WO2015113927A1

WO2015113927A1 - Amino-substituted isothiazoles

Info

Publication number: WO2015113927A1
Application number: PCT/EP2015/051459
Authority: WO
Inventors: Lars BÄRFACKER; Gerhard Siemeister; Tobias Heinrich; Stefan Prechtl; Detlef STÖCKIGT; Antje Rottmann
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2014-01-29
Filing date: 2015-01-26
Publication date: 2015-08-06

Abstract

The present invention relates to amino-substituted isothiazoles of general formula (I): in which A, R1 and R2 are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

Description

AMINO-SUBSTITUTED ISOTHIAZOLES

The present invention relates to amino-substituted isothiazole compounds of general formula (I ) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients. BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit the mitotic checkpoint (also known as spindle checkpoint, spindle assembly checkpoint) . The mitotic checkpoint is a surveillance mechanism that ensures proper chromosome segregation during mitosis. Every dividing cell has to ensure equal separation of the replicated chromosomes into the two daughter cells. Upon entry into mitosis, chromosomes are attached at their kinetochores to the microtubules of the spindle apparatus. The mitotic checkpoint is active as long as unattached kinetochores are present and prevents mitotic cells from entering anaphase and thereby completing cell division with unattached chromosomes [Suijkerbuijk and Kops, Biochemica et Biophysica Acta, 2008, 1786, 24-31 ; Musacchio and Salmon, Nat Rev Mol Cell Biol. , 2007, 8, 379-93] . Lack of attachment results in the production of a molecular inhibitor of the anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase marking cyclin B and securin for proteasomal degradation [Pines J. Cubism and the cell cycle: the many faces of the APC/C. Nat. Rev. Mol. Cell Biol. 12, 427-438, 2012] . Once all kinetochores are attached in a correct amphitelic, i. e. bipolar, fashion with the mitotic spindle, the checkpoint is satisfied, APC/C gets active, and the cell enters anaphase and proceeds through mitosis. On a molecular basis the inhibitor of APC/C, the mitotic checkpoint complex (MCC) represents a complex of mitotic arrest deficient (Mad)-2, budding uninhibited by benzimidazole (Bub)- related-1 (BubR-1 )/Mad-3, and Bub3 that directly binds and inactivates the essential APC/C stimulatory cofactor Cdc20. The protein kinase monopolar spindle-1 (Mps1 ) stimulates MCC assembly via Mad1 and, thus, represents the key activator of the spindle assembly checkpoint [recently reviewed in Vleugel at al. Evolution and function of the mitotic checkpoint. Dev. Cell 23, 239-250, 2012] . Furthermore, the protein kinase Bub1 contributes to APC/C inhibition by phosphorylation of Cdc20.

There is ample evidence linking reduced but incomplete mitotic checkpoint function with aneuploidy and tumorigenesis [Weaver and Cleveland, Cancer Research, 2007, 67, 10103-5; King, Biochimica et Biophysica Acta, 2008, 1786, 4- 14] . In contrast, complete inhibition of the mitotic checkpoint, e.g. by knockdown of protein components of the checkpoint, has been recognised to result in severe chromosome missegregation and induction of apoptosis in tumour cells [Kops et al. , Nature Reviews Cancer, 2005, 5, 773-85; Schmidt and Medema, Cell Cycle, 2006, 5, 159-63; Schmidt and Bastians, Drug Resistance Updates, 2007, 10, 162-81 ] .

Interference with cell cycle regulation by chemical substances has long been recognized as a therapeutic strategy for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation. Classical approaches focus on the inhibition of mitotic progression (e.g. with antitubulin drugs, antimetabolites or CDK-inhibitors). Recently, a novel approach has gathered attention in inhibiting the mitotic checkpoint [Manchado et al. , Cell Death and Differentiation, 2012, 19, 369-377; Colombo and Moll, Expert Opin. Ther. Targets, 201 1 , 15(5), 595-608; Janssen and Medema, Oncogene, 201 1 , 30(25), 2799-809] . Abrogation of the mitotic checkpoint is expected to increase erroneous chromosome segregation in cancer cells resulting in severe aneuploidy and cell death. Chemical inhibitors of Mps1 kinase activity have been published [Lan and Cleveland, J Cell Biol, 2010, 190, 21 -24; Colombo et al. , Cancer Res. , 2010, 70, 10255-64 ; Tardif et al. Characterization of the cellular and antitumor effects of MPI-0479605, a small- molecule inhibitor of the mitotic kinase Mps1 . Mol. Cancer Ther. 10, 2267-2275, 201 1 ] . WO201 1 /063908 (Bayer Intellectual Property GmbH) relates to triazolopyridine compounds which are monopolar spindle 1 kinase (MPS-1 or TTK) inhibitors. WO 2012/080230 (Bayer Intellectual Property GmbH) relates to substituted imidazopyrazine compounds which are monopolar spindle 1 kinase (MPS-1 or TTK) inhibitors.

These Mps1 -kinase directed compounds showed rapid inhibition of nocodazole- induced mitotic checkpoint activity, chromosome segregation defects and anti- proliferative activity in cellular assays, as well as tumor growth inhibitory effects in xenograft models.

The present invention relates to chemical compounds which inhibit the mitotic checkpoint in cellular assays without directly interfering with Mps1 kinase activity or with any other of the kinases reported of being involved in mitotic checkpoint such as Bub1 , BubR1 , Aurora A-C, or CDK1 . Thus, the present invention discloses a novel approach for chemical intervention with mitotic checkpoint function.

WO 201 1 /003793 (BASF SE) relates to pyridazine compounds for controlling invertebrate pests, to a method for controlling invertebrate pests, to a method for protecting plant propagation material and/or the plants which grow therefrom, to plant propagation material, comprising at least one such compound, to a method for treating or protecting an animal from infestation or infection by parasites and to an agricultural composition containing at least one such compound. WO 2002/068406 (Amgen Inc. ) relates to substituted amine derivatives for the prophylaxis and treatment of diseases, such as angiogenesis mediated diseases.

However, the state of the art described above does not describe the specific substituted isothiazole compounds of general formula (I ) of the present invention as defined herein, i. e. an isothiazole moiety, bearing : in its 3-position , a Ci -C3-alkyl-group, and in its 4-position, a group of structure:

O

. R²

wherein : - * indicates the point of attachment of said groups with the rest of the molecule , and

- R² represents phenyl or pyridinyl, which is optionally substituted as defined herein, and - in its 5-position, a group of structure:

H

wherein :

- * indicates the point of attachment of said groups with the rest of the molecule , and

A represents a heteroaryl group

- wherein * indicates the point of attachment of said heteroaryl group, which is as defined herein and which is optionally substituted as defined herein; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as "compounds of the present invention", or their pharmacological activity.

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

In particular, said compounds of the present invention have surprisingly been found to effectively inhibit the spindle assembly checkpoint and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof. DESCRIPTION of the INVENTION

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

(I) in which :

A represents a heteroaryl group selected from

wherein one of X¹, X² and X³ represents an N, 0 or S as ring atom and the others of X¹, X² and X³ represent carbon as ring atoms, and

wherein X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms or one of X⁴, X⁵,

X⁶ and X⁷ represent an N atom, and the others of X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms, and

wherein X¹ and X² or X² and X³ or X⁴ and X⁵ or X⁵ and X⁶ or X⁶ and X⁷ optionally form part of an additional 5-membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, and which ring is unsaturated or partially saturated, and

wherein * indicates the point of attachment of said groups with the rest of the molecule ,

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₆-haloalkoxy, C2-C₆-alkenyl, C2-C₆-alkynyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-, R⁶(R⁷)NC(=0)-(Ci -C₆-alkyl)-, R⁸S-(Ci -C₆-alkyl)-, R⁸S(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(Ci -C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(Ci -C₆-alkyl)-, R³OC(=0)-(Ci -C₆- alkyl)-, -NR⁴R⁵, -C(=0)N(R⁴)R⁵, phenyl, 5-membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group,

which is connected to said heteroaryl group via a carbon atom of the azetidine group,

or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl)-(Ci -C3- alkyl)- group,

wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl,

said phenyl and said 5-membered heteroaryl containing two heteroatoms being substituted, one or two times, identically or differently, with a substituent selected from: a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group, said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from: a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

-C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷-group, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from :

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

and, said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted, one or two times, identically or differently, with a substituent selected from :

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, or cyano,

represents a Ci -C₃-alkyl-group, represents a group selected from : phenyl or pyridinyl,

said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, phenyl, phenyloxy,

said phenyl and phenyloxy group being optionally substituted, one or two times, identically or differently, with a substituent selected from:

a halogen atom, or a Ci -C₃-alkyl-, or a Ci -C₃-alkoxy-group,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

represents :

a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

Ci-C₆-alkyl, Ci-C₆-haloalkyl, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

or with two halogen atoms,

said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from:

represents :

a hydrogen atom, or a group selected from Ci-C₆-alkyl, Ci-C₆-haloalkyl,

C₃-C₆-cycloalkyl, R¹¹(R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci-C₃-alkyl)-0-(C₂-C6-alkyl)-,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

said azetidine group optionally being substituted with a substituent selected from:

Ci-C₆-alkyl, Ci-C₆-haloalkyl, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano,

or with two halogen atoms, or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group being substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano,

R⁶ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, Cs-Ce-cycloalkyl, R^{1 1} (R¹²)N - (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-,

(Ci -C₃-alkyl)-0- (C₂-C₆-alkyl)-, R³OC(=0)- (Ci -C₆-alkyl)-, R⁸S- (C₂-C₆-alkyl)-, R⁸S(=0)- (C₂-C₆-alkyl)-, R⁸S(=0)₂- (C₂-C₆-alkyl)-, R⁸S(=N R⁹)(C=0)- (C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

said 5- or 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂,

said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR^{1 3}, or with two halogen atoms,

said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from :

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

R⁷ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, Cs-Ce-cycloalkyl, R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0- (C₂-C6-alkyl)-,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms,

or, R⁶ and R⁷ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times, identically or differently, with a substituent selected from :

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR³,

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group,

R⁹ represents: a hydrogen atom, or a group selected from cyano, or -C(=0)R¹⁰,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group,

R^{1 1} represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

or, R^{1 1} and R¹² together with the nitrogen to which they are attached represent: a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- to 6-membered heterocycloalkyl group optionally contains one further heteroatom selected from the group consisting of 0, N and S,

R¹³ represents a Ci -C₆-alkyl-group,

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

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

A represents a heteroaryl group selected from :

wherein one of X¹ , X² and X³ represents an N, 0 or S as ring atom and the others of X¹ , X² and X³ represent carbon as ring atoms, and

wherein X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms or one of X⁴, X⁵, X⁶ and X⁷ represent an N atom, and the others of X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms, and wherein X¹ and X² or X² and X³ or X⁴ and X⁵ or X⁵ and X⁶ or X⁶ and X⁷ optionally form part of an additional 5-membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, and which ring is unsaturated or partially saturated, and

or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl)-(Ci -C3- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl, said phenyl and said 5-membered heteroaryl containing two heteroatoms being substituted, one or two times, identically or differently, with a substituent selected from: a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group, said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from: a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, or cyano, R¹ represents a Ci -C3-alkyl-group,

R² represents a group selected from :

phenyl or pyridinyl,

a halogen atom, or a Ci -C₃-alkyl-, or a Ci -C₃-alkoxy-group,

R³ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents :

a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)2, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2,

or with two halogen atoms,

R⁵ represents :

a hydrogen atom, or a group selected from Ci-C₆-alkyl, Ci-C₆-haloalkyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group, said azetidine group optionally being substituted with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C6- cycloalkyl, C3-C6-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano, or with two halogen atoms,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group being substituted, one or two times, identically or differently, with a substituent selected from:

R⁶ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-,

(Ci -C₃-alkyl)-0- (C₂-C₆-alkyl)-, R³OC(=0)- (Ci -C₆-alkyl)-, R⁸S- (C₂-C₆-alkyl)-, R⁸S(=0)- (C₂-C₆-alkyl)-, R⁸S(=0)₂- (C₂-C₆-alkyl)-, R⁸S(=NR⁹)(C=0)- (C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

R⁷ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C6-alkyl)-,

or,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, with two halogen atoms,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times, identically or differently, with a substituent selected from:

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group,

R^{1 1} represents: a hydrogen atom, or a Ci -C₆-alkyl-group, ^! represents: a hydrogen atom, or a Ci -C₆-alkyl-grou

or,

R^{1 1} and R¹² together with the nitrogen to which they are attached represent: a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- to 6-membered heterocycloalkyl group optionally contains one further heteroatom selected from the group consisting of 0, N and S,

R¹³ represents a Ci -C₆-alkyl-group,

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

The term "halogen atom", "halo-" or "Hal-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom .

The term "Ci -C₆-alkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3, 3- dimethylbutyl, 2,2-dimethylbutyl, 1 , 1 -dimethylbutyl, 2,3-dimethylbutyl, 1 ,3- dimethylbutyl, or 1 ,2-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, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci -C3-alkyl"), e.g. a methyl, ethyl, n- propyl- or iso-propyl group.

The term "Ci -C6-haloalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci -C₆-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said Ci -C₆- haloalkyl group is, for example, -CF₃, -CHF2, -CH2F, -CF₂CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, or CH₂CH₂CF₃.

The term "Ci -C6-alkoxy" is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n- hexoxy group, or an isomer thereof.

The term "Ci -C6-haloalkoxy" is to be understood as meaning a linear or branched, saturated, monovalent Ci -C₆-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said Ci -C₆-haloalkoxy group is, for example, -OCF₃, -OCHF₂, -OCH₂F, -OCF₂CF₃, or -OCH₂CF₃.

The term "C₂-C₆-alkenyl" is to be understood as meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C₃- alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)- but-2-enyl, (E)-but-1 -enyl, (Z)-but-1 -enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)- pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1 -enyl, (Z)-pent-1 -enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)- hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1 -enyl, (Z)-hex-1 -enyl, isopropenyl, 2- methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-1 -enyl, (E)-1- methylprop-1 -enyl, (Z)-1 -methylprop-1 -enyl, 3-methylbut-3-enyl, 2-methylbut- 3-enyl, 1 -methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2- methylbut-2-enyl, (E)-1 -methylbut-2-enyl, (Z)-1 -methylbut-2-enyl, (E)-3- methylbut-1 -enyl, (Z)-3-methylbut-1 -enyl, (E)-2-methylbut-1 -enyl, (Z)-2- methylbut-1 -enyl, (E)-1 -methylbut-1 -enyl, (Z)-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, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1 -methylpent-3-enyl, (Z)- 1 -methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3- methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2- methylpent-2-enyl, (E)-1 -methylpent-2-enyl, (Z)-1 -methylpent-2-enyl, (E)-4- methylpent-1 -enyl, (Z)-4-methylpent-1 -enyl, (E)-3-methylpent-1 -enyl, (Z)-3- methylpent-1 -enyl, (E)-2-methylpent-1 -enyl, (Z)-2-methylpent-1 -enyl, (E)-1- methylpent-1 -enyl, (Z)-1 -methylpent-1 -enyl, 3-ethylbut-3-enyl, 2-ethylbut-3- enyl, 1 -ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2- ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1 -ethylbut-2-enyl, (Z)-1 -ethylbut-2- enyl, (E)-3-ethylbut-1 -enyl, (Z)-3-ethylbut-1 -enyl, 2-ethylbut-1 -enyl, (E)-1- ethylbut-1 -enyl, (Z)-1 -ethylbut-1 -enyl, 2-propylprop-2-enyl, 1 -propylprop-2- enyl, 2-isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, (E)-2-propylprop-1 -enyl, (Z)-2-propylprop-1 -enyl, (E)-1-propylprop-1-enyl, (Z)-1 -propylprop-1 -enyl, (E)-2- isopropylprop-1 -enyl, (Z)-2-isopropylprop-1 -enyl, (E)-1 -isopropylprop-1 -enyl, (Z)-1 -isopropylprop-1 -enyl, (E)-3,3-dimethylprop-1 -enyl, (Z)-3,3-dimethylprop-1 - enyl, 1 -(1 , 1 -dimethylethyl)ethenyl, buta-1 ,3-dienyl, penta-1 ,4-dienyl, hexa-1 ,5- dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.

The term "C2-C₆-alkynyl" is to be understood as meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, 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, 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-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2- ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2- methylpent-4-ynyl, 1 -methylpent-4-ynyl, 2-methylpent-3-ynyl, 1 -methylpent-3- ynyl, 4-methylpent-2-ynyl, 1 -methylpent-2-ynyl, 4-methylpent-1 -ynyl, 3- methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl, 1 - propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl, 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-inyl.

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

The term "C3-C6-cycloalkyloxy" is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon group of formula -O-cycloalkyl, in which the term "cycloalkyl" is defined supra, e.g. a. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group. The term "heteroaryl" is understood as meaning a monocyclic- , aromatic ring system having 5 or 6 ring atoms (a "5- or 6-membered heteroaryl" group), which contains one nitrogen atom, said "5- membered heteroaryl" containing one additional heteroatom being such as oxygen, nitrogen or sulfur, and said "6- membered heteroaryl" optionally containing one additional nitrogen atom, said "5- or 6-membered heteroaryl" optionally being condensed to a second 5- or 6- membered ring, this ring optionally containing one further heteroatom being such as oxygen, nitrogen or sulfur, and which second ring is unsaturated or partially saturated, thereby forming a bicyclic ring system. Particularly, "heteroaryl", which is a "5- or 6-membered heteroaryl" as defined above, which is condensed to another 5- or 6-membered ring, as defined above, thereby forming a bicyclic ring system, is selected from imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and annelated derivatives thereof, such as, for example, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, quinolinyl, quinazolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, thienopyrimidinyl, etc.

The term "5-membered heteroaryl containing three heteroatoms" is understood as meaning a monocyclic- , aromatic ring system having 5 ring atoms, which contains two nitrogen atoms and one oxygen atom, or which contains two nitrogen atoms and one sulphur atom, or which contains three nitrogen atoms. Particularly, "5-membered heteroaryl containing three heteroatoms" is selected from oxadiazolyl, thiadiazolyl, triazolyl.

The term "5- to 6-membered heterocycloalkyl", or "5- to 6-membered heterocyclyl", is to be understood as meaning a saturated, or partially unsaturated, monovalent, monocyclic ring which contains one N atom or one NH-group and 4 or 5 carbon atoms, wherein one carbon atom is optionally replaced by a further heteroatom selected from the group consisting of N, 0 and S , or by a heteroatom containing group S(=0), S(=0)2, NH. Said 5- to 6- membered heterocycloalkyl is for example, a pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl. The term "5- to 6-membered", as used throughout this text, is to be understood as meaning "5- or 6-membered"

In general, and unless otherwise mentioned, the heteroarylic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

The term "Ci -C₆", as used throughout this text, e.g. in the context of the definition of "Ci -Ce-alkyl", "Ci -Ce-haloalkyl", "Ci -Ce-alkoxy", or "Ci -C₆- haloalkoxy" is to be understood as meaning 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. It is to be understood further that said term "Ci -C₆" is to be interpreted as any sub- range comprised therein, e.g. Ci -C₆ , C2-C5 , C₃-C₄ , C1 -C2 , Ci -C₃ , Ci -C₄ , C1 -C5 _; particularly C1 -C2 , Ci -C₃ , Ci -C₄ , C1 -C5, Ci -C₆; more particularly Ci -C₄ ; in the case of "Ci -C6-haloalkyl" or "Ci -C6-haloalkoxy" even more particularly C1 -C2.

Similarly, as used herein, the term "C2-C6", as used throughout this text, e.g. in the context of the definitions of "C2-C₆-alkenyl" and "C2-C₆-alkynyl", is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i. e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C2-C6" is to be interpreted as any sub-range comprised therein, e.g. Ci-Cb , C₃-Cs , C₃-C₄ , C2-C₃ , C2-Q , C2-C5 _; particularly C2- C₃.

Further, as used herein, the term "C₃-C₆", as used throughout this text, e.g. in the context of the definition of "C₃-C₆-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i. e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C₃- C₆" is to be interpreted as any sub-range comprised therein, e.g. C₃-C₆ , C₄-Cs , C₃-C5 , C₃-C₄ , C₄-C₆, C5-C6 ; particularly C₃-C₆.

The term ^"substituted^" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom^'s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term ^"optionally substituted^" means optional substitution with the specified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system .

As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".

The invention also includes all suitable isotopic variations of a compound of the invention . An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³l, ¹²⁴l, ¹²⁹l and ¹³¹l, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as ³H or ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e. , ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.

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 this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms is present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may 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.

The compounds of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure:

, for example, in which * indicates atoms to which the rest of the molecule can be bound.

Substituents on a ring may also be present in either cis or trans form . It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.

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

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g. , chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g. , Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

In order to limit 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, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, namely :

1 H-tautomer 2H-tautomer

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 relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and 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. The amount of polar solvents, in particular water, may 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, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can 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, customarily used in pharmacy.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, 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, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, 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, persulfuric, 3-phenylpropionic, picric, pivalic, 2- hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 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, hemisulfuric, 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 or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N- methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 - amino-2, 3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Those skilled in the art will further recognise that acid addition salts of the claimed compounds may 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 invention are prepared by reacting the compounds of the 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 such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF3COOH^", "x Na⁺", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.

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.

As used herein, the term "in vivo hydrolysable ester" is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci -C₆ alkoxymethyl esters, e.g. methoxymethyl, Ci -C₆ alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-Ci -C₆ alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1 ,3-dioxolen-2-onylmethyl ; and Ci -C₆-alkoxycarbonyloxyethyl esters, e.g. 1 -methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha] - acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha] -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.

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 covers compounds of general formula (I ), supra, in which : A represents a heteroaryl group selected from :

wherein X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms or one of X⁴, X⁵, X⁶ and X⁷ represent an N atom, and the others of X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms, and

wherein ^* indicates the point of attachment of said groups with the rest of the molecule ,

Ci -C₆-haloalkoxy, C2-C₆-alkenyl, C2-C₆-alkynyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-, R⁶(R⁷)NC(=0)-(Ci -C₆-alkyl)-, R⁸S-(Ci -C₆-alkyl)-, R⁸S(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(Ci -C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(Ci -C₆-alkyl)-, R³OC(=0)-(Ci -C₆- alkyl)-, -NR⁴R⁵, -C(=0)N(R⁴)R⁵, phenyl, 5-membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group, which azetidine group is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which 5- to 6-membered heterocycloalkyl is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group,

or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C₃- alkyl)- group,

said phenyl and said 5-membered heteroaryl containing two heteroatoms being substituted, one or two times, identically or differently, with a substituent selected from:

a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group, said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from:

a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

-C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷-group,

or with two halogen atoms,

said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C₆-cycloalkyl, C3-C6-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, or cyano,

R¹ represents a methyl-group,

R² represents a group selected from : phenyl or pyridinyl,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, phenyl, phenyloxy,

said phenyl and phenyloxy group being optionally substituted, one or two times, identically or differently, with a substituent selected from: a halogen atom, or a Ci -C3-alkyl-, or a Ci -C3-alkoxy-group,

R³ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents :

a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R¹¹ (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

or with two halogen atoms,

R⁵ represents a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, Cs-Ce-cycloalkyl, R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0- (C₂-C6-alkyl)-,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano, or with two halogen atoms,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano,

R⁶ represents : a hydrogen atom, or a group selected from Ci-C₆-alkyl, Ci-C₆-haloalkyl, Cs-Ce-cycloalkyl, R¹¹(R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-,

(Ci-C₃-alkyl)-0-(C₂-C6-alkyl)-, R³OC(=0)-(Ci-C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(C=0)-(C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

Ci-C₆-alkyl, Ci-C₆-haloalkyl, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

or with two halogen atoms,

represents : a hydrogen atom, or a group selected from Ci-C₆-alkyl, Ci-C₆-haloalkyl,

CrCe-cycloalkyl, R¹¹(R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci-C₃-alkyl)-0-(C₂-C₆-alkyl)-, or,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times, identically or differently, with a substituent selected from : Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR³,

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group,

represents: a hydrogen atom, or a group selected from cyano, or -C(=0)R¹⁰,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group,

R^{1 1} represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

or,

R¹³ represents a Ci -C₆-alkyl-group,

In accordance with a variant of the second embodiment of the first aspect, the present invention covers compounds of general formula (I ), supra, in which : represents a heteroaryl group selected from :

which azetidine group is connected to said heteroaryl group via a carbon atom of the azetidine group,

or being substituted with a 5- to 6-membered heterocycloalkyl group, which 5- to 6-membered heterocycloalkyl is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group,

or being substituted with a (5- to 6-membered heterocycloalkyl)-(Ci -C₃- alkyl)- group,

a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group,

said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from:

a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

-C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷-group,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy,

C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from :

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

R¹ represents a methyl-group,

R² represents a group selected from : phenyl or pyridinyl,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, phenyl, phenyloxy, said phenyl and phenyloxy group being optionally substituted, one or two times, identically or differently, with a substituent selected from:

a halogen atom, or a Ci -C₃-alkyl-, or a Ci -C₃-alkoxy-group,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

represents :

a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂,

or with two halogen atoms,

said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C₃-C₆- cycloalkyl, C3-C6-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

R⁵ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, Cs-Ce-cycloalkyl, R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0- (C₂-C6-alkyl)-,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a substituent selected from:

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group being substituted, one or two times, identically or differently, with a substituent selected from: Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano,

represents :

(Ci -C₃-alkyl)-0- (C₂-C6-alkyl)-, R³OC(=0)- (Ci -C₆-alkyl)-, R⁸S- (C₂-C₆-alkyl)-, R⁸S(=0)- (C₂-C₆-alkyl)-, R⁸S(=0)₂- (C₂-C₆-alkyl)-, R⁸S(=N R⁹)(C=0)- (C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR^{1 3},

or with two halogen atoms,

represents a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, Cs-Ce-cycloalkyl, R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0- (C₂-C6-alkyl)-,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent:

a azetidine group,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR^{1 3},

or with two halogen atoms,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent:

a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR³, R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C6-cycloalkyl-group,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group,

R^{1 1} represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

or,

R¹³ represents a Ci -C₆-alkyl-group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

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

A represents a heteroaryl group selected from :

wherein ^* indicates the point of attachment of said groups with the rest of the molecule , said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from:

or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group,

a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group,

said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from: a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from :

R¹ represents a methyl-group,

R² represents a group selected from : phenyl or pyridinyl,

said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from: Ci -C₆-alkoxy, or a halogen atom,

R³ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents :

a group selected from:

d-Ce-haloalkyl, Cs-Ce-cycloalkyl, R¹¹ (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂,

or with two halogen atoms,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, R⁵ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl,

Cs-Ce-cycloalkyl, R¹¹(R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano,

or with two halogen atoms,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano, R⁶ represents : a hydrogen atom, or a group selected from Ci-C₆-alkyl, Ci-C₆-haloalkyl, Cs-Ce-cycloalkyl, R¹¹(R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-,

(Ci-C₃-alkyl)-0-(C₂-C6-alkyl)-,

R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(C=0)-(C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

or with two halogen atoms,

R⁷ represents :

a hydrogen atom, or a group selected from Ci-C₆-alkyl, Ci-C₆-haloalkyl, CrCe-cycloalkyl, R¹¹(R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci-C₃-alkyl)-0-(C₂-C₆-alkyl)-, or,

or,

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group, R⁹ represents: a hydrogen atom, or a group selected from cyano, or -C(=0)R¹⁰,

_R10 represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group,

R^{1 1} represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

or,

R¹³ represents a Ci -C₆-alkyl-group,

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

a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group,

a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

-C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷-group,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from : Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy,

C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

represents a methyl-group,

represents a group selected from : phenyl or pyridinyl,

Ci -C₆-alkoxy, or a halogen atom,

represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, represents : a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R¹¹ (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂,

or with two halogen atoms,

represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl,

CrCe-cycloalkyl, R¹¹(R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, or,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano, or with two halogen atoms,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group being substituted, one or two times, identically or differently, with a substituent selected from: Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl,

C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano,

(Ci -C₃-alkyl)-0- (C₂-C₆-alkyl)-, R³OC(=0)- (Ci -C₆-alkyl)-, R⁸S- (C₂-C₆-alkyl)-, R⁸S(=0)- (C₂-C₆-alkyl)-, R⁸S(=0)₂- (C₂-C₆-alkyl)-, R⁸S(=NR⁹)(C=0)- (C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)2, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from :

R⁷ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times, identically or differently, with a substituent selected from :

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C6-haloalkyl-group,

R¹¹ represents:

a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹² represents:

a hydrogen atom, or a Ci -C₆-alkyl-group,

or,

R¹¹ and R¹² together with the nitrogen to which they are attached represent: a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- to 6-membered heterocycloalkyl group optionally contains one further heteroatom selected from the group consisting of 0, N and S,

R¹³ represents a Ci -C₆-alkyl-group,

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

A represents a heteroaryl group selected from :

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: d-Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-,

R⁸S(=0)₂-(Ci -C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, -C(=0)N(R⁴)R⁵, 5- membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms,

or being substituted with an azetidine group,

said 5-membered heteroaryl containing two heteroatoms being substituted with a substituent selected from:

a -C(=0)OR³-group,

a Ci -C₃-alkyl-group,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from: Ci -C6-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

and,

said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from:

Ci -C₆-haloalkyl, or a halogen atom,

R¹ represents a methyl-group,

R² represents a group selected from

phenyl or pyridinyl,

Ci -C₆-alkoxy, or a halogen atom,

R³ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents :

a group selected from:

R¹¹(R¹²)N- (C₂-C₆-alkyl)-, (Ci -C₃-alkyl)-0-(C₂-C6-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(C₂-Ce-alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

said 5- or 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)2, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2,

d -Ce-haloalkyl, or -C(=0)OR^{1 3},

said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, or Ci -C₆-haloalkyl,

R⁵ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

said azetidine group optionally being substituted, with a substituent selected from:

amino,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl,

R⁶ represents :

a Ci -C₆-alkyl group,

represents :

a group selected from Ci -C₆-alkyl, or Ci -C₆-haloalkyl,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group,

said azetidine group optionally being substituted with a :

Ci -C₆-haloalkyl, or a halogen atom,

or with two halogen atoms,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent:

a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times, identically or differently, with a substituent selected from: Ci -C6-haloalkyl, or a halogen atom,

represents : a Ci -C₆-alkyl-group,

R^{1 1} represents: a hydrogen atom,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹³ represents a Ci -C₆-alkyl-group,

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

A represents a heteroaryl group selected from

d-Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-,

or being substituted with an azetidine group,

a -C(=0)OR³-group,

a Ci -C₃-alkyl-group, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

and,

Ci -C₆-haloalkyl, or a halogen atom,

represents a methyl-group, R² represents a group selected from :

phenyl or pyridinyl,

Ci -C₆-alkoxy, or a halogen atom,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents :

a group selected from:

R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, (Ci -C₃-alkyl)-0- (C₂-C6-alkyl)-, R³OC(=0)- (Ci -C₆-alkyl)-, R⁸S(=0)₂- (C₂-Ce-alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

d-Ce-haloalkyl, or -C(=0)OR^{1 3},

Ci -C₆-alkyl, or Ci -C₆-haloalkyl, R⁵ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

amino,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl,

R⁶ represents :

a Ci -C₆-alkyl group,

R⁷ represents : a group selected from Ci -C₆-alkyl, or Ci -C₆-haloalkyl, or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a : Ci -C₆-haloalkyl, or a halogen atom, or with two halogen atoms,

or,

Ci -C₆-haloalkyl, or a halogen atom,

R⁸ represents : a Ci -C₆-alkyl-group,

R^{1 1} represents: a hydrogen atom,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹³ represents a Ci -C₆-alkyl-group,

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

A represents a heteroaryl group selected from :

wherein X¹ and X² or X² and X³ or X⁴ and X⁵ or X⁵ and X⁶ or X⁶ and X⁷ optionally form part of an additional 5-membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, and which ring is unsaturated or partially saturated, and wherein * indicates the point of attachment of said groups with the rest of the molecule ,

d-Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-,

or being substituted with an azetidine group,

a -C(=0)OR³-group, said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from:

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, a halogen atom, or -C(=0)OR¹³,

and, said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from:

Ci -C₆-haloalkyl, or a halogen atom,

represents a methyl-group,

represents a group selected from : phenyl or pyridinyl,

Ci -C₆-alkoxy, or a halogen atom,

R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, (Ci -C₃-alkyl)-0-(C₂-C6-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

d-Ce-haloalkyl, or -C(=0)OR¹³, said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from:

Ci -C₆-alkyl, or Ci -C₆-haloalkyl,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

amino, or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl, or amino,

R⁶ represents :

a Ci -C₆-alkyl group,

R⁷ represents :

a group selected from Ci -C₆-alkyl, or Ci -C₆-haloalkyl,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent:

a azetidine group,

said azetidine group optionally being substituted with a :

Ci -C₆-haloalkyl, or a halogen atom,

or with two halogen atoms,

or, R⁶ and R⁷ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₆-haloalkyl, or a halogen atom,

R⁸ represents : a Ci -C₆-alkyl-group,

represents: a hydrogen atom,

represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹³ represents a Ci -C₆-alkyl-group,

In accordance with a further variant of the fourth embodiment of the first aspect, the present invention covers compounds of general formula (I ), supra, in which : represents a heteroaryl group selected from :

d-Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-,

or being substituted with an azetidine group,

a -C(=0)OR³-group,

a Ci -C₃-alkyl-group,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, a halogen atom, or -C(=0)OR¹³, and,

Ci -C₆-haloalkyl, or a halogen atom,

represents a methyl-group,

represents a group selected from :

phenyl or pyridinyl,

Ci -C₆-alkoxy, or a halogen atom,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

represents :

a group selected from:

R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(C₂-Ce-alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2,

d-Ce-haloalkyl, or -C(=0)OR¹³,

Ci -C₆-alkyl, or Ci -C₆-haloalkyl,

R⁵ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

amino,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl, amino, or hydroxy,

R⁶ represents :

a Ci -C₆-alkyl group,

represents :

a group selected from Ci -C₆-alkyl, or Ci -C₆-haloalkyl,

or,

said azetidine group optionally being substituted with a :

Ci -C₆-haloalkyl, or a halogen atom,

or with two halogen atoms,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent:

R⁸ represents : a Ci -C₆-alkyl-group,

R¹¹ represents: a hydrogen atom,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹³ represents a Ci -C₆-alkyl-group,

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

A represents a heteroaryl group selected from :

wherein X¹ represents an S as ring atom and X² and X³ represent carbon as ring atoms, and wherein X⁴, X⁵ , X⁶ and X⁷ represent carbon as ring atoms or X⁵ represents an N atom, and X⁴, X⁶ and X⁷ represent carbon as ring atoms, and

wherein X² and X³ optionally form part of an additional 6-membered ring, which ring is unsaturated or partially saturated, and

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, R⁶(R⁷)N- (Ci - C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, R³OC(=0) - (Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C3- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl,

said pyrazolyl being substituted with a substituent selected from : a -C(=0)OR³-group, said oxadiazolyl being substituted with a substituent selected from: a methyl-group, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from :

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom,

and, said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from: trifluoromethyl, or a chlorine atom,

R¹ represents a methyl-group,

R² represents a group selected from : phenyl or pyridinyl,

said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from: methoxy, or a fluorine, or a chlorine atom,

R³ represents : a hydrogen atom, or a group selected from Ci -C₂-alkyl,

R⁴ represents :

a group selected from:

R^{1 1} (R¹²)N- (C₂-C3-alkyl)-, (2-methoxy)ethyl-, R³OC(=0)-(Ci -C₂-alkyl)-,

R⁸S(=0)₂-(ethyl)-, or a azetidine group, or a 6-membered heterocycloalkyl group,

said 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, or a heteroatom containing group S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

d-Cs-haloalkyl, or -C(=0)OR¹³,

methyl, or Ci -C₃-haloalkyl,

R⁵ represents :

a hydrogen atom, or a group selected from methyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

said azetidine group optionally being substituted with a substituent selected from: amino, or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 6-membered heterocycloalkyl group, which contains one further heteroatom selected from the group consisting of N, said 5- to 6-membered heterocycloalkyl group being substituted with a substituent selected from :

Ci -C₃-haloalkyl,

R⁶ represents : a methyl group,

R⁷ represents : a group selected from methyl, or Ci -C₃-haloalkyl,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a : Ci -C₃-haloalkyl, or a fluorine atom, or with two fluorine atoms,

or, R⁶ and R⁷ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times with a substituent selected from:

Ci -C₃-haloalkyl, or a fluorine atom,

R⁸ represents : a methyl-group,

R¹¹ represents: a hydrogen atom,

R¹² represents: a hydrogen atom, or a methyl-group,

R¹³ represents a tert-butyl-group,

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

A represents a heteroaryl group selected from :

wherein X¹ represents an S as ring atom and X² and X³ represent carbon as ring atoms, and

wherein X⁴, X⁵ , X⁶ and X⁷ represent carbon as ring atoms or X⁵ represents an N atom, and X⁴, X⁶ and X⁷ represent carbon as ring atoms, and

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, R⁶(R⁷)N- (Ci - C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, R³OC(=0) - (Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group,

said pyrazolyl being substituted with a substituent selected from: a -C(=0)OR³-group,

said oxadiazolyl being substituted with a substituent selected from: a methyl-group,

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom,

and,

trifluoromethyl, or a chlorine atom,

represents a methyl-group, R² represents a group selected from phenyl or pyridinyl,

methoxy, or a fluorine, or a chlorine atom,

R³ represents :

a hydrogen atom, or a group selected from Ci -C₂-alkyl,

R⁴ represents :

a group selected from:

R^{1 1} ( R¹²)N- (C₂-C3-alkyl)-, (2-methoxy)ethyl-, R³OC(=0) - (Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, or a azetidine group, or a 6-membered heterocycloalkyl group,

said 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, or a heteroatom containing group S(=0)₂,

d -Cs-haloalkyl, or -C(=0)OR^{1 3},

methyl, or Ci -C₃-haloalkyl,

R⁵ represents a hydrogen atom, or a group selected from methyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a substituent selected from: amino,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 6-membered heterocycloalkyl group, which contains one furth heteroatom selected from the group consisting of N, said 5- to 6-membered heterocycloalkyl group being substituted with substituent selected from :

Ci -C₃-haloalkyl,

represents : a methyl group,

represents : a group selected from methyl, or Ci -C₃-haloalkyl,

or, R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a : Ci -C₃-haloalkyl, or a fluorine atom, or with two fluorine atoms,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times with a substituent selected from:

Ci -C₃-haloalkyl, or a fluorine atom,

R⁸ represents : a methyl-group,

R 1 1 represents: a hydrogen atom,

R 12 represents: a hydrogen atom, or a methyl-group, R¹³ represents a tert-butyl-group,

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

A represents a heteroaryl group selected from

wherein X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms or one of X⁵ and X⁷ represents an N atom, and and the others of X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms, and

trifluoromethoxy, vinyl, prop-1 -en-2-yl, R⁶(R⁷)N-(Ci -C₂-alkyl)-, R⁸S(=0)₂- (ethyl)-, R³OC(=0)-(Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group,

or being substituted with a (5- to 6-membered heterocycloalkyl)-(Ci -C₃- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl,

Ci -C₃-haloalkyl, Ci -C₂-alkoxy, or a fluorine atom,

Ci -C₃-haloalkyl, Ci -C₂-alkoxy, a fluorine atom, or -C(=0)OR¹³, and, said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from: trifluoromethyl, or a chlorine atom,

represents a methyl-group,

represents a group selected from : phenyl or pyridinyl,

said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from: methoxy, iso-propoxy, or a fluorine, or a chlorine atom,

represents : a hydrogen atom, or a group selected from Ci -C₂-alkyl,

represents : a group selected from :

R^{1 1} (R¹²)N- (C₂-C₃-alkyl)-, (2-methoxy)ethyl-, R³OC(=0)-(Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, or a azetidine group, or a 6-membered heterocycloalkyl group, said 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, or a heteroatom containing group S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

d -Cs-haloalkyl, or -C(=0)OR^{1 3},

methyl, or Ci -C₃-haloalkyl,

R⁵ represents :

a hydrogen atom, or a group selected from methyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a azetidine group,

amino,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of N,

said 5- to 6-membered heterocycloalkyl group being substituted with a substituent selected from:

Ci -C₃-haloalkyl, or amino, R⁶ represents : a methyl group,

R⁷ represents : a group selected from methyl, or Ci -C₃-haloalkyl,

or,

Ci -C₃-haloalkyl, or a fluorine atom,

R⁸ represents a methyl-group,

represents: a hydrogen atom,

represents: a hydrogen atom, or a methyl-g

R¹³ represents a methyl-group, or a tert-butyl-group,

A represents a heteroaryl group selected from :

wherein X¹ represents an S as ring atom and X² and X³ represent carbon as ring atoms, and wherein X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms or one of X⁵ and X⁷ represents an N atom, and and the others of X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms, and

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, prop- 1 -en-2-yl, R⁶(R⁷)N- (Ci -C₂-alkyl)-, R⁸S(=0)₂- (ethyl)-, R³OC(=0) - (Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C3- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl,

Ci -C₃-haloalkyl, Ci -C2-alkoxy, a fluorine atom, or -C(=0)OR¹³,

R¹ represents a methyl-group,

R² represents a group selected from : phenyl or pyridinyl,

R³ represents : a hydrogen atom, or a group selected from Ci -C₂-alkyl,

represents : a group selected from :

R^{1 1} (R¹²)N- (C₂-C₃-alkyl)-, 2-hydroxy-2-methylpropyl-, (2-methoxy)ethyl-, R³OC(=0)-(Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, or a azetidine group, or a 6- membered heterocycloalkyl group, said 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N and 0, or a heteroatom containing group S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₃-haloalkyl, or -C(=0)OR¹³, said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from : methyl, or Ci -C₃-haloalkyl,

represents : a hydrogen atom, or a group selected from methyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of N, said 5- to 6-membered heterocycloalkyl group being substituted, one or two times, identically or differently, with a substituent selected from: Ci -C₃-haloalkyl, amino, or hydroxy.

R⁶ represents : a methyl group,

R⁷ represents : a group selected from methyl, or Ci -C₃-haloalkyl,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a : Ci -C₃-haloalkyl, or a fluorine atom, or with two fluorine atoms, or,

Ci -C₃-haloalkyl, or a fluorine atom,

R⁸ represents : a methyl-group,

represents: a hydrogen atom,

represents: a hydrogen atom, or a methyl-group,

R¹³ represents a methyl-group, or a tert-butyl-group,

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), wherein :

A represents a heteroaryl group selected from :

a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group,

a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

-C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷-group,

or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from :

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, or cyano.

A represents a heteroaryl group selected from :

wherein X¹ and X² or X² and X³ optionally form part of an additional 5- membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, and which ring is unsaturated or partially saturated, and

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, or cyano. rther embodiment of the above-mentioned aspect, the invention relatespounds of formula (I ), wherein : represents a heteroaryl group selected from

X=X⁴

Χ^έ />—* ^>

wherein X⁴ and X⁵ or X⁵ and X⁶ or X⁶ and X⁷ optionally form part of an additional 5-membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, and which ring is unsaturated or partially saturated, and

Ci -C₆-haloalkoxy, C2-C₆-alkenyl, C2-C₆-alkynyl, R⁶(R⁷)N-(Ci -C₆-alkyl)- , R⁶(R⁷)NC(=0)-(Ci -C₆-alkyl)-, R⁸S-(Ci -C₆-alkyl)-, R⁸S(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(Ci -C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(Ci -C₆-alkyl)-, R³OC(=0)-(Ci -C₆- alkyl)-, -NR⁴R⁵, -C(=0)N(R⁴)R⁵, phenyl, 5-membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group,

said phenyl and said 5-membered heteroaryl containing two heteroatoms being substituted, one or two times, identically or differently, with a substituent selected from: a -C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷ group,

a halogen atom, or a Ci -C₃-alkyl-group, or a Ci -C₃-alkoxy-group, or a

-C(=0)OR³-group, or a -C(=0)N(R⁶)R⁷-group,

or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C₆-cycloalkyl, C3-C6-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

represents a Ci -C3-alkyl-group,

R² represents a group selected from : phenyl or pyridinyl,

a halogen atom, or a Ci -C₃-alkyl-, or a Ci -C₃-alkoxy-group.

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I), wherein :

R³ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl.

R⁴ represents :

a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂, said azetidine group being optionally substituted with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C6- cycloalkyl, C3-C6-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³,

or with two halogen atoms,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³.

R⁴ represents :

a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂, said azetidine group being optionally substituted with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C6- cycloalkyl, C3-C6-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from:

R⁵ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano.

R⁵ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl,

Cs-Ce-cycloalkyl, R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0- (C₂-C₆-alkyl)-.

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group, said azetidine group optionally being substituted with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C6- cycloalkyl, C3-C6-cycloalkyloxy, amino, hydroxy, a halogen atom, or cyano, or with two halogen atoms.

R⁶ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, C₃-C₆-cycloalkyl, R¹¹ (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-,

(Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(C=0)-(C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)2, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2, said azetidine group being optionally substituted with a substituent selected from:

(Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(C=0)-(C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)2, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2, said azetidine group being optionally substituted with a substituent selected from:

R⁷ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)- . In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), wherein :

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C₆-cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms.

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C3-C6- cycloalkyl, C3-C₆-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR³.

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), wherein : R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C6-cycloalkyl-group,

R⁹ represents: a hydrogen atom, or a group selected from cyano, or -C(=0)R¹⁰.

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group.

R^{1 1} represents: a hydrogen atom, or a Ci -C₆-alkyl-group.

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group.

R¹¹ and R¹² together with the nitrogen to which they are attached represent: a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- to 6-membered heterocycloalkyl group optionally contains one further heteroatom selected from the group consisting of 0, N and S.

R¹³ represents a Ci -C₆-alkyl-group.

R¹ represents a methyl-group.

R² represents a group selected from : phenyl or pyridinyl.

Ci -C₆-alkoxy, or a halogen atom .

A represents a heteroaryl group selected from :

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: d -Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N- (Ci -C₆-alkyl)-,

R⁸S(=0)₂- (Ci -C₆-alkyl)-, R³OC(=0) - (Ci -C₆-alkyl)-, -C(=0)N(R⁴)R⁵, 5- membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C3- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl, said 5-membered heteroaryl containing two heteroatoms being substituted with a substituent selected from: a -C(=0)OR³-group, said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from: a Ci -C₃-alkyl-group, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

Ci -C₆-haloalkyl, or a halogen atom.

A represents a heteroaryl group selected from

R⁸S(=0)₂- (Ci -C₆-alkyl)-, R³OC(=0) - (Ci -C₆-alkyl)-, -C(=0)N(R⁴)R⁵, 5- membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C3- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl,

a -C(=0)OR³-group,

said 5-membered heteroaryl containing three heteroatoms being optionally substituted with a substituent selected from: a Ci -C₃-alkyl-group,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

and,

Ci -C₆-haloalkyl, or a halogen atom.

A represents a heteroaryl group selected from :

d-Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-,

or being substituted with an azetidine group,

which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group,

a -C(=0)OR³-group,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

and,

Ci -C₆-haloalkyl, or a halogen atom. In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), wherein :

A represents a heteroaryl group selected from :

wherein X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms or X⁵ represents an N atom, and X⁴, X⁶ and X⁷ represent carbon as ring atoms, and

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, R⁶(R⁷)N-(Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, R³OC(=0)-(Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group,

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom,

and,

said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from: trifluoromethyl, or a chlorine atom. In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), wherein :

A represents a heteroaryl group selected from :

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, R⁶(R⁷)N-(Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, R³OC(=0)-(Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group,

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom,

and,

trifluoromethyl, or a chlorine atom. rther embodiment of the above-mentioned aspect, the invention relatespounds of formula (I), wherein : represents a heteroaryl group selected from

X=X⁴

X- N

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, R⁶(R⁷)N- (Ci - C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, R³OC(=0) - (Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C3- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl, said pyrazolyl being substituted with a substituent selected from: a -C(=0)OR³-group, said oxadiazolyl being substituted with a substituent selected from: a methyl-group, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom, said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom,

and, said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from: trifluoromethyl, or a chlorine atom.

R² represents a group selected from : phenyl or pyridinyl,

said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from: methoxy, or a fluorine, or a chlorine atom.

R³ represents : a hydrogen atom, or a group selected from Ci -C2-alkyl.

R⁴ represents : a group selected from:

R¹¹ (R¹²)N-(C₂-C₃-alkyl)-, (2-methoxy)ethyl-, R³OC(=0)-(Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, or a azetidine group, or a 6-membered heterocycloalkyl group, said 6-membered heterocyclyl group containing one heteroatom selected from the group consisting of N, or a heteroatom containing group S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₃-haloalkyl, or -C(=0)OR¹³, said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from: methyl, or Ci -C₃-haloalkyl.

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), wherein : R⁴ represents : a group selected from :

Ci -C₃-haloalkyl, or -C(=0)OR¹³, said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from : methyl, or Ci -C₃-haloalkyl.

R⁵ represents : a hydrogen atom, or a group selected from methyl.

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a substituent selected from: amino.

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 6-membered heterocycloalkyl group, which contains one further heteroatom selected from the group consisting of N, said 5- to 6-membered heterocycloalkyl group being substituted with a substituent selected from:

Ci -C3-haloalkyl.

R⁶ represents : a methyl group.

represents : a group selected from methyl, or Ci -C₃-haloalkyl, or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a :

Ci -C₃-haloalkyl, or a fluorine atom, or with two fluorine atoms,

or,

Ci -C₃-haloalkyl, or a fluorine atom.

R⁷ represents : a group selected from methyl, or Ci -C₃-haloalkyl,

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), wherein : R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a : Ci -C₃-haloalkyl, or a fluorine atom, or with two fluorine atoms.

Ci -C₃-haloalkyl, or a fluorine atom.

R⁸ represents : a methyl-group.

R¹¹ represents: a hydrogen atom. In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I), wherein :

R¹² represents:

a hydrogen atom, or a methyl-group.

R¹³ represents a tert-butyl-group.

A represents a heteroaryl group selected from

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, a halogen atom, or -C(=0)OR¹³,

Ci -C₆-haloalkyl, or a halogen atom. rther embodiment of the above-mentioned aspect, the invention relatespounds of formula (I ), wherein :

represents a heteroaryl group selected from

R⁸S(=0)₂- (Ci -C₆-alkyl)-, R³OC(=0) - (Ci -C₆-alkyl)-, -C(=0)N(R⁴)R⁵, 5- membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl)-(Ci -C₃- alkyl)- group,

a -C(=0)OR³-group,

a Ci -C₃-alkyl-group,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, a halogen atom, or -C(=0)OR¹³,

and,

Ci -C₆-haloalkyl, or a halogen atom. rther embodiment of the above-mentioned aspect, the invention relatespounds of formula (I), wherein : represents a heteroaryl group selected from

d-Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-,

or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group,

a Ci -C₃-alkyl-group,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, a halogen atom, or -C(=0)OR¹³,

Ci -C₆-haloalkyl, or a halogen atom .

A represents a heteroaryl group selected from :

wherein * indicates the point of attachment of said groups with the rest of the molecule , said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₃-haloalkyl, Ci -C₂-alkoxy, or a fluorine atom,

Ci -C₃-haloalkyl, Ci -C₂-alkoxy, a fluorine atom, or -C(=0)OR¹³, and,

trifluoromethyl, or a chlorine atom.

A represents a heteroaryl group selected from

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, prop-1 -en-2-yl, R⁶(R⁷)N-(Ci -C₂-alkyl)-, R⁸S(=0)₂- (ethyl)-, R³OC(=0)-(Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group,

Ci -C₃-haloalkyl, Ci -C₂-alkoxy, or a fluorine atom,

Ci -C₃-haloalkyl, Ci -C₂-alkoxy, a fluorine atom, or -C(=0)OR¹³, said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from: trifluoromethyl, or a chlorine atom .

A represents a heteroaryl group selected from :

said heteroaryl group, which is monocyclic or bicyclic, being substituted, one or two times, identically or differently, with a substituent selected from: trifluoromethoxy, vinyl, prop- 1 -en-2-yl, R⁶(R⁷)N-(Ci -C₂-alkyl)-, R⁸S(=0)₂- (ethyl)-, R³OC(=0)-(Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group,

Ci -C₃-haloalkyl, Ci -C2-alkoxy, or a fluorine atom,

Ci -C₃-haloalkyl, Ci -C2-alkoxy, a fluorine atom, or -C(=0)OR¹³,

and,

said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted with a substituent selected from: trifluoromethyl, or a chlorine atom. In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I), wherein :

Ci -C₆-haloalkyl, or amino.

R² represents a group selected from : phenyl or pyridinyl,

said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from: methoxy, iso-propoxy, or a fluorine, or a chlorine atom.

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of N, said 5- to 6-membered heterocycloalkyl group being substituted with a substituent selected from:

Ci -C₃-haloalkyl, or amino.

R^{1 3} represents a methyl-group, or a tert-butyl-group.

R⁴ represents : a group selected from:

R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, HO- (C₂-C₆-alkyl)-, (Ci -C₃-alkyl)-0- (C₂-C₆-alkyl)-,

R³OC(=0)- (Ci -C₆-alkyl)-, R⁸S(=0)₂- (C₂-Ce-alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

d-Ce-haloalkyl, or -C(=0)OR^{1 3}, said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from: Ci -C₆-alkyl, or Ci -C6-haloalkyl.

R⁴ represents : a group selected from:

R¹¹ (R¹²)N-(C₂-C₃-alkyl)-, 2-hydroxy-2-methylpropyl-, (2-methoxy)ethyl-, R³OC(=0)-(Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, or a azetidine group, or a 6- membered heterocycloalkyl group, said 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N and 0, or a heteroatom containing group S(=0)₂, said azetidine group being optionally substituted with a substituent selected from:

Ci -C₆-haloalkyl, amino, or hydroxy.

R⁴ and R⁵ together with the nitrogen to which they are attached represent: a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of N, said 5- to 6-membered heterocycloalkyl group being substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₃-haloalkyl, amino, or hydroxy.

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I ), according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

It is to be understood that the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra. More particularly still, the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.

In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.

In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I ), particularly in the method described herein. In particular, the present invention covers compounds of general formula (II ) :

(II)

in which R1 and R2 are as defined for the compound of general formula (I ) supra.

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula (II ) :

(II) in which R1 and R2 are as defined for the compound of general formula (I ) supra, for the preparation of a compound of general formula (I ) as defined supra.

EXPERIMENTAL SECTION

The following table lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical names were generated using the ICS naming tool of ACD labs. In some cases generally accepted names of commercially available reagents were used in place of ICS naming tool generated names.

ESI electrospray (ES) ionisation

H hour(s)

HATU 2-(7-aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 , 3, 3- tetramethyluronium hexafluorophosphate [CAS RN : 148893- 10- 1 ]

HPLC high performance liquid chromatography

LC-MS liquid chromatography mass spectrometry

M multiplet

Min minute(s)

MPLC medium performance liquid chromatography

MS mass spectrometry

MTBE methyl tert-butylether

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 using unless otherwise stated.

Pd(dppf)Cl₂-CH₂Cl₂ [1 , 1 '-bis(diphenylphosphino)ferrocene] - dichloropalladium(l l ), complex with

dichloromethane q quartet

Rt room temperature

Rt retention time (as measured either with HPLC or

UPLC) in minutes

S Singlet s br singlet, broad (NMR)

T triplet Tt triplet of triplet

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

2,4,6-trioxide [CAS RN: 68957-94-8]

THF tetrahydrofuran

UPLC ultra performance liquid chromatography

Xantphos 4, 5-bis(diphenylphosphino)-9,9- dimethylxanthene (CAS-RN : 221 31 -51 -7)

Other abbreviations have their meanings customary per se to the skilled person.

The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

Syntheses of Compounds (Overview):

The compounds of the present invention can be prepared as descibed in the following section. Scheme 1 and the procedures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in Scheme 1 can be modified in various ways. The order of transformations exemplified in the Scheme 1 is therefore not intended to be limiting. In addition, interconversion of any of the substituents, A and R2 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3^rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a "one-pot" reaction, as is well-known to the person skilled in the art.

Scheme 1 :

(II) (I)

in which A, R1 and R2 are as defined supra, and X represents a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group, for example a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group, or a boronic acid.

In the first step, a carboxylic acid of formula (1 ), which is either described in the literature [CAS-RN: 22131 -51 -7, for the synthesis, please see: J. Goerdeler, H. Horn, Chem. Ber. (1963), 96, 1551 -1560.] or which can be prepared in analogy to procedures described in the literature, can be reacted with thionyl chloride at elevated temperature, for example at 80 ° C, to give, after removal of volatile components, the corresponding carboxylic acid chloride of formula (2).

In the second step, a compound of formula (2) reacts with an amine of formula (3), which is either commercially available or which is known [CAS-RN: 578-54- 1 , CAS-RN: 6628-77-9, CAS-RN: 3863-1 1 -4] or which can be prepared by methods that are well known to the person skilled in the art, in the presence of a tertiary amine, as for example triethylamine, to give a compound of general formula (II ).

In the third step, a compound of general formula (II ) is reacted with a compound of general formula (III), which is either commercially available or which is known or which can be prepared by methods that are well known to the person skilled in the art, in a palladium catalyzed coupling reaction, employing, for example, palladium(ll ) acetate, in the presence of a suitable ligand, employing, for example, Xantphos, in the presence of cesium carbonate in solvents as for example dioxane, or DMF or mixtures thereof, at elevated temperatures, preferably using a microwave oven, which results in compounds of general formula (I ). Alternatively, compounds of the present inventions are accessible by other palladium- or copper-catalysed N-arylation conditions or strategies as exemplified in the literature [for a review article on N-aryl bond formation for the synthesis of biologically active compounds please see, C. Fischer, B. Koenig, Beilstein J. Org. Chem. (201 1 ), 7, 59-74] .

Compounds of general formula (II ) serve as central intermediates for the introduction of various heteroaryl groups A, which results in compounds of general formula (I ). Depending on the nature of A and R2 it may be necessary to introduce A bearing suitable protecting groups on functional groups which may disturb the desired reaction. It also may be nessecary to use protecting groups on functional groups at R2, which may disturb the desired reaction.

In accordance with an embodiment, the present invention also relates to a method of preparing a compound of general formula (I ) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (II ) :

(II) in which R1 and R2 are as defined for the compound of general formula (I ) supra, to react with a compound of general formula (III ) :

A— X

(ill) , in which A is as defined as for the compound of general formula (I ), supra, and X represents a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group, for example a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group, or a boronic acid, thereby giving a compound of general formula (I) :

in which A, R1 and R2 are as defined for the compound of general formula (I ) supra.

General part UPLC-MS Standard Procedures

Analytical UPLC-MS was performed using UPLC-MS Method 1 unless otherwise stated. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ES-).

Method 1 :

Instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.1 % formic acid, 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; injection: 2 μί; DAD scan: 210-400 nm; ELSD

Method 2:

Instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.2% ammonia, 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; injection: 2 μί; DAD scan: 210-400 nm; ELSD

Method 3:

Instrument: Waters Acquity UPLC-MS SQD; column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; Eluent A: water + 0.05% formic acid (98%), Eluent B: acetonitrile + 0.05% formic acid (98%); Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; Temperature: 60 °C; Injection: 2 μΐ; DAD scan: 210-400 nm; ELSD

Method 4: Instrument: Waters Acquity UPLC-MS SQD; column: Acquity UPLC BEH C18 1.7 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; Injection: 2 μΐ; DAD scan: 210-400 nm; ELSD

Method 5:

Instrument: Waters Acquity UPLC-MS SQD; column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: Wasser + 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; Injection: 2 μΐ; DAD scan: 210-400 nm; ELSD

Method 6

Instrument: Waters Acquity UPLC-MS SQD; column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.2% Vol. 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; Injection: 2 μΐ; DAD scan: 210-400 nm; ELSD

Preparative HPLC Standard Procedures

Method A: Instrument: Waters Autopurificationsystem SQD; column: Waters XBrigde C18 5μ 100x30mm; Eluent A: water + 0.1 % Vol. formic acid (99%), Eluent B: acetonitrile; gradient: 1 - 100% B (the gradient was adapted individually as required by the samples separated).

Intermediates Intermediate 1

5-Amino-N-(3,4-difluorophenyl)-3-methyl- 1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-3-methyl- 1 ,2-thiazole-4-carboxylic acid [CAS-RN : 221 31 - 51 -7, for the synthesis, please see: J . Goerdeler, H . Horn, Chem . Ber. (1 963), 96, 1 551 - 1 560. ] (1 5. 0 g, 94.8 mmol, 1 .0 eq) and thionyl chloride (62.3 ml_, 522 mmol, 9.0 eq) was stirred at 100 ° C for 2 h. After cooling, the volatile components were removed in vacuo. The crude acid chloride was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two more times. The acid chloride observed this way (21 .9 g) was diluted with THF (140 ml_). Then, 3,4-difluoroaniline [CAS-RN : 3863- 1 1 -4] (9.33 ml_, 94.1 mmol, 1 .5 eq) and triethyl amine (21 .9 ml_, 1 57 mmol, 2.5 eq) was added. The reaction mixture was stirred at rt overnight. After addition of 1 L water the crude reaction mixture was extracted with ethyl acetate (3x). The organic phase was washed with half-concentrated sodium chloride solution and dried with magnesium sulfate. After removal of the volatile components the crude product was diluted with 200 mL methyl tert-butylether and heated to 50° C for 20 min. The remaining solids were removed by filtration. Then, the solvent was removed in vacuo to give 10.0 g (55 % yield of theory, based on the intermediate acid chlorid) of the title compound in about 90%-purity (H-NMR). UPLC-MS (Method 3): Rt = 0.96 min; MS (El_neg): m /z = 268 [M-H]\ ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.34 (s, 3H), 7.22 (s br, 2H), 7.-29-7.41 (m, 2H), 8.36 (m, 1 H), 9.67 (s, 1 H).

Intermediate 2 5-[(6-Chloropyrazin-2-yl)amino]-N-(3,4-di luorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide

A mixture of 5-amino-N-(3,4-di luorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (3.19 g, 11.85 mmol, 1.0 eq), 2,6- dichloropyrazine [CAS RN: 4774-14-5] (3.31 g, 17.8 mmol, 1.5 eq) and cesium carbonate (8.88 g, 27.3 mmol, 2.3 eq) in 101 mL dioxane/DMF (7/1 ) was placed in a reaction flask and flushed with argon. Then, palladium(ll) acetate (266 mg, 1.19 mmol, 0.1 eq) and Xantphos (685 mg, 1.19 mmol, 0.1 eq) were added. The reaction mixture was stirred at reflux temperature overnight. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter. The crude material crystallized with dichloromethane/methanol (-5/1 ). The precipitate was isolated by filtration and washed with dichloromethane. The filtrate was concentrated in vacuo and again crystallized with dichloromethane/methanol (-15/1 ). The resulting precipitate was again washed with dichloromethane. The two samples were combined to yield 1.58 g (31 % yield of theory) of the title compound after drying.

UPLC-MS (Method 1 ): R_t = 1.29 min; MS (ESI_neg): m/z = 380 [M-H]\ ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.45 (s, 3H), 7.41 -7.50 (m, 2H), 7.94 (t, 1 H), 8.27 (s, 1 H), 8.67 (s, 1 H), 10.48 (s br, 1 H), 11.22 (s br, 1 H).

Intermediate 3 2-Chloro-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)pyrazine

6-Chloropyrazine-2-carboxylic acid [CAS RN: 23688-89-3] (700 mg, 4.42 mmol, 1.0 eq) in 30 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (6.57 mL, 11.0 mmol, 2.5 eq) and with N-hydroxyethanimidamide [CASRN: 22059-22-9] (327 mg, 4.42 mmol, 1.0 eq). The resulting solution was stirred at 65 °C overnight. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with a saturated sodium bicarbonate solution and with brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material was purified via preparative HPLC under basic conditions (column: Chromatorex C18, eluent: acetonitrile / 0.2% aqueous ammonia 15:85→ 55:45) to give 55 mg (6% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.88 min; MS (El_p∞): m/z = 197 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.10 (s, 1 H), 9.36 (s, 1 H), 1xCH₃ obscured by solvent signal. Intermediate 4

2-Chloro-5-(3-methyl-1 ,2,4-oxadiazol-5-yl)pyridine

6-Chloronicotinic acid [CAS RN: 5326-23-8] (1.00 g, 6.35 mmol, 1.0 eq) in 43 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (9.45 mL, 15.9 mmol, 2.5 eq) and with N-hydroxyethanimidamide [CAS-RN: 22059-22-9] (470 mg, 6.35 mmol, 1.0 eq). The resulting solution was stirred at 65 °C overnight. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with a saturated sodium bicarbonate solution and with brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: hexane -> hexane/ethyl acetate 1 /1 ) to give 700 mg (54% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.95 min; MS (El_pos): m/z = 196 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.44 (s, 3H), 7.78 (d, 1 H), 8.47 (dd, 1 H), 9.07 (d, 1 H).

Intermediate 5

2-Chloro-5-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)pyridine

6-Chloro-4-(trifluoromethyl)nicotinic acid [CAS RN : 261635-77-2] (500 mg, 2.22 mmol, 1 .0 eq) in 1 5 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (3.30 mL, 5.54 mmol, 2.5 eq) and with N- hydroxyethanimidamide [CAS-RN : 22059-22-9] (164 mg, 2.22 mmol, 1 .0 eq). The resulting solution was stirred at 65 ° C overnight. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with a saturated sodium bicarbonate solution and with brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 4/ 1 ) to give 60 mg (10% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .18 min; MS (El_pos): m /z = 264 [M+H]⁺.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.29 (s, 1 H ), 9. 16 (s, 1 H ), 1 xCH₃ obscured by solvent signal.

Intermediate 6

2-Chloro-4-(5-methyl-1 ,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridine

2-Chloro-5-(trifluoromethyl)isonicotinic acid [CAS RN: 505084-58-2] (400 mg, 1.77 mmol, 1.0 eq) in 5.6 mL phosphoryl chloride was treated with acetohydrazide [CAS-RN: 1068-57-1 ] (394 mg, 5.32 mmol, 3.0 eq). The resulting reaction mixture was stirred at 70 °C for 2 h. On cooling, the reaction mixture was concentrated in vacuo. The crude material was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two times. The crude material was hydrolysed, treated with 2M sodium carbonate solution and extracted with ethyl acetate (2x). The combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 4/1 -> ethyl acetate ) to give 150 mg (27% yield of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.64 (s, 3H), 8.21 (s, 1 H), 9.09 (s, 1 H).

Intermediate 7 2,5-Dichloro-4-(3-methyl-1 ,2,4-oxadiazol-5-yl)pyridine I

2,5-Dichloroisonicotinic acid [CAS RN: 88912-26-9] (500 mg, 2.60 mmol, 1.0 eq) in 17.7 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (3.88 mL, 6.51 mmol, 2.5 eq) and with N-hydroxyethanimidamide [CAS-RN: 22059-22-9] (193 mg, 2.60 mmol, 1.0 eq). The resulting solution was stirred at 65 °C overnight. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with a saturated sodium bicarbonate solution and with brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 250 mg (40% yield of theory) of the title compound.

UPLC-MS (Method 3): R_t = 1.13 min; MS (El_p∞): m/z = 230 [M]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.16 (s, 1 H), 8.82 (s, 1 H), 1xCH₃ obscured by solvent signal.

Intermediate 8

Ethyl N-[(6-chloropyrazin-2-yl)carbonyl]glycinate

Ethyl glycinate-hydrochloride [CAS-RN: 623-33-6] (484 mg, 3.47 mmol, 1.1 eq) was dissolved in 18 mL THF and triethylamine (1.98 mL, 14.2 mmol, 4.51 eq) was added. Then, 6-chloropyrazine-2-carbonyl chloride [CAS-RN: 148673-71 -6] (558 mg, 3.15 mmol, 1.0 eq) in 2 mL THF was added dropwise and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate, and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo to yield 260 mg (33% yield of theory) of the title compound in 96% purity (UPLC area%) that was used without further purification.

UPLC-MS (Method 1 ): R_t = 0.83 min; MS (El_p∞): m/z = 244 [M+1 ]⁺.

Intermediate 9

Ethyl 1 -(6-chloropyrazin-2-yl)-1 H-pyrazole-4-carboxylate

Sodium hydride (60% in mineral oil, 314 mg, 7.85 mmol, 1 .1 eq) was diluted with 20 mL dry DMSO. Then, ethyl 1 H-pyrazole-4-carboxylate [CAS-RN: 37622-90-5] (795 mg, 8.92 mmol, 2.5 eq) was added and the reaction mixture was stirred for 30 min at rt. 2,6-Dichloropyrazine [CAS-RN: 4774-14-5] (795 mg, 8.92 mmol, 2.5 eq) was added and the reaction mixture was stirred at rt for 30 min and at 100 °C for 5 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter and purification via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 4/1 ) followed by preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 30/70→ 70/30) to give 460 mg (24 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.18 min; MS (El_p∞): m/z = 253 [M+H]⁺. Intermediate 10

5-[(5-Bromopyrazin-2-yl)amino]-N-(3,4-di luorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide

A mixture of 5-amino-N-(3,4-di luorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (1 .00 g, 3.71 mmol, 1 .0 eq), 2, 5-dibromopyrazine [CAS RN: 23229-26-7] (883 mg, 3.71 mmol, 1 .0 eq) and cesium carbonate (2.78 g, 8.54 mmol, 2.3 eq) in 35 mL dioxane/DMF (7/ 1 ) was placed in a reaction flask and flushed with argon. Then, palladium(ll ) acetate (83 mg, 0.37 mmol, 0.1 eq) and Xantphos (215 mg, 0.37 mmol, 0.1 eq) were added. The reaction mixture was stirred at a temperature of 1 10 ° C (oil bath) overnight. On cooling, the reaction mixture was partitioned between dichloromethane/methanol (5/ 1 ) and water. The organic phase was washed with brine. The phases were separated by the use of a Whatman filter. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/ 1 -> ethyl acetate) yielding 312 mg (19 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .33 min; MS (ESI_neg): m/z = 426 [M]\

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.43 (s, 3H), 7.37-7.52 (m, 2H), 7.94 (dd, 1 H), 8.56 (d, 1 H), 8.61 (d, 1 H), 10.47 (s, 1 H), 1 1 .08 (s, 1 H). Intermediate 1 1

2-Chloro-5-[(4,4-difluoropiperidin-1 -yl)methyl]pyrazine

4,4-Difluoropiperidine hydrochloride [CAS RN: 144230-52-4] (495 mg, 3.14 mmol, 1.6 eq), 5-chloropyrazine-2-carbaldehyde [CAS RN: 88625-24-5] (280 mg, 3.14 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.32 g, 6.29 mmol, 3.2 eq) were suspended in 17 mL 1 ,2-dichloroethane. Then, triethylamine (0.55 mL, 3.93 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added and the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 320 mg (63% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.56 min; MS (El_p∞): m/z = 248 [M+H]⁺.

Intermediate 12

2-Chloro-5-[(3,3-difluoroazetidin-1 -yl)methyl]pyrazine

3,3-Difluoroazetidine hydrochloride [CAS RN: 288315-03-7] (436 mg, 3.37 mmol, 1.6 eq), 5-chloropyrazine-2-carbaldehyde [CAS RN: 88625-24-5] (300 mg, 2.11 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.47 g, 6.74 mmol, 3.2 eq) were suspended in 20 mL 1 ,2-dichloroethane. Then, triethylamine (0.59 mL, 4.21 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added and the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 330 mg (70% yield of theory) of the title compound. UPLC-MS (Method 1 ): R_t = 0.65 min; MS (El_p∞): m/z = 220 [M+H]⁺.

Intermediate 13

1 -(2,2,2-Trifluoroethyl)piperidin-4-amine dihydrochloride

tert-Butyl [1 -(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate [CAS-RN: 335653-59- 3] (2.27 g, 8.04 mmol, 1.0 eq) was dissolved in a sufficient amount of dichloromethane (~20ml_). Then, hydrogenchloride (4M in dioxane, 12.07 ml_, 48.3 mmol, 6.0 eq) was added dropwise. The reaction mixture was stirred at rt overnight. The precipitate was isolated by filtration and washed with ice-cooled dichloromethane. After drying of the white solid under high vacuum at 50° C 1.87 g (87% yield of theory) of the title compound was obtained.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.79 (m, 2H), 1.99 (m, 2H), 2.78 (m, 2H), 3.00-3.31 (m, 3H), 3.65 (m, 2H), 8.33 (s, 3H), 1 H not assigned.

Intermediate 14

5-Chloro-N-[1 -(2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (565 mg, 3.56 mmol, 1.0 eq) was dissolved in 8 mL THF, and CDI (578 mg, 3.56 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 70°C for 2 h. In a separate flask, 1 -(2,2,2-Trifluoroethyl)piperidin-4-amine dihydrochloride [Intermediate 13] was dissolved in THF and triethylamine (1.02 mL, 7.34 mmol, 2.06 eq) was added. Then, this solution was added to the solution of the preformed imidazolide and the reaction mixture was heated again to 70 °C for 2 h. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 343 mg (29% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.95 min; MS (El_pos): m/z = 323 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.65-1.74 (m, 4H), 2.42 (m, 2H), 2.91 (m, 2H), 3.15 (q, 2H), 3.80 (m, 1 H), 8.75 (d, 1 H), 8.84 (d, 1 H), 8.97 (d, 1 H).

Intermediate 15

6-Chloro-N-[1 -(2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

6-Chloropyrazine-2-carboxylic acid [CAS RN: 23688-89-3] (565 mg, 3.56 mmol, 1.0 eq) was dissolved in 8 mL THF, and CDI (578 mg, 3.56 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 70°C for 2 h. In a separate flask, 1 -(2,2,2-trifluoroethyl)piperidin-4-amine dihydrochloride [Intermediate 13] (936 mg, 3.67 mmol, 1.03 eq) was dissolved in THF and triethylamine (1.02 mL, 7.34 mmol, 2.06 eq) was added. Then, this solution was added to the solution of the preformed imidazolide and the reaction mixture was heated again to 70° C for 2 h. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 558 mg (44% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.95 min; MS (El_p∞): m/z = 323 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.63-1.79 (m, 4H), 2.43 (m, 2H), 2.92 (m, 2H), 3.16 (q, 2H), 3.80 (m, 1 H), 8.70 (d, 1 H), 8.99 (s, 1 H), 9.10 (s, 1 H).

Intermediate 16

5-Amino-N-(4-chloro-3-fluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-3-methyl-1 ,2-thiazole-4-carboxylic acid [CAS-RN: 22131 - 51 -7, for the synthesis, please see: J. Goerdeler, H. Horn, Chem. Ber. (1963), 96, 1551 -1560.] (5.00 g, 9.93 mmol, 1.0 eq) and thionyl chloride (20.7 ml_, 284 mmol, 9.0 eq) was stirred at 80 °C for 2 h. After cooling, the volatile components were removed in vacuo. The crude acid chloride was diluted with toluene and concentrated at the rotary evaporator. This process was repeated one more time. The acid chloride (1.75 g, 9.93 mmol, 1.0 eq) observed this way was dissolved in THF (15 ml_). Then, 4-chloro-3-fluoroaniline [CAS-RN: 367-22-6] (2.89 ml_, 19.9 mmol, 2.0 eq) and triethyl amine (2.01 ml_, 19.9 mmol, 2.0 eq) was added. The reaction mixture was stirred at rt overnight. After addition of water the crude reaction mixture was acidified with 1M hydrochloric acid and extracted with EtOAc. The organic phase was washed with brine and dried with sodium sulfate. After removal of the volatile components the product was crystallized from dichloromethane and methanol. The precipitate was isolated by filtration and dried under high vacuum to give the title compound (600 mg, -21 % yield of theory based on the intermediate acid chloride).

UPLC-MS (Method 2): Rt = 1.06 min; MS (El_neg): m/z = 284 [M-H]\

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.36 (s, 3H), 7.28 (s br, 2H), 7.41 (dd, 1 H), 7.51 (t, 1 H), 7.81 (dd, 1 H), 9.82 (s, 1 H).

Intermediate 17

(5-Chloropyrazin-2-yl)[4-(2,2-difluoroethyl)piperazin-1 -yl]methanone

1 -(2,2-Difluoroethyl)piperazine [CAS RN: 767609-14-3] (751 mg, 5.00 mmol, 2.0 eq) was dissolved in 16 mL THF and triethylamine (0.87 mL, 6.25 mmol, 2.5 eq) was added. Then, 5-chloropyrazine-2-carbonyl chloride [CAS RN: 88625-23-4] (442 mg, 2.50 mmol, 1.0 eq) was added dropwise as a solution in 3 mL THF and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extraxted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 4/1 -> ethyl acetate) to give 260 mg (36% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.74 min; MS (El_p∞): m/z = 291 [M+H]⁺. Intermediate 18

5-Chloro-N-[1 -(2,2-difluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

1 -(2,2-Difluoroethyl)piperidin-4-amine [CAS RN: 1119499-74-9] (406 mg, 2.48 mmol, 1.1 eq) was dissolved in 15 mL THF and triethylamine (0.78 ml_, 5.63 mmol, 2.5 eq) was added. Then, 5-chloropyrazine-2-carbonyl chloride [CAS RN: 88625-23-4] (398 mg, 2.25 mmol, 1.0 eq) was added dropwise as a solution in 3 mL THF and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extraxted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 2/3) to give 380 mg (55% yield of theory) of the title compound.

UPLC-MS (Method 5): R_t = 0.53 min; MS (El_pos): m/z = 305 [M+H]⁺.

Intermediate 19 tert-Butyl 3-{[(5-chloropyrazin-2-yl)carbonyl]amino}azetidine-1 -carboxylate

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (2.30 g, 14.5 mmol, 1.0 eq) was dissolved in 20 mL THF, and CDI (2.35 g, 14.5 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 70° C for 60 min. On cooling, DIPEA (0.55 mL, 3.92 mmol, 0.27 eq) was added. Then, a solution of tert-butyl 3-aminoazetidine-1 -carboxylate [CAS RN: 193269-78-2] (2.65 g, 14.9 mmol, 1.03 eq) was added and the reaction mixture was heated to 70°C was remained for 2 h. On cooling, the reaction mixture was partitioned between dichloro- methane/isopropanol (4/1 ) and water. The aqueous phase was extracted three times with dichloromethane/isopropanol (4/1 ) and the combined organic layers were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 1 /1 ) to give 1.00 g (21 % yield of theory) of the title compound. UPLC-MS (Method 1 ): R_t = 1.05 min; MS (El_neg): m/z = 31 1 [M-H]\

Intermediate 20

N-(Azetidin-3-yl)-5-chloropyrazine-2-carboxamide hydrochloride

tert-Butyl 3-{[(5-chloropyrazin-2-yl)carbonyl]amino}azetidine-1 -carboxylate [Intermediate 19] (1.00 g, 3.20 mmol, 1.0 eq) was dissolved in 30 mL dichloromethane. Under ice-cooling, a hydrogenchloride solution (4M in dioxane, 7.99 mL, 32.0 mmol, 10.0 eq) was added dropwise. The reaction mixture was stirred at rt overnight. The precipitate was isolated by filtration and washed with ice-cooled dichloromethane. After drying of the white solid under high vacuum at 50° C 770 mg (87% yield of theory) of the title compound was obtained. UPLC-MS (Method 1 ): R_t = 0.55 min; MS (El_neg): m/z = 213 [M-Cl]⁺.

Intermediate 21

5-Chloro-N-[1 -(2,2,2-trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide

N-(Azetidin-3-yl)-5-chloropyrazine-2-carboxamide hydrochloride [Intermediate 20] (367 mg, 1.47 mmol, 1.0 eq), potassium carbonate (733 mg, 5.30 mmol, 3.6 eq) and potassium iodide (26 mg, 0.16 mmol, 0.1 eq) were suspended in 17 mL acetonitrile. Then, 2,2,2-trifluoroethyltrifluoromethanesulfonate [CAS RN: 6226-25-1 ] (512 mg, 2.21 mmol, 1.5 eq) was added and the reaction mixture was heated to 70 °C for 17 h. On cooling, the reaction mixture was partitioned between dichloromethane/isopropanol (4/1 ) and water. The aqueous phase was extracted three times with dichloromethane/isopropanol (4/1 ) and the combined organic layers were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 1 /1 ) to give 124 mg (28% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.77 min; MS (El_pos): m/z = 295 [M]⁺. ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.22 (q, 2H), 3.38 (t, 2H), 3.70 (t, 2H), 4.58 (m, 1 H), 8.88 (d, 1 H), 8.97 (d, 1 H), 9.36 (d, 1 H). Intermediate 22

Methyl N-[(6-chloropyrazin-2-yl)carbonyl]-8-alaninate

Methyl 8-alaninate hydrochloride [CAS-RN: 3196-73-4] (484 mg, 3.15 mmol, 1.1 eq) was dissolved in 20 mL THF and triethylamine (1.98 mL, 14.2 mmol, 4.5 eq) was added. Then, 6-chloropyrazine-2-carbonyl chloride [CAS-RN: 148673- 71 -6] (558 mg, 3.15 mmol, 1.0 eq) in 2 mL THF was added dropwise and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo. The crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 4/1 -> ethyl acetate) to yield 150 mg (20% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.77 min; MS (El_pos): m/z = 244 [M+H]⁺.

Intermediate 23

(5-Chloropyrazin-2-yl)[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]methanone

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (560 mg, 3.53 mmol, 1.0 eq) was dissolved in 25 mL THF, and CDI (573 mg, 3.53 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 75° C for 120 min. On cooling, a solution of 1 -(2,2,2-trifluoroethyl)piperazine [CAS RN: 13349-90-1 ] (2.65 g, 14.9 mmol, 1.03 eq) in 5 mL THF was added and the reaction mixture was heated to 70° C was remained for 2 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 1 /1 ) to give 180 mg (17% yield of theory) of the title compound. UPLC-MS (Method 1 ): R_t = 1.00 min; MS (El_p∞): m/z = 309 [M+H]⁺.

Intermediate 24

6-Chloro-N-[1 -(2-fluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

6-Chloropyrazine-2-carboxylic acid [CAS RN: 23688-89-3] (218 mg, 1.38 mmol, 1.0 eq) was dissolved in 3 mL THF, and CDI (224 mg, 1.38 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 70° C for 2 h. Then, 1 -(2- fluoroethyl)piperidin-4-amine [CAS RN: 947263-70-9] (208 mg, 1.42 mmol, 1.03 eq) and triethylamine (0.40 mL, 2.85 mmol, 2.06 eq) as a solution in 2 mL THF were added. The reaction mixture was heated to 70 °C for 1 h and was allowed to stand at rt for 1 day. Subsequently, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: ethyl acetate -> ethyl acetate/ethanol 4/1 ) to give 100 mg (24% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.52 min; MS (El_p∞): m/z = 287 [M+H]⁺.

Intermediate 25 tert-Butyl {1 -[(6-chloropyrazin-2-yl)carbonyl]azetidin-3-yl}carbamate

A mixture of 6-chloropyrazine-2-carbonyl chloride [CAS-RN: 148673-71 -6, for the synthesis, please see: M. J. C. Scanio et al., J. Med. Chem. (2011 ), 54, 7678- 7692.] (558 mg, 3.15 mmol, 1.0 eq), triethylamine (1.54 ml_, 11 .0 mmol, 3.5 eq), and tert-butyl azetidin-3-ylcarbamate [CAS-RN: 91188-13-5] (597 mg, 3.47 mmol, 1.1 eq) in 15 mL THF was stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material obtained was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 8/2 -> ethyl acetate) to give 430 mg (44% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.01 min; MS (El_pos): m/z = 313 [M+1 ]⁺.

Intermediate 26

N-{1 -[(5-Chloropyrazin-2-yl)carbonyl]azetidin-3-yl}-2,2-dimethylpropanamide

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1] (210 mg, 1.33 mmol, 1.0 eq) was dissolved in 10 mL THF, and CDI (215 mg, 1.32 mmol, 1 eq) was added. Then, the reaction mixture was heated to 70° C for 45 min. On cooling, the reaction mixture observed this way was added dropwise to a solution of N- (azetidin-3-yl)-2,2-dimethylpropanamide [CAS-RN: 91188-13-5] (235 mg, 1.36 mmol, 1.03 eq) in 1.5 mL THF. The reaction mixture was stirred at 70°C for 60 min. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1) to give 69 mg (16% yield of theory) of the title compound.

UPLC-MS (Method 1): R_t = 1.01 min; MS (El_pos): m/z = 313 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.38 (s, 9H), 3.92 (m, 1H), 4.24-4.40 (m, 3H), 4.71 (m, 1H), 7.61 (s br, 1H), 8.84 (d, 1H), 8.92 (d, 1H).

Intermediate 27 tert-Butyl 3-{[(5-chloropyrazin-2-yl)carbonyl]amino}azetidine-1 -carboxylate

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (210 mg, 1.33 mmol, 1.0 eq) was dissolved in 10 mL THF, and CDI (215 mg, 1.32 mmol, 1 eq) was added. Then, the reaction mixture was heated to 70° C for 45 min. On cooling, the reaction mixture observed this way was added dropwise to a solution of tert-butyl 3-aminoazetidine-1 -carboxylate [CAS-RN: 193269-78-2] (235 mg, 1.36 mmol, 1 .03 eq) in 1.5 mL THF. The reaction mixture was stirred at 70°C for 60 min. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 138 mg (32% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.05 min; MS (El_neg): m/z = 31 1 [M-H]\

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.38 (s, 9H), 3.95 (m, 2H), 4.07 (m, 2H), 4.69 (m, 1 H), 8.88 (d, 1 H), 8.98 (d, 1 H), 9.57 (d, 1 H).

Intermediate 28

(6-Chloropyrazin-2-yl)[4-(2,2-difluoroethyl)piperazin-1 -yl]methanone

6-Chloropyrazine-2-carboxylic acid [CAS-RN: 23688-89-3] (300 mg, 1.89 mmol, 1.0 eq) was dissolved in 12 mL THF, and CDI (338 mg, 2.08 mmol, 1 eq) was added. Then, the reaction mixture was heated to 70° C for 60 min. On cooling, a solution of 1 -(2,2-difluoroethyl)piperazine [CAS-RN: 767609-14-3] (313 mg, 2.08 mmol, 1.03 eq) in 1.5 mL THF was added. The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to g mg (55% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.75 min; MS (El_p∞): m/z = 292 [M+1 ]⁺.

Intermediate 29 tert-Butyl (3-{[(5-chloropyrazin-2-yl)carbonyl]amino}propyl)carbamate

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (210 mg, 1.33 mmol, 1.0 eq) was dissolved in 10 mL THF, and CDI (238 mg, 1.36 mmol, 1.03 eq) was added. Then, the reaction mixture was heated to 75 °C for 2 h. On cooling, a solution of tert-butyl (3-aminopropyl)carbamate [CAS-RN: 75178-96-0] (235 mg, 1.36 mmol, 1.03 eq) in 1.5 mL THF was added dropwise. The reaction mixture was stirred at 70 °C for 60 min. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 154 mg (33% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.03 min; MS (El_p∞): m/z = 315 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.36 (s, 9H), 1 .61 (m, 2H), 2.94 (m, 2H). 3.28 (m, 2H), 6.61 (t, 1 H), 8.86 (d, 1 H), 8.91 -9.05 (m, 2H).

Intermediate 30

5-Chloro-N-[2-(methylsulfonyl)ethyl]pyrazine-2-carboxamide

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (210 mg, 1.33 mmol, 1.0 eq) was dissolved in 10 mL THF, and CDI (238 mg, 1.36 mmol, 1.03 eq) was added. Then, the reaction mixture was heated to 75 °C for 45 min. On cooling, the resulting solution was added dropwise to a solution of 2-(methylsulfonyl)- ethanamine [CAS-RN: 49773-20-8] (218 mg, 1.36 mmol, 1.03 eq) in 1.5 mL THF. The reaction mixture was stirred at 70° C for 60 min. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 100 mg (27% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.63 min; MS (El_pos): m/z = 264 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.03 (s, 3H), 3.39 (t, 2H), 3.74 (q, 2H), 8.89 (d, 1 H), 9.01 (d, 1 H), 9.13 (t, 1 H).

Intermediate 31

5-Chloro-N-(1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)pyrazine-2-carboxamide

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (420 mg, 2.65 mmol,

1.0 eq) was dissolved in 10 mL THF, and CDI (430 mg, 2.65 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 75 °C for 45 min. On cooling, the resulting solution was added dropwise to a solution of tetrahydro-2H- thiopyran-4-amine-1 , 1 -dioxide hydrochloride [CAS-RN: 116529-31 -8] (507 mg, 2.73 mmol, 1 .03 eq) in 3.0 mL THF. The reaction mixture was stirred at 70° C for 60 min. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 172 mg (19% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.67 min; MS (El_p∞): m/z = 290 [M+H]⁺.

Intermediate 32 tert-Butyl (2-{[(5-chloropyrazin-2-yl)carbonyl](methyl)amino}ethyl)methyl- carbamate

5-Chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (420 mg, 2.65 mmol, 1.0 eq) was dissolved in 10 mL THF, and CDI (430 mg, 2.65 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 75°C for 45 min. On cooling the resulting solution was added dropwise to a solution of tert-butyl methyl[2- (methylamino)ethyl]carbamate [CAS-RN: 112257-19-9] (513 mg, 2.73 mmol, 1.03 eq) in 3 mL THF. The reaction mixture was stirred at 70°C for 60 min. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 -> hexane/ethyl acetate 2/3) to give 322 mg (37% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.07 min; MS (El_p∞): m/z = 329 [M+H]⁺. Intermediate 33

5-Amino-N-(6-methoxypyridin-3-yl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-3-methyl-1 ,2-thiazole-4-carboxylic acid [CAS-RN: 22131 - 51 -7, for the synthesis, please see: J. Goerdeler, H. Horn, Chem. Ber. (1963), 96, 1551 -1560.] (7.50 g, 47.4 mmol, 1.0 eq) and thionyl chloride (38.0 mL, 522 mmol, 11.0 eq) was stirred at 90 ° C for 5 h. After cooling, the volatile components were removed in vacuo. The crude acid chloride was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two more times. The acid chloride observed this way [11.0 g, -80% purity (LC-MS area-%), -40 mmol] was diluted with THF (240 mL). Then, 6-methoxypyridin-3- amine [CAS-RN: 6628-77-9] (6.62 g, 50.7 mmol, 1.2 eq) and triethyl amine (17.7 mL, 127 mmol, 3.0 eq) was added. The reaction mixture was stirred at rt overnight. After addition of water the crude reaction mixture was extracted with dichloromethane (2x). The combined organic phases were dried with sodium sulfate. After removal of the volatile components by the use of a rotary evaporator the crude material was purified via preparative MPLC (Biotage Isolera; 100 g SNAP cartridge: hexane/ethyl acetate 6/4 -> ethyl acetate) to give 6.80 g (-61 % yield of theory, based on the intermediate acid chlorid) of the title compound.

UPLC-MS (Method 1 ): Rt = 0.73 min; MS (El_neg): m/z = 263 [M-H]\

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.36 (s, 3H), 2.79 (s, 3H), 6.77 (d, 1 H), 7.22 (s br, 2H), 7.89 (dd, 1 H),8.36 (d, 1 H), 9.43 (s, 1 H). Intermediate 34

5-(2-Chloro-1 ,3-thiazol-5-yl)-3-methyl-1 ,2,4-oxadiazole

2-Chloro-1 ,3-thiazole-5-carboxylic acid [CAS RN: 101012-12-8] (500 mg, 2.96 mmol, 1.0 eq) in 20 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (4.41 mL, 7.41 mmol, 2.5 eq) and with N-hydroxyethanimidamide [CAS-RN: 22059-22-9] (219 mg, 2.96 mmol, 1.0 eq). The resulting solution was stirred for 2 h at 80 °C. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. After phase separation via a Whatman-filter the volatile components were removed. The material observed this way 310 mg (52% yield of theory) were used in the following step without further purification.

UPLC-MS (Method 1 ): R_t = 1.01 min; MS (El_pos): m/z = 202 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.40 (s, 3H), 8.59 (s, 1 H).

Intermediate 35

2-(2-Chloro-1 ,3-thiazol-5-yl)-5-methyl-1 ,3,4-oxadiazole

2-Chloro-1 ,3-thiazole-5-carboxylic acid [CAS RN: 101012-12-8] (500 mg, 2.96 mmol, 1.0 eq) in 20 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (4.41 mL, 7.41 mmol, 2.5 eq) and with acetohydrazide [CAS-RN:

1068-57-1 ] (219 mg, 2.96 mmol, 1.0 eq). The resulting solution was stirred for

6.5 h at 80 °C. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. After phase separation via a Whatman-filter the volatile components were removed. The material observed this way (230 mg, 26% yield of theory, -70 % purity based on UPLC area-%) was used in the following step without further purification. UPLC-MS (Method 1 ): R_t = 0.80 min; MS (El_p∞): m/z = 202 [M+H]⁺.

Intermediate 36

2-Chloro-N-(2-methoxyethyl)-N-methyl-1 ,3-thiazole-5-carboxamide

A mixture of 2-chloro-1 ,3-thiazole-5-carboxylic acid [CAS-RN: 101012-12-8] (1.00 g, 6.11 mmol, 1.0 eq), 2-methoxy-N-methylethylamine [CAS-RN: 38256-93-8] (3.67 mL, 7.34 mmol, 1.0 eq), HATU (2.79 g, 7.34 mmol, 1.2 eq) and DIPEA (3.19 mL, 18.3 mmol, 3.0 eq) was dissolved in 28 mL DMF and stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and filtered through a Whatman filter. The volatile components were removed in vacuo and the crude material obtained was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: hexane-> hexane/ethyl acetate 2/1 ) to give 957 mg (50% yield of theory) of the title compound in 75% purity (UPLC area-%). UPLC-MS (Method 1 ): R_t = 0.81 min; MS (El_p∞): m/z = 235 [M+H]⁺.

Intermediate 37

2-(2-Chloro-1 ,3-thiazol-4-yl)-5-methyl-1 ,3,4-oxadiazole

2-Chloro-1 ,3-thiazole-4-carboxylic acid [CAS RN: 5198-87-8] (430 mg, 2.55 mmol, 1.0 eq) in 17 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (3.80 mL, 6.37 mmol, 2.5 eq) and with acetohydrazide [CAS- RN: 1068-57-1 ] (189 mg, 2.55 mmol, 1.0 eq). The resulting solution was stirred at 80 °C overnight. The reaction mixture was hydrolysed with ice-water and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material contained 350 mg (50% yield of theory) of the title compound in 80% purity (UPLC area-%), which were used without further purification.

UPLC-MS (Method 2): R_t = 0.90 min; MS (El_p∞): m/z = 202 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.41 (s, 3H), 8.71 (s, 1 H).

Intermediate 38

2-Chloro-N-(2-methoxyethyl)-N-methyl-1 ,3-thiazole-5-carboxamide

A mixture of 2-chloro-1 ,3-thiazole-5-carboxylic acid [CAS-RN: 5198-87-8] (1 .00 g, 6.11 mmol, 1.0 eq), 2-methoxy-N-methylethanamine [CAS-RN: 38256-93-8] (654 mg, 7.34 mmol, 1.2 eq), HATU (2.79 g, 7.34 mmol, 1.2 eq) and DIPEA (3.19 ml_, 18.3 mmol, 3.0 eq) was dissolved in 28 mL DMF and stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and filtered through a Whatman filter. The volatile components were removed in vacuo and the crude material obtained was purified via preparative MPLC (Biotage Isolera; 50 g NH2-SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 957 mg (50% yield of theory) of the title compound in 75% purity (UPLC area%), which was used without further purification.

UPLC-MS (Method 1 ): R_t = 0.81 min; MS (El_p∞): m/z = 235 [M+H]⁺.

Intermediate 39

5-Chloro-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide

5-Hydroxypyrazine-2-carboxylic acid [CAS RN: 34604-60-9] (500 mg, 3.57 mmol, 1.0 eq) was treated with thionyl chloride (3.90 mL, 53.5 mmol, 15 eq) and 0.04 mL DMF. Then, the reaction mixture was heated to reflux temperature for 4 h. On cooling, the volatile components were removed in vacuo. The crude material remaining was diluted with toluene and the resulting solution was concentrated by the use of a rotary evaporator. This procedure was repeated two more times. Then, the remaining material was treated with 4 mL DMF and with 2-methoxy-N- methylethanamine [CAS-RN: 38256-93-8] (795 mg, 8.92 mmol, 2.5 eq). The reaction mixture was stirred at rt overnight. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 -> ethyl acetate ) to give 290 mg (34% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.76 min; MS (El_p∞): m/z = 230 [M+H]⁺. Intermediate 40

N'-Acetyl-2,5-dichloroisonicotinohyd

2,5-Dichloroisonicotinic acid [CAS RN: 88912-26-9] (500 mg, 2.60 mmol, 1.0 eq) in 17.6 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (3.88 mL, 6.51 mmol, 2.5 eq) and with acetohydrazide [CAS-RN: 1068-57-1] (193 mg, 2.60 mmol, 1.0 eq). The resulting solution was stirred at 80 °C for 6.5 h. The reaction mixture was hydrolysed with ice-water and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material was stirred with dichlorormethane/methanol. The precipitate formed was isolated by filtration and dried to give 353 mg (59% yield of theory) of the title compound.

UPLC-MS (Method 1): R_t = 0.58 min; MS (El_pos): m/z = 248 [M]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.91 (s, 3H), 7.61 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H), 10.64 (s br, 1H).

Intermediate 41

2,5-Dichloro-4-(5-methyl-1 ,3,4-oxadiazol-2-yl)pyridine

N'-Acetyl-2,5-dichloroisonicotinohydrazide [Intermediate 40] (345 mg, 1.39 mmol, 1 .0 eq) in 1 1.5 mL acetonitrile was treated with phosphoryl chloride (0.26 mL, 2.78 mmol, 2.0 eq). The resulting solution was stirred at reflux temperature for 16 h. On cooling, the reaction mixture was concentrated in vacuo. The crude material was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two times to result 484 mg of a yellow solid of 94 % purity (UPLC area-%) that was used in the following step without further purification.

UPLC-MS (Method 3): R_t = 0.92 min; MS (El_pos): m/z = 230 [M]⁺.

Intermediate 42 6-Chloro-N-[2-(methylsulfonyl)ethyl]pyrazine-2-carboxamide

6-Chloropyrazine-2-carboxylic acid [CAS-RN: 23688-89-3] (300 mg, 1.89 mmol, 1.0 eq) was dissolved in 12 mL THF, and CDI (338 mg, 2.08 mmol, 1 eq) was added. Then, the reaction mixture was heated to 70°C for 60 min. On cooling, a solution of 2-(methylsulfonyl)ethanamine [CAS-RN: 49773-20-8] (256 mg, 2.08 mmol, 1.1 eq) in 1.5 mL THF and triethylamine (0.53 mL, 3.78 mmol, 2.0 eq) was added. The reaction mixture was stirred at 70°C for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo to yield 350 mg (53% yield of theory) of the title compound in 76% purity (UPLC area%) that was used without further purification.

UPLC-MS (Method 1 ): R_t = 0.61 min; MS (El_p∞): m/z = 264 [M+1 ]⁺.

Intermediate 43 (6-Chloropyrazin-2-yl)[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]methanone

1 -(2,2,2-Trifluoroethyl)piperazine [CAS-RN: 13349-90-1 ] (570 mg, 3.39 mmol, 1.2 eq) was dissolved in 18 mL THF, and triethylamine (1.18 mL, 8.48 mmol, 3.0 eq) was added. Then, 6-chloropyrazine-2-carbonyl chloride [CAS-RN: 148673- 71 -6] (500 mg, 2.83 mmol, 1.0 eq) in 2 mL THF was added dropwise and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo. The crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 4/1 -> ethyl acetate) to yield 300 mg (34% yield of theory) of the title compound.

Alternative Method:

(6-Chloropyrazin-2-yl)(piperazin-1 -yl)methanone hydrochloride [Intermediate 55] (367 mg, 1.40 mmol, 1.0 eq), potassium carbonate (694 mg, 5.02 mmol, 3.6 eq) and potassium iodide (25 mg, 0.15 mmol, 0.1 eq) were suspended in 16 mL acetonitrile. Then, 2,2,2-trifluoroethyltrifluoromethanesulfonate [CAS RN: 6226-25-1 ] (486 mg, 2.09 mmol, 1.5 eq) was added and the reaction mixture was heated to 70 °C for 17 h. On cooling, the reaction mixture was partitioned between dichloromethane/isopropanol (4/1 ) and water. The aqueous phase was extracted three times with dichloromethane/isopropanol (4/1 ) and the combined organic layers were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 124 mg (29% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.00 min; MS (El_pos): m/z = 309 [M+H]⁺.

Intermediate 44 5-Chloro-N-[1 -(2-fluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

1 -(2-Fluoroethyl)piperidin-4-amine [CAS RN: 947263-70-9] (658 mg, 4.50 mmol, 2.0 eq) was dissolved in 15 mL THF, and triethylamine (0.78 mL, 5.63 mmol, 2.5 eq) was added. Then, 5-chloropyrazine-2-carbonyl chloride [CAS RN: 88625-23-4] (398 mg, 2.25 mmol, 1.0 eq) was added dropwise as a solution in 3 mL THF and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extraxted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 2/3) to give 530 mg (76% yield of theory) of the title compound.

UPLC-MS (Method 5): R_t = 0.49 min; MS (El_p∞): m/z = 287 [M+H]⁺.

Intermediate 45

2-Chloro-5-[(3,3-difluoropyrrolidin-1 -yl)methyl]pyrazine

3,3-Difluoropyrrolidine hydrochloride [CAS RN: 163457-23-6] (415 mg, 2.89 mmol, 1.6 eq), 5-chloropyrazine-2-carbaldehyde [CAS RN: 88625-24-5] (258 mg, 1.81 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.12 g, 5.78 mmol, 3.2 eq) were suspended in 17 mL 1 ,2-dichloroethane. Then, triethylamine (0.50 mL, 3.61 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added and the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 250 mg (57% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.70 min; MS (El_p∞): m/z = 234 [M+H]⁺.

Intermediate 46

2-Chloro-5-[(3-fluoroazetidin-1 -yl)methyl]pyrazine

3-Fluoroazetidine hydrochloride [CAS RN: 617718-46-4] (250 mg, 2.25 mmol, 1.6 eq), 5-chloropyrazine-2-carbaldehyde [CAS RN: 88625-24-5] (200 mg, 1.40 mmol, 1.0 eq) and sodium triacetoxyborohydride (0.952 g, 4.49 mmol, 3.2 eq) were suspended in 17 mL 1 ,2-dichloroethane. Then, triethylamine (0.39 mL, 2.81 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added. After stirring for 10 min, the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 180 mg (50% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.79 min; MS (El_p∞): m/z = 202 [M+H]⁺.

Intermediate 47 (6-Chloropyrazin-2-yl)[4-(2,2-difluoroethyl)piperazin-1 -yl]methanone

6-Chloropyrazine-2-carboxylic acid [CAS RN: 23688-89-3] (300 mg, 1.89 mmol, 1.0 eq) was dissolved in 12 mL THF, and CDI (338 mg, 2.08 mmol, 1.1 eq) was added. Then, the reaction mixture was heated to 70°C for 1 h. Then, 1 -(2,2- difluoroethyl)piperazine [CAS RN: 767609-14-3] (313 mg, 2.08 mmol, 1.1 eq) in 5 mL THF was added. The reaction mixture was heated to 70 °C for 2 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 300 mg (55% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.76 min; MS (El_p∞): m/z = 291 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.62 (t, 2H), 2.78 (dt, 2H), 3.40 (t, 2H), 3.64 (t, 2H), 6.15 (tt, 1 H), 8.82 (s, 1 H), 8.90 (s, 1 H), 2H's obscured by solvent signal.

Intermediate 48

5-Amino-N-(3,4-dichlorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-3-methyl-1 ,2-thiazole-4-carboxylic acid [CAS-RN: 22131 - 51 -7, for the synthesis, please see: J. Goerdeler, H. Horn, Chem. Ber. (1963), 96, 1551 -1560.] (11 .0 g, 69.5 mmol, 1.0 eq) and thionyl chloride (45.7 ml_, 626 mmol, 9.0 eq) was stirred at 80 °C for 2 h. After cooling, the volatile components were removed in vacuo. The crude acid chloride was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two times. The acid chloride (1 1.0 g, 62.3 mmol, 1.0 eq) observed this way was dissolved in THF (400 ml_). Then, 3,4-dichloroaniline [CAS-RN: 95-76-1 ] (20.2 g, 125 mmol, 2.0 eq) and triethyl amine (17.4 ml_, 125 mmol, 2.0 eq) was added. The reaction mixture was stirred at rt overnight. After addition of water the crude reaction mixture was extracted with EtOAc. The organic phase was washed with brine. The phases were separated by the use of a Whatman filter. During this process a white precipitate remained on the filter. This solid was dried under high vacuum to give the title compound (6.69 g, 26% yield) in 93% purity (based on UPLC-MS area-%). UPLC-MS (Method 1 ): Rt = 1.16 min; MS (El_neg): m/z = 300 [M-H]\

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.36 (s, 3H), 7.29 (s br, 2H), 7.55-7.59 (m, 2H), 8.02 (s, 1 H), 9.78 (s, 1 H).

Intermediate 49

2-Chloro-5-[(3,3-difluoropiperidin-1 -yl)methyl]pyrazine

3,3-Difluoropiperidine hydrochloride [CAS RN: 496807-97-7] (531 mg, 3.37 mmol, 1.6 eq), 5-chloropyrazine-2-carbaldehyde [CAS RN: 88625-24-5] (300 mg, 2.11 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.43 g, 6.74 mmol, 3.2 eq) were suspended in 20 mL 1 ,2-dichloroethane. Then, triethylamine (0.59 ml_, 4.21 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added. After stirring for 10 min, the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 340 mg (58% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 1.09 min; MS (El_p∞): m/z = 248 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.64 (m, 2H), 1.86 (m, 2H), 2.73 (t, 2H), 3.78 (s, 2H), 8.49 (d, 1 H), 8.74 (d, 1 H), 2H's obscured by solvent signal. Intermediate 50 tert-Butyl 3-{[(6-chloropyrazin-2-yl)carbonyl]amino}azetidine-1 -carboxylate

tert-Butyl 3-aminoazetidine-1 -carboxylate [CAS-RN: 193269-78-2] (1.625 g, 9.44 mmol, 1.0 eq) was dissolved in 60 mL THF, and triethylamine (2.63 ml_, 18.9 mmol, 2.0 eq) was added. Then, 6-chloropyrazine-2-carbonyl chloride [CAS- RN: 148673-71 -6] (1.67 g, 9.44 mmol, 1.0 eq) in 5 mL THF was added dropwise and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo. The crude material was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 9/1 ) to yield 2.13 g (62% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 1.04 min; MS (El_pos): m/z = 313 [M+H]⁺.

Intermediate 51

N-(Azetidin-3-yl)-6-chloropyrazine-2-carboxamide hydrochloride

tert-Butyl 3-{[(6-chloropyrazin-2-yl)carbonyl]amino}azetidine-1 -carboxylate [Intermediate 50] (2.17 g, 6.94 mmol, 1.0 eq) was dissolved in 50 mL dichloromethane. Under ice-cooling, a hydrogenchloride solution (4M in dioxane, 11.56 mL, 35.0 mmol, 5.0 eq) was added dropwise. The reaction mixture was stirred at rt for 3h. The precipitate was isolated by filtration and washed with ice-cooled dichloromethane. After drying of the white solid under high vacuum 850 mg (58% yield of theory) of the title compound were obtained.

UPLC-MS (Method 1 ): R_t = 0.46 min; MS (El_p∞): m/z = 213 [M-Cl]⁺.

Intermediate 52

6-Chloro-N-[1 -(2,2,2-trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide

N-(Azetidin-3-yl)-6-chloropyrazine-2-carboxamide hydrochloride [Intermediate 51 ] (367 mg, 1.47 mmol, 1.0 eq), triethylamine (0.56 mL, 4.01 mmol, 4.0 eq) and 2,2,2-trifluoroethyltrifluoromethanesulfonate [CAS RN: 6226-25-1 ] (256 mg, 1.10 mmol, 1.1 eq) were dissolved in 6.5 mL THF and the reaction mixture was heated to 70 °C overnight. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 4/6) to give 170 mg (46% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.91 min; MS (El_neg): m/z = 293 [M-H]\ Intermediate 53

6-Chloro-N-[1 -(2-fluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide

N-(Azetidin-3-yl)-6-chloropyrazine-2-carboxamide hydrochloride [Intermediate 51 ] (250 mg, 1.00 mmol, 1.0 eq), potassium carbonate (694 mg, 5.02 mmol, 5.0 eq) and potassium iodide (17 mg, 0.10 mmol, 0.1 eq) were suspended in 10 mL acetonitrile. Then, 2-fluoroethyl 4-methylbenzenesulfonate [CAS RN: 383-50- 6] (329 mg, 1.51 mmol, 1 .5 eq) was added and the reaction mixture was heated to 70 °C for 12 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % ammonia in water, 15/85→ 55/45) to give 140 mg (54 % yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.72 min; MS (El_pos): m/z = 259 [M+1 ]⁺.

Intermediate 54

6-Chloro-N-(1 -methylpiperidin-4-yl)pyrazine-2-carboxamide

1 -Methylpiperidin-4-amine [CAS-RN: 41838-46-4] (593 mg, 5.20 mmol, 2.0 eq) was dissolved in 17 mL THF, and triethylamine (0.91 mL, 6.50 mmol, 2.5 eq) was added. Then, 6-chloropyrazine-2-carbonyl chloride [CAS-RN: 148673-71 -6] (460 mg, 2.60 mmol, 1.0 eq) in 5 mL THF was added dropwise and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between dichloromethane/isopropanol (4/1 ) and water. The water phase was extracted with dichloromethane/isopropanol (4/1 ) and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo to give 510 mg (62% yield of theory) crude material containing the title compound in 89 % purity (UPLC-MS area-%) which was used without further purification.

UPLC-MS (Method 2): R_t = 0.78 min; MS (El_p∞): m/z = 255 [M+H]⁺.

Intermediate 55

6-Chloro-N-[1 -(2,2-difluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide

N-(Azetidin-3-yl)-6-chloropyrazine-2-carboxamide hydrochloride [Intermediate 51 ] (230 mg, 0.92 mmol, 1.0 eq), triethylamine (0.52 mL, 3.69 mmol, 4.0 eq) and 2,2-difluoroethyl trifluoromethanesulfonate [CAS RN: 74427-22-8] (217 mg, 1.02 mmol, 1.1 eq) were dissolved in 6.0 mL THF and the reaction mixture was heated to 70 °C overnight. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The phases were separated by the use of a Whatman filter, the volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 9/1 ) to give 180 mg (59% yield of theory) of the title compound in 84% purity (UPLC area-%), that was used without further purification. UPLC-MS (Method 1 ): R_t = 0.50 min; MS (El_p∞): m/z = 277 [M+H]⁺.

Intermediate 56

N-[(5-Chloropyrazin-2-yl)methyl]-2,2,2-trifluoro-N-methylethanamine

2,2,2-Trifluoro-N-methylethanamine [CAS RN: 2730-67-8] (254 mg, 2.25 mmol, 1.6 eq), 5-chloropyrazine-2-carbaldehyde [CAS RN: 88625-24-5] (200 mg, 1.40 mmol, 1.0 eq) and sodium triacetoxyborohydride (952 mg, 4.49 mmol, 3.2 eq) were suspended in 20 mL 1 ,2-dichloroethane. Then, triethylamine (0.39 mL, 2.81 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added. After stirring for 10 min, the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 100 mg (29% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.13 min; MS (El_p∞): m/z = 240 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.39 (s, 3H), 3.37 (q, 2H), 3.92 (s, 2H), 8.50 (d, 1 H), 8.74 (d, 1 H).

Intermediate 57

2-Chloro-6-[(3-fluoroazetidin-1 -yl)methyl]pyrazine

3-Fluoroazetidine hydrochloride [CAS RN: 617718-46-4] (250 mg, 2.25 mmol, 1.6 eq), 6-chloropyrazine-2-carbaldehyde [CAS RN: 874114-34-8] (200 mg, 1.40 mmol, 1.0 eq) and sodium triacetoxyborohydride (952 mg, 4.49 mmol, 3.2 eq) were suspended in 20 mL 1 ,2-dichloroethane. Then, triethylamine (0.39 mL, 2.81 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added. After stirring for 10 min, the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 150 mg (53% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.60 min; MS (El_p∞): m/z = 202 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.21 -3.24 (m, 2H), 3.65 (m, 2H), 3.80 (s, 2H), 5.18 (dquint, 1 H), 8.59 (s, 1 H), 8.68 (s, 1 H).

Intermediate 58

2-Chloro-6-[(4,4-difluoropiperidin-1 -yl)methyl]pyrazine

4,4-Difluoropiperidine hydrochloride [CAS RN: 144230-52-4] (354 mg, 2.25 mmol, 1.6 eq), 6-chloropyrazine-2-carbaldehyde [CAS RN: 874114-34-8] (200 mg, 1.40 mmol, 1.0 eq) and sodium triacetoxyborohydride (952 mg, 4.49 mmol, 3.2 eq) were suspended in 20 mL 1 ,2-dichloroethane. Then, triethylamine (0.39 mL, 2.81 mmol, 2.0 eq) was added and the reaction mixture was stirred at rt overnight. Then, water was added. After stirring for 10 min, the resulting phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 200 mg (58% yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.75 min; MS (El_p∞): m/z = 248 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.97 (m, 4H), 2.57 (m, 4H), 3.73 (s, 2H) , 8.69 (s, 1 H) , 8.70 (s, 1 H).

Intermediate 59

6-Chloro-N-[1 -(2,2-difluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

6-Chloropyrazine-2-carboxylic acid [CAS RN: 23688-89-3] (300 mg, 1.89 mmol,

1.0 eq) was dissolved in 4 mL THF, and CDI (307 mg, 1.89 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 70°C for 2 h. Then, 1 -(2,2- difluoroethyl)piperidin-4-amine [CAS RN: 1119499-74-9] (320 mg, 1.95 mmol,

1.1 eq) and triethylamine (0.54 mL, 2.90 mmol, 2.1 eq) as a solution in 5 mL THF was added. The reaction mixture was heated to 70° C for 2 h. On cooling, the reaction mixture was partitioned between dichlorormethanol/isopropanol (4/1 ) and water. The organic phase was washed with water and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 150 mg (26% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.95 min; MS (El_p∞): m/z = 305 [M+H]⁺. Intermediate 60

N-(Azetidin-3-yl)-5-chloropyrazine-2-carboxamide hydrochloride

tert-Butyl 3-{[(5-chloropyrazin-2-yl)carbonyl]amino}azetidine-1 -carboxylate [prepared as described for Intermediate 27] (1.00 g, 3.20 mmol, 1.0 eq) was dissolved in 30 mL dichloromethane. Under ice-cooling, a hydrogenchloride solution (4M in dioxane, 7.99 mL, 32.0 mmol, 10.0 eq) was added dropwise. The reaction mixture was stirred at rt overnight. The precipitate was isolated by filtration and washed with ice-cooled dichloromethane. After drying of the white solid under high vacuum 770 mg (87% yield of theory) of the title compound were obtained.

UPLC-MS (Method 1 ): R_t = 0.46 min; MS (El_p∞): m/z = 213 [M-Cl]⁺.

Intermediate 61 5-Chloro-N-[1 -(2,2-difluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide

N-(Azetidin-3-yl)-5-chloropyrazine-2-carboxamide hydrochloride [Intermediate 60] (500 mg, 2.01 mmol, 1.0 eq), potassium carbonate (832 mg, 6.02 mmol, 3.0 eq) and potassium iodide (36 mg, 0.22 mmol, 0.1 eq) were suspended in 22.5 mL acetonitrile. Then, 2,2-difluoroethyl trifluoromethanesulfonate [CAS RN: 74427-22-8] (644 mg, 3.01 mmol, 1.5 eq) was added and the reaction mixture was heated to 70 °C for 17 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 95/5) to give 375 mg (64% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.81 min; MS (El_nep): m/z = 275 [ -H]\

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.83 (dt, 2H), 3.28 (t, 2H, partially covered by water signal), 3.63 (t, 2H), 4.55 (m, 1 H), 5.95 (tt, 1 H), 8.87 (d, 1 H), 8.96 (d, 1 H), 9.31 (d, 1 H).

Intermediate 62

6-Bromo-N-[1 -(2-fluoroethyl)piperidin-4-yl]pyridazine-3-carboxamide

6-Bromopyridazine-3-carboxylic acid [CAS RN: 65202-51 -9] (500 mg, 2.46 mmol, 1.0 eq) was dissolved in 10 mL THF, and CDI (399 mg, 2.46 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 70° C for 2 h. Then, 1 -(2- fluoroethyl)piperidin-4-amine hydrochloride [CAS RN: 947263-70-9] (498 mg, 2.54 mmol, 1.03 eq) and triethylamine (0.69 mL, 4.93 mmol, 2.0 eq) as a solution in 5 mL THF was added. The reaction mixture was heated to 70°C for 2 h. On cooling, the reaction mixture was partitioned between dichloromethane/isopropanol (4/1 ) and water. The organic phase was washed with water and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo to give 510 mg (63% yield of theory) of the title compound which was used without further purification.

UPLC-MS (Method 1 ): R_t = 0.62 min; MS (El_p∞): m/z = 331 [M] Intermediate 63

1 -(2,2-Di luoroethyl)piperidin-4-amine, salt with hydrochloric acid

tert-Butyl [1 -(2,2-difluoroethyl)piperidin-4-yl]carbamate [CAS RN: 1201694-07-6] (530 mg, 2.01 mmol, 1.0 eq) was dissolved in 5 mL dichloromethane and 2 mL methanol. Then, hydrogen chloride (4M solution in cyclopentylmethylether, 4.0 mL, 12.0 mmol, 6 eq) was added and the reaction mixture was stirred at rt overnight. The precipitate observed was filtered off to give 400 mg (94 % yield of theory) of the title compound which was used without further purification.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.82-2.21 (m, 4H), 2.87-3.37 (m, 3H, ), 3.33 (m, 4H), 6.61 (t, 1 H), 8.42 (s, 3H).

Intermediate 64 tert-Butyl 4-{[(6-chloropyrazin-2-yl)carbonyl]amino}piperidine-1 -carboxylate

A mixture of 6-chloropyrazine-2-carboxylic acid [CAS-RN: 23688-89-3] (1.00 g, 6.31 mmol, 1.0 eq), tert-butyl 4-aminopiperidine-1 -carboxylate [CAS-RN: 87120- 72-7] (1.39 g, 6.94 mmol, 1.1 eq), HATU (2.64 g, 6.94 mmol, 1.1 eq) and DIPEA (2.33 mL, 12.6 mmol, 2.0 eq) was dissolved in 38 mL DMF and stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and filtered through a Whatman filter. The volatile components were removed in vacuo and the crude material obtained was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: hexane-> hexane/ethyl acetate 2/3) to give 2.1 g (94% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 1 .14 min; MS (El_neg): m/z = 339 [M-H]\

Intermediate 65 6-Chloro-N-(piperidin-4-yl)pyrazine-2-carboxamide, salt with trifluoroacetic acid

tert-Butyl 4-{[(6-chloropyrazin-2-yl)carbonyl]amino}piperidine-1 -carboxylate [Intermediate 64] (2.10 g, 6.16 mmol, 1 .0 eq), was dissolved in 1 19 ml_ dichloromethane and trifluoroacetic acid (9.49 ml_, 123 mmol, 20.0 eq) was added. The reaction mixture was stirred overnight and the volatile components were removed in vacuo. Toluene was added and the solvent was removed by the use of a rotary evaporator. This procedure was repeated three times. The title compound was obtained in quantitative yield. The material was used without further purification. UPLC-MS (Method 2): R_t = 0.68 min; MS ( El neg) : m/z = 239 [M-H]\

Intermediate 66

6-Chloro-N-[1 -(3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide

6-Chloro-N-(piperidin-4-yl)pyrazine-2-carboxamide trifluoroacetic acid salt [Intermediate 65] (1.49 g, 6.20 mmol, 1.0 eq), and potassium carbonate (4.28 g, 31.0 mmol, 5.0 eq) were suspended in 33 mL acetonitrile. Then, 1 , 1 , 1 - trifluoro-3-iodopropane [CAS RN: 460-37-7] (2.08 g, 9.30 mmol, 1.5 eq) was added and the reaction mixture was heated to 70° C for 4 h. On cooling, the reaction mixture was diluted with water and extracted with dichloromethane/isopropanol (4/1 ) (2x). The combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 95/5) to give 900 mg (41 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.56 min; MS (ESI_pos): m/z = 337 [M+H]⁺.

Intermediate 67 tert-Butyl 4-{[(5-chloropyrazin-2-yl)carbonyl]amino}piperidine-1 -carboxylate

A mixture of 5-chloropyrazine-2-carboxylic acid [CAS RN: 36070-80-1 ] (1.00 g, 6.31 mmol, 1.0 eq), tert-butyl 4-aminopiperidine-1 -carboxylate [CAS-RN: 87120- 72-7] (1.39 g, 6.94 mmol, 1.1 eq), HATU (2.64 g, 6.94 mmol, 1.1 eq) and DIPEA (2.33 ml_, 12.6 mmol, 2.0 eq) was dissolved in 38 mL DMF and stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and filtered through a Whatman filter. The volatile components were removed in vacuo and the crude material obtained was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane-> hexane/ethyl acetate 2/3) to give 1.01 g (43% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 1.15 min; MS (El_neg): m/z = 339 [M-H]\

Intermediate 68

5-Chloro-N-(piperidin-4-yl)pyrazine-2-carboxamide, salt with trifluoroacetic acid

tert-Butyl 4-{[(5-chloropyrazin-2-yl)carbonyl]amino}piperidine-1 -carboxylate [Intermediate 67] (1.00 g, 2.93 mmol, 1.0 eq), was dissolved in 57 mL dichloromethane and trifluoroacetic acid (4.52 mL, 59 mmol, 20.0 eq) was added. The reaction mixture was stirred overnight and the volatile components were removed in vacuo. Toluene was added and the solvent was removed by the use of a rotary evaporator. This procedure was repeated three times. The title compound was obtained in quantitative yield. The material was used without further purification.

UPLC-MS (Method 2): R_t = 0.71 min; MS (El_neg): m/z = 239 [M-H]\ Intermediate 69

5-Chloro-N-[1 -(3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide

5-Chloro-N-(piperidin-4-yl)pyrazine-2-carboxamide trifluoroacetic acid salt [Intermediate 68] (722 mg, 3.00 mmol, 1.0 eq), and potassium carbonate (2.07 g, 15.0 mmol, 5.0 eq) were suspended in 33 mL acetonitrile. Then, 1 , 1 , 1 - trifluoro-3-iodopropane [CAS RN: 460-37-7] (1.01 g, 4.50 mmol, 1.5 eq) was added and the reaction mixture was heated to 70° C for 4 h. On cooling, the reaction mixture was diluted with water and extracted with dichloromethane/isopropanol (4/1 ) (2x). The combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 95/5) to give 900 mg (41 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.58 min; MS (ESI_pos): m/z = 337 [M+H]⁺.

Intermediate 70

2-Bromo-5-(prop-1 -en-2-yl)pyrazine

2-Bromo-5-iodopyrazine [CAS RN: 622392-04-5] (3.50 g, 12.3 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(prop-1 -en-2-yl)-1 ,3,2-dioxaborolane [CAS RN: 126726-62- 3] (3.10 g, 18.4 mmol, 1.5 eq), Pd(dppf)Cl2-CH₂Cl₂ (502 mg, 0.61 mmol, 0.05 eq) and cesium carbonate (12.0 g, 36.9 mmol, 3.0 eq) were dissolved in 130 mL dioxane/water (5/1 ). The reaction mixture was heated to 90°C for 2 h. On cooling, the reaction mixture was partitioned between water and dichloromethane. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 100 g SNAP cartridge: hexane -> hexane/ethyl acetate 9/1 ) to give 600 mg (25% yield of theory) of the title compound in a round 50% purity (UPLC-area%). The impurity was identified as 2,5-di(prop-1 -en-2-yl)pyrazine, that was not expected to interfere in the subsequent reaction step. The material obtained was used without further purification.

UPLC-MS (Method 4): R_t = 1.18 min; MS (ESI_pos): m/z = 199 [M]⁺.

Intermediate 71

Methyl 2-(5-chloropyrazin-2-yl)-2-methylpropanoate

Methyl 2-methylpropanoate [CAS RN: 547-63-7] (5.14 g, 50.3 mmol, 1.5 eq) was dissolved in 125 mL THF. At a temperature of -70 °C, lithium diisopropylamide [CAS RN: 4111 -54-0] (1.8 M solution in THF/hexane/ethylbenzene, 27.9 mL, 50.3 mmol, 1.5 eq) was added dropwise. The solution was stirred for 1 h at -70 °C. Then, 2,5-dichloropyrazine [CAS RN: 19745-07-4] (5.00 g, 33.6 mmol, 1.0 eq) was added and the reaction mixture was allowed to warm up to rt overnight while stirring. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3x). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 100 g SNAP cartridge: hexane -> hexane/ethyl acetate 1 /2) to give 2.50 mg (35% yield of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1 .56 (s, 6H), 3.59 (s, 3H, ), 8.61 (d, 1 H), 8.90 (d, 1 H).

Intermediate 72

5-Amino-N-(2-methoxypyridin-4-yl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-3-methyl-1 ,2-thiazole-4-carboxylic acid [CAS-RN: 22131 - 51 -7] for the synthesis, please see: J. Goerdeler, H. Horn, Chem. Ber. (1963), 96, 1551 -1560.] (3.40 g, 21.5 mmol, 1.0 eq) and thionyl chloride (17.2 ml_, 236 mmol, 11.0 eq) was stirred at 100 °C for 2 h. After cooling, the volatile components were removed in vacuo. The crude acid chloride was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two more times. A portion of the acid chloride observed this way (0.83 g) was diluted with THF (38 ml_). Then, 2-methoxypyridin-4-amine [CAS-RN: 20265-39- 8] (580 mg, 4.67 mmol, 1 .0 eq) and triethyl amine (1 .30 ml_, 9.34 mmol, 2.0 eq) was added. The reaction mixture was stirred at rt overnight. After addition of 1 L water the crude reaction mixture was extracted with ethyl acetate (3x). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 55 g NH2- cartridge: dichloromethane -> dichloromethane/ethanol 95/5) to give 150mg (13 % yield of theory, based on the intermediate acid chlorid) of the title compound in about 95%-purity (H-NMR). UPLC-MS (Method 1 ): Rt = 0.63 min; MS (El_neg): m/z = 263

Intermediate 73

Methyl 1 -(3,3,3-trifluoropropyl)piperidine-4-carboxylate

Methyl piperidine-4-carboxylate [CAS-RN: 2971 -79-1 ] (5.00 g, 34.9 mmol, 1.0 eq), and potassium carbonate (14.5 g, 105 mmol, 3.0 eq) were suspended in 184 mL acetonitrile. Then, 3,3,3-trifluoropropyl 4-methylbenzenesulfonate [CAS RN: 2342-67-8] (10.3 g, 38.4 mmol, 1.1 eq) was added and the reaction mixture was heated to 70 °C overnight. On cooling, the reaction mixture was diluted with water and extracted with dichloromethane/isopropanol (4/1 ) (2x). The combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 50 g SNAP cartridge: hexane/ethyl acetate 9/1 -> hexane/ethyl acetate 1 /1 ) to give 7.17 g (77% yield of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.52 (m, 2H), 1.78 (m, 2H, ), 1.99 (dt, 2H), 2.29 (m, 1 H), 2.78 (dt, 2H), 3.59 (s, 3H), 4H's not assigned.

Intermediate 74

5-Amino-N-(4-isopropoxyphenyl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-3-methyl-1 ,2-thiazole-4-carboxylic acid [CAS-RN: 22131 - 51 -7] for the synthesis, please see: J. Goerdeler, H. Horn, Chem. Ber. (1963), 96, 1551 -1560.] (3.40 g, 21.5 mmol, 1.0 eq) and thionyl chloride (17.2 ml_, 236 mmol, 11.0 eq) was stirred at 100 °C for 2 h. After cooling, the volatile components were removed in vacuo. The crude acid chloride was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two more times. A portion of the acid chloride observed this way (3.36 g) was diluted with THF (38 ml_). Then, 6-(propan-2-yloxy)pyridin-3-amine [CAS-RN: 52025-36-2] (3.47 g, 22.8 mmol, 1.2 eq) and triethyl amine (5.30 mL, 38.0 mmol, 2.0 eq) was added. The reaction mixture was stirred at rt overnight. After addition of 1 L water the crude reaction mixture was extracted with ethyl acetate (3x). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 55 g NH2-cartridge: dichloromethane -> dichloromethane/ethanol 95/5) to give 2.30 g (37 % yield of theory, based on the intermediate acid chlorid) of the title compound in about 90%-purity (H- NMR).

UPLC-MS (Method 1 ): Rt = 0.94 min; MS (El_neg): m/z = 291 [M-H]\ The compounds listed in Table A were prepared according to the amide formation protocols outlined below from the respective starting materials SM1 and SM2. The method starts either from the acid (Method A or Method C), or from the acid chloride (Method B). A typical reaction was run on 1.00-10.0 mmol scale:

Method A:

The carboxylic acid SM1 (5.00 mmol, 1.0 eq) was dissolved in 10 mL THF, and CDI (5.00 mmol, 1.0 eq) was added. Then, the reaction mixture was heated to 70°C for 2 h. Then, the amine SM2 (5.50 mmol, 1.1 eq) and triethylamine (10.5 mmol, 2.1 eq) as a solution in 10 mL THF was added. The reaction mixture was heated to 70 °C for 2 h. On cooling, the reaction mixture was partitioned between dichloromethane/isopropanol (4/1 ) and water. The organic phase was washed with water and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo. Purification was usually conducted via preparative MPLC (Biotage Isolera; SNAP cartridge: hexane -> hexane/ethyl acetate 1 /1 ) to give the title compounds.

Method B:

The amine SM2 (5.00 mmol, 2.0 eq) was dissolved in 17 mL THF, and triethylamine (6.25mmol, 2.5 eq) was added. Then, the acid chloride SM1 (2.50 mmol, 1.0 eq) in 5 mL THF was added dropwise and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between dichloromethane/isopropanol (4/1 ) and water. The water phase was extracted with dichloromethane/isopropanol (4/1 ) and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo. Purification was usually conducted via preparative MPLC (Biotage Isolera; SNAP cartridge: hexane -> hexane/ethyl acetate 1 /1 ) to give the title compounds.

Method C:

A mixture of the acid (1.0-10.0 mmol, 1.0 eq), the amine(1.1 eq), HATU (1.1 eq) and DIPEA (2.0 eq) was dissolved in DMF (5 mL/1 .0 mmol acid) and stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and filtered through a Whatman filter. The volatile components were removed in vacuo and the crude material obtained was purified via preparative MPLC (Biotage Isolera; SNAP cartridge: hexane-> hexane/ethyl acetate 2/3) to give the title compound.

Table A:

The compounds listed in Table B were prepared according to the reaction sequence outlined below from the respective starting materials SM1 and SM2:

The ester SM1 (-0.5-50 mmol, 1 .5 eq) was dissolved in TH F (-1 2.5 mL/10 mmol SM 1 ). At a temperature of -70 °C, lithium diisopropylamide [CAS RN : 41 1 1 -54-0] (1 .8 M solution in THF/hexane/ethylbenzene, 1 .5 eq) was added dropwise. The solution was stirred for 1 h at -70 °C. Then, the halosubstituted heterocycle (1 .0 eq) was added and the reaction mixture was allowed to warm up to rt overnight while stirring . The reaction mixture was quenched with saturated NH₄CI- solution and extracted with ethyl acetate (3x). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified e.g . via preparative MPLC (Biotage Isolera; 100 g SNAP cartridge: hexane -> hexane/ethyl acetate 1 /2) to give the title compounds.

Table B:

The compounds listed in Table C were prepared according to the procedure outlined below from the respective starting materials SM1 and SM2. A typical reaction was run on 0.1 -0.5 mmol scale:

The ester SM1 (0.50 mmol, 1 .0 eq) was dissolved in methanol (100 eq). then lithium hydroxide (6 eq). Then, the solution was stirring overnight at rt. In case of insufficient conversion was observed, the reaction mixture was heated to 60 °C. Then, stirring was maintened for another night. On cooling, hydrogen chloride (4M in doxane, 6eq) was added and the volatile components were removed. The crude material was forwarded to preparative HPLC or MPLC for purification.

Table C:

The compounds listed in Table D were prepared according to the reaction sequence outlined below from the respective starting materials SM1 and SM2:

A mixture of aminoisothiazole SM1 (0.50-3.00 mmol, 1 .0 eq), haloheterocycle SM2 (0.8-1 .2 eq) and cesium carbonate (2.3 eq) in dioxane/DMF (7/1 ) [-5.5 ml_ for 0.50 mmol of SM1 ] was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (0.1 eq) and Xantphos (0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 1 10 °C overnight. On cooling, the reaction mixture was partitioned between dichloromethane and water. After filtration over Celite, the organic phase was separated and concentrated in vacuo. The crude product was usually purified via preparative HPLC or via crystallization from a suitable solvent. The carbamate observed this way was dissolved in dichloromethane (300 eq, based on SM1 ) and trifluoroacetic acid (20.0 eq, based on SM1 ) was added. The reaction mixture was stirred overnight and the volatile components were removed in vacuo. Toluene was added and the solvent was removed by the use of a rotary evaporator. This procedure was repeated three times. In most cases the title compounds were already pure enough to be used without further purification. In some other cases a MPLC or HPLC was applied for purification.

Table D:

Intermediate 89 6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)pyrazine- 2-carboxylic acid

To a solution of methyl 6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2- thiazol-5-yl}amino)pyrazine-2-carboxylate [WO 2014/118186, example 66] (1.34 g, 3.31 mmol, 1.0 eq) in ethanol (8.3 mL) was added sodium hydroxide (1M aqueous solution, 8.26 mL, 16.5 mmol, 5.0 eq). The reaction mixture was stirred at 60° C for 5h. The volatile components were removed in vacuo. After addition of water, the the pH was adjusted to ~4 by the use of 2M hydrochloric acid. Then, the mixture was extracted four times with dichloromethane/isopropanol (4/1 ). In the course of this process a precipitate formed within the aqueous phase, that was separated by filtration. The solid observed this way was washed with water and dried under high vacuum to give 530 mg (38 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): Rt = 1.02 min; MS (El_neg): m/z = 390 [M-H]\ Intermediate 90

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)pyrazine- 2-carboxylic acid

To a solution of methyl 5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2- thiazol-5-yl}amino)pyrazine-2-carboxylate [WO 2014/118186, example 59] (593 mg, 2.46 mmol, 1.0 eq) in ethanol (4.3 mL) was added sodium hydroxide (1M aqueous solution, 3.66 mL, 16.5 mmol, 5.0 eq). The reaction mixture was stirred at 60° C for 5h. The volatile components were removed in vacuo. After addition of water, the the pH was adjusted to ~4 by the use of 2M hydrochloric acid. Then, the mixture was extracted four times with dichloromethane/isopropanol (4/1 ). In the course of this process a precipitate formed within the aqueous phase, that was separated by filtration. The solid observed this way was washed with water and dried under high vacuum to give 499 mg (78 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): Rt = 1.02 min; MS (El_neg): m/z = 390 [M-H]\

EXAMPLES

Example 1

N-(3,4-Difluorophenyl)-3-methyl-5-[(6-vinylpyrazin-2-yl)amino]-1 ,2-thiazole-4- carboxamide

A mixture of 5-[(6-chloropyrazin-2-yl)amino]-N-(3,4-difluorophenyl)-3-methyl- 1 ,2-thiazole-4-carboxamide [Intermediate 2] (1 .00 g, 2.62 mmol, 1 .0 eq), trivinylboroxin-pyridine complex [CAS RN: 95010-17-6] (423 mg, 2.62 mmol, 1 .0 eq), potassium carbonate (1 .09 g, 7.86 mmol, 3.0 eq), DavePhos (103 mg, 0.26 mmol, 0.1 eq) and palladium(ll ) acetate (29 mg, 0.13 mmol, 0.05 eq) were dissolved in 20 mL acetonitrile and 15 mL of water. Then, the reaction vessel was flushed with argon and the reaction mixture was stirred for 5 h at reflux temperature. Palladium(ll ) acetate, DavePhos and trivinylboroxin-pyridine complex in the amount mentioned above were added and stirring was prolonged for another 5 h at reflux temperature. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo. The crude material was diluted with dichloromethane and the resulting solid was isolated to give 380 mg (35 % yield of theory) of the title compound. The remaining mother liquor was concentrated by the use of a rotary evaporator and purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexan /ethyl acetate 9/ 1 -> hexane/ethyl acetate 1 /1 ) to give another 340 mg (30 % yield of theory) of the title compound after filtration and drying.

UPLC-MS (Method 1 ): R_t = 1.26 min; MS (ESI_neg): m/z = 372 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.40 (s, 3H), 5.74 (dd, 1 H), 6.56 (dd, 1 H), 6.92 (dd, 1 H), 7.36-7.52 (m, 2H), 7.95 (dd, 1 H), 8.22 (s, 1 H), 8.62 (s, 1 H), 10.43 (s, 1 H), 11.01 (s, 1 H).

Example 2

N-(3,4-Difluorophenyl)-5-({6-[2-(dimethylamino)ethyl]pyrazin-2-yl}amino)-3- methyl-1 ,2-thiazole-4-carboxamide

A mixture of N-(3,4-difluorophenyl)-3-methyl-5-[(6-vinylpyrazin-2-yl)amino]-1 ,2- thiazole-4-carboxamide [Example 1 ] (40 mg, 0.11 mmol, 1 .0 eq) was placed in a microwave vial and dissolved in 1.5 mL 2-butanol. N,N-Diisopropylethylamine (230 μΙ_, 1.34 mmol, 12.5 eq) and dimethyl amine hydrochloride [CAS RN : 506- 59-2] (87 mg, 1.07 mmol, 10 eq) were added. Then, the reaction mixture was heated in a single mode microwave oven for 5 h to 150°C. After cooling, purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85→ 55/45) to give 12 mg (28 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.87 min; MS (ESIneg) : m/z = 417 [M-H]\ ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.63 (s, 6H), 3.08 (t, 2H), 7.30-7.47 (m, 2H), 7.86 (s br, 1 H), 8.05 (s, 1 H), 8.13 (s, 1 H), 8.42 (s br, 1 H), 1 1.20 (s br, 1 H), 1xCH₃ and 1xCH₂ obscured by solvent signals.

Example 3

N-(3,4-Difluorophenyl)-3-methyl-5-({6-[2-(methylsulfonyl)ethyl]pyrazin-2- yl}amino)-1 ,2-thiazole-4-carboxamide

A mixture of N-(3,4-difluorophenyl)-3-methyl-5-[(6-vinylpyrazin-2-yl)amino]-1 ,2- thiazole-4-carboxamide [Example 1 ] (98 mg, 260 μητιοΐ, 1.0 eq) and sodium methanesulfinate [CAS RN: 20277-69-4] (134 mg, 1.31 mmol, 5.0 eq) in 3 ml_ sec-butanol was heated to 170°C for 3 h in a single mode microwave oven. The solvent was removed and purification was conducted via preparative HPLC (Method A) to give 5 mg (4 % yield of theory) of the title compound. UPLC-MS (Method 1 ): R_t = 1.05 min; MS (ESI_pos): m/z = 454 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.45 (s, 3H), 3.07 (s, 3H), 3.67 (t, 2H), 7.37-7.51 (m, 2H), 7.94 (dd, 1 H), 8.18 (s, 1 H), 8.58 (s, 1 H), 10.42 (s, 1 H), 10.96 (s, 1 H), 1xCH₂ obscured by water signal. Example 4

N-(3,4-Di luorophenyl)-3-methyl-5-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)py yl]amino}-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (85.6 mg, 0.32 mmol, 1.0 eq), 2-chloro-6-(3- methyl-1 ,2,4-oxadiazol-5-yl)pyrazine [Intermediate 3] (50 mg, 0.8 mmol, 0.8 eq) and cesium carbonate (238 mg, 0.73 mmol, 2.3 eq) in 3.1 mL dioxane/DMF (7/1 ) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (7 mg, 0.03 mmol, 0.1 eq) and Xantphos (18 mg, 0.03 mmol, 0.1 eq) were added. Then, the reaction mixture was heated to an environmental temperature of 110 °C overnight. On cooling, the volatile components were removed in vacuo. The crude product was partitioned between water and dichloromethane/methanol (4/1 ). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The crude material was then subjected to preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 30/70→ 70/30) to give 6 mg (4 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.23 min; MS (El_neg): m/z = 428 [M-H]\ ¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.42-7.51 (m, 2H), 7.96 (m, 1 H), 8.91 (s, 1 H), 8.97 (s, 1 H), 10.53 (s, 1 H), 11.36 (s, 1 H), 2xCH₃ not assigned. Example 5

N-(3,4-difluorophenyl)-3-methyl-5-{[5-(3-methyl-1 ,2,4-oxadiazol-5-yl)pyridin-2- yl]amino}-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (150 mg, 0.56 mmol, 1.0 eq), 2-chloro-5-(3- methyl-1 ,2,4-oxadiazol-5-yl)pyridine [Intermediate 4] (121 mg, 0.56 mmol, 1.0 eq) and cesium carbonate (417 mg, 1.28 mmol, 2.3 eq) in 5.4 mL dioxane/DMF (7/1 ) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (32 mg, 0.06 mmol, 0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the volatile components were removed in vacuo. The crude product was treated with water. After extraction with dichloromethane/isopropanol (4/1 ), which was repeated two times, the organic phase was washed with brine and the phases were separated by the use of a Whatman filter. On cooling, the volatile components of the resulting organic phase were removed in vacuo. The crude material was purified via preparative MPLC (Biotage Isolera; 50 g NH2-SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 59 mg (23 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.32 min; MS (El_neg): m/z = 427 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.41 (s, 3H), 2.43 (s, 3H), 7.37-7.55 (m, 3H), 7.94 (dd, 1 H), 8.33 (dd, 1 H), 9.06 (d, 1 H), 10.49 (s, 1 H), 11.09 (s, 1 H). Example 6

N-(3,4-Difluorophenyl)-3-methyl-5-{[5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-4- (trifluoromethyl)pyridin-2-yl]amino}-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (77 mg, 0.29 mmol, 1.0 eq), 2-chloro-5-(3- methyl-1 ,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)pyridine [Intermediate 5] (60 mg, 0.23 mmol, 0.8 eq) and cesium carbonate (213 mg, 0.65 mmol, 2.3 eq) in 2.8 mL dioxane/DMF (7/1 ) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (6 mg, 0.03 mmol, 0.1 eq) and Xantphos (16 mg, 0.03 mmol, 0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the reaction mixture was partitioned between dichloromethane/methanol (4/1 ) and water. The organic phase was passed through a Whatman filter. The solvent was removed by the use of a rotary evaporator and the crude product was subjected to preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 4/6 -> ethyl acetate). Then, the combined product fractions were crystallized with dichloromethane/methanol to give 25 mg (17 % yield of theory) of the title compound after drying under high vacuum.

UPLC-MS (Method 2): R_t = 1.02 min; MS (El_neg): m/z = 495 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.44 (s, 6H), 7.39-7.53 (m, 2H), 7.90- 8.03 (m, 2H), 9.12 (s, 1 H), 10.56 (s br, 1 H), 11.39 (s br, 1 H). Example 7

N-(3,4-Difluorophenyl)-3-methyl-5-{[4-(5-methyl-1 ,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)pyridin-2-yl]amino}-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (150 mg, 0.56 mmol, 1.0 eq), 2-chloro-4-(5- methyl-1 ,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridine [Intermediate 6] (147 mg, 0.56 mmol, 1.0 eq) and cesium carbonate (417 mg, 1.28 mmol, 2.3 eq) in 5.4 mL dioxane/DMF (7/1 ) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (32 mg, 0.06 mmol, 0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the volatile components were removed in vacuo. The crude material was partitioned between dichloromethane/methanol (-5/1 ) and water. The combined organic phases were washed with brine, passed through a Whatman filter and concentrated in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 30/70 → 70/30) to give 100 mg (36 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.32 min; MS (ESI_neg): m/z = 495 [M-H]\ ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.42 (s, 3H), 2.61 (s, 3H), 7.39-7.50 (m, 2H), 7.95 (m, 1 H), 8.02 (s, 1 H), 8.96 (s, 1 H), 10.56 (s, 1 H), 11.33 (s br, 1 H). Example 8

5-{[5-Chloro-4-(3-methyl-1 ,2,4-oxadiazol-5-yl)pyridin-2-yl]amino}-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (150 mg, 0.56 mmol, 1.0 eq), 2,5-dichloro-4-(3- methyl-1 ,2,4-oxadiazol-5-yl)pyridine [Intermediate 7] (142 mg, 0.56 mmol, 1.0 eq) and cesium carbonate (417 mg, 1.28 mmol, 2.3 eq) in 5.4 mL dioxane/DMF (7/1 ) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (32 mg, 0.06 mmol, 0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the volatile components were removed in vacuo. The crude material was treated with water and extracted three times with dichloromethane/isopropanol (-5/1 ). The combined organic phases were washed with brine, passed through a Whatman filter and concentrated in vacuo. The crude material was purified first via preparative MPLC (Biotage Isolera; 50 g NH2-SNAP cartridge: hexane/ethyl acetate 8/2 -> hexane/ethyl acetate 3/7) and the product fractions in the following via preparative HPLC (method A) to give 5 mg (2 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.41 min; MS (ESI_neg): m/z = 461 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.33 (s, 0.8 H), 2.07 (s, 2.2H), 7.41 (d, 0.7H), 7.45 (d, 1.4H), 7.88 (dd, 0.25H), 7.95 (dd, 0.75H), 8.09 (s, 0.25H), 8.13 (s, 0.75H), 8.70 (s, 0.25H), 8.72 (s, 0.75H), 10.42 (s, 0.25H), 10.48 (s, 0.75H), 10.98 (s, 0.7H) 11.04 (s, 0.3H), 1xCH₃ not assigned.

Example 9

Ethyl N-{[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)-pyrazin-2-yl]carbonyl}glycinate

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1] (251 mg, 0.93 mmol, 1.0 eq), ethyl N-[(6- chloropyrazin-2-yl)carbonyl]glycinate [Intermediate 8] (260 mg, 1.02 mmol, 1.1 eq) and cesium carbonate (607 mg, 1.86 mmol, 2.0 eq) in 9.9 mL dioxane/DMF (7/1) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (21 mg, 0.09 mmol, 0.1 eq) and Xantphos (54 mg, 0.09 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 4 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (Method A) to give 142 mg (31 % yield of theory) of the title compound.

UPLC-MS (Method 1): R_t = 1.17 min; MS (ESI_neg): m/z = 475 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (t, 3H), 4.18 (q, 2H), 4.26 (d, 2H), 7.39-7.53 (m, 2H), 7.95 (dd, 1H), 8.29 (t, 1H), 8.68 (s, 1H), 8.92 (s, 1H), 10.50 (s, 1H), 11.24 (s, 1H), 1xCH₃ obscured by solvent signal. Example 10

Ethyl 1 -[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)- pyrazin-2-yl]-1 H-pyrazole-4-carboxylate

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (446 mg, 1.66 mmol, 1.0 eq), ethyl 1 -(6- chloropyrazin-2-yl)-1 H-pyrazole-4-carboxylate [Intermediate 9] (460 mg, 1.82 mmol, 1.1 eq) and cesium carbonate (1.08 g, 3.31 mmol, 2.0 eq) in 16 ml_ dioxane/DMF (7/1 ) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (37 mg, 0.17 mmol, 0.1 eq) and Xantphos (96 mg, 0.17 mmol, 0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C for 4 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl actete and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter. The crude material was crystallized with dichloromethane/ methanol. The preciptitate was isolated via filtration and washed with dichloromethane. After drying, 152 mg (19 % yield of theory) of the title compound were obtained.

UPLC-MS (Method 1 ): R_t = 1.36 min; MS (ESI_neg): m/z = 484 [M-H]\ ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.33 (t, 3H), 4.33 (q, 2H), 7.36-7.53 (m, 2H), 7.95 (dd, 1 H), 8.33 (s, 1 H), 8.73 (s, 2H), 9.04 (s, 1 H), 10.56 (s, 1 H), 11 .34 (s, 1 H), 1xCH₃ obscured by solvent signal. Example 1 1

Methyl 3-[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]propanoate

5-[(6-Chloropyrazin-2-yl)amino]-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 2] (200 mg, 0.52 mmol, 1 .0 eq) was dissolved in 3 mL dioxane, and methyl prop-2-enoate [CAS RN: 96-33-3] (50 μΙ_, 0.58 mmol, 1 .0 eq), N-cyclohexyl-N-methylcyclohexanamine [CAS RN: 7560-83-0] (120 μΙ_, 0.58 mmol, 1 .0 eq), tn^'s(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol, 0.015 eq) and tri-teri-butylphosphonium tetrafluoroborate (9 mg, 0.03 mmol, 0.06 eq) were added. The reaction mixture was stirred at a temperature of 1 15 ° C for 2 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine. The phases were separated by the use of a Whatman filter. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/ 1 -> hexane/ethyl acetate 2/8) yielding -200 mg of methyl 3-[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]acrylate in 75% purity (UPLC) as being the product of the primary Heck coupling protocol. The crude material observed this way was directly forwarded to the hydrogenation step and was therefore diluted with 3 mL of methanol. After addition of palladium on carbon (10%, -50 mg) the reaction flask was stirred for a total of 9 h at rt under a hydrogen atmosphere (balloon, 1 atm). The catalyst was removed by filtration over Celite. After washing with ethanol the volatile components were removed in vacuo. Purification was conducted via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 9/ 1 -> hexane/ethyl acetate 1 / 1 ) yielding 10 mg (5 % yield of theory) of the title compound. UPLC-MS (Method 1 ): R_t = 1 .19 min; MS (ESI_neg): m/z = 432 [M]\

¹ H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.44 (s, 3H), 2.95 (t, 2H), 3.08 (t, 2H), 3.59 (s, 3H), 7.38-7.50 (m, 2H), 7.94 (m, 1 H), 8.1 1 (s, 1 H), 8.53 (s, 1 H), 10.40 (s, 1 H), 10.90 (s, 1 H).

Example 1 2

N-(3,4-Difluorophenyl)-3-methyl-5-[(5-vinylpyrazin-2-yl)amino]-1 ,2-thiazole-4- carboxamide

A mixture of 5-[(5-bromopyrazin-2-yl)amino]-N-(3,4-difluorophenyl)-3-methyl- 1 ,2-thiazole-4-carboxamide [Intermediate 10] (225 mg, 0.53 mmol, 1 .0 eq), 2,4,6-trivinylboroxin-pyridine complex [CAS RN: 95010-17-6] (127 mg, 0.53 mmol, 1 .0 eq), DavePhos (21 mg, 0.53 mmol, 0.1 eq), palladium(ll ) acetate (5.9 mg, 0.26 mmol, 0.05 eq) and potassium carbonate (219 mg, 1 .58 mmol, 3.0 eq) in 4.3 mL acetonitrile was placed in a reaction flask and flushed with argon. The reaction mixture was stirred at a temperature of 150 ° C in a single mode microwave oven for 2 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate and the combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/ 1 ) to yield 39 mg (18 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .32 min; MS (ESI_neg): m/z = 372 [M-H]\

¹ H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.44 (s, 3H), 5.41 (dd, 1 H), 6.17 (dd, 1 H), 6.82 (dd, 1 H), 7.40-7.52 (m, 2H), 7.95 (dd, 1 H), 8.46 (s, 1 H), 8.70 (s, 1 H), 10.44 (s, 1 H), 1 1 .04 (s, 1 H).

Example 1 3

N-(3,4-Difluorophenyl)-5-({5-[(4,4-difluoropiperidin-1 -yl)methyl]pyrazin-2-yl}- amino)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (167 mg, 0.62 mmol, 1 .0 eq), 2-chloro-5-[(4,4- difluoropiperidin-1 -yl)methyl]pyrazine [Intermediate 1 1 ] (230 mg, 0.93 mmol, 1 .5 eq) and cesium carbonate (403 mg, 1 .24 mmol, 2.0 eq) in 6.6 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (14 mg, 0.06 mmol, 0.1 eq) and Xantphos (36 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C for 6 h. On cooling, the reaction mixture was partitioned between dichloro- methane/isopropanol (4/ 1 ) and water. The combined organic phases were washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (Method A) to give 25 mg (8 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.98 min; MS (El_neg): m/z = 479 [M-H]\

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1 .85-2.07 (m, 4H), 2.45 (s, 3H), 2.51 - 2.66 (m, 4H), 3.68 (s, 2H), 7.35-7.52 (m, 2H), 7.94 (dd, 1 H), 8.39 (d, 1 H), 8.68 (d, 1 H), 10.38 (s br, 1 H), 10.92 (s br, 1 H).

Example 14

5-({5-[(3,3-Difluoroazetidin-1 -yl)methyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (270 mg, 1 .00 mmol, 1 .0 eq), 2-chloro-5-[(3,3- difluoroazetidin-1 -yl)methyl]pyrazine [Intermediate 1 2] (330 mg, 1 .50 mmol, 1 .5 eq) and cesium carbonate (653 mg, 2.01 mmol, 2.0 eq) in 10.7 mL dioxane/DMF (7/ 1 ) was placed in a reaction flask that was flushed with argon. Then, palladium(ll ) acetate (23 mg, 0.10 mmol, 0.1 eq) and Xantphos (58 mg, 0.10 mmol, 0.1 eq) were added. Afterwards, the reaction mixture was stirred at 1 10 ° C (oil bath temperature) overnight. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85→ 55/45) to give 100 mg (22 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .08 min; MS (El_neg): m/z = 451 [M-H]\

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.44 (s, 3H), 3.69 (t, 4H), 3.82 (s, 2H), 7.37-7.54 (m, 2H), 7.95 (dd, 1 H), 8.36 (s, 1 H), 8.68 (s, 1 H), 10.41 (s br, 1 H), 10.94 (s br, 1 H).

Example 1 5

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (189 mg, 0.70 mmol, 1 .0 eq), 5-chloro-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 14] (340 mg, 1 .05 mmol, 1 .5 eq) and cesium carbonate (458 mg, 1 .41 mmol, 2.0 eq) in 7.8 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (16 mg, 0.07 mmol, 0.1 eq) and Xantphos (41 mg, 0.07 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C overnight. On cooling, the reaction mixture was partitioned between dichloro-methane/isopropanol (4/ 1 ) and water. The organic phase was separated and the water phase was extracted three times with dichloro- methane/isopropanol (4/ 1 ). The combined organic phases were washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. The crude material was dissolved in methanol and dichloromethane was added to initiate crystallization. The precipitate observed was isolated by filtration and dried under high vacuum to give 215 mg (55 % yield of theory) of the title compound. UPLC-MS (Method 1 ): R_t = 1 .31 min; MS (ESI_neg): m/z = 554 [M-H]\

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1 .57-1 .80 (m, 4H), 2.91 (m, 2H), 3.16 (q, 2H), 3.80 (m, 1 H), 7.38-7.52 (m, 2H), 7.96 (dd, 1 H), 8.48 (d, 1 H), 8.73 (d, 1 H), 8.89 (d, 1 H), 10.52 (s br, 1 H), 1 1 .29 (s br, 1 H), 5H's are partly obscured by solvent signal.

Example 16

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (152 mg, 0.57 mmol, 1 .0 eq), 6-chloro-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 1 5] (275 mg, 0.85 mmol, 1 .5 eq) and cesium carbonate (370 mg, 1 .14 mmol, 2.0 eq) in 6.3 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (33 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C overnight. On cooling, the reaction mixture was partitioned between dichloro-methane/isopropanol (4/ 1 ) and water. The organic phase was separated and the water phase was extracted three times with dichloro- methane/isopropanol (4/ 1 ). The combined organic phases were washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> ethyl acetate) to yield 172 mg (53 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .29 min; MS (ESI_neg): m/z = 554 [M-H]\

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1 .57-1 .79 (m, 2H), 1 .94 (m, 2H), 2.07 (s, 3H), 2.94 (m, 2H), 3.21 (q, 2H), 3.88 (m, 1 H), 7.35-7.52 (m, 2H), 7.86 (d, 1 H), 7.95 (dd, 1 H), 8.64 (s, 1 H), 8.89 (s, 1 H), 10.51 (s, 1 H), 1 1 .28 (s, 1 H), 2H's are partly obscured by solvent signal.

Example 17

6-({4-[(4-Chloro-3-fluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N- [1 -(2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(4-chloro-3-fluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 16] (153 mg, 0.54 mmol, 1 .0 eq), 6-chloro-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 1 5] (260 mg, 0.81 mmol, 1 .5 eq) and cesium carbonate (350 mg, 1 .08 mmol, 2.0 eq) in 5.9 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (12 mg, 0.05 mmol, 0.1 eq) and Xantphos (31 mg, 0.05 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C for 5h. On cooling, the reaction mixture was partitioned between dichloro-methane/isopropanol (4/ 1 ) and water. The organic phase was separated and the water phase was extracted three times with dichloro- methane/isopropanol (4/ 1 ). The combined organic phases were washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> ethyl acetate) to yield 104 mg (33 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .36 min; MS (ESI_neg): m/z = 570 [M-H]\ ¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1 .56-1 .75 (m, 2H), 1 .88-2.00 (m, 2H), 2.07 (s, 3H), 2.94 (m, 2H), 3.21 (q, 2H), 3.89 (m, 1 H), 7.46-7.64 (m, 2H), 7.87 (d, 1 H), 7.95 (d, 1 H), 8.64 (s, 1 H), 8.88 (s, 1 H), 10.61 (s, 1 H), 1 1 .30 (s, 1 H), 2H's are partly obscured by solvent signal.

Example 18

5-[(5-{[4-(2,2-Difluoroethyl)piperazin-1 -yl]carbonyl}pyrazin-2-yl)amino]-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (153 mg, 0.57 mmol, 1 .0 eq), (5-chloropyrazin-2- yl)[4-(2,2-difluoroethyl)piperazin-1 -yl]methanone [Intermediate 17] (248 mg,

0.85 mmol, 1 .5 eq) and cesium carbonate (371 mg, 1 .14 mmol, 2.0 eq) in 6.3 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, paUadium(ll ) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (33 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C for 5 h. On cooling, the reaction mixture was partitioned between dichloro- methane/isopropanol (4/ 1 ) and water, on which a precipitate was observed. This solid was isolated by filtration and dried under high vacuum to give 41 mg (14 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .14 min; MS (ESI_neg): m/z = 522 [M-H]\

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.45 (s, 3H), 2.52-2.66 (m, 4H), 2.78 (dt, 2H), 3.49-3.69 (m, 4H), 6.1 5 (tt, 1 H), 7.38-7.51 (m, 2H), 7.94 (dd, 1 H), 8.62 (s, 1 H), 8.68 (s, 1 H), 10.49 (s, 1 H), 1 1 .21 (s, 1 H).

Example 19

N-[1 -(2,2-Difluoroethyl)piperidin-4-yl]-5-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (58 mg, 0.22 mmol, 1 .0 eq), 5-chloro-N-[1 -(2,2- difluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 18] (100 mg, 0.33 mmol, 1 .5 eq) and cesium carbonate (141 mg, 0.43 mmol, 2.0 eq) in 2.4 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (5 mg, 0.02 mmol, 0.1 eq) and Xantphos (13 mg, 0.02 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C overnight. On cooling, the reaction mixture was partitioned between dichloro- methane/isopropanol (4/1 ) and water. The volatile components of the organic phase were removed in vacuo. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> ethyl acetate) to yield 28 mg (24 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.97 min; MS (ESI_neg): m/z = 536 [M-H]\

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.70 (m, 2H), 2.26 (m, 2H), 2.72 (t, 2H), 2.90 (m, 2H), 3.81 (m, 1 H), 6.13 (tt, 1 H), 7.35-7.52 (m, 2H), 7.97 (m, 1 H), 8.48 (m, 1 H), 8.72 (s, 1 H), 8.88 (s, 1 H), 10.52 (s, 1 H), 11.29 (s, 1 H), 5H's not assigned.

Example 20

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (93 mg, 0.34 mmol, 1.0 eq), 5-chloro-N-[1 -(2,2,2- trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide [Intermediate 21 ] (122 mg, 0.41 mmol, 1 .2 eq) and cesium carbonate (224 mg, 0.69 mmol, 2.0 eq) in 3.8 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (8 mg, 0.03 mmol, 0.1 eq) and Xantphos (20 mg, 0.03 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 ° C overnight. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 30/70→ 70/30) to give 40 mg (22 % yield of theory) of the title compound.

UPLC-MS (Method 5): R_t = 1.18 min; MS (El_neg): m/z = 526 [M-H]\

¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.46 (s, 3H), 3.23 (q, 2H), 3.37 (t, 2H), 3.70 (t, 2H), 4.59 (m, 1H), 7.40-7.50 (m, 2H), 7.97 (dd, 1H), 8.74 (s, 1H), 8.88 (d, 1H), 9.07 (d, 1H), 10.52 (s br, 1H), 11.30 (s br, 1H).

Example 21

N-{[6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]carbonyl}-8-alanine

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1] (165 mg, 0.62 mmol, 1.0 eq), methyl N-[(6- chloropyrazin-2-yl)carbonyl]-8-alaninate [Intermediate 22] (150 mg, 0.62 mmol, 1.0 eq) and cesium carbonate (401 mg, 1.23 mmol, 2.0 eq) in 5.3 mL dioxane was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (14 mg, 0.06 mmol, 0.1 eq) and Xantphos (36 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 4 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (Method A) to give 40 mg (13 % yield of theory) of methyl N-{[6-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)-pyrazin-2-yl]carbonyl}-8-alaninate {UPLC-MS (Method 1): R_t = 1.12 min; MS (ESI_neg): m/z = 475 [M-H] }. The sample methyl N- {[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)- pyrazin-2-yl]carbonyl}-8-alaninate (40 mg, 0.08 mmol, 1.0 eq) observed this way was dissolved in 1 mL methanol and a solution of lithium hydroxide (1M in water, 0,84 mL, 0.84 mmol, 10.0 eq) was added. The reaction mixture was stirred at rt for 3 h, at 60 °C for 3 h and at rt overnight. Under ice-cooling the reaction mixture was acidified (~pH4) with 2M hydrochloric acid. A precipitate formed, that was isolated by filtration and washed with methanol. This solid was then finally purified via preparative HPLC (Method A) to give 11 mg (28 % yield of theory based on methyl N-{[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl- 1 ,2-thiazol-5-yl}amino)-pyrazin-2-yl]carbonyl}-_j8-alaninate as starting material) of the title compound.

UPLC-MS (Method 1): R_t = 1.02 min; MS (El_neg): m/z = 461 [M-H]^". ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.47 (s, 3H), 2.60 (t, 2H), 3.64 (q, 2H), 7.38-7.52 (m, 2H), 7.94 (dd, 1H), 8.14 (t, 1H), 8.67 (s, 1H), 8.88 (s, 1H), 10.47 (s, 1H), 11.20 (s, 1H), 12.42 (s, 1H).

Example 22

N-(3,4-Difluorophenyl)-3-methyl-5-[(5-{[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]- carbonyl}pyrazin-2-yl)amino]-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (127 mg, 0.47 mmol, 1 .0 eq), (5-chloropyrazin-2- yl)[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]methanone [Intermediate 23] (175 mg, 0.57 mmol, 1 .2 eq) and cesium carbonate (308 mg, 0.95 mmol, 2.0 eq) in 5.1 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (1 1 mg, 0.05 mmol, 0.1 eq) and Xantphos (27 mg, 0.05 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C for 6 h. On cooling, the reaction mixture was partitioned between dichloromethane/isopropanol (4/ 1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85 → 55/45) followed by a second preparative HPLC (Method A) to give 35 mg (14 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .27 min; MS (El_neg): m/z = 540 [M-H]\ ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.45 (s, 3H), 2.59-2.78 (m, 4H), 3.23 (q, 2H), 3.48-3.74 (m, 4H), 7.40-7.53 (m, 2H), 7.94 (m, 1 H), 8.63 (s, 1 H), 8.67 (s, 1 H), 10.47 (s br, 1 H), 11.20 (s br, 1 H).

Example 23

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 -(2- fluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (60 mg, 0.22 mmol, 1.0 eq), 6-chloro-N-[1 -(2- fluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 24] (100 mg, 0.34 mmol, 1 .5 eq) and cesium carbonate (145 mg, 0.45 mmol, 2.0 eq) in 2.5 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (5 mg, 0.02 mmol, 0.1 eq) and Xantphos (13 mg, 0.02 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 5.5 h. On cooling, the reaction mixture was partitioned between dichloro- methane/isopropanol (4/1 ) and water. The volatile components of the organic phase were removed in vacuo. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: ethyl acetate -> ethyl acetate/ethanol 2/1 ) to yield 41 mg (23 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.95 min; MS (ESI_neg): m/z = 518 [M-H]\ ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.75 (m, 2H), 1.87 (m, 2H), 2.53 (s, 3H), 2.75-2.96 (m, 2H), 3.89 (m, 1 H), 4.59 (dt, 2H), 7.31 -7.49 (2H), 7.94 (m, 1 H), 8.05 (m, 1 H), 8.58 (m, 1 H), 8.85 (s, 1 H), 6H's not assigned.

Example 24

5-({6-[(3-Aminoazetidin-1 -yl)carbonyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide hydrochloride

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (336 mg, 1.25 mmol, 1.0 eq), tert-butyl {1 -[(6- chloropyrazin-2-yl)carbonyl]azetidin-3-yl}carbamate [Intermediate 25] (430 mg, 1.38 mmol, 1.1 eq) and cesium carbonate (814 mg, 2.50 mmol, 2.0 eq) in 13 ml_ dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (28 mg, 0.13 mmol, 0.1 eq) and Xantphos (72 mg, 0.13 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 4h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine. The phases were separated by the use of a Whatman filter. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 8/2 -> ethyl acetate) to give 130 mg (19 % yield of theory) of the intermediate compound tert-butyl (1 -{[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]carbonyl}-azetidin-3-yl)carbamate [UPLC-MS (Method 1 ): Rt = 1.20 min; MS (ESIneg) : m/z = 544 [M-H] ]. The sample of the compound observed this way was dissolved in dichloromethane (5 mL). Then, hydrogen chloride in dioxane (0.60 mL, 4M solution) was added and the reaction mixture was stirred at rt for 3 h. The resulting solid was isolated by filtration and dried to give 89 mg (19 % yield of theory based on the intermediate tert-butyl (1 -{[6- ({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)pyrazin-2- yl]carbonyl}-azetidin-3-yl)carbamate) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.78 min; MS (ESI_neg): m/z = 444 [M-H-HCl]^".

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.46 (s, 3H), 4.07-4.19 (m, 2H), 4.33- 4.50 (m, 2H), 4.66 (dd, 1 H), 7.38-7.54 (m, 2H), 7.96 (m, 1 H), 8.47 (s, 1 H), 8.58 (s br, 3H), 8.84 (s, 1 H), 10.56 (s, 1 H), 11.15 (s, 1 H).

Example 25

5-({5-[(3-Aminoazetidin-1 -yl)carbonyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide hydrochloride

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (54 mg, 0.20 mmol, 1.0 eq), N-{1 -[(5- chloropyrazin-2-yl)carbonyl]azetidin-3-yl}-2,2-dimethylpropanamide

[Intermediate 26] (66 mg, 0.20 mmol, 1.0 eq) and cesium carbonate (151 mg, 0.47 mmol, 2.3 eq) in 2.0 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (5 mg, 0.02 mmol, 0.1 eq) and Xantphos (12 mg, 0.01 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine. The phases were separated by the use of a Whatman filter. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/ethyl acetate 8/2 -> ethyl acetate) to give 39 mg (25 % yield of theory) of the intermediate compound tert-butyl (1 -{[5-({4-[(3,4- difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)pyrazin-2- yl]carbonyl}-azetidin-3-yl)carbamate [UPLC-MS (Method 1 ): R_t = 1.26 min; MS (ESIneg) : m/z = 544 [M-H] ]. The sample of the compound observed this way was dissolved in dichloromethane (2 mL). Then, hydrogen chloride in dioxane (0.13 mL, 4M solution) was added and the reaction mixture was stirred at rt overnight. The resulting solid was isolated by filtration and dried to give 21 mg (79 % yield of theory based on the intermediate tert-butyl (1 -{[5-({4-[(3,4- difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)pyrazin-2- yl]carbonyl}-azetidin-3-yl)carbamate) of the title compound in -90 % purity (UPLC area-%).

UPLC-MS (Method 1 ): R_t = 0.89 min; MS (ESIneg) : m/z = 444 [M-H-HCl]^".

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.40-7.53 (m, 2H), 7.97 (m, 1 H), 8.38 (s br, 3H), 8.77 (m, 1 H), 8.90 (m, 1 H), 10.53 (s, 1 H), 11 .31 (s, 1 H), 1xCH₃ and the 5 azetidine H's are partially obscured by solvent signals.

Example 26 tert-Butyl 3-({[5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}- amino)pyrazin-2-yl]carbonyl}amino)azetidine-1 -carboxylate

A mixture of 5-amino-N-(3,4-di luorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (116 mg, 0.43 mmol, 1.0 eq), tert-butyl 3-{[(5- chloropyrazin-2-yl)carbonyl]amino}azetidine-1 -carboxylate [Intermediate 27] (136 mg, 0.43 mmol, 1.0 eq) and cesium carbonate (325 mg, 1.00 mmol, 2.3 eq) in 4.3 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (10 mg, 0.04 mmol, 0.1 eq) and Xantphos (25 mg, 0.04 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 2.5 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. After extraction of the aqueous phase (dichloromethane/isopropanol 4/1 ) the volatile components of the organic phase were removed in vacuo up to a volume of ~5 mL. The precipitate observed was isolated by filtration and washed with dichloromethane to give 40 mg (17 % yield of theory) of the title compound after drying.

UPLC-MS (Method 1 ): R_t = 1.30 min; MS (ESI_neg): m/z = 544 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.38 (s, 9H), 2.45 (s, 3H), 3.94 (m, 2H), 4.06 (m, 2H), 4.69 (m, 1 H), 7.39-7.53 (m, 2H), 7.96 (m, 1 H), 8.75 (d, 1 H), 8.89 (s, 1 H), 8.33 (d, 1 H), 10.52 (s, 1 H), 11.30 (s, 1 H).

Example 27

5-[(6-{[4-(2,2-difluoroethyl)piperazin-1 -yl]carbonyl}pyrazin-2-yl)amino]-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (163 mg, 0.61 mmol, 1 .0 eq), (6-chloropyrazin-2- yl)[4-(2,2-difluoroethyl)piperazin-1 -yl]methanone [Intermediate 28] (300 mg, 1.03 mmol, 1 .7 eq) and cesium carbonate (396 mg, 1.21 mmol, 2.0 eq) in 6.7 ml_ dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (14 mg, 0.06 mmol, 0.1 eq) and Xantphos (35 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 ° C overnight. On cooling, the reaction mixture was partitioned between dichloromethane/isopropanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85→ 55/45) to give 68 mg (21 % yield of theory) of the title compound. UPLC-MS (Method 1 ): R_t = 1.11 min; MS (ESI_neg): m/z = 522 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.45 (s, 3H), 2.67 (m, 2H), 2.79 (dt, 2H), 3.42 (m, 2H), 3.69 (m, 2H), 6.15 (tt, 1 H), 7.37-7.52 (m, 2H), 7.96 (m, 1 H), 8.28 (s br, 1 H), 8.76 (s, 1 H), 10.48 (s br, 1 H), 11.15 (s br, 1 H), 2H's obscured by solvent signal.

Ĳ76 Example 28

N-(3-Aminopropyl)-5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxamide hydrochloride

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (112 mg, 0.42 mmol, 1.0 eq), tert-butyl (3-{[(5- chloropyrazin-2-yl)carbonyl]amino}propyl)carbamate [Intermediate 29] (145 mg, 0.42 mmol, 1.0 eq) and cesium carbonate (312 mg, 0.96 mmol, 2.3 eq) in 4.1 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (9 mg, 0.04 mmol, 0.1 eq) and Xantphos (24 mg, 0.04 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 2.5 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. After extraction of the aqueous phase (dichloromethane/isopropanol 4/1 ), the volatile components of the combined organic phases were removed in vacuo. Purification was achieved via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/1 ) to give 240 mg (95 % yield of theory) of the intermediate compound tert-butyl [3-({[5-({4-[(3,4- difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)pyrazin-2- yl]carbonyl}amino)propyl]carbamate in -90% purity as indicated by UPLC area-% [UPLC-MS (Method 1 ): R_t = 1.28 min; MS (ESI_neg): m/z = 546 [M-H] ]. The sample of the compound observed this way was dissolved in dichloromethane (5.8 mL). Then, hydrogen chloride in dioxane (1.04 mL, 4M solution, -10 eq) was added and the reaction mixture was stirred at rt overnight. The resulting solid was isolated by filtration and dried to give 182 mg (81 % yield of theory based on the intermediate tert-butyl [3-({[5-({4-[(3,4-di luorophenyl)carbamoyl]-3-methyl- 1 ,2-thiazol-5-yl}amino)pyrazin-2-yl]carbonyl}amino)propyl]carbamate) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.85 min; MS (ESI_neg): m/z = 446 [M-H-HCl]^". ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.82 (m, 2H), 2.80 (m, 2H), 3.36 (m, 2H), 7.39-7.52 (m, 2H), 7.84-8.05 (m, 4H), 8.76 (s, 1 H), 8.84-8.94 (m, 2H), 10.54 (s, 1 H), 11.30 (s, 1 H), IxChh obscured by solvent signal.

Example 29 5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[2- (methylsulfonyl)ethyl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (102 mg, 0.38 mmol, 1.0 eq), 5-chloro-N-[2- (methylsulfonyl)-ethyl]pyrazine-2-carboxamide [Intermediate 30] (100 mg, 0.38 mmol, 1 .0 eq) and cesium carbonate (284 mg, 0.87 mmol, 2.3 eq) in 3.7 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (9 mg, 0.04 mmol, 0.1 eq) and Xantphos (22 mg, 0.04 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 2.5 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/ 1 ) to give 22 mg (1 1 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .05 min; MS (ESI_neg): m/z = 495 [M-H]\ ¹ H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.45 (s, 3H), 3.03 (s, 3H), 3.39 (t, 2H), 3.73 (q, 2H), 7.39-7.51 (m, 2H), 7.95 (m, 1 H), 8.72 (s, 1 H), 8.86 (s br, 1 H), 8.91 (d, 1 H), 10.50 (s br, 1 H), 1 1 .30 (s br, 1 H).

Example 30 5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(1 , 1 - dioxidotetrahydro-2H-thiopyran-4-yl)pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (134 mg, 0.50 mmol, 1 .0 eq), 5-chloro-N-(1 , 1 - dioxidotetrahydro-2H-thiopyran-4-yl)pyrazine-2-carboxamide [Intermediate 31 ] (170 mg, 0.50 mmol, 1 .0 eq) and cesium carbonate (374 mg, 1 .1 5 mmol, 2.3 eq) in 4.9 mL dioxane/DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (1 1 mg, 0.05 mmol, 0.1 eq) and Xantphos (29 mg, 0.05 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of

1 10 ° C for 2.5 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/ 1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> hexane/ethyl acetate 2/ 1 ) to give 69 mg (25 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .07 min; MS (ESI_neg): m/z = 521 [M-H]\ ¹ H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.06 (m, 2H), 2.18 (q, 2H), 2.45 (s, 3H), 3.08 (d, 2H), 4.21 (m, 1 H), 7.37-7.52 (m, 2H), 7.95 (m, 1 H), 8.69-8.81 (m, 2H), 8.90 (d, 1 H), 10.50 (s br, 1 H), 1 1 .27 (s br, 1 H), 2H's obscured by solvent signal.

Example 31 5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N- methyl-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide hydrochloride

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (150 mg, 0.56 mmol, 1 .0 eq), tert-butyl (2-{[(5- chloropyrazin-2-yl)carbonyl](methyl)amino}ethyl)methyl-carbamate

[Intermediate 32] (183 mg, 0.56 mmol, 1 .0 eq) and cesium carbonate (417 mg, 1 .28 mmol, 2.3 eq) in 5.5 mL dioxane/ DMF (7/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (32 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C for 2.5 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. After extraction of the aqueous phase (3x dichloromethane/isopropanol 4/1 ), the volatile components of the combined organic phases were removed in vacuo. 346 mg (-0.55 mmol) tert- Butyl {2-[{[5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)^yrazin-2-yl]carbonyl}(methyl)amino]ethyl}methyl arbamate was observed in -90% purity as indicated by UPLC area-% [UPLC-MS (Method 1 ): R_t = 1 .30 min; MS (ESIneg) : m/z = 560 [M-H] ] . The sample of the compound observed this way was dissolved in dichloromethane (5.0 mL). Then, hydrogen chloride in dioxane (1 .38 mL, 4M solution, -10 eq) was added and the reaction mixture was stirred at rt overnight. The resulting solid was isolated by filtration and dried to give 184 mg (63 % yield of theory based on the intermediate tert-butyl {2-[{[5- ({4-[(3,4-difluorophenyl)-carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}-amino)pyrazin-2- yl]carbonyl}(methyl)amino]ethyl}methylcarbamate) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.77 min; MS (ESIneg) : m/z = 460 [M-H-HCl]^".

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.46 (s, 3H), 3.17 (m, 2H), 3.85 (t, 2H), 7.39-7.53 (m, 2H), 7.96 (m, 1 H), 8.62-8.77 (m, 2H), 8.85 (s br, 2H), 10.53 (s br, 1 H), 1 1 .27 (s br, 1 H), 2xCH₃ not assigned.

Example 32

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (129 mg, 0.48 mmol, 1 .0 eq), 6-chloro-N-[1 - (2,2,2-trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide [Intermediate 52] (170 mg, 0.58 mmol, 1 .2 eq) and cesium carbonate (313 mg, 0.96 mmol, 2.0 eq) in 5.0 mL dioxane/DMF (4/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll ) acetate (1 1 mg, 0.05 mmol, 0.1 eq) and Xantphos (28 mg, 0.05 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C for 4 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/ 1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % ammonia in water, 15/85→ 55/45) to give 35 mg (14 % yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.89 min; MS (ESI_neg): m/z = 526 [M-H]\

¹ H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 3.21 -3.41 (m, 4H, partially covered by water signal), 3.82 (t, 2H), 4.61 (m, 1 H), 7.37-7.52 (m, 2H), 7.96 (m, 1 H), 8.43 (d, 1 H), 8.62 (s br, 1 H), 8.88 (s, 1 H), 10.48 (s br, 1 H), 1 1 .24 (s br, 1 H), 1 xCH₃ obscured by solvent signal.

Example 33

N-[1 -(2,2-Difluoroethyl)azetidin-3-yl]-6-({4- [(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (1 18 mg, 0.44 mmol, 1 .0 eq), 6-chloro-N-[1 -(2,2- difluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide [Intermediate 55] (145 mg, 0.52 mmol, 1 .2 eq) and cesium carbonate (285 mg, 0.87 mmol, 2.0 eq) in 4.7 mL dioxane/DMF (4/1) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (10 mg, 0.04 mmol, 0.1 eq) and Xantphos (25 mg, 0.04 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 6 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso- propanol (4/1) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85 → 55/45) to give 110 mg (49 % yield of theory) of the title compound.

UPLC-MS (Method 1): R_t = 0.93 min; MS (ESI_neg): m/z = 508 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.95 (t, 2H), 3.81 (t, 2H), 4.61 (m, 1H), 6.02 (tt, 1H), 7.36-7.54 (m, 2H), 7.98 (m, 1H), 8.43 (d, 1H), 8.61 (s br, 1H), 8.88 (s, 1H), 10.49 (s br, 1H), 11.25 (s br, 1H), 1xCH₃ and 2H's obscured by solvent signal.

Example 34

N-(3,4-Difluorophenyl)-3-methyl-5-[(5-{[methyl(2,2,2- trifluoroethyl)amino]methyl}pyrazin-2-yl)amino]-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1] (134 mg, 0.50 mmol, 1.0 eq), N-[(5- chloropyrazin-2-yl)methyl]-2,2,2-trifluoro-N-methylethanamine [Intermediate 56] (180 mg, 0.75 mmol, 1 .5 eq) and cesium carbonate (326 mg, 1 .00 mmol, 2.0 eq) in 5.4 mL dioxane/DMF (4/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (1 1 mg, 0.05 mmol, 0.1 eq) and Xantphos (29 mg, 0.05 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 1 10 ° C for 6 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/ 1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 30/70 → 70/30) to give 6 mg (2 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .35 min; MS (ESI_neg): m/z = 471 [M-H]\

¹ H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.37 (s, 3H), 2.44 (s, 3H), 3.34 (q, 2H), 3.84 (s, 2H), 7.37-7.52 (m, 2H), 7.94 (dd, 1 H), 8.38 (s, 1 H), 8.69 (s, 1 H), 10.41 (s br, 1 H), 10.95 (s br, 1 H).

Example 35

N-(3,4-Difluorophenyl)-5-({6-[(3-fluoroazetidin-1 -yl)methyl]pyrazin-2-yl}amino)- 3-methyl-1 ,2-thiazole-4-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (122 mg, 0.46 mmol, 1 .0 eq), 2-chloro-6-[(3- fluoroazetidin-1 -yl)methyl]pyrazine [Intermediate 57] (1 10 mg, 0.55 mmol, 1.2 eq) and cesium carbonate (296 mg, 0.91 mmol, 2.0 eq) in 4.9 mL dioxane/DMF (4/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (10 mg, 0.05 mmol, 0.1 eq) and Xantphos (26 mg, 0.05 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 6 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso- propanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85→ 55/45) to give 40 mg (18 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.90 min; MS (ESI_neg): m/z = 433 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.45 (s, 3H), 3.36 (m, 2H, partially covered by water signal), 3.72 (m, 2H), 3.86 (s, 2H), 5.22 (dquint, 1 H), 7.37- 7.50 (m, 2H), 7.95 (m, 1 H), 8.11 (s, 1 H), 8.60 (s, 1 H), 10.40 (s br, 1 H), 10.94 (s br, 1 H).

Example 36

N-[1 -(2,2-Difluoroethyl)piperidin-4-yl]-6-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (88 mg, 0.33 mmol, 1.0 eq), 6-chloro-N-[1 -(2,2- difluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 59] (150 mg, 0.49 mmol, 1 .5 eq) and cesium carbonate (214 mg, 0.66 mmol, 2.0 eq) in 5.0 mL dioxane/DMF (4/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (7 mg, 0.03 mmol, 0.1 eq) and Xantphos (19 mg, 0.03 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 4 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso- propanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. From the resulting organic phase a precitate formed over time (4 days). The solid was isolated by filtration and diluted with dichloromethane and filtered again. The isolated solid was then dried to give 50 mg (28 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.01 min; MS (ESI_neg): m/z = 536 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.57-1.79 (m, 4H), 2.26 (t, 2H), 2.46 (s, 3H), 2.74 (m, 2H), 2.91 (m, 2H), 3.80 (m, 1 H), 6.14 (tt, 1 H), 7.38-7.52 (m, 2H), 7.96 (m, 1 H), 8.49 (m, 1 H), 8.722 (s br, 1 H), 8.88 (d, 1 H), 10.52 (s br, 1 H), 11.29 (s br, 1 H).

Example 37

N-[1 -(2,2-Difluoroethyl)azetidin-3-yl]-5-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (150 mg, 0.56 mmol, 1.0 eq), 5-chloro-N-[1 -(2,2- difluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide [Intermediate 61 ] (184 mg, 0.67 mmol, 1 .2 eq) and cesium carbonate (363 mg, 1.11 mmol, 2.0 eq) in 6.1 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (32 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 ° C overnight. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85→ 55/45 of a product fraction that was forwarded to another preparative HPLC (Method A) to give 58 mg (19 % yield of theory) of the title compound. UPLC-MS (Method 2): R_t = 0.85 min; MS (ESI_neg): m/z = 508 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.87 (dt, 2H), 3.65 (t, 2H), 4.56 (m, 1 H), 5.96 (tt, 1 H), 7.34-7.52 (m, 2H), 8.00 (s br, 1 H), 8.51 -9.13 (m, 3H, very broad signal), 10.54 (s br, 1 H), 11.30 (s br, 1 H), 1xCH₃ obscured by solvent signal and 2H's not assigned.

The compounds listed in Table 1 were prepared according to the procedure outlined below from the respective starting materials SM1 and SM2. A typical reaction was run on 0.5 mmol scale:

A mixture of SM1 (0.5 mmol, 1.0 eq), SM2 (0.8-1.2 eq) and cesium carbonate (2.3 eq) in -5.5 mL dioxane/DMF (7/1 ) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (0.1 eq) and Xantphos (0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the reaction mixture was partitioned between dichloromethane and water. After filtration over Celite, the organic phase was separated and concentrated in vacuo. The crude product was usually purified via preparative HPLC or via crystallization from a suitable solvent.

Example 62

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)azetidin-3-yl]pyrazine-2-carboxamide

N-(Azetidin-3-yl)-5-chloropyrazine-2-carboxamide hydrochloride [Example 82] (320 mg, 0.50 mmol, 1.0 eq, 70% purity), potassium carbonate (347 mg, 2.51 mmol, 3.0 eq) and potassium iodide (8.4 mg, 0.05 mmol, 0.1 eq) were suspended in 2.7 mL acetonitrile. To improve solubility around 0.4 mL DMF was added. Then, 1 , 1 , 1 -trifluoro-3-iodopropane [CAS RN: 460-37-7] (169 mg, 0.75 mmol, 1.5 eq) was added and the reaction mixture was heated to 70°C for 10 h. On cooling, the reaction mixture was diluted with water and extracted with dichloromethane/isopropanol (4/1 ) (2x). The combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was treated with a small amount of dichloromethane and methanol for crystallization. The precipitate was isolated by filtration to give 105 mg (38% yield of theory) of the title compound. The solvent of the mother liquor was removed and the remaining material was forwarded to preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % ammonia, 15/85 → 55/45) to give a second batch of 45 mg (17 % yield of theory) of the title compound.

UPLC-MS (Method 3): R_t = 0.97 min; MS (ESI_neg): m/z = 540 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 3.02 (m, 2H), 3.59 (m, 2H), 3.91 (m, 2H), 4.66 (m, 1 H), 7.41 (m, 2H), 8.02 (m, 1 H), 8.57 (m, 1 H), 8.82 (s, 1 H), 9.03 (m, 1 H), 10.55 (s br, 1 H), 11.22 (s br, 1 H), 5H's not assigned, signals are of broad shape.

Example 63 6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-di luorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (150 mg, 0.56 mmol, 1.0 eq), 6-chloro-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 66] (281 mg, 0.84 mmol, 1.5 eq) and cesium carbonate (363 mg, 1 .1 1 mmol, 2.0 eq) in 6.1 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (13 mg, 0.06 mmol, 0.1 eq) and Xantphos (32 mg, 0.06 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (Method A) to give 90 mg (27 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.88 min; MS (ESI_neg): m/z = 568 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.72 (m, 2H), 2.04 (m, 2H), 3.99 (m, 1 H), 7.30-7.55 (m, 2H), 8.00 (s br, 1 H), 8.58 (s br, 1 H, very broad signal), 8.82 (s br, 1 H), 10.50 (s br, 1 H), 11.29 (s br, 1 H), [list characteristic signals, signals show broad shape].

Example 64 5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (80.0 mg, 0.30 mmol, 1.0 eq), 5-chloro-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide [Intermediate 69] (110 mg, 0.33 mmol, 1.1 eq) and cesium carbonate (194 mg, 0.59 mmol, 2.0 eq) in 3.3 mL dioxane/DMF (7/1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (7 mg, 0.03 mmol, 0.1 eq) and Xantphos (17 mg, 0.03 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 ° C overnight. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (Method A) to give 75 mg (42 % yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.92 min; MS (ESI_neg): m/z = 568 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.55-1.93 (m, 4H), 3.04 (m, 2H), 3.31

(m, 2H), 3.87 (m, 1 H), 7.28-7.56 (m, 2H), 8.00 (m, 1 H), 8.43 (s br, 1 H), 8.63 (s br, 1H), 8.85 (s, 1H), 10.54 (s br, 1H), 11.30 (s br, 1H), [list characteristic signals, signals show broad shape].

The compounds listed in Table 2 were prepared according to the procedure outlined below from the respective starting materials SM1 and SM2. A typical reaction was run on 0.5 mmol scale:

A mixture of SM1 (0.5 mmol, 1.0 eq), SM2 (0.8-1.2 eq) and cesium carbonate (2.3 eq) in -5.5 mL dioxane/DMF (7/1) was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (0.1 eq) and Xantphos (0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the reaction mixture was partitioned between dichloromethane and water. After filtration over Celite, the organic phase was separated and concentrated in vacuo. The crude product was usually purified via preparative HPLC or via crystallization from a suitable solvent.

Table 2:

Example 69 F H₃C-0 UPLC-MS (Method 2): Rt =

SM1: 0.84 min; MS (El_neg): m/z =

Intermediate 563 [M-H]-.

72

1H-NMR (400 MHz, DMSO-

SM2:

d6): δ [ppm] = 1.55-1.85

Intermediate

6-({4-[(2-methoxypyridin-4- (m, 2H), 1.88-2.18 (m, 66

yl)carbamoyl]-3-methyl-1 ,2- 2H), 3.84 (s, 3H), 4.03 (m, thiazol-5-yl}amino)-N-[1 -(3,3,3- 1H), 7.15-7.34 (m, 2H), trifluoropropyl)piperidin-4- 7.86-8.20 (m, 2H), 8.65 (s yl]pyrazine-2-carboxamide, 6%

br, 1H), 8.89 (s br, 1H), 10.61 (s, 1H), 11.32 (s, 1H), [list characteristic signals, signals show broad shape].

Example 70 CH₃ UPLC-MS (Method 1): Rt =

F H₃C^

SM1: 1.02 min; MS (Elneg): m/z =

Intermediate 606 [M-H]^".

74

1H-NMR (400 MHz, DMSO-

SM2:

d6): δ [ppm] = 1.29 (d,

Intermediate

6H), 2.16 (m, 2H), 2.25- 82

methyl 4-[5-({4-[(6-isopropoxy- 2.42 (m, 4H), 2.57-2.68 pyridin-3-yl)carbamoyl]-3- (m, 2H), 3.61 (s, 3H), 5.21 methyl-1 ,2-thiazol-5- (sept, 1H), 6.79 (d, 1H), yl}amino)pyrazin-2-yl]-1 -(3,3,3- 8.02 (d, 1H), 8.47 (s br, trifluoropropyl)-piperidine-4- 1H), 8.49 (d, 1H), 8.70 (s, carboxylate, 75% 1H), 10.13 (s, 1H), 10.98

(s, 1H), 7H's not assigned.

The compounds listed in Table 3 were prepared according to the procedure outlined below from the respective starting materials SM1 and SM2. A typical reaction was run on 0.5 mmol scale: The amine/ammonium salt SM1 (0.50 mmol, 1 .0 eq), potassium carbonate (3.0-

5.0 eq) and potassium iodide 0.1 eq) were suspended in 2.7 mL acetonitrile. In some cases 0.4 mL DMF was added improve solubility around. Then, the alkylating agent SM2 (169 mg, 0.75 mmol, 1 .5 eq) was added and the reaction mixture was heated to 70° C overnight. On cooling, the reaction mixture was diluted with water and extracted with dichloromethane/isopropanol (4/ 1 ) (2x). The combined organic phases were washed with brine. Phase separation was conducted by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was either treated with a small amount of dichloromethane and methanol for crystallization or forwarded to preparative HPLC.

Table 3:

Example 80

N-(3,4-Difluorophenyl)-3-methyl-5-({5-[1 -(2,2,2-trifluoroethyl)piperidin-4- yl]pyrazin-2-yl}amino)-1 ,2-thiazole-4-carboxamide

N-4-[5-({4-[(3,4-difluorophenyl)-carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]-1 -(2,2,2-trifluoroethyl)piperidine-4-carboxylic acid

[Intermediate 84] (139 mg, 0.25 mmol, 1 .0 eq) was dissolved in 1 mL DMSO and heated to 150° C for 1 h. On cooling, the reaction mixture was directly forwarded to preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 30/70→ 70/30) to give 80 mg (62 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.37 min; MS (ESI_neg): m/z = 51 1 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.65-1.88 (m, 4H), 2.43 (s, 3H), 2.62- 2.77 (m, 2H), 3.00 (m, 2H), 3.19 (q, 2H), 7.31 -7.51 (m, 2H), 7.94 (m, 1 H), 8.31 (s, 1 H), 8.67 (s, 1 H), 10.38(s, 1 H), 10.85 (s, 1 H), 1 H not assigned.

Example 81

N-(3,4-Difluorophenyl)-3-methyl-5-({5-[1 -(3, 3,3-trifluoropropyl)piperidin-4- yl]pyrazin-2-yl}amino)-1 ,2-thiazole-4-carboxamide

4-[5-({4-[(3,4-difluorophenyl)-carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)- pyrazin-2-yl]-1 -(3,3,3-trifluoropropyl)piperidine-4-carboxylic acid [Intermediate 86] (513 mg, 0.90 mmol, 1 .0 eq) was dissolved in 1 mL DMSO and heated to 150° C for 1 h. On cooling, the reaction mixture was directly forwarded to preparative HPLC (column: Chromatorex C18, eluent: acetonitrile / 0.1 % formic acid, 15/85 → 85/ 15) to give 320 mg (67 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 0.96 min; MS (ESI_neg): m/z = 525 [M-H]\

¹ H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1 .64-1 .94 (m, 4H), 2.16 (t, 2H), 2.47 (s, 3H), 2.58-2.78 (m, 3H), 3.03 (m, 2H), 7.38-7.50 (m, 2H), 7.97 (m, 1 H), 8.14 (s, 1 H), 8.31 (d, 1 H), 8.67 (d, 1 H), 3H's not assigned.

Example 82

N-(Azetidin-3-yl)-5-({4- [(3,4-difluorophenyl)carbamoyl] -3-methyl- 1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxamide, salt with trifluoroacetic acid

tert-Butyl 3-({[5-({4- [(3,4-difluorophenyl)carbamoyl] -3-methyl- 1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]carbonyl}amino)azetidine- 1 -carboxylate [Example 26] (270 mg, 0.495 mmol, 1 .0 eq) was dissolved in 10 mL dichloromethane. Then, trifluoroacetic acid (0.76 mL, 9.90 mmol, 20 eq) was added and the reaction mixture was stirred at rt overnight. The volatile components were removed. Then, tolene was added and the volatile components were removed by the use of a rotary evaporator. The procedure was repeated 4x. After drying of the white solid under high vacuum 320 mg (87% yield of theory) of the title compound in around 70 % purity (LC-MS area%) were obtained.

UPLC-MS (Method 1 ): R_t = 0.87 min; MS (El_neg): m /z = 444 [M-H]\

Example 83 tert-Butyl 4- [6-({4- [(3,4-difluorophenyl)carbamoyl] -3-methyl- 1 ,2-thiazol-5- yl}amino)pyrazin-2-yl] -3,6-dihydropyridine-1 (2H )-carboxylate

5-[(6-Chloropyrazin-2-yl)amino]-N-(3,4-di luorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 2] (500 mg, 1.31 mmol, 1.0 eq), tert-butyl 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)- carboxylate [CAS RN: 286961 -14-6] (508 mg, 1.64 mmol, 1.0 eq), Pd(dppf)Cl2-CH₂Cl2 (61 mg, 0.08 mmol, 0.05 eq) and K₃P0₄ (634 mg, 2.99 mmol, 2.0 eq) were dissolved in 13 mL dioxane/water (5/1 ). The reaction mixture was heated to 100°C overnight and to 150° C for 1 h in a single mode microwave. On cooling, the reaction mixture was partitioned between water and dichloromethane. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 95/5) to give 360 mg (67% yield of theory) of the title compound.

UPLC-MS (Method 2): R_t = 0.95 min; MS (ESI_neg): m/z = 527 [M-H]\

Example 84

N-(3,4-Difluorophenyl)-3-methyl-5-{[6-(1 ,2,3,6-tetrahydropyridin-4-yl)pyrazin-2- yl]amino}-1 ,2-thiazole-4-carboxamide, salt with trifluoroacetic acid

tert-Butyl 4-[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]-3,6-dihydropyridine-1 (2H)-carboxylate [Intermediate 71 ] (370 mg, 0.49 mmol, 1.0 eq) was dissolved in 9.5 mL dichloromethane and trifluoroacetic acid (0.76 mL, 9.80 mmol, 20.0 eq) was added. The reaction mixture was stirred overnight and the volatile components were removed in vacuo. Toluene was added and the solvent was removed by the use of a rotary evaporator. This procedure was repeated three times. After drying at high vacuum 200 mg (79% of theory, based on Intermediate 1 ) of the title compound was observed. UPLC-MS (Method 2): R_t = 0.76 min; MS (ESI_neg): m/z = 427 [M-H]\

Example 85

5-({5-[(4-Aminopiperidin-1 -yl)carbonyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide, salt with trifluoroacetic acid

A mixture of 5-amino-N-(3,4-difluorophenyl)-3-methyl-1 ,2-thiazole-4- carboxamide [Intermediate 1 ] (200 mg, 0.74 mmol, 1.0 eq), tert-butyl {1 -[(5- chloropyrazin-2-yl)carbonyl]piperidin-4-yl}carbamate [Intermediate 76] (379 mg, 1.11 mmol, 1.5 eq) and cesium carbonate (484 mg, 1.49 mmol, 2.0 eq) in 8.3 mL dioxane/DMF (3/ 1 ) was placed in a microwave vial that was flushed with argon. Then, palladium(ll) acetate (17 mg, 0.07 mmol, 0.1 eq) and Xantphos (43 mg, 0.07 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 °C for 2.5 h. On cooling, the reaction mixture was partitioned between dichloromethane/iso-propanol (4/1 ) and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane -> ethyl acetate) to give 255 mg tert-butyl (1 -{[5-({4-[(3,4- difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)pyrazin-2- yl]carbonyl}piperidin-4-yl)carbamate. The carbamate observed this way was dissolved in 8.4 mL dichloromethane and trifluoroacetic acid (0.67 ml_, 8.72 mmol, 20.0 eq) was added. The reaction mixture was stirred overnight and the volatile components were removed in vacuo. Toluene was added and the solvent was removed by the use of a rotary evaporator. This procedure was repeated three times. After drying at high vacuum 205 mg (50% of theory, based on Intermediate 1 ) of the title compound was observed.

UPLC-MS (Method 2): R_t = 0.73 min; MS (ESI_neg): m/z = 472 [M-H]\

The compounds listed in Table 4 were prepared according to the reaction sequence outlined below from the respective starting materials SM1 and SM2: A mixture of aminoisothiazole SM1 (0.50-3.00 mmol, 1.0 eq), haloheterocycle SM2 (0.8-1.2 eq) and cesium carbonate (2.3 eq) in dioxane/DMF (7/1 ) [-5.5 mL for 0.50 mmol of SM1 ] was placed in a microwave vial and flushed with argon. Then, palladium(ll) acetate (0.1 eq) and Xantphos (0.1 eq) were added. The vial was capped and the reaction mixture was stirred at an environmental temperature of 110 °C overnight. On cooling, the reaction mixture was partitioned between dichloromethane and water. After filtration over Celite, the organic phase was separated and concentrated in vacuo. The crude product was usually purified via preparative HPLC or via crystallization from a suitable solvent. The carbamate observed this way was dissolved in dichloromethane (300 eq, based on SM1 ) and trifluoroacetic acid (20.0 eq, based on SM1 ) was added. The reaction mixture was stirred overnight and the volatile components were removed in vacuo. Toluene was added and the solvent was removed by the use of a rotary evaporator. This procedure was repeated three times. In most cases the title compounds were already pure enough to be used without further purification. In some other cases a MPLC or HPLC was applied for purification.

Table 4:

Example 89

N-(3,4-Difluorophenyl)-5-[(6-{[3-hydroxy-3-(trifluoromethyl)pyrrolid

carbonyl}pyrazin-2-yl)amino]-3-methyl-1 ,2-thiazole-4-carboxamide

To a solution of 3-(trifluoromethyl)pyrrolidin-3-ol [CAS RN: 1334147-81 -7] (142 mg, 0.25 mmol, 0.5 eq) in 1.6 mL THF was added bis(trimethylaluminum)-1 ,4- diazabicyclo[2.2.2]octane adduct [CAS RN: 286961 -14-6] (94 mg, 0.37 mmol, 1.5 eq). The reaction mixture was stirred at 40 °C for 1 h. Then, 1 mL N-Methyl-2- pyrrolidone was added and the reaction was stirred at 50 °C for an additional hour. Then, methyl 6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol- 5-yl}amino)pyrazine-2-carboxylate [WO 2014/118186, example 66] (142 mg, 0.25 mmol, 70% purity, 1.0 eq) was added and the reaction mixture was stirred at rt for 5 h. The reaction mixture was partitioned between dichloromethane and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (Method A) to give 5.5 mg (4 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.11 min; MS (ESI_neg): m/z = 527 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.04 (dd, 0.5H), 2.10 (dd, 0.5H), 2.20 (m, 0.5H), 2.29 (m, 0.5H), 2.44 (s, 3H), 3.56 (d, 0.5H), 3.70-3.78 (m, 1.5H), 3.83 (m, 1 H), 3.93 (m, 0.5H), 4.09 (d, 0.5H), 6.52 (s, 0.5H), 6.69 (s, 0.5H), 7.40- 7.49 (m, 2H), 7.94 (dd, 1 H), 8.38 (d, 1 H), 8.81 (d, 1 H), 10.48 (d, 1 H), 11 .13 (d, 1 H). Example 90

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-f2- hydroxy-2-methylpropyl)pyrazine-2-carboxamide

To a solution of 6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxylic acid [Intermediate 89] (100 mg, 0.20 mmol, 1.0 eq) in 1.0 mL THF was 1 , 1 -carbonyldiimidazole (32 mg, 0.20 mmol, 1 .0 eq). The reaction mixture was stirred at 70 °C for 2 h. Then, a solution of 1 -amino-2- methylpropan-2-ol [CAS RN: 2854-16-2] (18 mg, 0.21 mmol, 1.0 eq) in THF (0.7 mL) was added and the reaction mixture was stirred at 70 °C for 2 h. Subsequently, the reaction mixture was diluted with water and extracted three times with dichloromethane/isopropanol (4/1 ). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. Purification was conducted via preparative HPLC (Method A) to give 33 mg (35 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.05 min; MS (ESI_neg): m/z = 461 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (s, 6H), 2.40 (s, 3H), 3.37 (d, 2H), 4.85 (s, 1 H), 7.39-7.49 (m, 2H), 7.94 (dd, 1 H), 8.06 (t, 1 H), 8.70 (s, 1 H), 8.89 (s, 1 H), 10.48 (d, 1 H), 11.25 (d, 1 H). Example 91

N-(3,4-difluorophenyl)-5-[(5-{[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1 - yl]carbonyl}pyrazin-2-yl)amino]-3-methyl-1 ,2-thiazole-4-carboxamide

To a solution of 5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxylic acid [Intermediate 90] (100 mg, 0.20 mmol, 78% purity, 1 .0 eq) in 1 .0 mL THF was added 1 , 1 -carbonyldiimidazole (32 mg, 0.20 mmol, 1 .0 eq). The reaction mixture was stirred at 70 ° C for 2 h. Then, a solution of 3-(trifluoromethyl)pyrrolidin-3-ol [CAS RN: 1334147-81 -7] (18 mg, 0.21 mmol, 1 .0 eq), pre-stirred with triethylamine (29μΙ_, 0.21 mmol, 1 .0 eq) in THF (0.7 mL) for 1 h, was added and the reaction mixture was stirred at 70 ° C for 2 h. Subsequently, the reaction mixture was diluted with water and extracted three times with dichloromethane/isopropanol (4/ 1 ). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude product by the use of dichloromethane/methanol. Purification of this solid was conducted via preparative HPLC (Method A) to give 4 mg (4 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1 .19 min; MS (ESI_neg): m/z = 527 [M-H]\

Example 92

N-(3,4-di7luorophenyl)-5-[(5-{[4-hydroxy-4-(trifluoromethyl)piperidin-1 -yl]- carbonyl}pyrazin-2-yl)amino]-3-methyl-1 ,2-thiazole-4-carboxamide

To a solution of 5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxylic acid [Intermediate 90] (88 mg, 0.23 mmol, 1.0 eq) in 1.17 mL THF was added 1 , 1 -carbonyldiimidazole (37 mg, 0.23 mmol, 1.0 eq). The reaction mixture was stirred at 70 °C for 2 h. Then, a solution of 4-(trifluoromethyl)piperidin-4-ol [CAS RN: 373603-69-1 ] (39 mg, 0.23 mmol, 1.0 eq) in THF (0.8 mL) for 1 h was added and the reaction mixture was stirred at 70 °C for 2 h. Subsequently, the reaction mixture was diluted with water and extracted three times with dichloromethane/isopropanol (4/1 ). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo and the crude product by the use of dichloromethane/methanol. Purification of this solid was conducted via preparative HPLC (Method A) to give 33 mg (27 % yield of theory) of the title compound.

UPLC-MS (Method 1 ): R_t = 1.17 min; MS (ESI_neg): m/z = 541 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.57-1.88 (m, 4H), 2.45 (s, 3H), 3.01 (m, 1 H), 3.91 (m, 1 H), 4.46 (m, 1 H), 6.14 (s, 1 H), 7.39-7.51 (m, 2H), 7.94 (dd, 1 H), 8.64 (s, 1 H), 8.67 (s, 1 H), 10.46 (s, 1 H), 11.20 (s, 1 H), 1 H obscured by solvent signal. Example 93

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(2- hydroxy-2-methylpropyl)pyrazine-2-carboxamide

To a solution of 5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxylic acid [Intermediate 90] (60 mg, 0.15 mmol, 1.0 eq) in 1.60 mL THF was added 1 , 1 -carbonyldiimidazole (25 mg, 0.15 mmol, 1.03 eq). The reaction mixture was stirred at 70 °C for 2 h. Then, a solution of 1 - amino-2-methylpropan-2-ol [CAS RN: 2854-16-2] (14 mg, 0.16 mmol, 1.0 eq) in THF (0.8 mL) for 1 h was added and the reaction mixture was stirred at 70 ° C for 2 h. Subsequently, the reaction mixture was diluted with water and extracted three times with dichloromethane/isopropanol (4/1 ). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed. Throughout this process a yellowish precipitate formed, that was separated by filtration. The solid was dried by high vacuum to give 47 mg (62 % yield of theory) of the title compound in 95% purity (UPLC-area%).

UPLC-MS (Method 1 ): R_t = 1.09 min; MS (ESI_neg): m/z = 461 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.11 (s, 6H), 2.51 (s, 3H), 3.26 (d, 2H), 4.68 (s, 1 H), 7.11 (s, 1 H), 7.31 -7.58 (m, 1 H), 8.00-8.13 (m, 2H), 8.49 (s, 1 H), 8.80 (d, 1 H), 2H's not assigned. Example 94

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(tetra- hydro-2H-pyran-4-yl)pyrazine-2-carboxamide

To a solution of 5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxylic acid [Intermediate 90] (60 mg, 0.15 mmol, 1.0 eq) in 0.80 mL THF was added 1 , 1 -carbonyldiimidazole (25 mg, 0.15 mmol, 1.03 eq). The reaction mixture was stirred at 70 °C for 2 h. Then, a solution of tetrahydro-2H-pyran-4-amine [CAS RN: 38041 -19-9] (16 mg, 0.16 mmol, 1.0 eq) in THF (0.8 mL) for 1 h was added and the reaction mixture was stirred at 70 °C for 2 h. Subsequently, the reaction mixture was diluted with water and extracted three times with dichloromethane/isopropanol (4/1 ). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed. Throughout this process a yellowish precipitate formed, that was separated by filtration. The solid was dried by high vacuum to give 34 mg (44 % yield of theory) of the title compound in 95% purity (UPLC-area%).

UPLC-MS (Method 1 ): R_t = 1.14 min; MS (ESI_neg): m/z = 473 [M-H]\

¹H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.59-1.79 (m, 4H), 2.52 (s, 3H), 3.39 (m, 2H), 3.86 (m, 2H), 4.00 (m, 1 H), 7.05 (s, 1 H), 7.31 -7.51 (m, 2H), 7.74 (s, 1 H), 8.06 (m, 1 H), 8.41 (m, 1 H), 8.77 (m, 1 H), 1 H not assigned. Example 95

N-(3,4-Difluorophenyl)-5-({6- [1 -(2-fluoroethyl)piperidin-4-yl]pyrazin-2-yl}amino)- 3-methyl- 1 ,2-thiazole-4-carboxamide

N-(3,4-Difluorophenyl)-3-methyl-5-{[6-(1 ,2, 3,6-tetrahydropyridin-4-yl)pyrazin-2- yl]amino}- 1 ,2-thiazole-4-carboxamide, salt with trifluoroacetic acid [Example 84] (210 mg, 0.49 mmol, 1 .0 eq) was dissolved in 3.9 mL acetonitrile. Then, potassium carbonate (339 mg, 2.45 mmol, 5.0 eq) and 1 -fluoro-2-iodoethane [CAS RN : 38041 - 19-9] (128 mg, 0.74 mmol, 1 .5 eq) was added. The reaction mixture was stirred at 70 ° C overnight. The reaction mixture was partitioned between water and dichloromethane/isopropanol (4/ 1 ). The phases were separated by the use of a Whatman filter and the volatile components of the organic phase were removed in vacuo. The crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 3/ 1 ) to give 30 mg (1 3% yield of theory) of N-(3,4- difluorophenyl)-5-({6- [1 -(2-fluoroethyl)- 1 ,2, 3,6-tetrahydropyridin-4-yl]pyrazin-2- yl}amino)-3-methyl- 1 ,2-thiazole-4-carboxamide. For the hydrogenation, a solution of N-(3,4-difluorophenyl)-5-({6- [1 -(2-fluoroethyl)- 1 ,2, 3,6- tetrahydropyridin-4-yl]pyrazin-2-yl}amino)-3-methyl- 1 ,2-thiazole-4-carboxamide (30 mg, 0.06 mmol, 1 .0 eq) in methanol (0.26 mL) was treated with acetic acid (10 μΙ_, 0.1 3, 2.0 eq) and palladium (10% on carbon, 1 mg, 0.01 mmol). Then, the reaction mixture was stirred under a hydrogen atmosphere (balloon ) overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude material was purified via preparative MPLC (Biotage Isolera; 10 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 4/ 1 ) to give 5 mg (17% yield of theory based on of N-(3,4-difluorophenyl)-5-({6- [1 - (2- fluoroethyl)-1 ,2,3,6-tetrahydropyridin-4-yl]pyrazin-2-yl}amino)-3-methyl-1 ,2- thiazole-4-carboxamide) of the title compound.

UPLC-MS (Method 2): R_t = 0.79 min; MS (ESI_neg): m/z = 473 [M-H]\

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1 .92 (m, 2H), 2.07 (m, 2H), 2.40 (m, 2H, partially obscured by solvent signal), 2.47 (s, 3H), 2.72-3.04 (m, 3H), 3.20 (m, 2H), 4.67 (d, 2H), 7.31 -7.54 (m, 2H), 7.82-8.21 (m, 2H), 8.52 (s, 1 H), 10.45 (s br, 1 H), 10.93 (s br, 1 H).

Further, the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of 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.

Pharmaceutical compositions of the compounds of the invention

This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically- acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft- shelled gelatine type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both. Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 , 1 -dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol. Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g. , US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.

It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991 . The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et a/. , "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349 ; and Nema, S. et a/. , "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171 .

Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoal) ; aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF3) air displacement agents (examples include but are not limited to nitrogen and argon) ; antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers) ; buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colourants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red) ; clarifying agents (examples include but are not limited to bentonite) ; emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate) ; encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavourants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin ) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; levigating agents (examples include but are not limited to mineral oil and glycerin) ; oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ;

ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment) ;

penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalate and glycerol) ;

solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation) ; stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax) ;

suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)) ;

surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate) ;

suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) ; sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose) ;

tablet anti-adherents (examples include but are not limited to magnesium stearate and talc) ;

tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch) ;

tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch) ; tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ;

tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate) ;

tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch) ;

tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc) ;

tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate) ;

tablet/capsule opaquants (examples include but are not limited to titanium dioxide) ; tablet polishing agents (examples include but are not limited to carnuba wax and white wax) ;

thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin) ;

tonicity agents (examples include but are not limited to dextrose and sodium chloride) ;

viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth) ; and

wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can be illustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 min.

Lyophilised powder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 min.

Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water. Combination therapies

The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or 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 the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second 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 the said first active ingredient and the said second 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 the said first active ingredient and the said second 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 said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations. For example, the compounds of this invention can be combined with known chemotherapeutic agents or anti-cancer agents, e.g. anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.

The term "chemotherapeutic anti-cancer agents", includes but is not limited to

1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, 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, lanreotide, lapatinib, lasocholine, lenalidomide, 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, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, 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, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, 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, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

The compounds of the invention may also be administered in combination with protein therapeutics. Such protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma. ) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1 , bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS- 1402, B43-genistein, L-19 based radioimmunotherapeutics, AC-9301 , NY-ESO-1 vaccine, IMC-1 C11 , CT-322, rhCCI O, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311 , Endostatin, volociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321 , CNTO-328, MDX-21 , tigapotide, CAT-3888, labetuzumab, alpha-particle-emitting radioisotope-llinked lintuzumab, EM- 1421 , HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7, Javelin - prostate cancer, Javelin - melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab, zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept, denosumab, vaccine, CTP-37, efungumab, or 1311- chTNT-1 /B. Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

A compound of general formula (I) as defined herein can optionally be administered in combination with one or more of the following: ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM- 120, BYL-719, CAL-101 , CC-223, CH-5132799, deforolimus, E-6201 , enzastaurin , GDC-0032, GDC-0068, GDC-0623, GDC-0941 , GDC-0973, GDC-0980, GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, perifosine, PF- 04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO-4987655, RO-5126766, selumetinib, TAK-733, trametinib, triciribine, UCN-01 , WX-554, XL-147, XL-765, zotarolimus, ZSTK-474.

Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:

(1 ) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,

(5) provide for a higher response rate among treated patients,

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

(7) provide a longer time for tumor progression, and/or

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

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of the present invention may be used to sensitize a cell to radiation. That is, 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 invention. In one aspect, the cell is treated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the 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 the 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 the 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 one embodiment, a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the 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. , cisplatinum), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.

In another embodiment, 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 the 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 the 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 the 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. As mentioned supra, the compounds of the present invention have surprisingly been found to effectively inhibit the spindle assembly checkpoint and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are affected by inhibition of the spindle assembly checkpoint, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

In accordance with another aspect therefore, the present invention covers a compound of general formula (I ), 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, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.

Another particular aspect of the present invention is therefore the use of a compound of general 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 a disease.

Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.

The diseases referred to in the two preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.

Method of treating hyper-proliferative disorders

The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper- proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc. , cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder. Hyperproliferative disorders include but are not limited, e.g. , 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 cancer 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.

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, e.g. , the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc. , of a disease or disorder, such as a carcinoma.

Methods of treating angiogenic disorders

The present invention also provides methods of treating disorders and 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, e.g., 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 ; see, 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 the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., 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.

Dose and administration

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic 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 medicaments that are used to treat these conditions, the effective dosage of the compounds of this 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, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may 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.

Preferably, the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.

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.

Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.

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

Biological assays:

Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein

• the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and · the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

Spindle Assembly Checkpoint (SAC) Assays The spindle assembly checkpoint assures the proper segregation of chromosomes during mitosis. Upon entry into mitosis, chromosomes begin to condensate which is accompanied by the phosphorylation of histone H3 on serine 10. Dephosphorylation of histone H3 on serine 10 begins in anaphase and ends at early telophase. Accordingly, phosphorylation of histone H3 on serine 10 can be utilized as a marker of cells in mitosis. Nocodazole is a microtubule destabilizing substance. Paclitaxel is a microtubule stabilizing compound. Thus, nocodazole as well as paclitaxel interfere with microtubule dynamics and mobilize the spindle assembly checkpoint. The cells arrest in mitosis at G2/M transition and exhibit phosphorylated histone H3 on serine 10. An inhibition of the spindle assembly checkpoint overrides the mitotic blockage in the presence of nocodazole or paclitaxel, the cells complete mitosis prematurely, and their nuclei typically exhibit a multilobed phenotype. The mitotic breakthrough can be detected by the decrease of cells with phosphorylation of histone H3 on serine 10. This decline is used as a marker to determine the capability of compounds of the present invention to induce a mitotic breakthrough. The typical morphological alteration of nuclei with a prematurely completed mitosis after SAC-inhibition can be monitored via image analysis routines supporting those findings. The nocodazole and paclitaxel variations were used to focus on compounds that are capable of inhibiting a SAC induced by both microtubule destabilization as well as microtubule stabilization. When SAC inducing agents and compounds are given simultaneously, inhibitors that effectively block the SAC during formation or abrogation are identified. When cells are incubated with a SAC inducing agent and the SAC interfering compound is given after a defined time, inhibitors are identified that effectively block SAC abrogation.

SAC-Formation - Nocodazole-lnduced Assay Cultivated cells of the human cervical tumor cell line HeLa (ATCC CCL-2) were plated at a density of 1000 cells/well in a 1536-well microtiter plate in 2 μΐ PAA Ham's F12 Medium supplemented with 1 % (v/v) glutamine, 1 % (v/v) penicillin, 1 % (v/v) streptomycin and 10% (v/v) fetal calf serum. After incubation overnight at 37° C, 10 μΐ/well nocodazole at a final concentration of 0.1 Mg/ml were added to cells. Test compounds solubilized in dimethyl sulfoxide (DMSO) were added at various concentrations (0 μΜ, as well as in the range of 0.005 μΜ - 20 μΜ; the final concentration of the solvent DMSO was 0.5% (v/v)). Cells were incubated for 24 h at 37° C in the presence of test compounds in combination with nocodazole. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at 4°C overnight then permeabilized in 0.1 % (v/v) Triton X™ 100 in PBS at room temperature for 20 min and blocked in 0.5% (v/v) bovine serum albumin (BSA) in PBS at room temperature for 15 min. After washing with PBS, 5 μΐ/well antibody solution (anti-phospho-histone H3 clone 3H10, FITC; Millipore, Cat# 16-222; 1 : 1000 dilution) was added to cells, which were incubated for 2 h at room temperature. Afterwards, cells were washed with PBS and 5 μΐ/well solution of HOECHST 33342 dye (5 μg/ml) was added to cells and cells were incubated 15 min at room temperature in the dark. Cells were washed twice with PBS then covered with PBS and stored at 4°C until analysis. Images were acquired with a PERKIN ELMER OPERA™ High-Content Analysis reader. Images were analyzed with image analysis software MetaXpress™ from Molecular devices utilizing the Mitotic Index application module. In this assay both labels HOECHST 33342 and phosphorylated Histone H3 on serine 10 were measured. HOECHST 33342 labels the DNA and is used to count the cell number. The staining of phosphorylated Histone H3 on serine 10 determines the number of mitotic cells. After 24 h incubation, inhibition of SAC in presence of nocodazole decreases the number of mitotic cells indicating an inappropriate mitotic progression. Otherwise cells were arrested at G2/M phase of the cell cycle progression. The raw assay data were further analyzed by four- parametric hill equation using Genedata's Assay Analyzer and Condoseo software.

Table 2: SAC-Formation - Nocodazole-lnduced Assay

Example No. ICso [mol/l]

1 2.3E-7

2 7.3E-6

3 1.4E-6

4 3.8E-7

5 1.5E-7

6 4.4E-8

7 8.6E-8

8 4.8E-8

9 1.0E-8

10 2.0E-7

11 6.3E-7

12 4.2E-8

13 5.8E-7

14 2.3E-7

15 7.0E-8

16 1.1E-8

17 1.3E-8

18 1.5E-8

19 1.1E-7 Example No. ICso [mol/l]

20 5.8E-9

21 3.9E-6

22 2.0E-7

23 8.8E-8

24 1.9E-6

25 1.1E-6

26 1.7E-7

27 1.4E-7

28 1.2E-6

29 1.8E-7

30 2.6E-7

31 2.1E-6

32 1.6E-7

33 2.5E-7

34 5.5E-7

35 4.5E-8

36 2.9E-7

37 3.1E-8

38 2.6E-7

39 2.5E-6 Example No. ICso [mol/l]

40 6.9E-8

41 1.9E-6

42 4.8E-7

43 1.4E-6

44 9.7E-7

45 5.8E-7

46 1.2E-6

47 4.0E-7

48 6.0E-7

49 2.9E-6

50 1.3E-6

51 1.7E-7

52 3.9E-7

53 1.1E-7

54 9.1E-7

55 3.1E-6

56 1.3E-6

57 3.0E-7

58 2.0E-6

59 7.2E-7 Example No. ICso [mol/l]

60 3.8E-7

61 1.3E-6

62 2.5E-7

63 3.0E-8

64 1.1E-7

65 6.3E-6

66 1.3E-6

67 1.4E-6

68 6.2E-7

69 2.1E-7

70 5.4E-7

71 3.3E-7

72 1.4E-7

75 2.6E-7

76 6.7E-7

77 2.9E-7

78 1.0E-5

79 2.0E-6

80 2.9E-8 Example No. ICso [mol/l]

81 4.3E-7

82

83

84

85

86

87

88

89 1 .8 E-8

90 8.2 E-8

91 2.9 E-6

92 8.3 E-8

93 7.7 E-8

94 2.0 E-7

95 8.0 E-6

SAC-Formation - Paclitaxel-lnduced Assay

Cultivated cells of the human cervical tumor cell line HeLa (ATCC CCL-2) were plated at a density of 1000 cells/ well in a 1 536-well microtiter plate in 2 μΐ PAA Ham's F12 Medium supplemented with 1 % (v/v) glutamine, 1 % (v/v) penicillin, 1 % (v/v) streptomycin and 10% (v/v) fetal calf serum. After incubation overnight at 37° C, 10 μΐ/well paclitaxel at a final concentration of 0.05 μΜ were added to cells. Test compounds solubilized in dimethyl sulfoxide (DMSO) were added at various concentrations (0 μΜ, as well as in the range of 0.005 μΜ - 20 μΜ; the final concentration of the solvent DMSO was 0.5% (v/v)). Cells were incubated for 24 h at 37° C in the presence of test compounds in combination with paclitaxel. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at 4° C overnight then permeabilized in 0.1 % (v/v) Triton X™ 100 in PBS at room temperature for 20 min and blocked in 0.5% (v/v) bovine serum albumin (BSA) in PBS at room temperature for 15 min. After washing with PBS, 5 μΐ/well antibody solution (anti-phospho-histone H3 clone 3H10, FITC; Millipore, Cat# 16-222; 1 : 1000 dilution) was added to cells, which were incubated for 2 h at room temperature. Afterwards, cells were washed with PBS and 5 μΐ/well solution of HOECHST 33342 dye (5 μg/ml) was added to cells and cells were incubated 15 min at room temperature in the dark. Cells were washed twice with PBS then covered with PBS and stored at 4°C until analysis. Images were acquired with a PERKIN ELMER OPERA™ High-Content Analysis reader. Images were analyzed with image analysis software MetaXpress™ from Molecular devices utilizing the Mitotic Index application module. In this assay both labels HOECHST 33342 and phosphorylated Histone H3 on serine 10 were measured. HOECHST 33342 labels the DNA and is used to count the cell number. The staining of phosphorylated Histone H3 on serine 10 determines the number of mitotic cells. After 24 h incubation, inhibition of SAC in presence of paclitaxel decreases the number of mitotic cells indicating an inappropriate mitotic progression. Otherwise cells were arrested at G2/M phase of the cell cycle progression. The raw assay data were further analyzed by four- parametric hill equation using Genedata's Assay Analyzer and Condoseo software.

Table 3: SAC-Formation - Paclitaxel-lnduced Assay Example No. IC50 [mol/l]

1 8.2E-8

2 7.4E-6

3 6.4E-7

4 3.6E-7

5 2.6E-7

6 1.6E-7

7 1.5E-7

8 2.9E-7

9 7.0E-9

10 2.3E-7

11 3.0E-7

12 3.2E-8

13 3.3E-7

14 4.7E-7

15 2.5E-7

16 2.4E-8

17 3.2E-8

18 3.5E-6

19 1.5E-7

20 1.5E-7 Example No. IC50 [mol/l]

21 7.5E-6

22 3.5E-6

23 8.7E-7

24 6.0E-6

25 1.6E-6

26 6.4E-7

27 8.9E-7

28 1.1E-6

29 6.4E-6

30 1.6E-6

31 1.8E-6

32 1.5E-7

33 3.1E-7

34 2.3E-7

35 1.8E-7

36 1.3E-7

37 5.3E-7

38 2.4E-6

39 2.7E-6

40 2.0E-6 Example No. IC50 [mol/l]

41 1.5E-6

42 1.1E-6

43 9.5E-7

44 2.0E-6

45 1.4E-5

46 1.2E-5

47 5.8E-7

48 6.5E-7

49 1.4E-5

50 6.7E-7

51 3.5E-7

52 2.5E-7

53 4.2E-7

54 3.6E-7

55 8.8E-6

56 1.1E-6

57 5.4E-6

58 3.1E-6

59 7.4E-7

60 1.8E-7 Example No. IC50 [mol/l]

61 3.1E-6

61 1.3E-6

62 4.0E-7

63 9.0E-8

64 5.6E-8

65 6.3E-6

66 2.9E-7

67 1.4E-6

68 3.5E-7

69 2.0E-7

70 2.0E-6

71 3.7E-7

72 2.7E-8

75 5.6E-7

76 1.7E-6

77 4.7E-7

78 1.0E-5

79 4.2E-6

80 1.3E-7

81 9.5E-7 Example No. IC50 [mol/l]

82

83

84

85

86

87

88

89 7.0 E-8

90 3.9 E-7

91 1.9 E-6

92

93

94

95 > 2.0 E-5

SAC-Mult obed Assay

Cultivated cells of the human cervical tumor cell line HeLa (ATCC CCL-2) were plated at a density of 1000 cells/ well in a 1536-well microtiter plate in 2 μΐ PAA Ham's F12 Medium supplemented with 1 % (v/v) glutamine, 1 % (v/v) penicillin,

1 % (v/v) streptomycin and 10% (v/v) fetal calf serum. After incubation overnight at 37°C, 10 μΐ/well nocodazole at a final concentration of 0.1 Mg/ml were added to cells. Test compounds solubilized in dimethyl sulfoxide (DMSO) were added at various concentrations (0 μΜ, as well as in the range of 0.005 μΜ - 20 μΜ; the final concentration of the solvent DMSO was 0.5% (v/v)). Cells were incubated for 24 h at 37° C in the presence of test compounds in combination with nocodazole. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at 4°C overnight then permeabilized in 0.1 % (v/v) Triton X™ 100 in PBS at room temperature for 20 min and blocked in 0.5% (v/v) bovine serum albumin (BSA) in PBS at room temperature for 15 min. Afterwards, cells were washed with PBS and 5 μΐ/well solution of HOECHST 33342 dye (5 μg/ml) was added to cells and cells were incubated 15 min at room temperature in the dark. Cells were washed twice with PBS then covered with PBS and stored at 4°C until analysis. Images were acquired with a PERKIN ELMER OPERA™ High-Content Analysis reader. Images were analyzed with image analysis software MetaXpress™ from Molecular devices utilizing an image analysis routine that quantifies number of nuclei showing a multilobed shape. This number was related to the number of all nuclei counted with Count Nuclei application module resulting in a multilobed index. In this assay nuclei were identified via DNA staining with HOECHST 33342. After 24 h incubation, inhibition of SAC in presence of nocodazole increases the multilobed index i.e. number of nuclei with a multilobed shape related to all nuclei indicating an inappropriate mitotic progression. The raw assay data were further analyzed by four-parametric hill equation using Genedata's Assay Analyzer and Condoseo software.

SAC-Abrogation Assay

HeLa (cervical tumor; ATCC CCL-2) cells were plated at a density of 1000 cells/ well in a 1536 well microtiter plate in 2 μΐ growth medium. After incubation overnight at 37° C, 2 μΐ/well nocodazole at a final concentration of 0.1 Mg/ml was added to cells. After 24 h incubation, cells are arrested at G2/M phase of the cell cycle progression. Test compounds solubilized in DMSO were added at various concentrations (0 μΜ, as well as in the range of 0.005 μΜ - 10 μΜ; the final concentration of the solvent DMSO was 0.5% (v/v)). Cells were incubated for 4 h at 37° C in the presence of test compounds. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at 4°C overnight then permeabilized in 0.1 % (v/v) Triton X™ 100 in PBS at room temperature for 20 min and blocked in 0.5% (v/v) bovine serum albumin (BSA) in PBS at room temperature for 15 min. After washing with PBS, 5 μΐ/well antibody solution (anti-phospho-histone H3 clone 3H10, FITC; Millipore, Cat# 16-222; 1 : 1000 dilution) was added to cells, which were incubated for 2 h at room temperature. Afterwards, cells were washed with PBS and 5 μΐ/well solution of HOECHST 33342 dye (5 μg/ml) was added to cells and cells were incubated 15 min at room temperature in the dark. Cells were washed twice with PBS then covered with PBS and stored at 4°C until analysis. Images were acquired with a PERKIN ELMER OPERA™ High-Content Analysis reader. Images were analyzed with image analysis software MetaXpress™ from Molecular devices utilizing the Mitotic Index application module. In this assay both labels HOECHST 33342 and phosphorylated Histone H3 on serine 10 were measured. HOECHST 33342 labels the DNA and is used to count the cell number. The staining of phosphorylated Histone H3 on serine 10 determines the number of mitotic cells. After 24 h incubation, inhibition of SAC in presence of paclitaxel decreases the number of mitotic cells indicating an inappropriate mitotic progression. Otherwise cells were arrested at G2/M phase of the cell cycle progression. The raw assay data were further analyzed by four-parametric hill equation using Genedata's Assay Analyzer and Condoseo software. M-Arrest-Assay

HeLa (cervical tumor; ATCC CCL-2) cells were plated at a density of 1000 cells/ well in a 1536 well microtiter plate in 2 μΐ growth medium. After incubation overnight at 37° C, test compounds solubilized in DMSO were added at various concentrations (0 μΜ, as well as in the range of 0.005 μΜ - 10 μΜ; the final concentration of the solvent DMSO was 0.5% (v/v)). Cells were incubated for 24 h at 37° C in the presence of test compounds. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at 4°C overnight then permeabilized in 0.1 % (v/v) Triton X™ 100 in PBS at room temperature for 20 min and blocked in 0.5% (v/v) bovine serum albumin (BSA) in PBS at room temperature for 15 min. After washing with PBS, 5 μΐ/well antibody solution (anti-phospho-histone H3 clone 3H10, FITC; Millipore, Cat# 16-222; 1 : 1000 dilution) was added to cells, which were incubated for 2 h at room temperature. Afterwards, cells were washed with PBS and 5 μΐ/well solution of HOECHST 33342 dye (5 μg/ml) was added to cells and cells were incubated 15 min at room temperature in the dark. Cells were washed twice with PBS then covered with PBS and stored at 4°C until analysis. Images were acquired with a PERKIN ELMER OPERA™ High-Content Analysis reader. Images were analyzed with image analysis software MetaXpress™ from Molecular devices utilizing the Mitotic Index application module. In this assay both labels HOECHST 33342 and phosphorylated Histone H3 on serine 10 were measured. HOECHST 33342 labels the DNA and is used to count the cell number. The staining of phosphorylated Histone H3 on serine 10 determines the number of mitotic cells. After 24 h incubation, the majority of the cells have entered mitosis. A compound that is able to arrest cells in M-phase will increase the number of nuclei with phosphorylated histone H3 on serine 10, which will be reflected by an increase of the Mitotic Index. The assay was used to exclude compounds that lead to a considerable G2/M-arrest after 24h incubation. The raw assay data were further analyzed by four-parametric hill equation using Genedata's Assay Analyzer and Condoseo software.

Induction of cellular multinucleation by SAC Inhibition An abnormal mitosis by abrogating the mitotic spindle checkpoint can result in polyploidy and multi-nucleation in cells. Inhibition of SAC function by competent compounds impairs checkpoint activity and induces failures during cytokinesis. This is consequently associated with nuclear enlargement, multilobulation of nuclei and multinucleated cells resulting in extreme cellular phenotypes after several cell cycle turns with blocked SAC activity as depicted. Osteosarcoma cells U-2 OS (ATCC: HTB-96) were plated at a density of 2500 cells/well in a 384 well microtiter plate in 20 μΐ growth medium. After incubation overnight at 37° C, 20 μΐ/well SAC inhibitors at varying concentrations were added to cells in triplicates. Cells were incubated for Oh, 24h, 48h and 72h at 37° C in the presence of test compounds.

Thereafter, cells were fixed, then permeabilized and blocked. Nuclei were marked by a DNA label and alpha-tubulin structures were detected by antibody labeling. Images were acquired with a PERKIN ELMER OPERA™ High-Content Analysis reader. The images were used for a qualitative assessment of the multinucleation state in tested cells after SAC inhibition.

CDK2/CycE kinase assay

CDK2/CycE -inhibitory activity of compounds of the present invention was quantified employing the CDK2/CycE TR-FRET assay as described in the following paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and human CycE, expressed in insect cells (Sf9) and purified by Glutathion-Sepharose affinity chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). As substrate for the kinase reaction biotinylated peptide biotin-Ttds- YISPLKSPYKISEG (C-terminus in amid 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 CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl 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-triphosphate (ATP, 16.7 μΜ => final cone, in the 5 μΐ assay volume is 10 μΜ) and substrate (1.25 μΜ => final cone, in the 5 μΐ assay volume is 0.75 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 25 min at 22°C. The concentration of CDK2/CycE 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 130 ng/ml. The reaction was stopped by the addition of 5 μΐ of a solution of TR-FRET detection reagents (0.2 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti- RB(pSer807/pSer811 )-antibody from BD Pharmingen [# 558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077, as an alternative a Terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassays can be used]) 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 Rubystar (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 11 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 ηΜ, 13 ηΜ, 3.8 ηΜ, 1.1 ηΜ, 0.33 ηΜ and 0.1 ηΜ, the dilution series prepared separately before the assay on the level of the 100fold concentrated solutions in DMSO by serial 1 :3.4 dilutions) in duplicate values for each concentration and IC50 values were calculated by a 4 parameter fit.

Mps-1 kinase assay

The human kinase Mps-1 phosphorylates a biotinylated substrate peptide. Detection of the phosphorylated product is achieved by time-resolved fluorescence resonance energy transfer (TR-FRET) from Europium-labelled anti- phospho-Serine/Threonine antibody as donor to streptavidin labelled with cross- linked allophycocyanin (SA-XLent) as acceptor. Compounds are tested for their inhibition of the kinase activity.

N-terminally GST-tagged human full length recombinant Mps-1 kinase (purchased from Invitrogen, Karslruhe, Germany, cat. no PV4071 ) was used. As substrate for the kinase reaction a biotinylated peptide of the amino-acid sequence biotin- Ahx-PWDPDDADITEILG (C-terminus in amide form, purchased from Biosyntan GmbH, Berlin) was used.

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 μΐ of a solution of Mps-1 in assay buffer [0.1 mM sodium-ortho-vanadate, 10 mM MgC , 2 mM DTT, 25 mM Hepes pH 7.7, 0.05% BSA (w/v), 0.001 % Pluronic F-127] were added and the mixture was incubated for 15 min at 22° C to allow pre-binding of the test compounds to Mps- 1 before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΐ of a solution of 16.7 μΜ adenosine-tri-phosphate (ATP, 16.7 μΜ => final cone, in the 5 μΐ assay volume is 10 μΜ) and peptide substrate (1 .67 μΜ => final cone, in the 5 μΐ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 60 min at 22 °C. The concentration of Mps-1 in the assay was adjusted to the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme concentrations were in the range of about 0.5 nM (final cone, in the 5 μΐ assay volume). The reaction was stopped by the addition of 5 μΐ of a solution of TR-FRET detection reagents (100 mM Hepes pH 7.4, 0.1 % BSA, 40 mM EDTA, 140 nM Streptavidin-XLent [# 61 GSTXLB, Fa. Cis Biointernational, Marcoule, France], 1.5 nM anti-phospho(Ser/Thr)-Europium-antibody [#AD0180, PerkinElmer LAS, Rodgau-Jiigesheim, Germany]. Instead of the 1.5 nM anti-phospho(Ser/Thr)- Europium-antibody a mixture of 2 nM unlabeled anti-phospho ser/thr-pro antibody MPM-2 [Millipore cat. # 05-368] and 1 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077] can be used).

The resulting mixture was incubated 1 h at 22° C to allow the binding of the phosphorylated peptide to the anti-phospho(Ser/Thr)-Europium-antibody. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Europium-labelled anti- phospho(Ser/Thr) antibody to the Streptavidin-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a Viewlux TR-FRET reader (PerkinElmer LAS, Rodgau-Jiigesheim, Germany). The "blank-corrected normalized ratio" (a Viewlux specific readout, similar to the traditional ratio of the emissions at 665 nm and at 622 nm, in which blank and Eu-donor crosstalk are subtracted from the 665 nm signal before the ratio is calculated) 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 11 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 100fold concentrated solutions in DMSO by serial 1 :3.4 dilutions) in duplicate values for each concentration and IC50 values were calculated by a 4 parameter fit. Bub1 kinase assay

Bub1 -inhibitory activity of compounds of the present invention was quantified employing the Bub1 TR-FRET assay as described in the following paragraphs.

N-terminally His₆-tagged recombinant catalytic domain of human Bub1 (amino acids 704-1085), expressed in insect cells (Hi5) and purified by Ni-NTA affinity chromatography and subsequent size exclusion chromatography, was used as enzyme. As substrate for the kinase reaction the biotinylated peptide biotin- Ahx-VLLPKKSFAEPG (C-terminus in amid form) was used which can be purchased e.g. form the company Biosyntan (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 Bub1 in aqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mM magnesium chloride (MgC ), 200 mM potassium chloride (KG), 1 .0 mM dithiothreitol (DTT), 0.1 mM sodium ortho- vanadate, 1 % (v/v) glycerol, 0.01 % (w/v) bovine serum albumine (BSA), 0.005% (v/v) Trition X-100 (Sigma), 1 x Complete EDTA-free protease inhibitor mixture (Roche)] 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 μΐ assay volume is 10 μΜ) and substrate (1 .67 μΜ => final cone, in the 5 μΐ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 60 min at 22° C. The concentration of Bub1 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 200 ng/ml. The reaction was stopped by the addition of 5 μΐ of a solution of TR-FRET detection reagents (0.2 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-phosho-Serine antibody [Merck Millipore, cat. # 35-001 ] and 0.4 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077, as an alternative a Terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassays can be used]) in an aqueous EDTA-solution (50 mM EDTA, 0.2 % (w/v) bovine serum albumin in 100 mM HEPES 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 Rubystar or Pherastar (both from 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 ηΜ, 13 ηΜ, 3.8 ηΜ, 1 .1 ηΜ, 0.33 nM and 0.1 nM, the dilution series prepared separately before the assay on the level of the 100fold concentrated solutions in DMSO by serial 1 :3.4 dilutions) in duplicate values for each concentration and IC50 values were calculated by a 4 parameter fit.

Table 4: IC50 data for Bub1 , CDK2 and Mps1 kinase assays

Bub 1 CDK2 Mps1

Example No. avg avg avg

(ICso [mol/l]) (ICso [mol/l]) (ICso [mol/l])

4 2.0E-5 2.0E-5 2.0E-5

5 2.0E-5 2.0E-5 2.0E-5

6 2.0E-5 2.0E-5 2.0E-5

7 2.0E-5 2.0E-5 2.0E-5

8 2.0E-5 2.0E-5 2.0E-5

9 3.8E-6 2.0E-5 2.0E-5

10 2.0E-5 2.0E-5 2.0E-5

1 1 2.0E-5 2.0E-5 2.0E-5

12 1 .4E-5 1 .9E-5 2.0E-5

1 3 2.0E-5 2.0E-5 2.0E-5

14 2.0E-5 2.0E-5 2.0E-5

1 5 2.0E-5 2.0E-5 2.0E-5

16 2.0E-5 2.0E-5 2.0E-5

17 2.0E-5 2.0E-5 2.0E-5

18 2.0E-5 2.0E-5 2.0E-5

19 2.0E-5 2.0E-5 2.0E-5

20 2.0E-5 2.0E-5 2.0E-5 Bub 1 CDK2 Mps1

Example No. avg avg avg

(ICso [mol/l]) (ICso [mol/l]) (ICso [mol/l])

21 2.0E-6 2.0E-5 2.0E-5

22 2.0E-5 2.0E-5 2.0E-5

23 2.0E-5 2.0E-5 2.0E-5

24 2.0E-5 2.0E-5 2.0E-5

25 2.0E-5 2.0E-5 2.0E-5

26 2.0E-5 2.0E-5 2.0E-5

27 2.0E-5 2.0E-5 2.0E-5

28 2.0E-5 2.0E-5 2.0E-5

29 2.0E-5 2.0E-5 2.0E-5

30 2.0E-5 2.0E-5 1 .5E-5

31 2.0E-5

32 1 .3E-5 2.0E-5 2.0E-5

33 6.8E-6 2.0E-5 2.0E-5

34 2.0E-5 2.0E-5 2.0E-5

35 2.0E-5 2.0E-5 2.0E-5

36 2.0E-5 2.0E-5 2.0E-5

37 2.0E-5 2.0E-5 2.0E-5 Bub 1 CDK2 Mps1

Example No. avg avg avg

(ICso [mol/l]) (ICso [mol/l]) (ICso [mol/l])

38 2.0E-5 2.0E-5 2.0E-5

39 2.0E-5 2.0E-5 2.0E-5

40 2.0E-5 2.0E-5 2.0E-5

41 2.0E-5 2.0E-5 2.0E-5

42 2.0E-5 2.0E-5 2.0E-5

43 2.0E-5 2.0E-5 2.0E-5

44 2.0E-5 2.0E-5 2.0E-5

45 2.0E-5 2.0E-5 2.0E-5

46 1 .1 E-5 2.0E-5 2.0E-5

47 2.0E-5 2.0E-5 2.0E-5

48 2.0E-5 2.0E-5 2.0E-5

49 2.0E-5 2.0E-5 2.0E-5

50 2.0E-5 2.0E-5 2.0E-5

51 2.0E-5 2.0E-5 2.0E-5

52 2.0E-5 2.0E-5 2.0E-5

53 2.0E-5 2.0E-5 2.0E-5

54 2.0E-5 2.0E-5 2.0E-5 Bub 1 CDK2 Mps1

Example No. avg avg avg

(ICso [mol/l]) (ICso [mol/l]) (ICso [mol/l])

55 2.0E-5 2.0E-5

56 1 .2E-5 2.0E-5 2.0E-5

57 2.0E-5 2.0E-5 2.0E-5

58 1 .7E-5 2.0E-5 2.0E-5

59 2.0E-5 2.0E-5 2.0E-5

60 2.0E-5 2.0E-5 2.0E-5

61 2.0E-5 2.0E-5 2.0E-5

62

63

64

65

66

67

68

69

70

71 Bub 1 CDK2 Mps1

Example No. avg avg avg

(ICso [mol/l]) (ICso [mol/l]) (ICso [mol/l])

72

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89 Bub1 CDK2 Mps1

Example No. avg avg avg

(ICso [mol/l]) (ICso [mol/l]) (ICso [mol/l])

90

91

92

93

94

95

Proliferation Assay:

Cultivated tumor cells (cells were ordered from ATCC, except HeLa-MaTu and HeLa-MaTu-ADR, which were ordered from EPO-GmbH, Berlin) were plated at a density of 1000 to 5000 cells/well, depending on the growth rate of the respective cell line, in a 96- well multititer plate in 200 μΙ_ of their respective growth medium supplemented 10% fetal calf serum. After 24 hours, the cells of one plate (zero-point plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 μΐ), to which the test substances were added in various concentrations (0 μΜ, as well as in the range of 0.001 -10 μΜ; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test substances. Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed by adding 20 μΐ/measuring point of an 1 1 % glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were stained by adding 100 μΐ/measuring point of a 0.1 % crystal violet solution (pH 3.0). After three washing cycles of the stained cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100 μΐ/measuring point of a 10% acetic acid solution. Absorbtion was determined by photometry at a wavelength of 595 nm. The change of cell number, in percent, was calculated by normalization of the measured values to the aborbtion values of the zero-point plate (=0%) and the absorbtion of the untreated (0 μητι) cells (=100%). The IC50 values were determined by means of a 4 parameter fit.

Table 5: Compounds had been evaluated in the following cell lines, which examplify the sub-indications listed

Table 6: Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2 and B16F10 cells by compounds according to the present invention. All IC₅₀ (inhibitory concentration at 50% of maximal effect) values are indicated in [mol/L].

HeLa-

Example

HeLa MaTu- NCI-H460 DU145 Caco2 B16F10 No.

ADR

14 1.5E-6 5.3E-7 1.4E-6 1.1 E-6 6.6E-7 1.2E-6

15 1.1 E-6 1.4E-7 2.5E-7 2.8E-7 1.6E-7 3.1 E-7

16 1.1 E-6 3.6E-7 5.3E-7 5.6E-7 3.4E-7 4.4E-7

17 1.1 E-6 3.1 E-7 4.1 E-7 7.2E-7 2.9E-7 4.5E-7

18 8.2E-6

19 1.3E-6 5.7E-7 4.6E-7 4.8E-7 3.0E-7 6.1 E-7

20 5.7E-7 2.5E-7 4.2E-7 6.6E-7 2.1 E-7 6.0E-7

21 1.0E-5

22 2.6E-6

23 3.1 E-6

24 1.0E-5

25 1.0E-5

26 1.0E-5

27 3.6E-6

28 1.0E-5

29 1.0E-5

30 3.7E-6

31 1.0E-5

32 7.6E-7

33 1.5E-6

34 4.9E-7 4.5E-7 4.0E-7 5.2E-7 4.4E-7 1.4E-6

35 5.0E-6

36 4.7E-7 4.6E-7 4.1 E-7 4.8E-7 4.1 E-7 1.1 E-6

37 1.3E-6 2.7E-7 1.1 E-6 1.7E-6 1.1 E-6 2.5E-6

38 6.8E-6

39 9.4E-6

40 7.2E-6

41 4.9E-6 HeLa-

Example

HeLa MaTu- NCI-H460 DU145 Caco2 B16F10 No.

ADR

42 1.0E-5

43 5.2E-6

44 1.0E-5

45 8.6E-6

46 1.0E-5

47 1.1 E-6 3.8E-7 1.1 E-6 1.0E-6 2.1 E-7 4.0E-7

48 2.5E-6

49 1.0E-5

50 8.6E-6

51 1.9E-6

52 2.1 E-6

53 1.9E-6

54 1.5E-6 4.4E-7 6.1 E-7 1.3E-6 6.9E-7 6.5E-7

55 1.0E-5

56 4.6E-6

57 2.6E-6

58 8.0E-6

59 9.4E-7 8.1 E-8 6.0E-7 2.9E-7 3.0E-7 6.5E-7

60 2.6E-7 3.7E-7 4.5E-7 1.2E-6 3.3E-7 3.4E-7

61 7.4E-7 4.9E-7 5.1 E-7 8.2E-7 6.7E-7 4.6E-7

62

63

64

65

66

67

68

69 HeLa-

Example

HeLa MaTu- NCI-H460 DU 145 Caco2 B16F10 No.

ADR

70

71

72

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

89 Thus the compounds of the present invention effectively inhibit the spindle assembly checkpoint and tumor cell proliferation and are therefore suitable for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are haemotological tumours, solid tumours and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

Claims

1. A compound of formula (I)

in which :

represents a heteroaryl group selected from

R² represents a group selected from :

phenyl or pyridinyl,

a halogen atom, or a Ci -C₃-alkyl-, or a Ci -C₃-alkoxy-group,

R³ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents :

a group selected from:

or with two halogen atoms,

R⁵ represents :

a hydrogen atom, or a group selected from Ci-C₆-alkyl, Ci-C₆-haloalkyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

or,

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group,

or,

R¹³ represents a Ci -C₆-alkyl-group,

2. The compound according to claim 1 , wherein : A represents a heteroaryl group selected from :

wherein one of X¹ , X² and X³ represents an N, 0 or S as ring atom and the others of X¹ , X² and X³ represent carbon as ring atoms, and wherein X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms or one of X⁴, X⁵, X⁶ and X⁷ represent an N atom, and the others of X⁴, X⁵, X⁶ and X⁷ represent carbon as ring atoms, and

Ci -C₆-haloalkoxy, C2-C₆-alkenyl, C2-C₆-alkynyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-, R⁶(R⁷)NC(=0)-(Ci -C₆-alkyl)-, R⁸S-(Ci -C₆-alkyl)-, R⁸S(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(Ci -C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(Ci -C₆-alkyl)-, R³OC(=0)-(Ci -C₆- alkyl)-, -NR⁴R⁵, -C(=0)N(R⁴)R⁵, phenyl, 5-membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group, which azetidine group is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which 5- to 6-membered heterocycloalkyl is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C₃- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl,

and, said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted, one or two times, identically or differently, with a substituent selected from:

R¹ represents a methyl-group,

R² represents a group selected from : phenyl or pyridinyl,

R³ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents : a group selected from: d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R¹¹ (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)- , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)-, R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl)- , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)₂,

or with two halogen atoms,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl,

CrCe-cycloalkyl, R¹¹ (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-,

or, R⁴ and R⁵ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group optionally being substituted with a substituent selected from:

or,

R⁶ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl, C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-,

or,

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group, R^{1 1} represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

or,

R¹³ represents a Ci -C₆-alkyl-group,

3. The compound according to claim 1 or 2, wherein : A represents a heteroaryl group selected from :

Ci -C₆-haloalkoxy, C2-C₆-alkenyl, C2-C₆-alkynyl, R⁶(R⁷)N-(Ci -C₆-alkyl)- , R⁶(R⁷)NC(=0)-(Ci -C₆-alkyl)-, R⁸S-(Ci -C₆-alkyl)-, R⁸S(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(Ci -C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(Ci -C₆-alkyl)-, R³OC(=0)-(Ci -C₆- alkyl)-, -NR⁴R⁵, -C(=0)N(R⁴)R⁵, phenyl, 5-membered heteroaryl containing two heteroatoms, 5-membered heteroaryl containing three heteroatoms, or being substituted with an azetidine group, which is connected to said heteroaryl group via a carbon atom of the azetidine group, or being substituted with a 5- to 6-membered heterocycloalkyl group, which is connected to said heteroaryl group via a carbon atom of the 5- to 6-membered heterocycloalkyl group, or being substituted with a (5- to 6-membered heterocycloalkyl) - (Ci -C₃- alkyl)- group, wherein 5- to 6-membered heterocycloalkyl is connected to C1 -C3- alkyl via a carbon atom of 5- to 6-membered heterocycloalkyl,

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, and,

said heteroaryl group, which is monocyclic or bicyclic, optionally being additionally substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₆-alkyl, Ci -C₆-haloalkyl, Ci -C₆-alkoxy, Ci -C₆-haloalkoxy, C₃-C₆- cycloalkyl, C3-C₆-cycloalkyloxy, hydroxy, a halogen atom, or cyano,

represents a methyl-group,

represents a group selected from :

phenyl or pyridinyl,

Ci -C₆-alkoxy, or a halogen atom,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

represents :

a group selected from:

d-Ce-haloalkyl, C₃-C₆-cycloalkyl, R¹¹(R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl) , (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-, R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S-(C₂-C₆-alkyl)- R⁸S(=0)-(C₂-C₆-alkyl)-, R⁸S(=0)₂-(C₂-C₆-alkyl)-, R⁸S(=NR⁹)(=0)-(C₂-C₆-alkyl) , or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)2, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2, said azetidine group being optionally substituted with a substituent selected from:

or,

(Ci -C₃-alkyl)-0- (C₂-C₆-alkyl)-, R³OC(=0)- (Ci -C₆-alkyl)-, R⁸S- (C₂-C₆-alkyl)-, R⁸S(=0)- (C₂-C₆-alkyl)-, R⁸S(=0)₂- (C₂-C₆-alkyl)-, R⁸S(=NR⁹)(C=0)- (C₂-C₆- alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- or 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0, and S, or a heteroatom containing group S(=0) or S(=0)₂, or containing two heteroatoms, one of which is N and the other is selected from the group consisting of N, 0 or S or a heteroatom containing group S(=0) or S(=0)2, said azetidine group being optionally substituted with a substituent selected from:

R⁷ represents : a hydrogen atom, or a group selected from Ci -C₆-alkyl, Ci -C₆-haloalkyl,

C₃-C₆-cycloalkyl, R^{1 1} (R¹²)N-(C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, or (Ci -C₃-alkyl)-0-(C₂-C6-alkyl)-,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent: a azetidine group, said azetidine group being optionally substituted with a substituent selected from: Ci -C₆-alkyl, Ci -C6-haloalkyl, Ci -C₆-alkoxy, Ci -C6-haloalkoxy, C3-C₆-cycloalkyl, C3-C6-cycloalkyloxy, amino, hydroxy, a halogen atom, cyano, or -C(=0)OR¹³, or with two halogen atoms,

or,

R⁸ represents : a Ci -C₆-alkyl-group, or a C3-C₆-cycloalkyl-group,

R¹⁰ represents: a Ci -C₆-alkyl-group, or a Ci -C₆-haloalkyl-group, ¹ represents: a hydrogen atom, or a Ci -C₆-alkyl-grou

R¹² represents: a hydrogen atom, or a Ci -C₆-alkyl-group,

or,

and R¹² together with the nitrogen to which they are attached represent: a azetidine group, or a 5- to 6-membered heterocycloalkyl group, said 5- to 6-membered heterocycloalkyl group optionally contains one further heteroatom selected from the group consisting of 0, N and S,

R¹³ represents a Ci -C₆-alkyl-group,

4. The compound according to any one of claims 1 , 2 or 3, wherein : A represents a heteroaryl group selected from :

d-Ce-haloalkoxy, C₂-C₆-alkenyl, R⁶(R⁷)N-(Ci -C₆-alkyl)-,

or being substituted with an azetidine group,

a -C(=0)OR³-group,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, or a halogen atom,

Ci -C₆-haloalkyl, Ci -C₆-alkoxy, a halogen atom, or -C(=0)OR¹³,

and,

Ci -C₆-haloalkyl, or a halogen atom, R¹ represents a methyl-group,

R² represents a group selected from :

phenyl or pyridinyl,

Ci -C₆-alkoxy, or a halogen atom,

R³ represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

R⁴ represents : a group selected from:

R^{1 1} (R¹²)N- (C₂-C₆-alkyl)-, HO-(C₂-C₆-alkyl)-, (Ci -C₃-alkyl)-0-(C₂-C₆-alkyl)-,

R³OC(=0)-(Ci -C₆-alkyl)-, R⁸S(=0)₂-(C₂-Ce-alkyl)-, or a azetidine group, or a 5- to 6-membered heterocycloalkyl group,

d-Ce-haloalkyl, or -C(=0)OR¹³, said 5- to 6-membered heterocycloalkyl group being optionally substituted with a substituent selected from: Ci -C₆-alkyl, or Ci -C6-haloalkyl,

represents :

a hydrogen atom, or a group selected from Ci -C₆-alkyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

amino,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

Ci -C₆-haloalkyl, amino, or hydroxy,

R⁶ represents :

a Ci -C₆-alkyl g

R⁷ represents a group selected from Ci -C₆-alkyl, or Ci -C6-haloalkyl,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent:

a azetidine group,

said azetidine group optionally being substituted with a :

Ci -C₆-haloalkyl, or a halogen atom,

or with two halogen atoms,

or,

Ci -C₆-haloalkyl, or a halogen atom,

R⁸ represents :

a Ci -C₆-alkyl-group,

represents:

a hydrogen atom, ^! represents: a hydrogen atom, or a Ci -C₆-alkyl-grou

R¹³ represents a Ci -C₆-alkyl-group,

5. The compound according to any one of claims 1 to 4, wherein : A represents a heteroaryl group selected from :

trifluoromethoxy, vinyl, prop-1 -en-2-yl, R⁶(R⁷)N-(Ci -C₂-alkyl)-, R⁸S(=0)₂-

(ethyl)-, R³OC(=0)-(Ci -C₂-alkyl)-, -C(=0)N(R⁴)R⁵, pyrazolyl, oxadiazolyl, or being substituted with an azetidine group,

Ci -C₃-haloalkyl, Ci -C₂-alkoxy, or a fluorine atom,

said 5- to 6-membered heterocycloalkyl group being optionally substituted, one or two times, identically or differently, with a substituent selected from: Ci -C3-haloalkyl, Ci -C2-alkoxy, a fluorine atom, or -C(=0)OR^{1 3},

R¹ represents a methyl-group,

R² represents a group selected from phenyl or pyridinyl,

R³ represents : a hydrogen atom, or a group selected from Ci -C₂-alkyl,

R⁴ represents : a group selected from :

R^{1 1} (R¹²)N- (C₂-C₃-alkyl)-, 2-hydroxy-2-methylpropyl-, (2-methoxy)ethyl-, R³OC(=0)- (Ci -C₂-alkyl)-, R⁸S(=0)₂-(ethyl)-, or a azetidine group, or a 6- membered heterocycloalkyl group, said 6-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N and 0, or a heteroatom containing group S(=0)₂,

d -Cs-haloalkyl, or -C(=0)OR^{1 3},

methyl, or Ci -C₃-haloalkyl,

R⁵ represents :

a hydrogen atom, or a group selected from methyl,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a azetidine group,

amino,

or,

R⁴ and R⁵ together with the nitrogen to which they are attached represent:

a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of N, said 5- to 6-membered heterocycloalkyl group being substituted, one or two times, identically or differently, with a substituent selected from:

Ci -C₃-haloalkyl, amino, or hydroxy.

R⁶ represents :

a methyl group,

represents :

a group selected from methyl, or Ci -C₃-haloalkyl,

or,

said azetidine group optionally being substituted with a :

Ci -C₃-haloalkyl, or a fluorine atom,

or with two fluorine atoms,

or,

R⁶ and R⁷ together with the nitrogen to which they are attached represent:

a 5- to 6-membered heterocycloalkyl group, which optionally contains one further heteroatom selected from the group consisting of 0, N and S, said 5- to 6-membered heterocycloalkyl group optionally being substituted, one or two times with a substituent selected from:

Ci -C₃-haloalkyl, or a fluorine atom, represents a methyl-g

represents: a hydrogen atom

R¹² represents: a hydrogen atom, or a methyl-group,

R¹³ represents a methyl-group, or a tert-butyl-group,

6. The compound according to any one of claims 1 to 5, which is selected from the group consisting of :

N-(3,4-Difluorophenyl)-3-methyl-5- [(6-vinylpyrazin-2-yl)amino] - 1 ,2-thiazole-4- carboxamide ; N-(3,4-Difluorophenyl)-5-({6- [2-(dimethylamino)ethyl]pyrazin-2-yl}amino)-3- methyl- 1 ,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-({6- [2-(methylsulfonyl)ethyl]pyrazin-2- yl}amino)- 1 ,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-{[6-(3-methyl- 1 ,2,4-oxadiazol-5-yl)pyrazin-2- yl]amino}- 1 ,2-thiazole-4-carboxamide ; N-(3,4-difluorophenyl)-3-methyl-5-{[5-(3-methyl-1 ,2,4-oxadiazol-5-yl)pyridin-2- yl]amino}-1 ,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-{[5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-4- (trifluoromethyl)pyridin-2-yl]amino}-1 ,2-thiazole-4-carboxamide ; N-(3,4-Difluorophenyl)-3-methyl-5-{[4-(5-methyl-1 ,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)pyridin-2-yl]amino}-1 ,2-thiazole-4-carboxamide ;

5-{[5-Chloro-4-(3-methyl-1 ,2,4-oxadiazol-5-yl)pyridin-2-yl]amino}-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide ;

Ethyl N-{[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)-pyrazin-2-yl]carbonyl}glycinate ;

Ethyl 1 -[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)- pyrazin-2-yl]-1H-pyrazole-4-carboxylate;

Methyl 3-[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]propanoate ; N-(3,4-Difluorophenyl)-3-methyl-5-[(5-vinylpyrazin-2-yl)amino]-1 ,2-thiazole-4- carboxamide ;

N-(3,4-Difluorophenyl)-5-({5-[(4,4-difluoropiperidin-1 -yl)methyl]pyrazin-2-yl}- amino)-3-methyl-1 ,2-thiazole-4-carboxamide ;

5- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide ;

6- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide ;

6-({4-[(4-Chloro-3-fluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N- [1 -(2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide ; 5-[(5-{[4-(2,2-Difluoroethyl)piperazin-1 -yl]carbonyl}pyrazin-2-yl)amino]-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide ;

N-[1 -(2,2-Difluoroethyl)piperidin-4-yl]-5-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide ; 5- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide ;

N-{[6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]carbonyl}-8-alanine ; N-(3,4-Difluorophenyl)-3-methyl-5-[(5-{[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]- carbonyl}pyrazin-2-yl)amino]-1 ,2-thiazole-4-carboxamide ;

6- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 -(2- fluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide ;

5-({6-[(3-Aminoazetidin-1 -yl)carbonyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide hydrochloride ;

5-({5-[(3-Aminoazetidin-1 -yl)carbonyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide hydrochloride ; tert-Butyl 3-({[5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}- amino)pyrazin-2-yl]carbonyl}amino)azetidine-1 -carboxylate ; 5-[(6-{[4-(2,2-difluoroethyl)piperazin-1 -yl]carbonyl}pyrazin-2-yl)amino]-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide ;

N-(3-Aminopropyl)-5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxamide hydrochloride ;

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[2- (methylsulfonyl)ethyl]pyrazine-2-carboxamide ;

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(1 ,1 - dioxidotetrahydro-2H-thiopyran-4-yl)pyrazine-2-carboxamide ;

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N- methyl-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide hydrochloride ; 6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide ;

N-[1 -(2,2-Difluoroethyl)azetidin-3-yl]-6-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide ; N-(3,4-Difluorophenyl)-3-methyl-5-[(5-{[methyl(2,2,2- trifluoroethyl)amino]methyl}pyrazin-2-yl)amino]-1 ,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-5-({6-[(3-fluoroazetidin-1 -yl)methyl]pyrazin-2-yl}amino)- 3-methyl-1 ,2-thiazole-4-carboxamide ; N-[1 -(2,2-Difluoroethyl)piperidin-4-yl]-6-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide ;

N-[1 -(2,2-Difluoroethyl)azetidin-3-yl]-5-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide ;

N-(6-Methoxypyridin-3-yl)-3-methyl-5-{[5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 ,3- thiazol-2-yl]amino}-1 ,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-{[5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 ,3- thiazol-2-yl]amino}-1 ,2-thiazole-4-carboxamide ;

N-(6-Methoxypyridin-3-yl)-3-methyl-5-{[5-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 ,3- thiazol-2-yl]amino}-1 ,2-thiazole-4-carboxamide ; N-(3,4-Difluorophenyl)-5-({5-[(2-methoxyethyl)(methyl)carbamoyl]-1 ,3-thiazol-2- yl}amino)-3-methyl-1 ,2-thiazole-4-carboxamide ;

N-(6-Methoxypyridin-3-yl)-3-methyl-5-{[4-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 ,3- thiazol-2-yl]amino}-1 ,2-thiazole-4-carboxamide ;

N-(4-Chloro-3-fluorophenyl)-5-({5-[(2-methoxyethyl)(methyl)-carbamoyl]-1 ,3- thiazol-2-yl}amino)-3-methyl-1 ,2-thiazole-4-carboxamide ;

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(2- methoxyethyl)-N-methyl-pyrazine-2-carboxamide ;

5-{[5-Chloro-4-(5-methyl-1 ,3,4-oxadiazol-2-yl)pyridin-2-yl]amino}-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide ; 6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[2- (methylsulfonyl)-ethyl]pyrazine-2-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-[(6-{[4-(2,2,2-trifluoroethyl)-piperazin-1 -yl]- carbonyl}pyrazin-2-yl)amino]-1 ,2-thiazole-4-carboxamide ; 5- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 -(2- fluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide ;

N-(3,4-Difluorophenyl)-5-({5-[(3,3-difluoropyrrolidin-1 -yl)methyl]pyrazin-2-yl}- amino)-3-methyl-1 ,2-thiazole-4-carboxamide ; N-(3,4-Difluorophenyl)-5-({5-[(3-fluoroazetidin-1 -yl)methyl]pyrazin-2-yl}amino)- 3-methyl-1 ,2-thiazole-4-carboxamide, salt with formic acid ;

N-(4-Chloro-3-fluorophenyl)-5-[(6-{[4-(2,2-difluoroethyl)piperazin-1 -yl]carbonyl}- pyrazin-2-yl)amino]-3-methyl-1 ,2-thiazole-4-carboxamide ;

N-(3,4-Dichlorophenyl)-5-[(6-{[4-(2,2-difluoroethyl)piperazin-1 - yl]carbonyl}pyrazin-2-yl)amino]^-methyl-1,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-5-({5-[(3,3-difluoropiperidin-1 -yl)methyl]pyrazin-2-yl}- amino)-3-methyl-1 ,2-thiazole-4-carboxamide ;

N-(6-Methoxypyridin-3-yl)-3-methyl-5-{[6-(trifluoromethoxy)-1 ,3-benzothiazol-2- yl]amino}-1 ,2-thiazole-4-carboxamide ; 5-({5-[(2-Methoxyethyl)(methyl)carbamoyl]-1 ,3-thiazol-2-yl}amino)-N-(6- methoxypyridin-3-yl)-3-methyl-1 ,2-thiazole-4-carboxamide ;

6- ({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 -(2- fluoroethyl)azetidin-3-yl]pyrazine-2-carboxamide ;

6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(1 - methylpiperidin-4-yl)pyrazine-2-carboxamide ;

N-[1 -(2,2-di7luoroethyl)azetidin -yl]-6-({4-[(6-methoxypyridin-3-yl)carbamoyl]- 3-methyl-1 ,2-thiazol-5-yl}amino)pyrazine-2-carboxamide ;

6-({4-[(6-methoxypyridin-3-yl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide ; 6-({4-[(3,4-dichlorophenyl)-carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (2,2,2-trifluoroethyl)piperidin-4-yl]pyrazine-2-carboxamide ;

N-(3,4-difluorophenyl)-5-({6-[(4,4-difluoropiperidin-1 -yl)methyl]pyrazin-2- yl}amino)-3-methyl-1 ,2-thiazole-4-carboxamide ; 5- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)azetidin-3-yl]pyrazine-2-carboxamide ;

6- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide ; 5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide ;

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 -(2- fluoroethyl)piperidin-4-yl]pyridazine-3-carboxamide ;

N-[1 -(2,2-Difluoroethyl)piperidin-4-yl]-6-({4-[(3,4-difluorophenyl)carbamoyl]-3- methyl-1 ,2-thiazol-5-yl}amino)pyridazine-3-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-{[5-(prop-1 -en-2-yl)pyrazin-2-yl]amino}-1 ,2- thiazole-4-carboxamide ;

Methyl 2-[5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)-pyrazin-2-yl]-2-methylpropanoate ; 6-({4-[(2-methoxypyridin-4-yl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyrazine-2-carboxamide ;

Methyl 4-[5-({4-[(6-isopropoxy-pyridin-3-yl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]-1 -(3,3,3-trifluoropropyl)-piperidine-4-carboxylate ;

Methyl 4-[5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]-1 -(3,3,3-trifluoropropyl)piperidine-4-carboxylate ;

Methyl 4-[5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]-1 -(2,2,2-trifluoroethyl)piperidine-4-carboxylate ;

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)azetidin-3-yl]pyrazine-2-carboxamide ; N-(3,4-difluorophenyl)-3-methyl-5-[(6-{[4-(3,3,3-trifluoropropyl)piperazin-1 - yl]carbonyl}pyrazin-2-yl)amino]-1 ,2-thiazole-4-carboxamide ;

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-[1 - (3,3,3-trifluoropropyl)piperidin-4-yl]pyridazine-3-carboxamide ; N-(3,4-Difluorophenyl)-3-methyl-5-[(6-{[4-(3,3,3-trifluoropropyl)piperazin-1 - yl]carbonyl}pyridazin-3-yl)amino]-1 ,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-({6-[1 -(3,3,3-trifluoropropyl)-1 ,2,3,6-tetra- hydropyridin-4-yl]pyrazin-2-yl}amino)-1 ,2-thiazole-4-carboxamide ; N-(3,4-Difluorophenyl)-3-methyl-5-({5-[1 -(2,2,2-trifluoroethyl)piperidin-4- yl]pyrazin-2-yl}amino)-1 ,2-thiazole-4-carboxamide ;

N-(3,4-Difluorophenyl)-3-methyl-5-({5-[1 -(3,3,3-trifluoropropyl)piperidin-4- yl]pyrazin-2-yl}amino)-1 ,2-thiazole-4-carboxamide ;

N-(Azetidin-3-yl)-5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxamide, salt with trifluoroacetic acid ; tert-Butyl 4-[6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazin-2-yl]-3,6-dihydropyridine-1 (2H)-carboxylate ;

N-(3,4-Difluorophenyl)-3-methyl-5-{[6-(1 ,2,3,6-tetrahydropyridin-4-yl)pyrazin-2- yl]amino}-1 ,2-thiazole-4-carboxamide, salt with trifluoroacetic acid ; 5-({5-[(4-Aminopiperidin-1 -yl)carbonyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide, salt with trifluoroacetic acid ;

5- ({6-[(4-Aminopiperidin-1 -yl)carbonyl]pyrazin-2-yl}amino)-N-(3,4- difluorophenyl)-3-methyl-1 ,2-thiazole-4-carboxamide, salt with trifluoroacetic acid ;

N-(Azetidin-3-yl)-6-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5- yl}amino)pyrazine-2-carboxamide, salt with trifluoroacetic acid ;

6- ({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N- (piperidin-4-yl)pyridazine-3-carboxamide, salt with trifluoroacetic acid ; N-(3,4-Difluorophenyl)-5-[(6-{[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1 -yl]- carbonyl}pyrazin-2-yl)amino]-3-methyl-1 ,2-thiazole-4-carboxamide ;

6-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(2- hydroxy-2-methylpropyl)pyrazine-2-carboxamide ; N-(3,4-di7luorophenyl)-5-[(5-{[3-hydroxy -(tri7luoromethyl)pyrrolidin-1 -yl]- carbonyl}pyrazin-2-yl)amino]-3-methyl-1 ,2-thiazole-4-carboxamide ;

N-(3,4-di7luorophenyl)-5-[(5-{[4-hydroxy-4-(trifluoromethyl)piperidin-1 -yl]- carbonyl}pyrazin-2-yl)amino]-3-methyl-1 ,2-thiazole-4-carboxamide ;

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(2- hydroxy-2-methylpropyl)pyrazine-2-carboxamide ;

5-({4-[(3,4-Difluorophenyl)carbamoyl]-3-methyl-1 ,2-thiazol-5-yl}amino)-N-(tetra- hydro-2H-pyran-4-yl)pyrazine-2-carboxamide ; and

N-(3,4-Difluorophenyl)-5-({6-[1 -(2-fluoroethyl)piperidin-4-yl]pyrazin-2-yl}amino)- 3-methyl-1 ,2-thiazole-4-carboxamide .

7. A method of preparing a compound of general formula (I) according to any one of claims 1 to 6, said method comprising the step of allowing an intermediate compound of general formula (II) :

in which R1 and R2 are as defined for the compound of general formula (I) according to any one of claims 1 to 6,

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

A-X

(Hi) , in which A is as defined for the compound of general formula (I) according to any one of claims 1 to 6, and X represents a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group, for example a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group, or a boronic acid,

thereby giving a compound of general formula (I) :

(I) in which A, R1 and R2 are as defined for the compound of general formula (I) according to any one of claims 1 to 6.

8. A compound of general formula (I), 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, according to any one of claims 1 to 6, for use in the treatment or prophylaxis of a disease.

9. A pharmaceutical composition comprising a compound of general formula (I), 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, according to any one of claims 1 to 6, and a pharmaceutically acceptable diluent or carrier.

10. A pharmaceutical combination comprising :

- one or more first active ingredients selected from a compound of general formula (I) according to any of claims 1 to 6, and - one or more second active ingredients selected from chemotherapeutic anti-cancer agents.

11. Use of a compound of general formula (I), 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, according to any one of claims 1 to 6, for the prophylaxis or treatment of a disease.

12. Use of a compound of general formula (I), 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, according to any one of claims 1 to 6, for the preparation of a medicament for the prophylaxis or treatment of a disease.

13. Use according to claim 8, 11 or 12, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haematological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

14. Use of a compound of general formula (II)

(II) in which R1 and R2 are as defined for the compound of general formula (I) according to any one of claims 1 to 6,

for the preparation of a compound of general formula (I) according to any one of claims 1 to 6.