and animals by administering an effective amount of at least one compound of the general formula (I), as defined supra, or of a medicament comprising the 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 excipients), 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 a hyperproliferative disorder, particularly cancer.

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 for the treatment and/or prophylaxis of a hyperproliferative disorder, more particularly cancer.

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 agents for the treatment and/or prophylaxis of cancer.

Examples of agents for the treatment and/or prophylaxis of cancer include: 131 1-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 hyperproliferative and/or inflammatory disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

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

To the extent specified herein, NMR peak multiplicities and peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

The ¹H-NMR data of selected examples are listed in the form of ¹H-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,), ... , δ_η (intensity,,).

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 ¹H-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 ¹H- 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.

Abbreviation Meaning

ESI electrospray (ES) ionisation

h hour(s)

HATU 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate

HBTU (o-benzotriazole-10yl)-N,N,N',N,-tetramethyluronium hexafluorophosphate

HCI hydrochloric acid, hydrogen chloride

HPLC high performance liquid chromatography

LC-MS liquid chromatography mass spectrometry

m multiplet

min minute(s)

MeCN acetonitrile

MeOH methanol

MS mass spectrometry

NBS /V-bromosuccinimide

NCS /V-chlorosuccinimide

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

PdC (dppf) [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(l l)

Pd(dba)₂ bis(dibenzylideneacetone)palladium

PyBOP (benzotriazol-l -yloxy)tripyrrolidinophosphonium

hexafluorophosphate

q quartet

r.t. or rt room temperature

rac racemic

Rt retention time (as measured either with HPLC or U PLC) in minutes

s singlet

sat. saturated

SIBX stabilized 2-iodoxybenzoic acid

SM starting material Abbreviation Meaning

SQD Single-Quadru pole-Detector

t triplet

T3P propylphosphonic anhydride

TBAF tetra-n-butylammonium fluoride

TBDMS ie f-butyldimethylsilyl

TBTU Λ/-[(1 /-/-benzotriazol-1 -yloxy)(dimethylamino)methylene]- /V-methylmethanaminium tetrafluoroborate

TCDI di-1 H-imidazol-1 -ylmethanethione

(Thiocarbonyldiimidazole)

td triple-doublet

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

UPLC ultra performance liquid chromatography

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 (herein also referred to as "silicagel 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.

UPLC-MS Standard Procedures

Analytical UPLC-MS was performed as described below. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ESI-). In most of the cases method 1 is used. If not, it is indicated.

Method 1 :

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μηι, 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 2:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μηι, 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 3:

column: Ascentis Express C18, 2.7 μηη, 3 cm x 2.1 mm

column temp.: 30 °C injection volume: 1 μΙ

detection: MM-ES + APCI +DAD (254 n

fragment.potential: 50 V

mass range 80-800 m/z

mobile phase A: water / 0.1 % formic acid

mobile phase B: methanol / 0.1 % formic acid

system time delay: 0.2 min

gradient:

Preparative HPLC procedure

Unless specified otherwise, the term "preparative HPLC" in the experimental section refers to the following HPLC method:

Instrument: Waters Autopurification MS SingleQuad; Colum: Waters XBrigde C18 5μ 100x30mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 °C; DAD scan: 210-400 nm.

EXPERIMENTAL SECTION - INTERMEDIATES

Intermediate 01 -01

2-(4-ethylpyridin-2-yl)-1 H-isoindole-1 ,3(2H)-dione

To a stirred solution of 4-ethylpyridin-2-amine (20.0 g, 164 mmol) in dichloromethane (600 mL) was added benzene-1 ,2-dicarbonyl dichloride (26 mL, 180 mmol), followed by triethylamine (60 mL, 430 mmol) with water bath cooling. The mixture was stirred at r.t. for 1 h. The mixture was washed with water, the organic phase was separated, dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 37.0 g (90 % yield) of the title compound.

LC-MS (Method 3): R_t = 3.21 min; MS (ESIpos): m/z = 253 [M+H]⁺

Intermediate 01 -02

(rac)-2-{4-[1 -bromoethyl]pyridin-2-yl}-1 H-isoindole-1 ,3(2H)-dione

To a stirred suspension of 2-(4-ethylpyridin-2-yl)-1 H-isoindole-1 ,3(2H)-dione (see Intermediate 01 -01 ; 24.7 g, 97.9 mmol) and NBS (19.0 g, 107 mmol) in 1 ,2-dichloroethane (300 mL) was added AIBN (800 mg, 4.87 mmol), and the mixture was stirred at reflux for 1 h. The mixture was washed with water, the organic phase was separated, dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Diethyl ether was added and the mixture was stirred at r.t. for 19 h. A precipitated solid was collected by filtration to give 27.8 g (86 % yield) of the title compound.

LC-MS (Method 3): R_t = 3.34 min; MS (ESIpos): m/z = 331 [M+H]⁺ Intermediate 01 -03

(rac)-tert-butyl 4-[1 -{2-[(2-{[4-(tert-butoxycarbonyl)piperazin-1 - yl]carbonyl}benzoyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate

To a stirred suspension of (rac)-2-{4-[1 -bromoethyl]pyridin-2-yl}-1 H-isoindole-1 ,3(2H)-dione (see Intermediate 01 -02; 41 .7 g, 126 mmol)in acetonitrile (200 mL) was added potassium carbonate (22.0 g, 159 mmol) and tert-butyl piperazine-1 -carboxylate (53.0 g, 285 mmol). The mixture was stirred at 75° C for 1 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with half- saturated sodium chloride solution, dried (magnesium sulfate) and the solvent was removed in vacuum to give 91.6 g of the title compound as a crude product, that was used for the next step without further purification.

LC-MS (Method 3): R_t = 3.36 min; MS (ESIpos): m/z = 623 [M+H]⁺

Intermediate 01 -04

(rac)-tert-butyl 4-[1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate

To a stirred solution of (rac)-tert-butyl 4-[1 -{2-[(2-{[4-(tert-butoxycarbonyl)piperazin-1 - yl]carbonyl}benzoyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (see Intermediate 01 -03; 91.6 g, approx. 1 13 mmol) in dioxane (350 mL) was added hydrazine hydrate (50 mL, 1.0 mol), and the mixture was stirred at reflux for 3 h. The mixture was cooled to r.t, and a precipitate was removed by filtration. Diethyl ether was added and the mixture was washed with water. The organic phase was separated, dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 32.35 g of the title compound.

LC-MS (Method 3): R_t = 0.71 min; MS (ESIpos): m/z = 307 [M+H]⁺ Intermediate 01 -05

tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (Single

Stereoisomer A)

To a stirred solution of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid (5.85 g, 16.3 mmol) in 2- propanol (200 mL) was added (rac)-tert-butyl-4-[1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 - carboxylate (see Intermediate 01 -04; 10.0 g, 32.6 mmol), dissolved in warm 2-propanol (420 mL). A clear solution formed, and after 30 minutes a precipitate started to form. The mixture was stirred at r.t. for 16 h. The precipitate was collected by filtration and was dissolved in dichloromethane / methanol (100:1 ) and half-saturated potassium carbonate solution. The phases were separated, the organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum to give 3.42 g of enantiomerically enriched tert-butyl 4-[(1 R or 1 S)-1 - (2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (Optical rotation:[a]D = +17.5° from DMSO solution, c = 4.4 mg/mL; enantiomeric purity: 92.5%)

The enantiomerically enriched tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine- 1 -carboxylate (3.40 g, 1 1 .1 mmol) was dissolved in warm 2-propanol (130 mL) and added to a stirred solution of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid (3.38 g, 9.43 mmol) in 2- propanol (50 mL). A clear solution formed, and after 30 minutes a precipitate started to form. The mixture was stirred at r.t. for 72 h. The precipitate was collected by filtration and was dissolved in dichloromethane / methanol (100:1 ) and half-saturated potassium carbonate solution. The phases were separated, the organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum to give 3.04 g of the title compound.

Optical rotation :[a]_D = +20. from DMSO solution, c = 3.5 mg/mL;

Chiral HPLC (Instrument: Agilent HPLC 1260; Column : Chiralpak ΙΑ 3μ 100x4, 6mm; Eluent A: acetonitrile + 0.1 Vol-% diethylamine (99%); isocratic: 100% A; Flow 1.0 mL/min; Temperature: 25 °C; DAD 280 nm): R_t = 5.34 min (99.15%); (Minor Isomer: R_t = 3.24 min (0.85%)).

LC-MS (Method 2): R_t = 1 .01 min; MS (ESIpos): m/z = 307 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .027 (0.93), 1 .042 (0.92), 1 .053 (0.51 ), 1 .200 (1 .79), 1 .216 (1 .84), 1 .370 (16.00), 3.332 (3.69), 5.757 (5.64), 5.808 (1 .32), 6.355 (0.91 ), 6.409 (0.54), 6.413 (0.51 ), 6.422 (0.56), 6.426 (0.52), 7.803 (0.75), 7.804 (0.73), 7.816 (0.73). Intermediate 01 -06

1 -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole

To a stirred solution of 4-(4, 4,5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 H-pyrazole (purchased from Acros, CAS 269410-08-4, 8.00 g, 41 .2 mmol) in DMF (130 mL) was added potassium carbonate (17.1 g, 124 mmol) and (bromomethyl)cyclopropane (6.0 mL, 62 mmol). The mixture was stirred at 60° C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 % yield) of the title compound.

LC-MS (Method 2): R_t = 1.12 min; MS (ESIpos): m/z = 249 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65), 0.471 (0.53), 0.476 (0.61 ), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1 .219 (1 .70), 1 .224 (16.00), 3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1 .07), 7.544 (1 .08), 7.932 (1.09).

Intermediate 01 -07

5-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-3-fluorobenzene-1 ,2-diamine

1 -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (see Intermediate 01 -06; 2.00 g, 8.06 mmol), 5-bromo-3-fluorobenzene-1 ,2-diamine (purchased from Aalenchem, CAS 517920-69-3, 1 .27 g, 6.20 mmol), bis(triphenylphosphine)palladium(ll)dichloride (218 mg, 310 μηηοΙ), triphenylphosphine (81.3 mg, 310 μηηοΙ) and aqueous potassium carbonate solution (9.3 ml, 2.0 M, 19 mmol) were dissolved in 56 mL 1 -propanol and stirred at 120°C for 2 hours under argon atmosphere. The propanol was removed in vacuo and the residue was treated with dichloromethane and water. The aqueous layer was extracted with dichloromethane three times, washed with water and brine once, filtered through a silicone coated filter and concentrated under reduced pressure. The crude product was purified by flash chromatography to provide the 90% pure target compound: 607 mg, 28% yield.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.31 - 0.40 (m, 2H), 0.47 - 0.57 (m, 2H), 1.14 - 1.30 (m, 1 H), 3.92 (d, 2H), 4.34 (s, 2H), 4.81 (s, 2H), 6.48 - 6.59 (m, 2H), 7.58 - 7.61 (m, 1 H), 7.91 (s, 1 H).

Intermediate 02-01

3-chloro-5-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]benzene-1 ,2-di

Starting with 1 -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (see Intermediate 01 -06; 2.00 g, 8.06 mmol), the target compound was prepared analogously to the procedure for the preparation of Intermediate 01 -07.

Yield: 882 mg of the 86% pure title compound.

LC-MS (Method 2): R_t = 0.99 min; MS (ESIpos): m/z = 263 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.31 - 0.41 (m, 2H), 0.47 - 0.56 (m, 2H), 1.14 - 1.33 (m, 1 H), 3.92 (d, 2H), 4.61 (s, 2H), 4.86 (s, 2H), 6.67 (d, 1 H), 6.75 (d, 1 H), 7.60 (d, 1 H), 7.93 (d, 1 H).

Intermediate 03-01

5-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-3-methylbenzene-1 ,2-diamine

Starting with 1 -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (see Intermediate 01 -06; 2.00 g, 8.06 mmol), the target compound was prepared analogously to the procedure for the preparation of Intermediate 01 -07.

Yield: 315 mg of the 82% pure title compound. LC-MS (Method 2): R_t = 0.87 min; MS (ESIpos): m/z = 243 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.31 - 0.43 (m, 2H), 0.46 - 0.58 (m, 2H), 1.15 - 1.32 (m, 1 H), 1 .99 - 2.09 (m, 3H), 3.92 (d, 2H), 4.16 (s, 2H), 4.44 (s, 2H), 6.53 (d, 1 H), 6.60 (d, 1 H), 7.54 (d, 1 H), 7.82 (d, 1 H).

Intermediate 04-01

4-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methylbenzene-1 ,2-diamine

4-bromo-5-methylbenzene-1 ,2-diamine (400 mg, 1 .99 mmol), 1 -(cyclopropylmethyl)-4-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 H-pyrazole (see Intermediate 01 -06; 543 mg, 2.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (1 15 mg, 99.5 μηιοΙ) were added to an aq. solution of potassium carbonate (3.0 ml, 2.0 M, 6.0 mmol) and 1 -propanol (8.2 ml). The mixture was stirred under an atmosphere of argon for 2h at 120°C. The mixture was then concentrated under reduced pressure and purified by flash chromatography on silica gel to give 510 mg (59 % purity, 62 % yield) of the title compound.

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.33 - 0.56 (m, 4H), 1 .18 - 1 .30 (m, 1 H), 2.12 (s, 3H), 3.95 (d, 2H), 4.19 - 4.43 (m, 4H), 6.37 (s, 1 H), 6.53 (s, 1 H), 7.42 (d, 1 H), 7.71 (d, 1 H).

LC-MS (Method 2): R_t = 0.93 min; MS (ESIpos): m/z = 243 [M+H]⁺

Intermediate 04-02

tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5- methylphenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate

Imidazole (28.7 mg, 421 μηηοΙ) and 1 ,1 '-thiocarbonyldiimidazole (450 mg, 2.53 mmol) were solubilised in dichloromethane (27 ml) under an atmosphere of argon. The solution was cooled to 0°C and tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 645 mg, 2.1 1 mmol) was added. The mixture was allowed to warm up to rt overnight. 4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-methylbenzene-1 ,2-diamine (see Intermediate 04-01 ; 510 mg, 2.1 1 mmol) was added and the mixture was stirred for 4h at rt. The reaction mixture was diluted with water and extracted three times with dichlomethane. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure. The crude title compound (1 .52 g) was used without further purification.

LC-MS (Method 2): R_t = 1 .36 min; MS (ESIpos): m/z = 591 [M+H]⁺

Intermediate 05-01

5-chloro-4-iodo-2-nitroaniline

5-chloro-2-nitroaniline (5.00 g, 29.0 mmol), potassium acetate (5.69 g, 57.9 mmol) and iodine monochloride (9.41 g, 57.9 mmol) were stirred in acetic acid (100 ml) at 60°C for 18h. Water was added to the mixture and the resulting suspension was filtered, washed with water and dried at 60°C under reduced pressure to give 7.2 g (84 % yield) of the title compound.

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.26 (s, 1 H) 7.60 (s, 2 H) 8.36 (s, 1 H)

Intermediate 05-02

5-chloro-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-2-nitroaniline

5-chloro-4-iodo-2-nitroaniline (see Intermediate 05-01 ; 500 mg, 1 .68 mmol), 1 - (cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole see Intermediate 01 -06; 831 mg, 3.35 mmol), potassium phosphate (71 1 mg, 3.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (96.8 mg, 83.8 μηηοΙ) were stirred in dioxane (15 ml) for 2h at 95°C. The reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 165 mg (87 % purity, 29 % yield) of the title compound.

LC-MS (Method 2): R_t = 1 .1 1 min; MS (ESIpos): m/z = 293 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.336 (0.58), 0.340 (0.49), 0.347 (0.52), 0.351 (0.55), 0.362 (0.64), 0.374 (1 .65), 0.378 (1 .38), 0.386 (1 .52), 0.389 (1 .60), 0.400 (0.72), 0.492 (0.52), 0.497 (0.53), 0.509 (0.88), 0.513 (0.67), 0.518 (1 .67), 0.523 (1.59), 0.528 (1 .02), 0.535 (0.77), 0.539 (1 .56), 0.544 (1 .49), 0.554 (0.55), 1.156 (4.73), 1.227 (0.40), 1 .232 (0.54), 1 .246 (16.00), 1 .265 (0.73), 1 .282 (0.41 ), 2.518 (0.89), 2.523 (0.69), 3.159 (0.51 ), 3.172 (0.46), 3.949 (1.13), 3.967 (1 .12), 3.981 (3.24), 3.999 (3.23), 7.212 (4.49), 7.492 (2.57), 7.565 (0.97), 7.732 (3.25), 7.734 (3.03), 7.940 (0.48), 7.958 (1 .06), 7.960 (1 .05), 8.063 (4.45), 8.1 19 (3.05), 8.121 (2.92).

Intermediate 05-03

4-chloro-5-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]benzene-1 ,2-diamine

5-chloro-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-2-nitroaniline (see Intermediate 05-02; 440 mg, 1 .50 mmol) was solubilised in THF (10 ml) and the flask was purged three times with argon. Platinium (1 %) and vanadium (2%) on activated charcoal (1 .47 g, 1 % purity, 75.2 μηηοΙ) in THF (5 ml) was added and the mixture was purged with hydrogen. The mixture was stirred 3h at rt under an atmosphere of hydrogen. The mixture was filtered over Celite^® , washed with dichloromethane and the filtrate was concentrated under reduced pressure to give 353 mg (90 % purity, 80 % yield) of the title compound that was used without further purification.

LC-MS (Method 2): R_t = 0.91 min; MS (ESIpos): m/z = 263 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.31 - 0.40 (m, 2H), 0.48 - 0.56 (m, 2H), 1.25 (s, 1 H), 3.94 - 3.99 (m, 2H), 4.55 - 5.03 (m, 4H), 6.58 (s, 1 H), 6.67 (s, 1 H), 7.56 (s, 1 H), 7.90 (s, 1 H). Intermediate 05-04

tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-5-chloro-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4- yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate

Imidazole (18 mg, 0.27 mmol) and 1 ,1 '-thiocarbonyldiimidazole (287 mg, 1 .61 mmol) were solubilised in dichloromethane (17 ml) under an atmosphere of argon. The solution was cooled to 0°C and tert-butyl 4-[(1 R)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 41 1 mg, 1 .34 mmol) was added. The mixture was allowed to warm up to rt overnight. 4-chloro-5-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine (see Intermediate 05-03; 353 mg, 1 .34 mmol) was added and the mixture was stirred for 4h at rt. The mixture was diluted with water and extracted three times with DCM. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure to give 390 mg of a crude mixture that was used without further purification.

Intermediate 06-01

4-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-fluorobenzene-1 ,2-diamine

4-bromo-5-fluorobenzene-1 ,2-diamine (500 mg, 2.44 mmol), 1 -(cyclopropylmethyl)-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (see Intermediate 01 -06; 1.21 g, 4.88 mmol), an aq. solution of sodium carbonate (3.0 ml, 2.0 M, 6.1 mmol) and 1 ,1 '- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (49.8 mg, 61.0 μηηοΙ) were stirred in THF (1 1 ml) overnight at 60°C. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 350 mg (90 % purity, 52 % yield) of the title compound.

LC-MS (Method 2): R_t = 0.84 min; MS (ESIpos): m/z = 247 [M+H]⁺

¹H-NMR (400MHz, DMSO-d₆): δ [ppm]= 0.32 - 0.39 (m, 2H), 0.49 - 0.56 (m, 2H), 1.24 (s, 1 H), 3.96 (d, 2H), 4.26 - 4.38 (m, 2H), 4.76 (s, 2H), 6.35 (d, 1 H), 6.71 (d, 1 H), 7.57 (dd, 1 H), 7.84 (dd, 1 H).

Intermediate 06-02

tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-5-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4- fluorophenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate

Imidazole (19.3 mg, 284 μηηοΙ) and 1 ,1 '-thiocarbonyldiimidazole (304 mg, 1 .71 mmol) were solubilised in dichloromethane (18 ml) under an atmosphere of argon. The solution was cooled to 0°C and tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 435 mg, 1 .42 mmol) was added. The mixture was allowed to warm up to rt overnight. 4-[1 -(Cyclopropylmethyl)-I H-pyrazol-4-yl]-5-fluorobenzene-1 ,2-diamine (see Intermediate 06-01 ; 350 mg, 1 .42 mmol) was added and the mixture was stirred for 4h at rt. The mixture was diluted with water and extracted three times with DCM. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure to give 620 mg of the title compound as a crude mixture.

LC-MS (Method 2): Rt = 1.36 min; MS (ESIpos): m/z = 595 [M+H]⁺

Intermediate 07-01

4-fluoro-5-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)benzene-1 ,2-diamine

4-bromo-5-fluorobenzene-1 ,2-diamine (5.00 g, 24.4 mmol) was solubilised in 1 ,4-dioxane (200 ml). 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (7.43 g, 29.3 mmol), potassium acetate (12.0 g, 122 mmol) and dichlorobis(tricyclohexylphosphine)palladium(ll) (900 mg, 1 .22 mmol) were added and the mixture was stirred overnight at 1 10°C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 3.23 g (90 % purity, 47 % yield) of the title compound.

LC-MS (Method 2): R_t = 0.75 min; MS (ESIpos): m/z = 253 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (0.59), 1 .156 (2.87), 1 .230 (16.00), 5.191 (1.07), 6.172 (1.00), 6.200 (1.04), 6.739 (0.89), 6.755 (0.89).

Intermediate 07-02

tert-butyl 4-{(1 R or 1 S)-1 -[2-({[2-amino-5-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]carbamothioyl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate

Imidazole (108 mg, 1.59 mmol) and 1 ,1 '-thiocarbonyldiimidazole (1 .70 g, 9.52 mmol) were solubilised in dichloromethane (100 ml) under an atmosphere of argon. The solution was cooled to 0°C and tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 2.43 g, 7.93 mmol) was added. The mixture was stirred 24h at -20°C. 4-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (see Intermediate 07-01 ; 2.00 g, 7.93 mmol) was added and the mixture was stirred overnight at rt. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure to give 4.80 g (101 % calculated yield) of the title compound.

LC-MS (Method 2): R_t = 1 .46 min; MS (ESIneg): m/z = 599 [M-H]⁺ Intermediate 07-03

tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate

tert-butyl 4-{(1 R or 1 S)-1 -[2-({[2-amino-5-fluoro-4-(4_!4_!5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]carbamothioyl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (see Intermediate 07-02; 4.80 g, 7.99 mmol) and 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1 .53 g, 7.99 mmol) were stirred in dichloromethane (140 ml) under argon overnight at rt. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were dried over a silicone filter and concentrated under reduced pressure, to give 4.52 g (1 16 % calculated yield) of the title compound without further purification.

LC-MS (Method 2): R_t = 1 .42 min; MS (ESIneg): m/z = 567 [M-H]⁺

Intermediate 08-01

1 -(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole

4-(4,4_!5_!5-tetramethyl-1 _!3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 10.3 mmol), (bromomethyl)cyclobutane (3.5 ml, 31 mmol) and potassium carbonate (5.70 g, 41 .2 mmol) were stirred in N,N-dimethylacetamide (16 ml) overnight at 80°C. The mixture was concentrated under reduced pressure, the residue was dissolved with ethyl acetate, and the resulting solution was washed three times with water. The combined organic layers were dried over a silicone filter and concentrated under reduced pressure to give 2.40 g (90 % purity, 80 % yield) of the title compound. LC-MS (Method 2): R_t = 1 .21 min; MS (ESIpos): m/z = 263 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.24 (s, 12H), 1 .67 - 1 .99 (m, 6H), 2.67 - 2.77 1 H), 4.12 (d, 2H), 7.55 (s, 1 H), 7.90 (d, 1 H).

Intermediate 08-02

4-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5-fluorobenzene-1 ,2-diamine

4-bromo-5-fluorobenzene-1 ,2-diamine (500 mg, 2.44 mmol), 1 -(cyclobutylmethyl)-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (see Intermediate 08-01 ; 703 mg, 2.68 mmol), triphenylphosphine (32.0 mg, 122 μηηοΙ) and bis(triphenylphosphine)palladium(ll) dichloride (85.6 mg, 122 μηηοΙ) were added to an aq. solution of potassium carbonate (3.7 ml, 2.0 M, 7.3 mmol) and 1 -propanol (10 ml). The mixture was stirred under an atmosphere of argon for 2h at 120°C. The mixture was filtered over a silicone filter and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 233 mg (37 % yield) of the title compound.

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1 .70 - 2.03 (m, 6H), 2.69 - 2.78 (m, 1 H), 4.1 1 (d, 2H), 4.31 (br s, 2H), 4.76 (s, 2H), 6.34 (d, 1 H), 6.69 (d, 1 H), 7.54 - 7.56 (m, 1 H), 7.77 (d, 1 H).

Intermediate 08-03

tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-4-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5- fluorophenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate

Imidazole (13.9 mg, 204 μηηοΙ) and 1 ,1 '-thiocarbonyldiimidazole (218 mg, 1 .22 mmol) were solubilised in dichloromethane (20 ml) under an atmosphere of argon. The solution was cooled to 0°C, tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 312 mg, 1 .02 mmol) was added and the mixture was allowed to warm up to rt overnight. 4-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-5-fluorobenzene-1 ,2-diamine (see Intermediate 08-02; 265 mg, 1 .02 mmol) was added to the mixture and it was stirred overnight at rt. The mixture was diluted with water and then extracted three times with dichloromethane. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure to give 650 mg of a crude mixture that was used without further purification.

Intermediate 10-01

(rac)-4-(1 -{[2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-methylbenzene-1 ,2-di

A mixture of (rac)-1 -{[2,2-difluorocyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 H-pyrazole (see intermediate 12-01 , 1.50 g), 4-bromo-5-methylbenzene-1 ,2-diamine (817 mg), bis(triphenylphosphine)palladium(ll)chloride (143 mg), triphenylphosphine (53 mg) and potassium carbonate solution (2 M in water, 6.1 mL) were dissolved in 38 mL 1 -propanol. This mixture was stirred at 120 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and dichloromethane/lsopropanol (7:3). The layers were separated and the aqueous layer was extracted with dichloromethane/lsopropanol twice. The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash chromatography to provide the target compound: 876 mg, 85% purity.

LC-MS (Method 2): R_t = 0.86 min; MS (ESIpos): m/z = 279 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1 .42 - 1 .57 (m, 1 H), 1 .68 (tdd, 1 H), 2.12 (s, 3H), 2.16 - 2.31 (m, 1 H), 4.14 - 4.32 (m, 4H), 4.39 (s, 2H), 6.37 (s, 1 H), 6.53 (s, 1 H), 7.48 (d, 1 H), 7.72 (s, 1 H). Intermediate 10-02

tert-butyl 4-{(1 R or 1 S)-1 -[2-({[2-amino-4-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-5-methylphenyl]carbamothioyl}am

1 H-imidazole (36.2 mg) and di-1 H-imidazol-1 -ylmethanethione (497 mg) were dissolved in 10 mL dichloromethane and cooled with an ice bath, tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4- yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 870 mg), dissolved in 10 mL dichloromethane, was added. This mixture was stirred under cooling for 30 min and stored in the fridge overnight. Now (rac)-4-(1 -{[()-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5- methylbenzene-1 ,2-diamine (870 mg, 85 % purity), dissolved in 6 mL dichloromethane, was added and the mixture was stirred for 3 hours at rt. The resulting precipitate was filtered off. The filtrate was diluted with water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were filtered through a water resistant filter and concentrated. The crude product was purified by flash chromatography to provide the target compound: 940 mg, 91 % purity.

LC-MS (Method 2): R_t = 1 .37 min; MS (ESIpos): m/z = 628 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]: 1 .150 (0.96), 1 .168 (1 .89), 1 .186 (0.99), 1 .196 (0.67), 1 .213 (0.77), 1 .229 (0.57), 1 .253 (1 .93), 1.270 (1.90), 1.366 (5.64), 1 .377 (16.00), 1.983 (3.82), 2.220 (1 .99), 2.256 (3.20), 2.280 (0.73), 2.292 (0.80), 2.318 (0.74), 2.323 (0.87), 2.327 (0.67), 2.355 (0.57), 2.518 (1 .81 ), 2.660 (0.46), 2.665 (0.63), 2.669 (0.46), 3.473 (0.51 ), 3.489 (0.48), 4.013 (0.86), 4.031 (0.85), 4.259 (0.41 ), 4.279 (0.40), 4.728 (0.50), 4.852 (0.95), 5.755 (0.75), 5.803 (0.50), 6.652 (1 .07), 6.816 (0.77), 7.028 (0.56), 7.041 (0.57), 7.121 (0.60), 7.21 1 (1.27), 7.263 (0.75), 7.579 (1 .33), 7.628 (0.90), 7.858 (1 .23), 7.935 (0.70), 8.178 (1 .04), 8.191 (0.97), 10.785 (0.67), 13.031 (0.43). Intermediate 12-01

(rac)-1 -{[2,2-difluorocyclopropyl]methyl}-4-(4,4,5_!5-tetramethyl-1 ,3,2-dioxaborolan-2-yl^ pyrazole

4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (7.57 g) was dissolved in 76 mL DMF. Potassium carbonate (16.2 g) and (rac)-2-(bromomethyl)-1 ,1 -difluorocyclopropane (10.0 g; (CAS# 77613-65-1 ) were added. This mixture was stirred at 80 °C overnight. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried using a water resistant filter. The filtrate was evaporated under reduced pressure. The crude title compound was used without further purification: 10.90 g, 94% purity.

LC-MS (Method 2): R_t = 1 .06 min; MS (ESIpos): m/z = 285 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.25 (s, 12H), 1.49 (dtd, 1 H), 1.59 - 1.73 (m, 1 H), 2.15 - 2.30 (m, 1 H), 4.16 - 4.33 (m, 2H), 7.61 (s, 1 H), 7.98 (s, 1 H).

Intermediate 12-02

(rac)-4-(1 -{[2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-fluorobenzene-1 ,2-di

A mixture of (rac)-1 -{[2,2-difluorocyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 H-pyrazole and (1 .50 g), 4-bromo-5-fluorobenzene-1 ,2-diamine (833 mg), bis(triphenylphosphine)palladium(ll)chloride (143 mg), triphenylphosphine (53 mg) and potassium carbonate solution (2 M in water, 6.1 mL) were dissolved in 39 mL 1 -propanol. This mixture was stirred at 120 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and dichloromethane/lsopropanol (7:3). The layers were separated and the aqueous layer was extracted with dichloromethane/lsopropanol twice. The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash chromatography to provide the target compound: 850 mg, 85% purity.

LC-MS (Method 2): R_t = 0.87 min; MS (ESIpos): m/z = 283 [M+H]⁺

1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1 .42 - 1 .57 (m, 1 H), 1 .60 - 1 .78 (m, 1 H), 2.14 - 2.31 (m, 1 H), 4.24 (br d, 2H), 4.28 - 4.45 (m, 2H), 4.79 (s, 2H), 6.36 (d, 1 H), 6.71 (d, 1 H), 7.59 - 7.68 (m, 1 H), 7.86 (d, 1 H).

Intermediate 12-03

tert-butyl 4-{(1 R or 1 S)-1 -[2-({[2-amino-4-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-5-fluorophenyl]carbamothioyl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate

1 H-imidazole (34.7 mg) and di-1 H-imidazol-1 -ylmethanethione (477 mg) were dissolved in 10 mL dichloromethane and cooled with an ice bath, tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4- yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 781 mg), dissolved in 10 mL dichloromethane, was added. This mixture was stirred under cooling for 30 min and stored in the fridge overnight. Now (rac)-4-(1 -{[2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5- fluorobenzene-1 ,2-diamine (847 mg, 85 % purity), dissolved in 5 mL dichloromethane, was added and the mixture was stirred for 3 hours at rt. The reaction mixture was diluted with water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were filtered through a water resistant filter and concentrated. The crude product was purified by flash chromatography to provide the target compound: 1.49 g, 82 % purity.

LC-MS (Method 2): R_t = 1 .37 min; MS (ESIpos): m/z = 631 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]: 1.261 (1 .68), 1 .278 (1.67), 1.370 (3.37), 1.382 (16.00), 1 .987 (0.50), 2.257 (0.42), 2.261 (0.44), 2.272 (0.52), 2.283 (0.52), 2.297 (0.61 ), 2.309 (0.45), 2.326 (0.45), 2.359 (0.45), 2.518 (1 .15), 2.522 (0.79), 3.484 (0.46), 3.501 (0.45), 4.256 (0.41 ), 5.230 (1 .02), 5.758 (3.10), 6.577 (0.77), 6.610 (0.74), 7.039 (0.54), 7.049 (0.60), 7.272 (0.88), 7.440 (0.69), 7.460 (0.68), 7.756 (1 .01 ), 8.003 (0.79), 8.007 (0.75), 8.197 (0.81 ), 8.21 1 (0.73), 10.857 (0.61 ), 12.988 (0.49).

Intermediate 13-01

4-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-3,5-difluorobenzene-1 ,2-diamine

4-bromo-3,5-difluorobenzene-1 ,2-diamine (550 mg, 2.47 mmol), 1 -(cyclopropylmethyl)-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (see Intermediate 01 -06; 796 mg, 3.21 mmol), triphenylphosphine (32.3 mg, 123 μηιοΙ) and bis(triphenylphosphin)palladium(ll)chloride (86.5 mg, 123 μηιοΙ) were added to K2CO3 (3.7 ml, 2.0 M solution in water, 7.4 mmol) and n-Propanol (18 ml). The mixture was stirred in a sealed tube at 1 10°C for 1 h. The reaction mixture was filtered through a silicone filter and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 230 mg (66 % purity, 23 % yield) of the title compound.

LC-MS (Method 2): R_t = 0.89 min; MS (ESIpos): m/z = 265 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.32 - 0.41 (m, 2H), 0.48 - 0.58 (m, 2H), 1.25 (s, 1 H), 3.99 (d, 2H), 4.28 (s, 2H), 5.13 (s, 2H), 6.28 (dd, 1 H), 7.63 (d, 1 H), 7.92 (s, 1 H).

Intermediate 13-02

tert-butyl 4-({2-[({2-amino-4-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-3,5- difluorophenyl}carbamothioyl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate

Imidazole (7.73 mg, 1 14 μηιοΙ) and TCDI (121 mg, 681 μηιοΙ) were solubilised in dichloromethane (5.0 ml) under inert atmosphere. The solution was cooled to 0°C and tert- butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (can be prepared e.g. from 4- (bromomethyl)pyridine-2 -amine hydrobromide and tert-butyl piperazine-1 -carboxylate in the presence of potassium carbonate in acetonitrile; 166 mg, 568 μηηοΙ) dissolved in dichloromethane (5.0 ml) was added. The mixture was stored overnight in the fridge and then 4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-3,5-difluorobenzene-1 ,2-diamine (150 mg, 568 μηιοΙ) was added and the mixture was stirred for 2 h at rt. The mixture was diluted with water and extracted three times with DCM. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure. The crude mixture (422 mg) containing the title compound was used without further purification.

LC-MS (Method 2): R_t = 1 .38 min; MS (ESIpos): m/z = 599 [M+H]⁺

EXPERIMENTAL SECTION - EXAMPLES

Example 01 -01 :

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate

1 H-imidazole (33.2 mg, 487 μηηοΙ), di-1 H-imidazol-1 -ylmethanethione (507 mg, 90 % purity, 2.56 mmol) and tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 746 mg, 2.44 mmol) were dissolved in 1 1 mL dichloromethane and the mixture was stirred at room temperature under argon atmosphere overnight. 5-[1 - (cyclopropylmethyl)-1 H-pyrazol-4-yl]-3-fluorobenzene-1 ,2-diamine (see Intermediate 01 -07; 600 mg, 2.44 mmol), dissolved in 1 1 mL dichloromethane, was added and the reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was treated with water and dichloromethane. The organic layer was extracted with dichloromethane three times, washed with water and brine once, filtered through a silicone coated filter and concentrated under reduced pressure the provide the crude intermediate, which was used without further purification.

Said intermediate tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-4-[1 -(cyclopropylmethyl)-1 H-pyrazol- 4-yl]-6-fluorophenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (1 .45 g, 2.44 mmol) was dissolved in 31 mL dichloromethane and treated with N,N'-dipropan-2- ylcarbodiimide (1 .1 ml, 7.3 mmol). The reaction mixture was stirred for 2 days at room temperature under argon atmosphere. Further N,N'-dipropan-2-ylcarbodiimide (0.6 ml, 3.7 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was directly purified by flash chromatography to provide the 87% pure target compound: 767 mg, 49 % yield.

LC-MS (Method 2): R_t = 1 .37 min; MS (ESIpos): m/z = 561 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.35 - 0.44 (m, 2H), 0.50 - 0.60 (m, 2H), 1.22 - 1.31 (m, 4H), 1 .38 (s, 9H), 2.23 - 2.44 (m, 4H), 3.24 - 3.32 (m, 4H), 3.44 (q, 1 H), 3.98 (d, 2H), 6.90 - 7.18 (m, 3H), 7.46 - 7.51 (m, 1 H), 7.79 (s, 1 H), 8.13 (s, 1 H), 8.26 (d, 1 H), 10.73 (s, 1 H), 12.27 (s, 1 H). Example 01-02:

6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-fluoro-N-{4-[(1 R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt

tert-Butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (see Example 01-01; 655 mg, 1.17 mmol) was dissolved in 6 mL dichloromethane and 4.5 mL methanol and treated with hydrogen chloride in dioxane (4.4 ml, 4.0 M, 18 mmol). The mixture was stirred at room temperature under argon atmosphere for two hours. The solvent was removed in vacuo to provide the 95% pure crude product which was used without further purification: 1.03 g.

LC-MS (Method 2): R_t = 1.08 min; MS (ESIpos): m/z = 461 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.34 - 0.46 (m, 2H), 0.51 - 0.60 (m, 2H), 1.19 - 1.35 (m, 1H), 1.69 (brd, 3H), 3.19-3.54 (m, 8H), 3.91 -4.06 (m, 1H), 4.00 (d, 2H), 7.45 - 7.66 (m, 5H), 7.90 (s, 1 H), 8.26 (s, 1 H), 8.52 (br d, 1 H), 9.72 (br s, 2H).

Example 01-03:

cyclopropyl(4-{(1 R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone

6-[1-(Cyclopropylmethyl)-1H-pyrazol-4-yl]-4-fluoro-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 01-02; 200 mg), cyclopropanecarboxylic acid (84 μΙ, 1.1 mmol), [0-(7-Azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium-hexafluorphosphate] (400 mg, 1.05 mmol) and sodium bicarbonate (177 mg, 2.1 1 mmol) were dissolved in 3 mL DMF and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and without further workup purified by preparative HPLC to provide the 91 % pure target compound: 50 mg.

LC-MS (Method 2): R_t = 1 .13 min; MS (ESIpos): m/z = 529 [M+H]⁺

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.36 - 0.44 (m, 2H), 0.51 - 0.59 (m, 2H), 0.62 - 0.74 (m, 4H), 1 .18 - 1 .36 (m, 4H), 1 .89 - 2.00 (m, 1 H), 2.23 - 2.45 (m, 4H), 3.40 - 3.55 (m, 3H), 3.67 (br s, 2H), 3.98 (d, 2H), 6.93 - 7.00 (m, 1 H), 7.10 - 7.19 (m, 2H), 7.50 (s, 1 H), 7.80 (s, 1 H), 8.13 (s, 1 H), 8.27 (d, 1 H), 10.74 (br s, 1 H), 12.30 (br s, 1 H).

Example 01 -04:

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-fluoro-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one

6-[1 -(Cyclopropylmethyl)-I H-pyrazol-4-yl]-4-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 01 -02; 200 mg), 3,3,3-trifluoropropanoic acid (93 μΙ, 1 .1 mmol), [0-(7-Azabenzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium-hexafluorphosphate] (400 mg, 1 .05 mmol) and sodium bicarbonate (177 mg, 2.1 1 mmol) were dissolved in 2.7 mL DMF and the mixture stirred at room temperature overnight. The reaction mixture was filtered and without further workup purified by preparative HPLC to provide the 95% pure target compound: 87 mg.

LC-MS (Method 2): R_t = 1 .16 min; MS (ESIpos): m/z = 571 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.36 - 0.43 (m, 2H), 0.52 - 0.60 (m, 2H), 1.20 - 1.35 (m, 4H), 2.27 - 2.47 (m, 4H), 3.39 - 3.52 (m, 5H), 3.62 (q, 2H), 3.98 (d, 2H), 6.95 (d, 1 H), 7.09 - 7.19 (m, 2H), 7.50 (s, 1 H), 7.80 (s, 1 H), 8.13 (s, 1 H), 8.27 (d, 1 H), 10.74 (br s, 1 H), 12.26 (br s, 1 H).

Example 01 -05: 6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-fluoro-N-(4-{(1 R or 1 S)-1 -[4-(2,2,2- trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-1 H-benzimidazol-2 -amine

6-[1 -(Cyclopropylmethyl)-I H-pyrazol-4-yl]-4-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 01 -02; 200 mg), was dissolved in 1 .3 mL DMF and treated with N,N-diisopropylethylamine (140 μΙ, 780 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (51 μΙ, 350 μηηοΙ). The mixture was stirred overnight at room temperature. Additional portions of N,N-diisopropylethylamine (140 μΙ, 780 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (51 μΙ, 350 μmol) were added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and without further workup purified by preparative HPLC to provide the 95% pure target compound: 90 mg.

LC-MS (Method 2): R_t = 1 .30min; MS (ESIpos): m/z = 543 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.35 - 0.43 (m, 2H), 0.51 - 0.60 (m, 2H), 1.20 - 1.32 (m, 4H), 2.29 - 2.46 (m, 4H), 2.57 - 2.66 (m, 4H), 3.14 (q, 2H), 3.38 (q, 1 H), 3.98 (d, 2H), 6.93 (dd, 1 H), 7.09 - 7.18 (m, 2H), 7.49 (s, 1 H), 7.80 (s, 1 H), 8.13 (s, 1 H), 8.25 (d, 1 H), 10.73 (br s, 1 H), 12.30 (br s, 1 H).

Example 02-01 :

tert-butyl 4-{(1 R or 1 S)-1 -[2-({4-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate

Starting from tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 1.16 g, 3.79 mmol) and 3-chloro-5-[1 -(cyclopropylmethyl)-1 H-pyrazol-4- yl]benzene-1 ,2-diamine (see Intermediate 02-01 ; 995 mg, 3.79 mmol), the target compound was prepared analogously to the procedure for the preparation of example 01 -01 .

Yield: 216 mg of the 63% pure title compound.

LC-MS (Method 2): R_t = 1 .42 min; MS (ESIpos): m/z = 577 [M+H]⁺

1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.34 - 0.45 (m, 2H), 0.51 - 0.60 (m, 2H), 1.16 - 1.32 (m, 4H), 1.38 (s, 9H), 2.21 - 2.43 (m, 4H), 3.24 - 3.32 (m, 4H), 3.45 (q, 1 H), 3.98 (d, 2H), 6.95 (d, 1 H), 7.10 (s, 1 H), 7.37 (d, 1 H), 7.61 (s, 1 H), 7.80 (s, 1 H), 8.15 (s, 1 H), 8.26 (d, 1 H), 10.91 (br s, 1 H), 12.30 (s, 1 H).

Example 02-02:

4-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt

Starting from tert-butyl 4-{(1 R or 1 S)-1 -[2-({4-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (see Example 02-01 ; 914 mg, 1.58 mmol), the target compound was prepared analogously to the procedure for the preparation of example 01 -02.

Yield: 893 mg of the 92% pure title compound.

LC-MS (Method 2): R_t = 1 .13 min; MS (ESIpos): m/z = 477 [M+H]⁺

1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.31 - 0.44 (m, 2H), 0.49 - 0.59 (m, 2H), 1.19 - 1.35 (m, 1 H), 1.70 (br d, 3H), 2.50 - 2.55 (m, 4H), 3.30 (br s, 1 H), 3.40 - 3.54 (m, 4H), 4.00 (d, 2H), 4.67 (br s, 3H), 7.50 - 7.67 (m, 2H), 7.72 (d, 1 H), 7.91 (d, 1 H), 8.28 (s, 1 H), 8.53 (d, 1 H), 9.80 (br s, 2H), 1 1.17 - 13.99 (m, 1 H). Example 02-03:

(4-{(1 R or 1 S)-1 -[2-({4-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)(cyclopropyl)methanone

Starting from 4-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin- 1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 02-02; 200 mg), the target compound was prepared analogously to the procedure for the preparation of example 01 -03.

Yield: 42 mg of the 96% pure title compound.

LC-MS (Method 2): R_t = 1 .22 min; MS (ESIpos): m/z = 545 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.37 - 0.43 (m, 2H), 0.52 - 0.59 (m, 2H), 0.63 - 0.73 (m, 4H), 1 .21 - 1 .33 (m, 4H), 1 .88 - 1 .98 (m, 1 H), 2.24 - 2.45 (m, 4H), 3.41 - 3.53 (m, 3H), 3.68 (br s, 2H), 3.98 (d, 2H), 6.97 (d, 1 H), 7.10 (s, 1 H), 7.37 (d, 1 H), 7.62 (d, 1 H), 7.80 (s, 1 H), 8.15 (s, 1 H), 8.27 (d, 1 H), 10.93 (s, 1 H), 12.30 (br s, 1 H).

Example 02-04:

1 -(4-{(1 R or 1 S)-1 -[2-({4-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one

Starting from 4-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin- 1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 02-02; 200 mg), the target compound was prepared analogously to the procedure for the preparation of example 01 -04.

Yield: 90 mg of the 91 % pure title compound.

LC-MS (Method 2): R_t = 1.25 min; MS (ESIpos): m/z = 587 [M+H]^{+ 1}H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.37 - 0.44 (m, 2H), 0.52 - 0.61 (m, 2H), 1.19 - 1.33 (m, 4H), 2.27 - 2.46 (m, 4H), 3.42 - 3.52 (m, 5H), 3.62 (q, 2H), 3.98 (d, 2H), 6.96 (d, 1H), 7.09 (s, 1H), 7.37 (d, 1H), 7.61 (s, 1H), 7.80 (s, 1H), 8.15 (s, 1H), 8.27 (d, 1H), 10.94 (br s, 1H), 12.26 (brs, 1H).

Example 02-05:

4-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -[4-(2,2,2- trifluoroethyl)piperazin-1-yl]ethyl}pyridin-2-yl)-1 H-benzimidazol-2 -amine

Starting from 4-chloro-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-N-{4-[(1R or 1S)-1-(piperazin- 1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 02-02; 200 mg), the target compound was prepared analogously to the procedure for the preparation of example 01-05.

Yield: 60 mg of the 100% pure title compound.

LC-MS (Method 2): R_t = 1.39 min; MS (ESIpos): m/z = 559 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.37 - 0.44 (m, 2H), 0.52 - 0.59 (m, 2H), 1.21 - 1.33 (m, 4H), 2.30 - 2.47 (m, 4H), 2.60 - 2.70 (m, 4H), 3.14 (q, 2H), 3.38 (q, 1H), 3.98 (d, 2H), 6.94 (d, 1H), 7.07 (s, 1H), 7.37 (d, 1H), 7.61 (s, 1H), 7.80 (s, 1H), 8.15 (s, 1H), 8.26 (d, 1H), 10.92 (s, 1H), 12.31 (s, 1H).

Example 03-01 :

tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-methyl-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate

Starting from tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 01 -05; 655 mg, 2.14 mmol) and 5-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-3- methylbenzene-1 ,2-diamine (see Intermediate 03-01 ; 518 mg, 2.14 mmol), the target compound was prepared analogously to the procedure for the preparation of example 01 -01 . Yield: 877 mg of the 87% pure title compound.

LC-MS (Method 2): R_t = 1.47 min; MS (ESIpos): m/z = 557 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.379 (0.47), 0.390 (1 .10), 0.394 (0.99), 0.405 (0.95), 0.529 (0.54), 0.538 (0.87), 0.542 (0.82), 0.548 (0.54), 0.558 (0.88), 0.563 (0.72), 1 .259 (0.66), 1 .272 (1 .95), 1 .288 (1 .60), 1 .370 (4.50), 1.376 (16.00), 1 .383 (5.03), 2.053 (0.87), 2.126 (0.79), 2.295 (0.49), 2.307 (0.57), 2.379 (0.56), 2.392 (0.47), 2.470 (2.64), 2.518 (0.43), 3.321 (1.43), 3.335 (12.49), 3.965 (1.38), 3.983 (1.36), 5.758 (7.16), 6.899 (0.43), 6.91 1 (0.43), 7.1 10 (0.75), 8.042 (0.55), 8.232 (0.51 ), 8.245 (0.48).

Example 03-02

6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt

Starting from tert-butyl tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]- 4-methyl-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (see Example 03-01 ; 870 mg, 1 .56 mmol) the target compound was prepared analogously to the procedure for the preparation of Example 01 -02.

Yield: 1.12 g of the 72% pure title compound.

LC-MS (Method 2): R_t = 1 .09 min; MS (ESIpos): m/z = 458 [M+H]⁺

Example 03-03:

cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-methyl-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone

Starting from 6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin- 1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 03-02; 200 mg), the target compound was prepared analogously to the procedure for the preparation of example 01 -03.

Yield: 40 mg of the 90% pure title compound.

LC-MS (Method 2): R_t = 1 .16 min; MS (ESIpos): m/z = 525 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.36 - 0.42 (m, 2H), 0.52 - 0.59 (m, 2H), 0.62 - 0.73 (m, 4H), 1.21 - 1 .34 (m, 4H), 1 .89 - 1 .98 (m, 1 H), 2.25 - 2.43 (m, 4H), 2.47 (s, 3H), 3.40 - 3.54 (m, 3H), 3.67 (br s, 2H), 3.98 (d, 2H), 6.93 (br d, 1 H), 7.1 1 (s, 2H), 7.46 (s, 1 H), 7.74 (s, 1 H), 8.05 (s, 1 H), 8.25 (d, 1 H), 10.69 (s, 1 H), 1 1 .99 (s, 1 H).

Example 03-04:

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-methyl-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one

Starting from 6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-4-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin- 1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 03-02; 200 mg), the target compound was prepared analogously to the procedure for the preparation of example 01 -04.

Yield: 65 mg of the 84% pure title compound.

LC-MS (Method 2): R_t = 1 .20 min; MS (ESIpos): m/z = 567 [M+H]^{+ 1}H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.36 - 0.43 (m, 2H), 0.51 - 0.59 (m, 2H), 1.20 - 1.34 (m, 4H), 2.29 - 2.44 (m, 4H), 2.47 (s, 3H), 3.40 - 3.52 (m, 5H), 3.62 (q, 2H), 3.98 (d, 2H), 6.92 (br d, 1 H), 7.1 1 (br s, 2H), 7.46 (s, 1 H), 7.74 (s, 1 H), 8.05 (s, 1 H), 8.25 (d, 1 H), 10.69 (s, 1 H), 1 1.99 (s, 1 H).

Example 03-05:

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-methyl-N-(4-{(1 R or 1 S)-1 -[4-(2,2,2- trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-1 H-benzimidazol-2 -amine

Starting from 6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin- 1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 03-02; 200 mg), the target compound was prepared analogously to the procedure for the preparation of example 01 -05.

Yield: 65 mg of the 93% pure title compound.

LC-MS (Method 2): R_t = 1 .33 min; MS (ESIpos): m/z = 539 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.35 - 0.43 (m, 2H), 0.51 - 0.59 (m, 2H), 1.19 - 1.34 (m, 4H), 2.29 - 2.44 (m, 4H), 2.47 (s, 3H), 2.56 - 2.68 (m, 4H), 3.14 (q, 2H), 3.35 - 3.41 (m, 1 H), 3.97 (d, 2H), 6.90 (d, 1 H), 7.10 (br d, 2H), 7.46 (s, 1 H), 7.74 (s, 1 H), 8.04 (s, 1 H), 8.23 (d, 1 H), 10.67 (s, 1 H), 12.00 (s, 1 H).

Example 04-01

tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-methyl-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate

tert-butyl 4-[(1R or 1S)-1-{2-[({2-amino-4-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5- methylphenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate (see Intermediate 04-02; 1.52 g, 2.57 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (493 mg, 2.57 mmol) were stirred in dichloromethane (46 ml) under argon overnight at rt. The reaction mixture was then concentrated under reduced pressure and purified by flash chromatography to give 526 mg (37 %) of the title compound.

LC-MS (Method 2): R_t = 1.36 min; MS (ESIpos): m/z = 557 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.42 (m, 2H), 0.52 - 0.58 (m, 2H), 1.28 (d, 4H), 1.38 (s,9H), 2.25-2.43 (m, 7H), 3.33 (s, 4H), 3.43 (q, 1H), 4.01 (d, 2H), 6.91 (dd, 1H), 7.14 (s, 1H), 7.17 - 7.45 (m, 2H), 7.56 - 7.63 (m, 1H), 7.87 - 7.95 (m, 1H), 8.23 (d, 1H), 10.46 - 10.55 (m, 1H), 11.86 - 11.96 (m, 1H).

Example 04-02

6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-methyl-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (see Example 04-01 ; 7.20 mg, 12.9 μηηοΙ) was stirred in a mixture of dichloromethane (81 μΙ) and methanol (41 μΙ). HCI in dioxane (16 μΙ, 4.0 M, 65 μηηοΙ) was added and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure to give 9.60 mg of the title compound.

LC-MS (Method 2): R_t = 1 .07 min; MS (ESIpos): m/z = 457 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.44 (m, 2H), 0.52 - 0.59 (m, 2H), 1 .24 - 1.35 (m, 1 H), 1 .40 - 1.72 (m, 4H), 2.47 (s, 4H), 3.35 (br s, 4H), 4.03 (d, 2H), 7.40 - 7.55 (m, 3H), 7.59 (s, 1 H), 7.67 (s, 1 H), 8.04 (d, 1 H), 8.47 - 8.56 (m, 1 H), 9.34 (br s, 1 H), 12.82 (br s, 1 H), 13.22 (br s, 1 H).

Example 04-03

cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (see Example 04-02; (129 mg), cyclopropanecarboxylic acid (58.9 mg, 684 μηιοΙ), sodium bicarbonate (1 15 mg, 1 .37 mmol) and HATU (260 mg, 684 μηηοΙ) were stirred in DMF (2.7 ml) overnight at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 42.7 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .15 min; MS (ESIpos): m/z = 525 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.43 (m, 2H), 0.52 - 0.58 (m, 2H), 0.62 - 0.74 (m, 4H), 1 .22 - 1 .35 (m, 4H), 1 .89 - 1 .97 (m, 1 H), 2.24 - 2.47 (m, 7H), 3.40 - 3.53 (m, 3H), 3.67 (br s, 2H), 4.01 (d, 2H), 6.92 (dd, 1 H), 7.13 - 7.47 (m, 3H), 7.60 (br s, 1 H), 7.91 (s, 1 H), 8.24 (d, 1 H), 10.54 (br s, 1 H), 1 1.86 - 12.00 (m, 1 H).

Example 04-04

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (see Example 04-02; 129 mg), 3,3,3-trifluoropropanoic acid (60 μΙ, 680 μηιοΙ), sodium bicarbonate (1 15 mg, 1.37 mmol) and HATU (260 mg, 684 μηηοΙ) were stirred in DMF (2.7 ml) overnight at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 57.0 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .19 min; MS (ESIpos): m/z = 567 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.38 - 0.42 (m, 2H), 0.51 - 0.58 (m, 2H), 1 .24 - 1.33 (m, 4H), 2.31 - 2.38 (m, 2H), 2.38 - 2.47 (m, 5H), 3.40 - 3.51 (m, 5H), 3.62 (q, 2H), 4.01 (d, 2H), 6.92 (dd, 1 H), 7.15 (s, 1 H), 7.18 - 7.47 (m, 2H), 7.59 (br s, 1 H), 7.91 (br s, 1 H), 8.24 (d, 1 H), 10.52 (br s, 1 H), 1 1 .92 (br d, 1 H). Example 04-05

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-N-(4-{(1 R or 1 S)-1 -[4-(2,2,2- trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-1 H-benzimidazol-2 -amine

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (see Example 04-02; 129 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (33 μΙ, 230 μmol), and N,N-diisopropylethylamine (89 μΙ, 510 μιτιοΙ) were stirred in DMF (2.7 ml) overnight at rt. Additional portions of 2,2,2- trifluoroethyl trifluoromethanesulfonate (33 μΙ, 230 μηηοΙ) and N,N-diisopropylethylamine (89 μΙ, 510 μmol) were added to the mixture and the mixture was stirred for 1 h at rt. The crude mixture was filtered and without further workup and purified by preparative HPLC to give 13.0 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .33 min; MS (ESIpos): m/z = 537 [M+H]⁺

1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.43 (m, 2H), 0.50 - 0.58 (m, 2H), 1 .24 - 1.32 (m, 4H), 2.33 - 2.38 (m, 2H), 2.40 (s, 3H), 2.42 - 2.47 (m, 2H), 2.63 (br s, 4H), 3.14 (q, 2H), 3.37 (br s, 1 H), 4.00 (d, 2H), 6.89 (dd, 1 H), 7.13 (s, 1 H), 7.19 - 7.45 (m, 2H), 7.59 (s, 1 H), 7.91 (s, 1 H), 8.23 (d, 1 H), 10.51 (br s, 1 H), 1 1 .93 (br s, 1 H).

Example 04-06

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -[4-(2,2-difluoroethyl)piperazin-1 - yl]ethyl}pyridin-2-yl)-5-methyl-1 H-benzimidazol-2 -amine

6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-methyl-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (see Example 04-02; 129 mg), 2,2-difluoroethyl trifluoromethanesulfonate (48.8 mg, 228 μηηοΙ), and N,N- diisopropylethylamine (89 μΙ, 510 μmol) were stirred in DMF (2.7 ml) overnight at rt. Additional portions of 2,2-difluoroethyl trifluoromethanesulfonate (48.8 mg, 228 μηηοΙ) and N,N- diisopropylethylamine (89 μΙ, 510 μηηοΙ) were added to the mixture and the mixture was stirred for 1 h at rt. The crude mixture was filtered and without further workup purified by preparative HPLC followed by preparative TLC to give 2.00 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 1.24 min; MS (ESIpos): m/z = 521 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.42 (m, 2H), 0.52 - 0.58 (m, 2H), 1 .22 - 1.30 (m, 4H), 2.31 - 2.37 (m, 2H), 2.40 (s, 5H), 2.52 - 2.57 (m, 4H), 2.65 - 2.75 (td, 2H), 3.36 (br s, 1 H), 4.01 (d, 2H), 5.95 - 6.27 (m, 1 H), 6.89 (d, 1 H), 7.13 (s, 1 H), 7.18 - 7.45 (m, 2H), 7.59 (br s, 1 H), 7.91 (br s, 1 H), 8.23 (d, 1 H), 10.51 (br s, 1 H), 1 1 .93 (br s, 1 H).

Example 05-01

tert-butyl 4-{(1 R or 1 S)-1 -[2-({5-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate

tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-5-chloro-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4- yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (see Intermediate 05-04; 390 mg, 638 μηηοΙ) and 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 638 μηηοΙ) were stirred in dichloromethane (12 ml) under an atmosphere of argon overnight at rt. The mixture was then concentrated under reduced pressure, and purified by flash chromatography on silica gel to give 122 mg (87 % purity, 29 % yield) of the title compound.

LC-MS (Method 2): R_t = 1 .39 min; MS (ESIpos): m/z = 577 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.40 (br d, 2H), 0.55 (br d, 2H), 1.25 - 1 .32 (m, 4H), 1 .38 (s, 9H), 2.24 - 2.43 (m, 4H), 3.34 (s, 4H), 3.44 (q, 1 H), 3.98 - 4.05 (m, 2H), 6.95 (dd, 1 H), 7.14 (br s, 1 H), 7.43 (d, 1 H), 7.60 (d, 1 H), 7.68 - 7.78 (m, 1 H), 8.09 (d, 1 H), 8.26 (d, 1 H), 10.70 (br s, 1 H), 12.1 1 - 12.22 (m, 1 H).

Example 05-02

5-chloro-6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt

tert-butyl 4-{(1R or 1S)-1-[2-({5-chloro-6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (see Example 05-01; 180 mg, 312 μηηοΙ) was stirred in a mixture of dichloromethane (2.0 ml) and methanol (980 μΙ). HCI (390 μΙ, 4.0 M in doxane, 1.6 mmol), was added and the mixture stirred overnight at rt. The mixture was concentrated under reduced pressure to give 233 mg of crude material that was used without further purification.

LC-MS (Method 2): R_t = 1.10 min; MS (ESIpos): m/z = 477 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.38 - 0.43 (m, 2H), 0.52 - 0.58 (m, 2H), 1.25 - 1.34 (m, 1H), 1.65 (brs, 3H), 3.19 (br s, 3H), 3.42 (br s, 4H), 4.05 (d, 2H), 7.53 (s, 1H), 7.61 (br s, 1H), 7.75 (s, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 8.20 (s, 1H), 8.55 (brd, 1H), 9.65 (brs, 2H), 13.17 (brs, 1H).

Example 05-03

(4-{(1 R or 1 S)-1 -[2-({5-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)(cyclopropyl)methanone

5-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (see Example 05-02; 1 16 mg), cyclopropanecarboxylic acid (47 μΙ, 590 μηιοΙ), sodium bicarbonate (100 mg, 1 .19 mmol) and HATU (226 mg, 595 μηηοΙ) were stirred in DMF (2.3 ml) overnight at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 32.4 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .19 min; MS (ESIpos): m/z = 545 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.43 (m, 2H), 0.52 - 0.58 (m, 2H), 0.63 - 0.74 (m, 4H), 1 .21 - 1 .36 (m, 4H), 1 .88 - 1 .98 (m, 1 H), 2.23 - 2.45 (m, 4H), 3.39 - 3.56 (m, 2H), 3.67 (br s, 2H), 4.02 (d, 2H), 6.97 (d, 1 H), 7.17 (s, 1 H), 7.38 - 7.65 (m, 2H), 7.73 (br s, 1 H), 8.09 (s, 1 H), 8.27 (d, 1 H), 10.72 (br s, 1 H), 12.19 (br s, 1 H).

Example 05-04

1 -(4-{(1 R or 1 S)-1 -[2-({5-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one

5-chloro-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (see Example 05-02; 116 mg), 3,3,3-trifluoropropanoic acid (76.2 mg, 595 μηιοΙ), sodium bicarbonate (100 mg, 1.19 mmol) and HATU (226 mg, 595 μηηοΙ) were stirred in DMF (2.3 ml) overnight at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 31.0 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 1.23 min; MS (ESIpos): m/z = 587 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.38 - 0.44 (m, 2H), 0.55 (br d, 2H), 1.26 - 1.33 (m, 4H), 2.30 - 2.39 (m, 2H), 2.43 (br dd, 2H), 3.40 - 3.51 (m, 5H), 3.62 (q, 2H), 4.02 (t, 2H), 6.96 (dd, 1H), 7.15 (brs, 1H), 7.44 (d, 1H), 7.60 (d, 1H), 7.68 - 7.78 (m, 1H), 8.09 (d, 1H), 8.27 (d, 1H), 10.71 (brs, 1H), 12.11 - 12.22 (m, 1H).

Example 06-01

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate

tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5- fluorophenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (see Intermediate 06-02; 620 mg, 1.04 mmol) and 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg, 1 .04 mmol) were stirred in dichloromethane (19 ml) under argon overnight at rt. The mixture was concentrated under reduced pressure. The crude mixture was purified by preparative HPLC to give 287 mg (79 % purity, 39 % yield) of the title compound.

LC-MS (Method 2): R_t = 1 .35 min; MS (ESIpos): m/z = 561 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.43 (m, 2H), 0.52 - 0.58 (m, 2H), 1 .21 - 1.33 (m, 4H), 1 .38 (s, 9H), 2.25 - 2.44 (m, 4H), 3.33 (s, 4H), 3.44 (q, 1 H), 4.02 (br d, 2H), 6.94 (br d, 1 H), 7.1 1 - 7.36 (m, 2H), 7.54 - 7.89 (m, 2H), 8.01 - 8.14 (m, 1 H), 8.25 (d, 1 H), 10.55 - 10.69 (m, 1 H), 12.05 - 12.19 (m, 1 H).

Example 06-02

6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt

tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (see Example 06-01; 267 mg, 476 μηηοΙ) was solubilsed in dichloromethane (2.7 ml) and HCI in dioxane (680 μΙ, 4.0 M, 2.7 mmol) was added. The mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure to give 297 mg (90 % purity) of the title compound.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.388 (0.55), 0.400 (1.92), 0.403 (1.67), 0.412 (1.83), 0.415 (1.76), 0.425 (0.65), 0.524 (0.71), 0.535 (1.63), 0.539 (1.53), 0.545 (0.91), 0.555 (1.71), 0.559 (1.36), 0.571 (0.48), 1.270 (0.48), 1.277 (0.45), 1.289 (0.72), 1.301 (0.42), 1.309 (0.42), 1.681 (1.88), 1.696 (1.49), 2.518 (1.71), 2.522 (1.14), 3.160 (16.00), 3.261 (0.78), 3.332 (0.42), 3.424 (0.85), 3.465 (1.17), 3.562 (0.50), 3.892 (1.00), 4.039 (3.48), 4.057 (3.55), 4.085 (1.02), 4.159 (1.46), 7.533 (2.05), 7.542 (1.80), 7.559 (1.94), 7.668 (0.47), 7.854 (1.63), 7.870 (3.23), 8.191 (1.71), 8.196 (1.61), 8.411 (0.69), 8.424 (0.62), 8.564 (1.06), 8.577 (0.99), 9.753 (0.47).

Example 06-03

cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone

6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (see Example 06-02; 100 mg), cyclopropanecarboxylic acid (42 μΙ, 530 μηιοΙ), sodium bicarbonate (88.4 mg, 1.05 mmol) and HATU (200 mg, 526 μηηοΙ) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was purified filtered and without further workup by preparative HPLC to give 36.7 mg (95 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .15 min; MS (ESIpos): m/z = 529 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.43 (m, 2H), 0.51 - 0.58 (m, 2H), 0.63 - 0.74 (m, 4H), 1 .21 - 1 .34 (m, 4H), 1 .89 - 1 .99 (m, 1 H), 2.25 - 2.43 (m, 4H), 3.39 - 3.54 (m, 3H), 3.67 (br s, 2H), 4.02 (br d, 2H), 6.95 (br d, 1 H), 7.13 - 7.35 (m, 2H), 7.55 - 7.90 (m, 2H), 8.02 - 8.15 (m, 1 H), 8.26 (d, 1 H), 10.55 - 10.71 (m, 1 H), 12.08 - 12.20 (m, 1 H).

Example 06-04

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-fluoro-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (see Example 06-02, 100 mg), 3,3,3-trifluoropropanoic acid (46 μΙ, 530 μηιοΙ), sodium bicarbonate (88.4 mg, 1.05 mmol) and HATU (200 mg, 526 μηηοΙ) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 37.7 mg (95 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .19 min; MS (ESIpos): m/z = 571 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.44 (m, 2H), 0.51 - 0.60 (m, 2H), 1 .21 - 1.35 (m, 4H), 2.27 - 2.46 (m, 4H), 3.46 (dt, 5H), 3.62 (q, 2H), 3.96 - 4.07 (m, 2H), 6.90 - 6.98 (m, 1 H), 7.10 - 7.37 (m, 2H), 7.55 - 7.89 (m, 2H), 8.02 - 8.15 (m, 1 H), 8.26 (d, 1 H), 10.54 - 10.71 (m, 1 H), 12.02 - 12.21 (m, 1 H).

Example 06-06

6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -[4-(2,2-difluoroethyl)piperazin-1 - yl]ethyl}pyridin-2-yl)-5-fluoro-1 H-benzimidazol-2-amine

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (see Example 06-02, 100 mg), 2,2-difluoroethyl trifluoromethanesulfonate (37.6 mg, 175 μηηοΙ), and N,N- diisopropylethylamine (180 μΙ, 1 .1 mmol) were stirred in DMF (2.0 ml) overnight at rt. An additional portion of 2,2-difluoroethyl trifluoromethanesulfonate (37.6 mg, 175 μηηοΙ) was added and the mixture was stirred for 2h at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 24.4 mg (94 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .23 min; MS (ESIneg): m/z = 523 [M-H]^"

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.43 (m, 2H), 0.50 - 0.59 (m, 2H), 1 .18 - 1.34 (m, 4H), 2.27 - 2.46 (m, 4H), 2.63 - 2.77 (m, 2H), 3.28 - 3.42 (m, 5H), 4.02 (br d, 2H), 5.93 - 6.28 (m, 1 H), 6.92 (br d, 1 H), 7.09 - 7.37 (m, 2H), 7.54 - 7.90 (m, 2H), 8.01 - 8.15 (m, 1 H), 8.24 (d, 1 H), 10.52 - 10.70 (m, 1 H), 12.04 - 12.20 (m, 1 H).

Example 07-01

tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate

tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 07-03 (480 mg, 847 μηηοΙ), 4-bromo-6-methylpyrimidine (161 mg, 932 μηηοΙ), sodium carbonate (1.1 ml, 2.0 M in water, 2.1 mmol) and Pd(dppf)C x CH2CI2 (104 mg, 127 μηηοΙ) were stirred in 1 ,4-dioxane (48 ml) /water (4.8 ml, 46 mmol) overnight at 1 10°C. The crude mixture was purified by flash chromatography on silica gel to give 215 mg (90 % purity, 43 % yield) of the title compound.

LC-MS (Method 2): R_t = 1 .27 min; MS (ESIpos): m/z = 533 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.28 (d, 3H), 1 .37 (s, 3H), 1.38 (s, 9H), 2.26 - 2.31 (m, 2H), 2.37 - 2.44 (m, 2H), 3.25 - 3.32 (m, 4H), 3.44 (m, 1 H), 6.92 - 7.00 (m, 1 H), 7.15 (s, 1 H), 7.22 - 7.46 (m, 1 H), 7.76 (s, 1 H), 8.19 - 8.30 (m, 2H), 9.10 (s, 1 H), 10.75 - 10.87 (m, 1 H), 12.32 - 12.42 (m, 1 H).

Example 07-02

5-fluoro-6-(6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride salt

tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Example 07-01 ; 215 mg, 404 μηηοΙ) was dissolved in a mixture of dichloromethane (4.0 ml) and methanol (2.0 ml). HCI in dioxane (1 .0 ml, 4.0 M, 4.0 mmol) was added and the mixture was stirred for 4h at rt. The mixture was concentrated under reduced pressure to give 266 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 0.92 min; MS (ESIpos): m/z = 433 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.65 (br s, 3H), 2.57 (s, 3H), 3.04 - 3.53 (m, 9H), 7.53 (br s, 1 H), 7.60 (br d, 2H), 7.84 (s, 1 H), 8.36 (d, 1 H), 8.55 (br d, 1 H), 9.19 (d, 1 H), 9.57 (br s, 2H), 12.71 - 13.34 (m, 1 H).

Example 07-03

cyclopropyl{4-[(1 R of 1 S)-1 -(2-{[5-fluoro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone

5-fluoro-6-(6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride salt (see Example 07-02; 133 mg), cyclopropanecarboxylic acid (59 μΙ, 740 μηηοΙ), sodium bicarbonate (124 mg, 1 .47 mmol) and HATU (280 mg, 736 μηηοΙ) were stirred in DMF (1.9 ml) for 90 min at rt. The crude mixture was purified filtered and without further workup by preparative HPLC to give 38.0 mg (95 % purity) of the title compound.

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.65 - 0.72 (m, 4H), 1 .30 (d, 3H), 1.90 - 1 .99 (m, 1 H), 2.25 - 2.46 (m, 4H), 2.52 (s, 3H), 3.47 (br d, 3H), 3.67 (br s, 2H), 6.98 (d, 1 H), 7.17 (s, 1 H), 7.21 - 7.50 (m, 1 H), 7.76 (s, 1 H), 8.28 (d, 2H), 9.10 (d, 1 H), 10.85 (br s, 1 H), 12.33 - 12.44 (m, 1 H).

LC-MS (Method 2): R_t = 1 .03 min; MS (ESIpos): m/z = 501 [M+H]⁺

Example 07-04

3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1-one

5-fluoro-6-(6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride (see Example 07-02; 133 mg), 3,3,3-trifluoropropanoic acid (65 μΙ, 740 μηηοΙ), sodium bicarbonates (124 mg, 1.47 mmol) and HATU (280 mg, 736 μηηοΙ) were stirred in DMF (1 .8 ml) for overnight at rt. Additional portions of 3,3,3- trifluoropropanoic acid (43 μΙ, 490 μηιοΙ), sodium bicarbonate (82.5 mg, 982 μηιοΙ) and HATU (187 mg, 491 μηηοΙ) were added. The mixture was stirred overnight at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 39.0 mg (95 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .07 min; MS (ESIpos): m/z = 543 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.30 (d, 3H), 2.29 - 2.38 (m, 2H), 2.43 (br dd, 2H), 2.52 (s, 3H), 3.43 (br t, 2H), 3.46 - 3.52 (m, 3H), 3.62 (q, 2H), 6.98 (br d, 1 H), 7.16 (s, 1 H), 7.25 (d, 1 H), 7.76 (s, 1 H), 7.95 - 8.29 (m, 2H), 9.10 (s, 1 H), 10.86 (s, 1 H), 12.33 - 12.43 (m, 1 H). Example 08-01

tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate

tert-butyl 4-[(1R or 1S)-1-{2-[({2-amino-4-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-5- fluorophenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate (see Intermediate 08-03; 650 mg, 1.07 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (205 mg, 1.07 mmol) were stirred in a mixture of dichloromethane (23 ml) and methanol (5.8 ml) under an atmosphere of argon overnight at rt. The mixture was concentrated under reduced pressure and the crude mixture was purified by flash chromatography on silica gel to give 300 mg (90 % purity, 44 % yield) of the title compound.

LC-MS (Method 2): Rt = 1.43 min; MS (ESIpos): m/z = 575 [M+H]+

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.28 (d, 3H), 1.38 (s, 9H), 1.77 - 1.89 (m, 4H), 1.99 (br dd, 2H), 2.23 - 2.34 (m, 2H), 2.38 (br d, 2H), 2.74 - 2.84 (m, 1 H), 3.28 - 3.33 (m, 4H), 3.40 - 3.47 (m, 1H), 4.17 (brd, 2H), 6.93 (brd, 1H), 7.12 - 7.35 (m, 2H), 7.55 - 7.71 (m, 1H), 7.76 (br s, 1H), 7.98 (brs, 1H), 8.25 (d, 1H), 10.55- 10.69 (m, 1H), 12.12 (br s, 1H).

Example 08-02

6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1

yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (see Example 08-01 ; 300 mg, 522 μηηοΙ) was dissolved in a mixture of dichloromethane (5.0 ml) and methanol (2.5 ml). HCI in dioxane (1 .3 ml, 4.0 M, 5.2 mmol) was added and the mixture stirred for overnight at rt. The mixture was concentrated under reduced pressure to give 335 mg (90 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .14 min; MS (ESIpos): m/z = 475 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.69 (br d, 3H), 1 .77 - 1.91 (m, 4H), 1.94 - 2.05 (m, 2H), 2.73 - 2.83 (m, 1 H), 3.04 - 3.77 (m, 9H), 4.21 (d, 2H), 7.50 - 7.59 (m, 2H), 7.64 - 7.71 (m, 1 H), 7.83 - 7.87 (m, 2H), 8.14 (d, 1 H), 8.57 (d, 1 H), 9.75 (br s, 2H), 13.00 - 13.35 (m, 1 H).

Example 08-03

(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5-fluoro-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)(cyclopropyl)methanone

6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 08-02; 1 10 mg), cyclopropanecarboxylic acid (45 μΙ, 570 μηιοΙ), sodium bicarbonate (94.9 mg, 1 .13 mmol) and HATU (215 mg, 565 μηηοΙ) were stirred in DMF (1 .4 ml) for 90 min at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 45.0 mg (95 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .23 min; MS (ESIpos): m/z = 543 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.63 - 0.73 (m, 4H), 1 .29 (d, 3H), 1.74 - 1 .89 (m, 4H), 1 .89 - 1 .95 (m, 1 H), 1 .95 - 2.03 (m, 2H), 2.25 - 2.47 (m, 4H), 2.78 (s, 1 H), 3.40 - 3.53 (m, 3H), 3.62 - 3.71 (m, 2H), 4.17 (br d, 2H), 6.95 (br d, 1 H), 7.16 (br s, 2H), 7.53 - 7.71 (m, 1 H), 7.76 (br s, 1 H), 7.96 - 8.09 (m, 1 H), 8.26 (d, 1 H), 10.57 - 10.70 (m, 1 H), 12.05 - 12.18 (m, 1 H).

Example 08-04

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5-fluoro-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one

6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (see Example 08-02 (1 10 mg), 3,3,3-trifluoropropanoic acid (50 μΙ, 570 μηιοΙ), sodium bicarbonate (94.9 mg, 1.13 mmol) and HATU (215 mg, 565 μηηοΙ) were stirred in DMF (1 .4 ml) for 90 min at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 53.0 mg (95% purity) of the title compound.

LC-MS (Method 2): R_t = 1 .26 min; MS (ESIpos): m/z = 585 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1 .29 (d, 3H), 1 .83 (br s, 4H), 1 .94 - 2.03 (m, 2H), 2.29 - 2.38 (m, 2H), 2.39 - 2.47 (m, 2H), 2.73 - 2.84 (m, 1 H), 3.43 (br t, 2H), 3.47 (br t, 3H), 3.62 (d, 2H), 4.17 (br d, 2H), 6.94 (br d, 1 H), 7.12 - 7.35 (m, 2H), 7.68 (br d, 1 H), 7.76 (s, 1 H), 7.99 (br s, 1 H), 8.26 (d, 1 H), 10.57 - 10.69 (m, 1 H), 12.06 - 12.16 (m, 1 H).

Example 08-06

6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -[4-(2,2-difluoroethyl)piperazin-1 - yl]ethyl}pyridin-2-yl)-5-fluoro-1 H-benzimidazol-2-amine

6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (see Example 08-02; 1 10 mg), 2,2-difluoroethyl trifluoromethanesulfonate (75 μΙ, 570 μmol), and N,N-diisopropylethylamine (200 μΙ, 1 .1 mmol) were stirred in DMF (2.2 ml) for 72 h at rt. The crude mixture was filtered and without further workup purified by preparative HPLC to give 42 mg (95 % purity) of the title compound.

LC-MS (Method 2): R_t = 1 .27 min; MS (ESIpos): m/z = 539 [M+H]⁺

¹H-NMR (400MHz, DMSO-d6): δ [ppm]= 1 .23 - 1 .29 (m, 3H), 1 .76 - 1 .90 (m, 4H), 1 .96 - 2.04 (m, 2H), 2.27 - 2.40 (m, 4H), 2.52 (d, 5H), 2.63 - 2.74 (m, 2H), 2.74 - 2.83 (m, 1 H), 4.12 - 4.20 (m, 2H), 5.94 - 6.27 (m, 1 H), 6.92 (br s, 1 H), 7.1 1 - 7.35 (m, 2H), 7.67 (br d, 1 H), 7.76 (s, 1 H), 7.98 (s, 1 H), 8.24 (br d, 1 H), 10.55 - 10.68 (m, 1 H), 12.06 - 12.16 (m, 1 H).

Example 09-01

tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(3-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate

To a stirred solution of tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Intermediate 07-03; 150 mg, 265 μηηοΙ) in 1 -propanol (1 .2 mL) was added 4-chloro-3-methoxy- 2-methylpyridine (83.5 mg, 530 μπιοΙ), Pd(dppf)CI₂ x CH₂CI₂ (21 .6 mg, 26.5 μπιοΙ), triphenylphosphine (6.95 mg, 26.5 μmol) and aq. sodium carbonate solution (400 μΙ, 2.0 M, 790 μηηοΙ). The mixture was heated to reflux for 14 h. The solvent was removed in vacuum. Silicagel chromatography gave 70.0 mg (47 % yield) of the title compound as a solid.

LC-MS (Method 2): R_t = 1 .29 min; MS (ESIpos): m/z = 562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (16.00), 1.070 (1.19), 1.088 (1 .32), 1 .106 (0.67), 1 .275 (0.41 ), 1 .375 (4.20), 2.467 (0.53), 2.518 (0.74), 2.522 (0.50), 3.371 (0.81 ), 3.381 (0.55), 3.388 (0.70), 3.937 (2.73).

Example 09-02

5-fluoro-6-(3-methoxy-2-methylpyridin-4-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2- yl}-1 H-benzimidazol-2-amine hydrochloride salt

To a stirred solution of tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(3-methoxy-2-methylpyridin-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (see Example 09- 01 ; 71 .0 mg, 126 μηηοΙ) in dichloromethane (2.0 mL) and methanol (0.2 mL) was added HCI in dioxane (320 μΙ, 4.0 M, 1 .28 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give a solid. The solid was triturated with dichloromethane to give 70.0 mg of the title compound as crude product that was used for the next step without purification.

LC-MS (Method 2): R_t = 0.97 min; MS (ESIpos): m/z = 562 [M+H]⁺

Example 09-03

3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(3-methoxy-2-methylpyridin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one

To a stirred solution of crude 5-fluoro-6-(3-methoxy-2-methylpyridin-4-yl)-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (see Example 09-02; 70.0 mg) in DMF (2.6 mL) was added sodium bicarbonate (82.4 mg, 981 mol), 3,3,3- trifluoropropanoic acid (16 μΙ, 180 mol) and HATU (74.6 mg, 196 mol). The mixture was stirred at r.t. for 2 h. An aqueous solution of sodium bicarbonate was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing trifluoroacetic acid as additive) gave 20.0 mg of the title compound.

LC-MS (Method 2): R_t = 1 .1 1 min; MS (ESIpos): m/z = 572 [M+H]⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .145 (0.70), 1 .231 (1 .54), 1 .283 (13.89), 1.289 (1 1 .93), 1 .299 (14.60), 1 .305 (1 1.09), 2.323 (5.75), 2.327 (7.30), 2.332 (6.46), 2.336 (5.33), 2.427 (4.49), 2.518 (14.46), 2.523 (10.53), 2.539 (10.53), 2.665 (2.95), 2.669 (4.07), 2.673 (2.81 ), 3.242 (0.42), 3.286 (1.12), 3.299 (1.96), 3.381 (16.00), 3.431 (8.00), 3.456 (6.04), 3.473 (10.39), 3.576 (2.95), 3.603 (8.42), 3.631 (8.00), 3.658 (2.53), 4.015 (1.96), 6.813 (1 .12), 6.838 (0.98), 6.933 (2.81 ), 6.950 (3.65), 6.965 (2.67), 7.086 (0.98), 7.1 1 1 (1 .12), 7.140 (3.51 ), 7.156 (3.79), 7.195 (3.65), 7.207 (3.65), 7.225 (1 .54), 7.251 (1 .68), 7.291 (1 .12), 7.389 (0.70), 7.418 (1 .26), 7.518 (1 .54), 7.534 (1.40), 8.238 (5.47), 8.250 (8.14), 8.263 (5.47), 8.276 (2.81 ), 10.634 (0.98), 10.745 (0.70), 12.142 (0.84).

The following example compounds were prepared in an analogy to the example compounds 07-01 to 07-04, or to example compounds 08-01 to 08-06.

LC-MS (Method 2): R_t = 1 .21 min; MS (ESIpos): m/z = 489 [M+H]⁺

EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS & BIOLOGICAL DATA PART

Abbreviations:

The following Table 2 lists the abbreviations used herein, in particular in the Biological Assys & Biological Data part of the Experimental Section:

Table 2:

ΙΚΚα inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase alpha

ΙΚΚβ inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta

ΙΚΚε inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon

IL-6 interleukin 6 (interferon, beta 2)

IRF interferon regulatory factor

Kras v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

Luc2 Firefly Luciferase 2

MgC Magnesiumchloride

μΜ micromolar

mM millimolar

NF-kB nuclear factor of kappa light polypeptide gene enhancer in B-cells

Ni-NTA Nitrilotriacetic acid

nM nanomolar

nm nanometer

ON over night

Pea prostate cancer

polylC Polyinosinic:polycytidylic acid

Poly

(l:C)_HMW Polyinosinic:polycytidylic acid, high molecular weight

pSer phospho-serine

v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding

RalB protein)

RANTES chemokine (C-C motif) ligand 5

TBK1 TANK-binding kinase 1

TR-FRET Time-resolved-Fluorescence Resonance Energy Transfer

v/v volume by volume

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 : TBK1 low ATP kinase assay

TBK1 -inhibitory activity of compounds of the present invention at a low ATP concentration after pre-incubation of enzyme and test compounds was quantified employing the TR-FRET- based TBK1 assay as described in the following paragraphs.

Recombinant full-length N-terminally His-tagged human TBK1 , expressed in insect cells and purified by Ni-NTA affinity chromatography, was purchased from Life Technologies (Cat. No PR5618B) and used as enzyme. As substrate for the kinase reaction biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosyntan (Berlin-Buch, Germany).

For the assay 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of TBK1 in aqueous assay buffer [50 mM HEPES pH 7.0, 10 mM MgC , 1 .0 mM dithiothreitol, 0.05 % (w/v) bovine serum albumine, 0.01 % (v/v) Nonidet-P40 (Sigma), protease inhibitor mixture ("Complete w/o EDTA" from Roche, 1 tablet per 5 ml)] were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 16.7 μΜ => final cone, in the 5 μΙ assay volume is 10 μΜ) and substrate (1 .67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22°C. The concentration of TBK1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, a typical concentration is 0.01 μg ml. The reaction was stopped by the addition of 5 μΙ of a solution of TR-FRET detection reagents (0.2 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France], 1 .5 nM anti-phosho-Serine anti-body [Merck Millipore, "STK antibody", cat. # 35-002] and 0.75 nM LANCE EU-W1024 labeled anti-mouse IgG anti-body [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.13 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22°C to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.1 nM (20 μΜ, 5.9 μΜ, 1.7 μΜ, 0.51 μΜ, 0.15 μΜ, 44 nM, 13 nM, 3.8 nM, 1 .1 nM, 0.33 nM and 0.1 nM), the dilution series prepared separately before the assay on the level of the 10Ofold concentrated solutions in DMSO by serial 1 :3.4 dilutions) in duplicate values for each concentration and I C50 values were calculated using Genedata Screener™ software.

In vitro assay 2: TBK1 high ATP kinase assay

TBK1 -inhibitory activity of compounds of the present invention at a high ATP concentration after pre-incubation of enzyme and test compounds was quantified employing the TR-FRET- based TBK1 assay as described in the following paragraphs.

Recombinant full-length N-terminally His-tagged human TBK1 , expressed in insect cells and purified by Ni-NTA affinity chromatography, was purchased from Life Technologies (Cat. No PR5618B) and used as enzyme. As substrate for the kinase reaction biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosyntan (Berlin-Buch, Germany).

For the assay 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of TBK1 in aqueous assay buffer [50 mM HEPES pH 7.0, 10 mM MgC , 1 .0 mM dithiothreitol, 0.05 % (w/v) bovine serum albumine, 0.01 % (v/v) Nonidet-P40 (Sigma), protease inhibitor mixture ("Complete w/o EDTA" from Roche, 1 tablet per 5 ml)] were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 1 .67 mM => final cone, in the 5 μΙ assay volume is 1 mM) and substrate (1 .67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22°C. The concentration of TBK1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical concentrations were in the range of 0.002-0.004 μg ml. The reaction was stopped by the addition of 5 μΙ of a solution of TR-FRET detection reagents (0.2 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France], 1 .5 nM anti-phosho-Serine anti-body [Merck Millipore, "STK antibody", cat. # 35-002] and 0.75 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.13 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22°C to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalized (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.1 nM (20 μΜ, 5.9 μΜ, 1.7 μΜ, 0.51 μΜ, 0.15 μΜ, 44 nM, 13 nM, 3.8 nM, 1 .1 nM, 0.33 nM and 0.1 nM), the dilution series prepared separately before the assay on the level of the 10Ofold concentrated solutions in DMSO by serial 1 :3.4 dilutions) in duplicate values for each concentration and I C50 values were calculated using Genedata Screener™ software.

In vitro assay 3: CDK9/CycT1 high ATP kinase assay

CDK9/CycT1 -inhibitory activity of compounds of the present invention at a high ATP concentration after preincubation of enzyme and test compounds was quantified employing the CDK9/CycT1 TR-FRET assay as described in the following paragraphs.

Recombinant full-length His-tagged human CDK9 and CycT1 , expressed in insect cells and purified by Ni-NTA affinity chromatography, were purchased from Life Technologies (Cat. No PV4131 ). As substrate for the kinase reaction biotinylated peptide biotin-Ttds- YISPLKSPYKISEG (C-terminus in amide form) was used which can be purchased e.g. form the company JERINI peptide technologies (Berlin, Germany). For the assay 50 nl of a 10Ofold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of CDK9/CycT1 in aqueous assay buffer [50 mM Tris/HCI pH 8.0, 10 mM MgC , 1 .0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01 % (v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 3.3 mM => final cone, in the 5 μΙ assay volume is 2 mM) and substrate (1 .67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 25 min at 22°C. The concentration of CDK9/CycT1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical concentrations were in the range of 0.5 μg ml. The reaction was stopped by the addition of 5 μΙ of a solution of TR-FRET detection reagents (0.2 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-RB(pSer807/pSer81 1 )-anti-body from BD Pharmingen [# 558389] and 1 .2 nM LANCE EU-W1024 labeled anti-mouse IgG anti-body [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.2 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated 1 h at 22°C to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.1 nM (20 μΜ, 5.9 μΜ, 1.7 μΜ, 0.51 μΜ, 0.15 μΜ, 44 nM, 13 nM, 3.8 nM, 1 .1 nM, 0.33 nM and 0.1 nM), the dilution series prepared separately before the assay on the level of the 10Ofold concentrated solutions in DMSO by serial 1 :3.4 dilutions) in duplicate values for each concentration and I C50 values were calculated using Genedata Screener™ software.

In vitro assay 4: ΙΚΚε low ATP kinase assay

ΙΚΚε -inhibitory activity of compounds of the present invention at a low ATP concentration after preincubation of enzyme and test compounds was quantified employing the TR-FRET-based ΙΚΚε assay as described in the following paragraphs. A recombinant fusion protein of GST (N-terminally) and full-length human ΙΚΚε, expressed in insect cells and purified by glutathione affinity chromatography, was purchased from Life Technologies (Cat. No PV4876) and used as enzyme. As substrate for the kinase reaction biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosyntan (Berlin-Buch, Germany).

For the assay 50 nl of a 10Ofold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of ΙΚΚε in aqueous assay buffer [50 mM HEPES pH 7.0, 10 mM MgC , 1 .0 mM dithiothreitol, 0.05 % (w/v) bovine serum albumin, 0.01 % (v/v) Nonidet-P40 (Sigma), protease inhibitor mixture ("Complete w/o EDTA" from Roche, 1 tablet per 5 ml)] were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 16.7 μΜ => final cone, in the 5 μΙ assay volume is 10 μΜ) and substrate (1 .67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22°C. The concentration of ΙΚΚε was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, a typical concentration is 0.01 μg ml. The reaction was stopped by the addition of 5 μΙ of a solution of TR-FRET detection reagents (0.2 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France], 1 .5 nM anti-phosho-Serine antibody [Merck Millipore, "STK antibody", cat. # 35-002] and 0.75 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.13 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.5). The resulting mixture was incubated 1 h at 22°C to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.1 nM (20 μΜ, 5.9 μΜ, 1.7 μΜ, 0.51 μΜ, 0.15 μΜ, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separately before the assay on the level of the 10Ofold concentrated solutions in DMSO by serial 1 :3.4 dilutions) in duplicate values for each concentration and I C50 values were calculated using Genedata Screener™ software. In vitro assay 5: Assay for the detection of lkke/TBK1 inhibition in MDA-MB231 cells

ΤΒΚ1/ΙΚΚε kinases are involved in the regulation of the Toll-like receptor 3 dependent innate immune response pathway. Stimulation of TLR3 by poly-l:C activates ΤΒΚ1/ΙΚΚε which in turn phosphorylate the transcription factor IRF3. IRF3 translocates into the cell nucleus and activates the transcription of interferon regulated genes (e.g., IFN-beta, RANTES). The cellular assay for the determination of inhibition of ΙΚΚε and TBK1 was performed in MDA-MB231 cells (ATCC, Manassas, USA) that stably express an ISRE-Luciferase reporter responsive for IRF3. The promoter sequence was based on the pISRE-TA-Luc vector (available from Clontech) containing five copies of the ISRE enhancer element, located upstream of the minimal TA promoter. The coding sequence of optimized firefly luciferase Iuc2 (Promega) was placed downstream of the ISRE-TA element. The final reporter plSRE-TA-luc2 containing a Hygromycin resistance gene was integrated into a lentiviral expression system that was used to generate the stable reporter cells. The coding sequence of the ISRE promoter and luciferase gene is as follows:

ISRE-TA-luc2 sequence

1843 AATAGTAGACATAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAAATTACAAA

1903 AATTCAAAATTTTATCGATACTAGTTCTTACGCGTGGTACCGAGCTCTTACGCGTGCTAG

1963 CGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAAC

2023 TAGATCTGGGTATATAATGGAAGCTTGGCATTCCGGTACTGTTGGTAAAGCCACCATGGA

2083 AGATGCCAAAAACATTAAGAAGGGCCCAGCGCCATTCTACCCACTCGAAGACGGGACCGC

2143 CGGCGAGCAGCTGCACAAAGCCATGAAGCGCTACGCCCTGGTGCCCGGCACCATCGCCTT

2203 TACCGACGCACATATCGAGGTGGACATTACCTACGCCGAGTACTTCGAGATGAGCGTTCG

2263 GCTGGCAGAAGCTATGAAGCGCTATGGGCTGAATACAAACCATCGGATCGTGGTGTGCAG

2323 CGAGAATAGCTTGCAGTTCTTCATGCCCGTGTTGGGTGCCCTGTTCATCGGTGTGGCTGT

2383 GGCCCCAGCTAACGACATCTACAACGAGCGCGAGCTGCTGAACAGCATGGGCATCAGCCA

2443 GCCCACCGTCGTATTCGTGAGCAAGAAAGGGCTGCAAAAGATCCTCAACGTGCAAAAGAA

2503 GCTACCGATCATACAAAAGATCATCATCATGGATAGCAAGACCGACTACCAGGGCTTCCA

2563 AAGCATGTACACCTTCGTGACTTCCCATTTGCCACCCGGCTTCAACGAGTACGACTTCGT

2623 GCCCGAGAGCTTCGACCGGGACAAAACCATCGCCCTGATCATGAACAGTAGTGGCAGTAC

2683 CGGATTGCCCAAGGGCGTAGCCCTACCGCACCGCACCGCTTGTGTCCGATTCAGTCATGC

2743 CCGCGACCCCATCTTCGGCAACCAGATCATCCCCGACACCGCTATCCTCAGCGTGGTGCC

2803 ATTTCACCACGGCTTCGGCATGTTCACCACGCTGGGCTACTTGATCTGCGGCTTTCGGGT

2863 CGTGCTCATGTACCGCTTCGAGGAGGAGCTATTCTTGCGCAGCTTGCAAGACTATAAGAT

2923 TCAATCTGCCCTGCTGGTGCCCACACTATTTAGCTTCTTCGCTAAGAGCACTCTCATCGA

2983 CAAGTACGACCTAAGCAACTTGCACGAGATCGCCAGCGGCGGGGCGCCGCTCAGCAAGGA

3043 GGTAGGTGAGGCCGTGGCCAAACGCTTCCACCTACCAGGCATCCGCCAGGGCTACGGCCT

3103 GACAGAAACAACCAGCGCCATTCTGATCACCCCCGAAGGGGACGACAAGCCTGGCGCAGT

3163 AGGCAAGGTGGTGCCCTTCTTCGAGGCTAAGGTGGTGGACTTGGACACCGGTAAGACACT

3223 GGGTGTGAACCAGCGCGGCGAGCTGTGCGTCCGTGGCCCCATGATCATGAGCGGCTACGT

3283 TAACAACCCCGAGGCTACAAACGCTCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGA

3343 CATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTGGACCGGCTGAAGAGCCTGAT 3403 CAAATACAAGGGCTACCAGGTAGCCCCAGCCGAACTGGAGAGCATCCTGCTGCAACACCC

3463 CAACATCTTCGACGCCGGGGTCGCCGGCCTGCCCGACGACGATGCCGGCGAGCTGCCCGC

3523 CGCAGTCGTCGTGCTGGAACACGGTAAAACCATGACCGAGAAGGAGATCGTGGACTATGT

3583 GGCCAGCCAGGTTACAACCGCCAAGAAGCTGCGCGGTGGTGTTGTGTTCGTGGACGAGGT

3643 GCCTAAAGGACTGACCGGCAAGTTGGACGCCCGCAAGATCCGCGAGATTCTCATTAAGGC

3703 CAAGAAGGGCGGCAAGATCGCCGTGTAATAATTCTAGAACGAAGCGGCCGCAGGGTTTAA

ISRE-TA 1945-2040

Luc2 2078-3730 (1652bp)

The ISRE-luc2-MDA-MB231 cells were cultured in DMEM/ Ham^'s F12 (Gibco # 21041 ) supplemented with 10% fetal calf serum (typically but not exclusively used: FCS Gold Gibco- No. 10500-064), 2 mM L-glutamine (Gibco-No. 35050-038), 150 g/ml Hygromycin B, cryopreserved in 90% FCS + 10% dimethylsulphoxide (DMSO) and stored as frozen aliquots of typically 5-10 million cells/vial at -150°C or below until further use.

For the assay, sufficient cells were rapidly thawed in a 37°C water bath and pipetted into pre- warmed assay medium (DMEM/ Ham^'s F12, 10% FCS, 2 mM L-glutamine, 1 % Penicillin/Streptomycin (Biochrom AG; # A2213)). The cells were centrifuged for 5 min at 180 x g. The supernatant was removed and the cell pellet was resuspended in fresh medium to give a suspension of 2.4 million cells / ml. Poly (l:C)_HMW (InvivoGen, # tlrl-pic) was diluted in assay medium to 0.2 mg/L and subsequently mixed with the cell suspension in 1 :1 ratio.

Fifty nl of a 100-fold concentrated solution of the test compound in DMSO were transferred into a white microtiter test plate (384 or 1536, Greiner Bio-One, Frickenhausen, Germany). For this, either a Hummingbird liquid handler (Digilab, MA, USA) or an Echo acoustic system (Labcyte, CA, USA) was used. Five μΙ of a freshly prepared cell suspension was added to the wells of a test plate and incubated at 37°C in a 5% CO2 atmosphere. The inhibitor control cell suspension was added to empty wells at the side of the test plate. After completion of the incubation for 20-24 hours, 2.5 μΙ of Steady-Glo® Luciferase detection solution (Promega), prepared as recommended by the supplier, were added to all wells. The test plate was incubated at 20°C for 30 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Data were normalized (cells without inhibitor = 0% inhibition, cells with reference inhibitor = 100% inhibition). Compounds were tested in duplicates at up to 1 1 concentrations (for example 20 μΜ, 5.7 μΜ, 1 .6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 ηΜ, 1 1 ηΜ, 3.1 ηΜ, 0.89 ηΜ, 0.25 ηΜ and 0.073 ηΜ). Dilution series were made prior to the assay in a 10Ofold concentrated form by serial dilution. I C50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland). To prepare the inhibitor control cell suspension, a part of prepared the cell suspension mixture was supplemented with 10 μΜ of a reference inhibitor, for the generation of above mentioned 100% inhibition reference for data normalization.

In vitro assay 6: Counterassay for the detection of off-target inhibition in MDA-MB231 cells

The cellular assay for the determination of off-target inhibition for ΙΚΚε and TBK1 was performed in MDA-MB231 (ATCC, Manassas, USA) cells that stably express a constitutively active CMV-Luciferase reporter. Selective ΙΚΚε / TBK1 inhibitors are inactive, whereas inhibition of the firefly luciferase assay indicates off-target inhibition, e.g. transcriptional or translational inhibition, toxicity or inhibition of the luciferase activity. The coding sequence of the CMV promoter and luciferase gene is as follows:

1 CTCGAGATCCGGCCATTAGCCATATTATTCATTGGTTATATAGCATAAATCAATATTGGC

61 TATTGGCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGT

121 CCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACG

181 GGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGC

241 CCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCC

301 ATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACT

361 GCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAAT

421 GACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACT

481 TGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTAC

541 ATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGAC

601 GTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAAC

661 TCCGCCCCATTGACGCAAATGGGCGGTAGGCATGTACGGTGGGAGGTCTATATAAGCAGA

721 GCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCAT

781 AGAAGACACCGGGACCGATCCAGCCTCCGCGGCCCCAAGCTTGGCAATCCGGTACTGTTG

841 GTAAAGCCACCATGGAAGATGCCAAAAACATTAAGAAGGGCCCAGCGCCATTCTACCCAC

901 TCGAAGACGGGACCGCCGGCGAGCAGCTGCACAAAGCCATGAAGCGCTACGCCCTGGTGC

961 CCGGCACCATCGCCTTTACCGACGCACATATCGAGGTGGACATTACCTACGCCGAGTACT

1021 TCGAGATGAGCGTTCGGCTGGCAGAAGCTATGAAGCGCTATGGGCTGAATACAAACCATC

1081 GGATCGTGGTGTGCAGCGAGAATAGCTTGCAGTTCTTCATGCCCGTGTTGGGTGCCCTGT

1141 TCATCGGTGTGGCTGTGGCCCCAGCTAACGACATCTACAACGAGCGCGAGCTGCTGAACA

1201 GCATGGGCATCAGCCAGCCCACCGTCGTATTCGTGAGCAAGAAAGGGCTGCAAAAGATCC

1261 TCAACGTGCAAAAGAAGCTACCGATCATACAAAAGATCATCATCATGGATAGCAAGACCG

1321 ACTACCAGGGCTTCCAAAGCATGTACACCTTCGTGACTTCCCATTTGCCACCCGGCTTCA

1381 ACGAGTACGACTTCGTGCCCGAGAGCTTCGACCGGGACAAAACCATCGCCCTGATCATGA

1441 ACAGTAGTGGCAGTACCGGATTGCCCAAGGGCGTAGCCCTACCGCACCGCACCGCTTGTG

1501 TCCGATTCAGTCATGCCCGCGACCCCATCTTCGGCAACCAGATCATCCCCGACACCGCTA

1561 TCCTCAGCGTGGTGCCATTTCACCACGGCTTCGGCATGTTCACCACGCTGGGCTACTTGA

1621 TCTGCGGCTTTCGGGTCGTGCTCATGTACCGCTTCGAGGAGGAGCTATTCTTGCGCAGCT

1681 TGCAAGACTATAAGATTCAATCTGCCCTGCTGGTGCCCACACTATTTAGCTTCTTCGCTA

1741 AGAGCACTCTCATCGACAAGTACGACCTAAGCAACTTGCACGAGATCGCCAGCGGCGGGG

1801 CGCCGCTCAGCAAGGAGGTAGGTGAGGCCGTGGCCAAACGCTTCCACCTACCAGGCATCC

1861 GCCAGGGCTACGGCCTGACAGAAACAACCAGCGCCATTCTGATCACCCCCGAAGGGGACG 1921 ACAAGCC GGCGCAGTAGGCAAGG GG GCCC C CGAGGCTAAGG GG GGAC GG

1981 ACACCGGTAAGACACTGGGTGTGAACCAGCGCGGCGAGCTGTGCGTCCGTGGCCCCATGA

2041 TCATGAGCGGCTACGTTAACAACCCCGAGGCTACAAACGCTCTCATCGACAAGGACGGCT

2101 GGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTGGACC

2161 GGCTGAAGAGCCTGATCAAATACAAGGGCTACCAGGTAGCCCCAGCCGAACTGGAGAGCA

2221 TCCTGCTGCAACACCCCAACATCTTCGACGCCGGGGTCGCCGGCCTGCCCGACGACGATG

2281 CCGGCGAGCTGCCCGCCGCAGTCGTCGTGCTGGAACACGGTAAAACCATGACCGAGAAGG

2341 AGATCGTGGACTATGTGGCCAGCCAGGTTACAACCGCCAAGAAGCTGCGCGGTGGTGTTG

2401 TGTTCGTGGACGAGGTGCCTAAAGGACTGACCGGCAAGTTGGACGCCCGCAAGATCCGCG

2461 AGATTCTCATTAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAATAATTCTAGAACGAAG

2521 CGGCCGCAGGGTTTAAACACGGTCGACGGTACCGCGGGCCCAACATCGATAAAATAAAAG

2581 ATTTTATTTAGTCTCCAGAAAAAGGGGGGAATGAAAGACCCCACCTGTAGGTTTGGCAAG

2641 CTAGCTTAAGTAACGCCATTTTGCAAGGCATGGAAAAATACATAACTGAGAATAGAGAAG

2701 TTCAGATCAAGGTCAGGAACAGATGGAACAGCTGAA ATGGGCCAAACAGGA ATCTGTG

CMV promoter 1-813

Luc2 852-2504 (1652bp)

The CMV-luc2-MDA-MB231 cell were cultured in DMEIW Ham^'s F12 (Gibco # 21041 ) supplemented with 10% fetal calf serum (typically but not exclusively used: FCS Gold Gibco- No. 10500-064), 150 g/ml Hygromycin B, cryopreserved in 90% culture medium + 10% dimethylsulfoxide (DMSO) and stored as frozen aliquots of typically 5-10 million cells/vial at - 150°C or below until further use.

For the assay, sufficient cells were rapidly thawed in a 37°C water bath and pipetted into pre- warmed assay medium (DMEIW Ham^'s F12, 10% FCS, 2 mM L-glutamine, 1 % Penicillin/Streptomycin (Biochrom AG; # A2213)). The cells were centrifuged for 5 min at 180 x g. The supernatant was removed and the cell pellet was resuspended in fresh medium to give a suspension of 0.3 million cells / ml. Poly (l:C)_HMW (InvivoGen, # tlrl-pic) was diluted in assay medium to 0.2 mg/L and subsequently mixed with the cell suspension in 1 :1 ratio.

To prepare the inhibitor control cell suspension, a part of prepared the cell suspension mixture was supplemented with 5 μΜ of Actinomycin D (Sigma A1410).

Fifty nl of a 100-fold concentrated solution of the test compound in DMSO were transferred into a white microtiter test plate (384 or 1536, Greiner Bio-One, Frickenhausen, Germany). For this, either a Hummingbird liquid handler (Digilab, MA, USA) or an Echo acoustic system (Labcyte, CA, USA) was used. Five μΙ of a freshly prepared cell suspension was added to the wells of a test plate and incubated at 37°C in a 5% CO2 atmosphere. The inhibitor control cell suspension was added to empty wells at the side of the test plate. After completion of the incubation for 20-24 hours, 2.5 μΙ of Steady-Glo® Luciferase detection solution (Promega), prepared as recommended by the supplier, were added to all wells. The test plate was incubated at 20°C for 30 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Data were normalized (cells without inhibitor = 0% inhibition, cells with reference inhibitor = 100% inhibition). Compounds were tested in duplicates at up to 1 1 concentrations (for example 20 μΜ, 5.7 μΜ, 1 .6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 nM, 1 1 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM). Dilution series were made prior to the assay in a 10Ofold concentrated form by serial dilution. I C50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland).

In vitro assay 7: plRF3 cell based mechanistic assay

ΙΚΚε and TBK1 are highly homologous serine/threonine kinases which are in involved in innate anti-viral immunity and which phosphorylates Interferon regulatory factor 3. plRF3 (Ser 386) is measured in an HTRF assay (CisBio, Codolet, France). This assay is designed for the quantitative determination of phosphoSer(385/386) of human IRF3 protein. pSer(385/386) IRF3 is measured in a sandwich assay format using 2 different specific antibodies, one labelled with Cryptate (donor) and the second with d2 (acceptor). The two conjugates bind to the phosphorylated IRF3 present in the sample, thereby generating FRET. The intensity of the signal obtained is proportional to the number of antigen-antibody complexes formed and therefore the signal is proportional to the concentration of the pSer(385/386) IRF3.

Protocol:

The cellular assay for the determination of inhibition of ΙΚΚε and TBK1 was performed in MDA- MB231 cells (ATCC, Manassas, USA) that stably overexpress human IRF3 (human interferon regulatory factor 3 (IRF3; NM_001571 )) under the control of the CMV promoter. The coding sequence for human IRF3 (from cDNA clone pCMV6-XL4-IRF3, Origene, Rockville, MD; USA) was cloned into a lentiviral expression system containing a Hygromycin resistance gene. Derived lentiviral particles were used to generate the stable reporter cells. The clone MDA MB 231 mlRF3 #12 was selected for the assays.

The coding sequence of the CMV promoter and IRF3 gene is as follows:

ACTAGTATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTAC

GTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGA

TAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTG

TTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACG

CAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAAC

CGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGATTCTAGAGC

TAGCGCTCAACTTTGTATAGAAAAGTTGACTAGTCCAGTGTGGTGGAATTCTGCAGATAT

CAACAAGTTTGTACAAAAAAGCAGGCTGCCACCATGGGAACCCCAAAGCCACGGATCCTG

CCCTGGCTGGTGTCGCAGCTGGACCTGGGGCAACTGGAGGGCGTGGCCTGGGTGAACAAG

AGCCGCACGCGCTTCCGCATCCCTTGGAAGCACGGCCTACGGCAGGATGCACAGCAGGAG

GATTTCGGAATCTTCCAGGCCTGGGCCGAGGCCACTGGTGCATATGTTCCCGGGAGGGAT

AAGCCAGACCTGCCAACCTGGAAGAGGAATTTCCGCTCTGCCCTCAACCGCAAAGAAGGG

TTGCGTTTAGCAGAGGACCGGAGCAAGGACCCTCACGACCCACATAAAATCTACGAGTTT

GTGAACTCAGGAGTTGGGGACTTTTCCCAGCCAGACACCTCTCCGGACACCAATGGTGGA

GGCAGTACTTCTGATACCCAGGAAGACATTCTGGATGAGTTACTGGGTAACATGGTGTTG GCCCCACTCCCAGATCCGGGACCCCCAAGCCTGGCTGTAGCCCCTGAGCCCTGCCCTCAG

CCCCTGCGGAGCCCCAGCTTGGACAATCCCACTCCCTTCCCAAACCTGGGGCCCTCTGAG AACCCACTGAAGCGGCTGTTGGTGCCGGGGGAAGAGTGGGAGTTCGAGGTGACAGCCTTC TACCGGGGCCGCCAAGTCTTCCAGCAGACCATCTCCTGCCCGGAGGGCCTGCGGCTGGTG GGGTCCGAAGTGGGAGACAGGACGCTGCCTGGATGGCCAGTCACACTGCCAGACCCTGGC ATGTCCCTGACAGACAGGGGAGTGATGAGCTACGTGAGGCATGTGCTGAGCTGCCTGGGT GGGGGACTGGCTCTCTGGCGGGCCGGGCAGTGGCTCTGGGCCCAGCGGCTGGGGCACTGC CACACATACTGGGCAGTGAGCGAGGAGCTGCTCCCCAACAGCGGGCATGGGCCTGATGGC GAGGTCCCCAAGGACAAGGAAGGAGGCGTGTTTGACCTGGGGCCCTTCATTGTAGATCTG ATTACCTTCACGGAAGGAAGCGGACGCTCACCACGCTATGCCCTCTGGTTCTGTGTGGGG GAGTCATGGCCCCAGGACCAGCCGTGGACCAAGAGGCTCGTGATGGTCAAGGTTGTGCCC ACGTGCCTCAGGGCCTTGGTAGAAATGGCCCGGGTAGGGGGTGCCTCCTCCCTGGAGAAT ACTGTGGACCTGCACATTTCCAACAGCCACCCACTCTCCCTCACCTCCGACCAGTACAAG GCCTACCTGCAGGACTTGGTGGAGGGCATGGATTTCCAGGGCCCTGGGGAGAGCTGA

MDA MB 231 mlRF3 #12 cells were plated in 384well plates at 10.000 cells/well in 30 μΙ DMEM / Ham's F12 + 10% FCS per well. After ON incubation at 37°C/5% C0₂, the medium was exchanged for phenol red-free medium. Compounds were added by HP Dispenser with compounds diluted in DMSO, maximal compound concentration was30 μΜ, then 1 :3 dilution steps, i.e. 30 μΜ, 10 μΜ, 3.3, μΜ etc, were applied using a HP D300 digital dispenser (Tecan, Germany). Normalization was done with DMSO to a final concentration of 0.6% per well. The cells were incubated for 1 h in an incubator, then poly IC was added to stimulate the cells (100 μΜ poly IC were diluted in 1000 μΙ OptiMEM (Gibco); in parallel 300 μΙ Lipofectamine 2000 (Life Technologies) were diluted in 1000 μΙ OptiMEM. Both solutions were mixed and incubated for 20 min at room temperature, then 3 μΙ per well (= 0,15μ9/30μΙ ^g/ml) PolylC/Lipofectamine2000) were added to all cells except for control cells (representing the 100% inhibition value for normalization). The cells were incubated for another hour in an incubator, then the plate was assayed according to the manufacturer (Cisbio Bioassays, Codolet, France, item # 6FRF3PEH, IRF3 phospho-S385/386 kit): the medium was removed, then 18 μΙ of supplemented Lysis buffer #2 (1.9 ml Lysis buffer #2 (4x), + 58 μΙ Blocking Reagent, included in Kit (1 OOx), +3.84 ml ultrapure water) were added. 16 μ I of the lysate were transferred into a 384well small volume white plate (Greiner Bio-One, Germany), the antibodies (included in the kit) were added and the plate was sealed with foil and incubated for 3 h at room temperature. Finally the measurement was done in a Pherastar (BMG, Germany) with 2 wavelengths (665 nm und 620 nm). The data were normalised (cells stimulated with poly IC but without inhibitor = 0 % inhibition, cells without poly IC stimulation = 100 % inhibition). IC50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland). In vitro assay 8: ACHN Anti proliferation assay

Tissue cultured ACHN human kidney renal cell adenocarcinoma cells (ATCC, Manassas, USA) were plated at 300 cells/well in 50 μΙ Earle's MEM (Biochrom; # FG 0325, with stable glutamine and 10% FCS, typically but not exclusively used: FCS Gold Gibco-No. 10500-064) in 384well microtiter plates (Corning 3707 white/clear bottom, Corning, Germany). All plates were incubated ON in an incubator at 37°C, 5% CO2. The next day one plate was measured for time zero determination (using CTG solution, see below). The rest of the plates were treated with test compounds by a HP D300 digital dispenser (Tecan, Germany) with a starting concentration of 30 μΜ and subsequent 1 :3 dilution steps. The plates were incubated at 37°C for 96h. Thereafter the plates were measured by addition of 40 ul/well CTG solution (Promega Cell Titer Glo solution (catalog number G755B and G756B)), incubation for 30 min on a shaker (Heidolph Titramax 1000, Heidolph, Germany) in the dark and afterwards luminescence was measured in a VICTOR V (Perkin Elmer). IC50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland).

In vitro assay 9: Calu-1 Antiproliferation assay

Tissue cultured Calu-1 human lung epidermoid carcinoma cells (CLS Cell Lines Services, Eppelheim, Germany) were plated at 870 cells/well in 50 μΙ McCoy's 5A (Biochrom; # F 1015 and 10% FCS, typically but not exclusively used: FCS Gold Gibco-No. 10500-064) in 384well microtiter plates (Corning 3707 white/clear bottom, Corning, Germany). All plates were incubated ON in an incubator at 37°C, 5% CO2. The next day one plate was measured for time zero determination (using CTG solution, see below). The rest of the plates were treated with test compounds by a HP D300 digital dispenser (Tecan, Germany) with a starting concentration of 30 μΜ and subsequent 1 :3 dilution steps. The plates were incubated at 37°C for 96h. Thereafter the plates were measured by addition of 40 ul/well CTG solution (Promega Cell Titer Glo solution (catalog number G755B and G756B)), incubation for 30 min on a shaker (Heidolph Titramax 1000, Heidolph, Germany) in the dark and afterwards luminescence was measured in a VICTOR V (Perkin Elmer). IC50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland). Table 3: TBK1 low ATP kinase assay: IC₅o values of examples in in vitro assay 1

TBK1 low ATP kinase

Example

assay IC₅o [M]

Example 05-04 1 .8 E-9

Example 06-01 3.8 E-9

Example 06-02 nd

Example 06-03 2.8 E-10

Example 06-04 3.5 E-10

Example 06-06 1 .9 E-9

Example 07-01 4.7 E-8

Example 07-02 5.3 E-7

Example 07-03 1 .9 E-8

Example 07-04 2.6 E-8

Example 08-01 1 .1 E-8

Example 08-02 1 .1 E-8

Example 08-03 1 .2 E-9

Example 08-04 1 .4 E-9

Example 08-06 8.0 E-9

Example 09-01 nd

Example 09-02 nd

Example 09-03 1 .4 E-8

Example 10-01 8.4E-8

Example 10-02 1 .4E-7

Example 10-03 9.0E-9

Example 10-04 9.9E-9

Example 10-05 3.2E-8

Example 1 1 -01 1 .7E-8

Example 1 1 -02 nd

Example 12-01 3.7E-9 TBK1 low ATP kinase

Example

assay IC₅o [M]

Example 12-02 1 .4E-8

Example 12-03 2.6E-10

Example 12-04 4.6E-10

Example 12-05 1 .8E-9

Example 13-01 nd

Example 13-02 nd

Example 13-03 6.9E-9

Example 13-04 6.6E-9

Example 14-01 nd

Example 14-02 nd

Example 14-04 2.2E-8 nd: not determined.

Claims

1 . A compound of general formula (I):

in which :

R¹ represents a group selected from

pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R⁷ group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R⁸ group,

or

R¹ represents a group selected from

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

in which "^*" represents the point of attachment to the rest of the molecule,

or

R¹ represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R⁹ group; represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;

R⁴ represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy; represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl; represents a hydrogen atom, a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-haloalkyl, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom; represents a hydrogen atom, a halogen atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom; represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3-

C6-cycloalkyl and (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-,

said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl group; represents a halogen atom or a group selected from d-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-hydroxyalkyl, (Ci-C₃-alkoxy)-(Ci-C₃-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, C4-C8-cycloalkenyl, (Cs-Cs-cycloalkyl)- (Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7- membered heterocycloalkenyl, phenyl, heteroaryl, -CN, -C(=0)R¹⁴, -C(=0)-OR¹⁴, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a, -N(R¹⁷)-C(=0)-R¹⁴, -N(R¹⁷)-S(=0)₂-R¹⁴, -N(R¹⁷)-C(=0)-N(R¹²)R^12a, -N(R¹⁷)-C(=0)-OR¹⁴, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)-(Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH₂)x-phenyl, -0-(CH₂)x-heteroaryl, -0-C(=0)-R¹⁴ -0-C(=0)-N(R¹²)R^12a, d-Ce-alkylsulfanyl, Ci-C₆-haloalkylsulfanyl, -S(=0)₂-R¹⁴, -S(=0)₂-N(R¹²)R^12a and -S(=0)(=NR¹⁸)R¹⁴; and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(0-CH₂-0)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -(S-(CH₂)₂)-, -(0-(CH₂)₃)-, -((CH₂)₃)-, -((CH₂)₄)-, -(0-CH=CH)-, -(S-CH=CH); represents a hydrogen atom or a group selected from methyl, ethyl, methoxy and ethoxy; represents a hydrogen atom or a Ci-C3-alkyl group; represents a hydrogen atom or a group selected from Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C₄-haloalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, C3-C6-cycloalkyl and benzyl,

or

and R^12a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C₃-alkyl, -C(=0)R¹⁹, C(=0)OR¹⁹ and S(=0)₂R¹⁹; represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, Cs- Ce-cycloalkyl, (C3-C₆-cycloalkyl)-(Ci-C3-alkyl)-, C₂-C₆-alkenyl, C₂-C₆-alkynyl, 4- to 7- membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; represents a group selected from Ci-C₄-alkyl and benzyl; and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, C3-C6-cycloalkyl and benzyl,

or

and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxy, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)- (Ci-C₃-alkyl)-; R¹⁶ represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,

said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy;

R¹⁷ represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl;

R¹⁸ represents a hydrogen atom or a group selected from -CN, -C(=0)OR¹⁴, Ci-C4-alkyl and benzyl;

R¹⁹ represents a Ci-C3-alkyl group; x represents an integer selected from 1 , 2, 3 and 4, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

in which "^*" represents the point of attachment to the rest of the molecule, the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

or

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule; represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;

R⁴ represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl; R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a halogen atom or a group selected from Ci-C3-alkyl and trifluoromethyl, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom; R^6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,

said C3-C4-cycloalkyl and said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;

R⁸ represents a halogen atom or a group selected from d-Ce-alkyl, Ci-C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, C₃-C₄-cycloalkyl, (C₃-C₄- cycloalkyl)-(methyl)-, (phenyl)-(Ci-C₃-alkyl)-, -C(=0)-N(R¹²)R^12a, -N(R¹²)R^12a, Ci-C₆- alkoxy, Ci-C4-fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)- and Ci-C4-alkylsulfanyl, or

R⁷ and R⁸, or two R⁸ groups, when being attached to adjacent ring atoms of the group R¹, together form a group selected from:

-(O-CH2-O)-, -(0-(CH₂)₂-0)-, -(0-(CH₂)₂)-, -((CH₂)₃)-, -((CH₂)₄)-;

R⁹ represents a hydrogen atom or a group selected from methoxy and ethoxy;

R¹⁰ represents a hydrogen atom or a methyl or ethyl group;

R¹¹ represents a hydrogen atom or a group selected from Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶,

-S(=0)₂N(R¹⁵)R^15a and phenyl,

said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;

R¹² and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl and benzyl,

or

R¹² and R^12a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group, said group being optionally substituted once with a methyl group;

represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl and (C₃-C₆-cycloalkyl)-(Ci-C₂-alkyl)-;

represents a group selected from Ci-C4-alkyl and benzyl; R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,

or

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl and C1-C3- fluoroalkyl;

R¹⁶ represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl and C3-C6-cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

The compound according to claim 1 or 2, wherein

represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted further one or two times, differently or identically, with a R⁸ group,

represents a group selected from

in which "*" represents the point of attachment to the rest of the molecule;

represents a group selected from

in which "*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom, a fluorine atom, a chlorine atom, or a group selected from methyl, ethyl, methoxy and ethoxy;

R⁴ represents a hydrogen atom, or a group selected from methyl and trifluoromethyl;

R⁵ represents a hydrogen atom;

R⁶ⁱ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a Ci-C2-alkyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

_R6I represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl ,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group;

R¹ represents a fluorine, atom, a chlorine atom, or a group selected from Ci-C6-alkyl, Ci- C₄-fluoroalkyl, (Ci-C₂-alkoxy)-(Ci-C₂-alkyl)-, (C₃-C₄-cycloalkyl)-(methyl)-, -N(R¹²)R^12a, Ci-C4-alkoxy, Ci-C4-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-;

R⁹ represents a hydrogen atom or a methoxy group;

represents a hydrogen atom or a methyl group; represents a group selected from Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C₄-fluoroalkyl, -C(=0)R¹³, -C(=0)OR¹⁴, -C(=0)N(R¹⁵)R^15a, -S(=0)₂R¹⁶, -S(=0)₂N(R¹⁵)R^15a and 2-chlorophenyl;

and R^12a, independently from each other, represent a hydrogen atom or a group selected from Ci-C2-fluoroalkyl, methyl and ethyl;

R¹³ represents a group selected from Ci-C₄-alkyl, Ci-C3-fluoroalkyl, C3-C₄-cycloalkyl and (cyclopropyl)-(methyl)-;

R¹⁴ represents a Ci-C₄-alkyl group;

R¹⁵ and R^15a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,

or

R¹⁵ and R^15a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a methyl group;

R¹⁶ represents a group selected from methyl, ethyl and trifluoromethyl,

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 , 2 or 3, wherein

R¹ represents a group selected from

in which "*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

represents a group

in which "*" represents the point of attachment to the rest of the molecule;

R³ represents represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R^6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents a represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group;

R⁸ represents a fluorine atom or a group selected from Ci-C3-alkyl, (Ci-C2-alkoxy)-(Ci-C2- alkyl)-, -N(R¹²)R^12a, Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from Ci-C₃-fluoroalkyl, -C(=0)R¹³ and -C(=0)OR¹⁴;

R¹² and R^12a, independently from each other, represent a group selected from methyl and ethyl;

R¹³ represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;

R¹⁴ represents a tert-butyl group,

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

The compound according to claim 1 , 2, 3 or 4, wherein

represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule,

the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

R² represents a group

in which "^*" represents the point of attachment to the rest of the molecule;

R³ represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R^6a and R^6b represents a hydrogen atom and the other of the groups R^6a and R^6b is different from a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group;

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;

R⁸ represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;

_R10 represents a hydrogen atom or a methyl group;

R11 represents a group selected from Ci-C3-fluoroalkyl and -C(=0)R¹³;

R13 represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6. The compound according to claim 1 , 2, 3, 4 or 5, wherein

R¹ represents a group selected from

in which "^*" represents the point of attachment to the rest of the molecule, the ring of said group being, besides R⁷, optionally substituted, identically or differently, with one or two further R⁸ groups;

represents a group

in which "^*" represents the point of attachment to the rest of the molecule; R³ represents a hydrogen atom or a fluorine atom;

R⁴ represents a hydrogen atom;

R⁵ represents a hydrogen atom;

R^6a represents a fluorine atom, a chlorine atom or a methyl group;

R^6b represents a hydrogen atom;

R⁷ represents represents a (C3-C4-cycloalkyl)-(methyl)- group,

said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;

R⁸ represents a group selected from methyl, methoxy, (methoxy)-(methyl)- and (cyclopropyl)-(methoxy)-;

R¹⁰ represents a hydrogen atom or a methyl group;

R¹¹ represents a group selected from 2,2-difluoroethyl, 2,2,2-trifluoroethyl and -C(=0)R¹³;

R¹³ represents a group selected from 2,2,2-trifluoroethyl and cyclopropyl; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

7. The compound according to claim 1 , which is selected from the group consisting of:

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]- 4-fluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 - carboxylate,

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-fluoro-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4- yl]-4-fluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 - yl)methanone,

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4- fluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)- 3,3,3-trifluoropropan-1 -one,

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-fluoro-N-(4-{(1 R or 1 S)-1 -

[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-1 H- benzimidazol-2-amine,

tert-butyl 4-{(1 R or 1 S)-1 -[2-({4-chloro-6-[1 -(cyclopropylmethyl)-1 H- pyrazol-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine- 1 -carboxylate,

4-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

(4-{(1 R or 1 S)-1 -[2-({4-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 - yl)(cyclopropyl)methanone,

1 -(4-{(1 R or 1 S)-1 -[2-({4-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4- yl]-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3- trifluoropropan-1 -one,

4-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -

[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-1 H- benzimidazol-2-amine,

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]- 4-methyl-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 - carboxylate, 6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-methyl-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4- yl]-4-methyl-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 - yl)methanone,

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4- methyl-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)- 3,3,3-trifluoropropan-1 -one,

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-4-methyl-N-(4-{(1 R or 1 S)-1 -

[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-1 H- benzimidazol-2-amine,

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-

5- methyl-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 - carboxylate,

6- [1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4- yl]-5-methyl-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 - yl)methanone,

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5- methyl-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)- 3,3,3-trifluoropropan-1 -one,

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5-methyl-N-(4-{(1 R or 1 S)-1 -

[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-1 H- benzimidazol-2-amine,

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -[4-(2,2- difluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-5-methyl-1 H- benzimidazol-2-amine,

tert-butyl 4-{(1 R or 1 S)-1 -[2-({5-chloro-6-[1 -(cyclopropylmethyl)-1 H- pyrazol-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine- 1 -carboxylate,

5-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

(4-{(1 R or 1 S)-1 -[2-({5-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 - yl)(cyclopropyl)methanone,

1 -(4-{(1 R or 1 S)-1 -[2-({5-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4- yl]-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3- trifluoropropan-1 -one.

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-

5- fluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 - carboxylate,

6- [1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S )-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4- yl]-5-fluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 - yl)methanone,

1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5- fluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)- 3,3,3-trifluoropropan-1 -one,

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -[4-(2,2- difluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-5-fluoro-1 H-benzimidazol- 2-amine,

tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(6-methylpyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate, 5-fluoro-6-(6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt, cyclopropyl{4-[(1 R of 1 S)-1 -(2-{[5-fluoro-6-(6-methylpyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone, 3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(6-methylpyrimidin-4-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 - one,

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-

5- fluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 - carboxylate,

6- [1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-5-fluoro- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 - yl)(cyclopropyl)methanone, 1 - (4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-5-fluoro- 1 H-benzimidazol-2 -yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3, 3,3- trifluoropropan-1 -one,

6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-N-(4-{(1 R or 1 S)-1 -[4-(2,2- difluoroethyl)piperazin-1 -yl]ethyl}pyridin-2-yl)-5-fluoro-1 H-benzimidazol-

2- amine,

tert-butyl 4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(3-methoxy-2-methylpyridin-4- yl)-1 H-benzimidazol-2 -yl]amino}pyridin-4-yl)ethyl]piperazine-1 - carboxylate,

5- fluoro-6-(3-methoxy-2-methylpyridin-4-yl)-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[5-fluoro-6-(3-methoxy-2- methylpyridin-4-yl)-1 H-benzimidazol-2 -yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}propan-1 -one,

tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 RS)-2,2- difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-methyl-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate,

6- (1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-methyl- N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2- amine hydrochloride salt,

cyclopropyl{4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 RS)-2,2- difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-methyl-1 H-benzimidazol-

2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone,

1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-5-methyl-1 H-benzimidazol-2 -yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one,

6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-methyl-

N-(4-{(1 R or 1 S)-1 -[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2- yl)-1 H-benzimidazol-2-amine,

tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-

5- fluoro-1 H-benzimidazol-2 -yl}amino)pyridin-4-yl]ethyl}piperazine-1 - carboxylate,

6- [6-(cyclopropylmethoxy)pyrimidin-4-yl]-5-fluoro-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt,

tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 RS)-2,2- difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-fluoro-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate,

6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-fluoro- N-{4-[(1 R or1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2- amine hydrochloride salt,

cyclopropyl{4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 RS)-2,2- difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-fluoro-1 H-benzimidazol-

2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone,

1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-5-fluoro-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one,

6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-5-fluoro-

N-(4-{(1 R or 1 S)-1 -[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]ethyl}pyridin-2- yl)-1 H-benzimidazol-2-amine,

tert-butyl 4-{[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5,7-difluoro- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 - carboxylate,

6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5,7-difluoro-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride salt,

cyclopropyl(4-{[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-5,7- difluoro-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazin-1 - yl)methanone,

1 -(4-{[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-5,7-difluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3- trifluoropropan-1 -one,

tert-butyl 4-{(1 R or 1 S)-1 -[2-({5-fluoro-6-[6-(methoxymethyl)pyrimidin-4- yl]-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 - carboxylate,

5-fluoro-6-[6-(methoxymethyl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine

hydrochloride salt, and

3,3,3-trifluoro-1 -(4-{(1 R or 1 S)-1 -[2-({5-fluoro-6-[6-

(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]ethyl}piperazin-1 -yl)propan-1 -one,

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. A method of preparing a compound of general formula (I) according to any one claims 1 to 7, said method comprising the steps of

i. allowing an intermediate compound of general formula (Xlla) :

(Xlla),

in which R², R⁴ and R⁵ are as defined for the compound of general formula (I) according to any one of claims 1 to 7,

to react with a reagent selected from thiophosgene and di-1 H-imidazol-1 - ylmethanethione, in the presence of a catalytic amount of 1 H-imidazole, followed by the addition of an intermediate compound of general formula (XXXIV) :

(XXXIV),

in which R¹, R³, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7,

thereby giving a regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVI a) :

(XXXVI) (XXXVIa), in which R\ R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7, followed by ii. allowing said regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa):

(XXXVI) (XXXVIa), in which R¹ , R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7,

to react with a carbodiimide of formula R^D1-N=C=N-R^D2 (or a salt thereof), in which R^D1 and R^D2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N-dimethylamino group,

thereby giving a compound of general formula (I) :

in which R¹ , R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7,

A method of preparing a compound of general formula (I) according to any one of claims 1 to 7, said method comprising the step of allowing an intermediate compound of general formula (XXI) :

(XXI), in which R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7, and in which R^B, which can be different or identical, represent a hydrogen atom or a Ci-C4-alkyl group, or both R^B groups together form a C2-C6-alkylene group,

to react with a compound of general formula (XXI I) :

(XXII),

in which R¹ is as defined for the compound of general formula (I) according to any one of claims 1 to 7, and in which LG⁴ represents a leaving group,

in the presence of a palladium catalyst,

thereby giving a compound of general formula (I) :

in which R¹ , R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7.

A compound of general formula (I) according to any one of claims 1 to 7 for use in the treatment or prophylaxis of a disease.

A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 7 and one or more pharmaceutically acceptable excipients.

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 7, and

one or more further active ingredients, in particular anticancer agents.

Use of a compound of general formula (I) according to any one of claims 1 to 7 for the treatment or prophylaxis of a disease. Use of a compound of general formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prophylaxis of a disease.

Use according to claim 10, 13 or 14, wherein the disease is a hyperproliferative or an inflammatory disorder, such as a cancer, for example.

A compound of general formula (XXI):

(XXI),

in which R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7, and in which R^B, which can be different or identical, represent a hydrogen atom or a Ci-C4-alkyl group, or both R^B groups together form a C2-C6-alkylene group.

17. Use of a compound of general formula (XXI)

(XXI),

in which R², R³, R⁴, R⁵, R^6a and R^6b are as defined for the compound of general formula (I) according to any one of claims 1 to 7, and in which R^B, which can be different or identical, represent a hydrogen atom or a Ci-C4-alkyl group, or both R^B groups together form a C2-C6-alkylene group,

for the preparation of a compound of general formula (I) according to any one of claims 1 to 7.