The present invention relates to novel compounds which act as modulators of indoleamine 2,3-dioxygenase (ID01 ) and to the use of said compounds in the prophylaxis and/or treatment of diseases or conditions mediated by indoleamine 2,3-dioxygenase. The invention further relates to pharmaceutical compositions comprising the novel compounds.

Tryptophan is an essential amino acid and naturally serves as a building block for proteins. The majority of adult Tryptophan intake is not utilized for protein synthesis though, but channeled into two conversion pathways. The first pathway leading to the production of Serotonine degrades approximately 1 % of ingested Tryptophan, whereas the majority of -90% of Tryptophan fuels the so called Kynurenine pathway (Le Floc ^' h et al.; Amino Acids. 201 1 ; 41 (5):1 195-205).

The Kynurenine pathway of Tryptophan degradation is initialized by a specific set of enzymes, including Indoleamine 2,3-dioxygenase 1 (ID01 ) and Tryptophan 2,3- dioxygenase (TD02). The product of this reaction, N-Formylkynurenine is subsequently converted to Kynurenine, which can be further metabolized to such diverse products as Xanthurenic acid, Anthranilic acid or Nicotinamide to name a few (Stone, Darlington; Nat Rev Drug Discov. 2002; 1 (8):609-20).

Under physiological conditions the expression of TDO is restricted to the liver (Bertazzo et al.; Biochim Biophys Acta. 2001 ; 15; 1527(3): 167-75) and the brain (Miller et al.; Neurobiol Dis. 2004 ;15(3):618-29). ID01 in contrast is found in a variety of tissues such as lung, digestive tract, uterus and secondary lymphoid organs (Theate et al.; Cancer Immunol Res. 2015;3(2):161 -72) and is readily (further) induced by pro inflammatory cytokines (Taylor, Feng; FASEB J. 1991 ;5(11 ):2516-22 1991 ).

Initially, ID01 has been implicated in a protective role in fetal rejection. Mice, treated with the ID01 inhibitor 1 -Methyl-T ryptophan lost their allogeneic concepti in a T cell dependent manner (Munn et al.; Science. 1998;281 (5380): 1 191-3).

It was then conceived that ID01 creates an immunosuppressive environment by catabolizing Tryptophan, thereby locally depleting this amino acid and creating immune privilege sites. Tryptophan depletion is most likely sensed through the General Control Nonderepressable Kinase 2 (GCN2) and leads to activation of the integrated stress response of cells (Munn et al.; Immunity. 2005;22(5):633-42) with consecutive inhibition of T cell proliferation (Munn et al.; J Exp Med. 1999;189(9):1363-72). Additionally, a low Tryptophan environment also sensitizes activated T cells to apoptosis via Fas (Lee et al.; Immunology. 2002;107(4):452-60). More recently, the mechanism of how ID01 can lead to immune suppression has been expanded, focusing on the catabolites of Tryptophan enzymatic conversion by ID01 , collectively called Kynurenines. It has been demonstrated that Kynurenine, 3-Hydroxykynurenine, 3-Hydroxyanthranilic acid and Quinolinic acid led to dose dependent inhibition of T cell proliferation (Terness et al.; J Exp Med. 2002;196(4):447-57). In part, this may be due to cell type specific apoptosis of Thymocytes in response to incubation with the aforementioned Tryptophan metabolites (Fallarino et al.; Cell Death Differ. 2002;9(10):1069-77).

The immune suppression observed concurrently with ID01 expression is also associated with an increase in T cells displaying a regulatory phenotype (Treg). Treg cells are important to maintain immune homeostasis and induce immune tolerance to avoid inappropriate immune response as is the case in autoimmune disease (Sakaguchi et al.; Eur J Immunol. 2007;37 Suppl 1 :S1 16-23). In mice, expression of the transcription factor FOXP3 is an important marker for regulatory T cells (Fontenot et al.; Nat Immunol. 2003;4(4):330-6) and co-cultivation of murine naive CD4+ T cells with IDO positive Dendritic cells led to a remarkable increase in FOXP3 expression of the CD4+ population. This polarization could be mimicked by incubation of naive CD4+ T cells in low Tryptophan medium supplemented with Kynurenines and was shown to be dependent on GCN2 (Fallarino et al.; Transpl Immunol. 2006;17(1 ):58-60). In humans, AML patients with elevated levels of ID01 also displayed an increase in circulating Treg cells. Analogous to the situation in mice, human CD3+ cells were polarized towards a regulatory phenotype in an ID01 dependent manner when co-cultivated with ID01 positive cells derived from AML patients (Curti et al.; Blood. 2007;109(7):2871 -7).

Several Kynurenines such as Kynurenine itself, 3-Flydroxykynurenine and Kynurenic acid also serve as ligands for the Aryl Flydrocarbon Receptor (AHR) albeit with differentially reported efficacies (DiNatale et al.; Toxicol Sci. 2010; 115(1 ):89-97, Mezrich et al.; J Immunok 2010;185(6):3190-8). This is of particular interest because firstly, the AHR has been implicated in the transcriptional regulation of ID01 via a self-sustaining autocrine feed-forward loop with the AHR acting either directly on ID01 transcription (Li et al.; J Immunok 2016;197(3):962-70) or with IL-6 as mediator (Litzenburger et ak; Oncotarget. 2014;5(4): 1038-51 ). Secondly, because the polarization of naive CD4+ T cells towards Treg cells by Kynurenines is dependent on the AHR (Kimura et ak; Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9721 -6, Mezrich et ak; J Immunok 2010;185(6):3190-8).

Whether the depletion of Tryptophan or the generation of Kynurenines or the combined action of both is the key in creating an immune suppressive environment needs to be further investigated. The net result though, is a key factor not only for immune homeostasis in healthy individuals but also for how tumors can escape immune surveillance.

The importance of ID01 for cancer development is supported by several lines of evidence. ID01 has been detected in most human tumors, such as prostate, pancreas, lung, ovarian, colorectal cancer, melanoma and leukemia (Uyttenhove et al.; Nat Med. 2003;9(10):1269-74; Hanagiri et al.; J Clin Cell Immunol 2014, 5:5, Okamoto et al.; Clin Cancer Res. 2005;11 (16):6030-9; Ferdinande et al.; Br J Cancer. 2012; 106(1 ): 141 -7, Brody et al.; Cell Cycle. 2009;8(12):1930-4, Chamuleau et al.; Haematologica. 2008;93(12):1894-8, Theate et al.; Cancer Immunol Res. 2015;3(2):161 -72). Interestingly, ID01 positive cells were also often found in immune cells in the tumor stroma and adjoining tumor draining lymph nodes (Astigiano et al.; Neoplasia. 2005;7(4):390-6, Chen et al.; Breast Cancer Res. 2014;16(4):410, Polak et al.; Br J Cancer. 2007;96(12):1879-87, Theate et al.; Cancer Immunol Res. 2015;3(2):161 -72). A negative correlation of ID01 expression either in tumor or in stromal cells with markers of disease progression has been observed in most of these cases.

Apart from these correlative analysis, elegant studies using mouse models underpinned the importance of ID01 in tumor immune escape. When immunogenic mouse tumor cells lacking ID01 were injected into immune competent mice, no tumor growth was observed. In contrast, if the cells constitutively expressed ID01 , tumors grew as expected. Pharmacologic inhibition of ID01 in turn, resulted in a marked reduction of tumor outgrowth. As indicated above, this effect was dependent on the hosts ^' immune system, as immune compromised mice injected with the ID01 positive and negative cell lines developed tumors to the same extent. Also, lower numbers of CD8+ T cells were found in mice injected with ID01 positive cells in comparison to mice injected with ID01 negative cells (Uyttenhove et al.; Nat Med. 2003;9(10):1269-74).

Although tumor derived ID01 is a decisive factor for immune escape, research also investigated the role of ID01 in immune cells. Munn et al. found a subset of plasmacytoid Dendritic cells in Tumor draining lymph nodes expressing ID01. Although these cells comprised less than 1 % of all lymph node cells they acted as potent and dominant suppressors of T cell proliferation (Munn et al.; J Clin Invest. 2004; 114(2): 280-290). The relative contribution of ID01 from immune cells versus tumor derived ID01 is still under debate. Koblish et al. observed that pharmacologic inhibition of ID01 reduced tumor size, when ID01 positive tumor cells were transplanted into immune competent ID01 -/- mice (Koblish et al.; Mol Cancer Ther. 2010;9(2):489-98). In contrast, Banerjee et al. reported no effect on tumor size when using a syngeneic mouse tumor model in ID01 negative mice and administration of an ID01 inhibitor (Banerjee et al.; Oncogene. 2008;27(20):2851 -7). Both studies though, were able to demonstrate the efficacy of IDO inhibitors in preclinical mouse models as single agents. Moreover, synergistic or additive effects were observed when ID01 inhibitors where used in combination with chemotherapeutics, irradiation, tumor vaccines or immune checkpoint inhibitors (Muller et al.; Nat Med. 2005;11 (3):312-9, Hou et al.; Cancer Res. 2007 Jan 15;67(2):792-801 , Sharma et al.; Blood. 2009 Jun 1 1 ; 113(24):6102-11 , Spranger et al.; J Immunother Cancer. 2014;2:3)

The studies referenced herein did not report any potent toxicity of ID01 inhibition and it is of interest to note that IDO knockout mice are viable and exhibit no major abnormal phenotype apart from defects in acquired tolerance (Mellor et al.; J Immunol. 2003;171 (4):1652-5). Therefore it seems unlikely that ID01 inhibition in humans will encounter profound dose limiting toxicities.

Apart from its relevance for tumor immune evasion, ID01 is implicated in a plethora of other medical conditions.

Throughout HIV disease progression, an altered Th17/Treg balance has been observed, favoring the latter in later stages. Favre et al. were able to demonstrate a crucial role for the Kynurenine 3-Hydroxykynurenine in this process and it is therefore hypothesized that patients with HIV may benefit from ID01 inhibition together with antiretroviral therapy (Favre et al.; Sci Transl Med. 2010 May 19;2(32):32ra36.).

IDO has also been implicated in the onset and progression of other viral and bacterial infections such as tuberculosis (TB), hanta virus infection, and leprae (Kim et al. 2017; Immunology. 151 (2): 177-190; Adu-Gyamfi et al. ; Clin. Infect Dis. 2017 Oct 15;65(8):1356-1358; Koivula et al.; Pathog Dis. 2017 Feb;75(1 ); de Mattos Barbosa et al.; Microbes Infect. 2017 Jul 3.) The description of the involvement of IDO in cardiovascular disease, endometriosis, type 2 diabetic nephropathy, chronic obstructive pulmonary disease (COPD), and osteoporosis, (H. Mangge et al.; Curr Med Chem. 2014 Jun; 21 (17): 1931-1937; Mei et al.; Mol Med Rep. 2017 Apr;15(4):2255-2260; Wei et al.; Cell Death Dis. 2016 Dec 1 ;7(12); Zhang et al. ; J Diabetes Complications. 2017 Jan;31 (1 ):223-227 ; Gulcev et al. ; Int J Chron Obstruct Pulmon Dis. 2016 Sep 29; 11 :2435-2446; Refaey et al. ; J Bone Miner Res. 2017 Jul 20 ; Meier et al. ; Lung. 2017 Jun;195(3):303-311 ) suggest that such disease states could be treated with positive outcome with IDO inhibitors As expected from the mode of action in the immune system, IDO is also involved in autoimmune diseases like rheumatoid arthritis, multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriasis, and systemic lupus erythematosus, (Merlo et al.; Clin Immunol. 2017 Jun;179:8-16; Lovelace et al.; Front Immunol. 2016 Aug 4;7:246; Negrotto et al. J Immunol. 2017 Mar 1 ;198(5):1900-1909; Sznurkowska et al. J Biol Regul Homeost Agents. 2017 Jan-Mar;31 (1 ):125-131 ; Jamie et al. ;J Allergy Clin Immunol. 2016 Jun; 137(6): 1830-1840 ; Wang et al. ; Arthritis Rheumatol. 2014 Aug; 66(8): 2234-2245) again here the inhibition of the enzyme could lead to beneficial effects in treating these diseases.

ID01 also seems to be involved in disorders of the central nervous system because its downstream products 3-Hydroxykynurenine and quinolinic acid act as neurotoxins (Okuda et al.; J Neurochem. 1998;70(1 ):299-307, Schwarcz et al.; Science. 1983;219(4582):316-8). Thereby, ID01 is also implicated in the disease development of Huntington ^' s disease, Amyotrophic lateral sclerosis, Alzheimer ^' s disease, Parkinson ^' s disease, Schizophrenia and epilepsy (Thevandavakkam et al.; CNS Neurol Disord Drug Targets. 2010;9(6):791-800; Chen et al.; Neurotox Res. 2010;18(2):132-42; Guillemin et al.; Neuropathol Appl Neurobiol. 2005;31 (4):395-404; Lim et al.; Prog Neurobiol. 2016;pii: S0301 -0082(15)30055-1 , Kegel et al.; Int J Tryptophan Res. 2014; 7: 15-22; Singh et al.; Neurochem Int. 2017 Mar; 104:27-33; Kaur et al.; Epilepsy Behav. 2017 Jul;72:8- 16.).

ID01 inhibitors may therefore be of high potential value for the treatment of HIV and CNS disorders and the reported preclinical data on efficacy against tumors either alone or in combination with other drugs validate the use of ID01 inhibitors as a treatment option for antineoplastic therapies.

Compounds acting as ID01 inhibitors are known in the art. WO 2006/122150 discloses compounds with a N-hydroxyamidino motif as potential modulators of ID01. The efficacy of compounds having said motif is demonstrated e.g. in WO 2008/036642, WO 2008/036643, WO 2008/036652, WO 2008/036653 and WO 2008/05178.

Compounds having an oxalamide motif are described as inhibitors for other receptors than ID01. As an example, the compounds disclosed in WO 2018/049089 can be mentioned.

The compounds detailed herein and compositions thereof as well as the methods described will serve to meet the future need for potent ID01 inhibitors. It is the object of the present invention to provide novel compounds which are suitable as potent ID01 inhibitors.

Said object is solved by the compounds of Formulae (1 ) and (2)

wherein A, A’, B, C, D, Y, Z, R ¹ , R ² , m, n and o are defined as in the appended claims.

It is further an object of the present invention to provide compounds according to Formulae (1 ) and (2) for use in the prophylaxis and/or treatment of diseases and conditions mediated by indoleamine 2,3-dioxygenase.

The present invention further relates to the use of the compounds according to Formulae

(1 ) or (2) for the preparation of a medicament for the treatment and/or prophylaxis of a disease or condition mediated by indoleamine 2,3-dioxygenase.

Moreover, the present invention also relates to a method for treating or preventing a disease or condition mediated by indoleamine 2,3-dioxygenase, the method comprising administering an effective amount of a compound according to Formulae (1 ) and (2) to a patient in need thereof.

Accordingly, the present invention provides a compound represented by Formulae (1 ) or

(2)

an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof wherein

A and A’ represent C3-10 cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R ^a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S and wherein the (hetero)cyclic ring may be unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl or oxo;

R ^a represents halogen, CN, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, hydroxy-Ci- ₆ -alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN;

B represents a bond or Ci _-2 -alkylene wherein alkylene is unsubstituted or substituted with one or two Ci _-4 -alkyl;

C represents 6- to 10-membered mono- or bicyclic aryl or 5- to 14-membered mono-, bi- or tricyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^y , 0-R ^y , 0C(0)-R ^y , S-R ^y , S(0) ₂ -R ^y , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^y , C(0)N(R ¹ ) ₂ , C(0)0-R ^y , C(0)-R ^y , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the aryl or heteroaryl ring systems together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S,

wherein the heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, CN and oxo;

R ^y represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ , CN and phenyl;

D represents 6- to 10-membered mono- or bicyclic aryl or 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^z , 0-R ^z , 0C(0)-R ^z , S-R ^z , S(0) ₂ -R ^z , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^z , C(0)N(R ¹ ) ₂ , C(0)0-R ^z , C(0)-R ^z , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo Ci- ₆ -alkyl, or

two substituents on the aryl or heteroaryl ring systems together with the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S,

wherein the heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, CN and oxo;

R ^z represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN;

Y is absent or represents hydrogen, OR ⁴ , halogen, C1-6 alkyl or halo-Ci- ₆ alkyl;

Z represents -C2-3-alkylene-, -O-Ci-2-alkylene-, -Ci-2-alkylene-O-, -NR ³ C(0)-Co-i- alkylene-, -C(0)NR ³ -Co-i-aikylene-, -Co-i-aikylene-NR ³ C(0)-, -Co-i-alkylene C(0)NR ³ -, - S(0) _t -Ci- ₂ -alkylene-, -Ci- ₂ -alkylene-S(0) _t -, -NR ⁹ -Ci-2-alkylene- or -C-i-2-alkylene-NR ⁹ -, wherein alkylene is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of OR ⁴ , Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl;

R ⁹ is hydrogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl;

R ¹ is hydrogen or Ci- ₆ -alkyl;

R ² is halogen, C1-6 alkyl, C3-6-cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ , S(0) ₂ N(R ¹ ) ₂ , S(0) ₂ -Ci- ₆ - alkyl, S(0) ₂ -C _3-6 -cycloalkyl, S(0) ₂ -halo-Ci- ₆ -alkyl, S(0) ₂ N(R ¹ ) ₂ , C(0)N(R ¹ ) ₂ , CN or oxo or two R ² on the same carbon atom form together with the carbon atom to which they are attached a C3-io-cycloalkyl group, or two R ² at different carbon atoms form together a - CH2-, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, CH ₂ -CH(CH ₃ )-, -CH2-CH2- or -CH2-CH2-CH2- group;

R ³ is hydrogen or Ci- ₆ -alkyl;

R ⁴ is hydrogen or Ci- ₆ -alkyl;

m is 0-2;

n is 0-2;

o is 0-4; and

t is 0, 1 or 2;

with the proviso that C is not wherein R ^’ is H, Cl, CN, Ci _-4 -alkyl,

Ci-3-fluoroalkyl, Ci-3-hydroxy-fluoroalkyl, C3-6-cycloalkyl, -C(0)0(Ci- ₃ -alkyl) or tetrahydropyranyl, R ^” is halogen, CN, OH, Ci-3-alkyl, Ci-2-fluoroalkyl, O-Ci-3-alkyl or C3-6- cycloalkyl, R’” is F, Cl, CN, Ci-2-alkyl, Ci-2-fluoro-alkyl or OCH ₃ , b is 0 to 4 and c is 0, 1 or 2. In a preferred embodiment in combination with any of the above and below embodiments, the compound is represented by Formula (1 ).

In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents C3-10 cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R ^a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOFI, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6-cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S and wherein the (hetero)cyclic ring may be unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl or oxo;

R ^a represents halogen, CN, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, hydroxy-Ci- ₆ -alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl;and

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents C3-6-cycloalkyl, 3- to 7- membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S and wherein the (hetero)cyclic ring may be unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl or oxo; and

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents 6- to 10- membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S and wherein the (hetero)cyclic ring may be unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl or oxo; and

R ^x represents Ci- ₆ -alkyl or C3-6-cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a further preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents phenyl or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein phenyl and heteroaryl are substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , CN, COOH and 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C _3-6 - cycloalkyl and halo-Ci- ₆ -alkyl; and

R ^x represents Ci- ₆ -alkyl or C3-6-cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ and CN.

In a more preferred embodiment of the compounds according to Formula (1 ) in

combination with any of the above and below embodiments, A is wherein

X represents hydrogen, halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, O-Ci- ₆ -alkyl, S-Ci- ₆ -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN; R ⁵ is independently selected from hydrogen, halogen and Ci- ₆ -alkyl;

U is N or CR ⁵ ; and

p is 0, 1 , 2, or 3.

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents phenyl which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6- membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, and

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN.

In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, R ^x represents Ci- ₆ -alkyl or C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 4 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In an even more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents

In an equally more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, A represents

In a further preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, B represents a bond.

In a further preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, R ¹ is hydrogen.

In an equally preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, R ¹ is Ci- ₆ alkyl.

In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, R ² is halogen, Ci- ₆ alkyl, C3-6 cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ , CN, oxo or two R ² on the same carbon atom form together with the carbon atom to which they are attached a C3-6 cycloalkyl group, or two R ² at different carbon atoms form together a -CFI2-, -CFI(CFl3)-, -C(CFl3)2-, CFl2-CFI(CFl3)-, -CFI2-CFI2- or -CFI2-CFI2-CFI2- and o is 0, 1 or 2.

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, R ² is halogen, Ci- ₆ -alkyl, C3- ₆ -cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ or oxo or two R ² at different carbon atoms form together a -CH2-, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, CH ₂ -CH(CH ₃ )-, -CH2-CH2- or -CH ₂ -CH ₂ -CH ₂ - and o is 0, 1 or 2.

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, o is 0.

In a preferred embodiment of the compounds according to Formula (1 ) in combination

with any of the above and below embodiments,

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments,

In a further more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments,

In an equally more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments,

And in an additionally more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments,

In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, C represents a 6- to 10-membered mono- or bicyclic aryl or 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^y , 0-R ^y , 0C(0)-R ^y ,

5-R ^y , N(R ¹ ) ₂ , NR ¹ C(0)R ^y , C(0)N(R ¹ ) ₂ , C(0)0-R ^y , C(0)-R ^y , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl, and halo-Ci- ₆ -alkyl; and

R ^y represents Ci- ₆ -alkyl or C3-6-cycloalkyl,

wherein alkyl or cycloalkyl and are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ , CN and phenyl.

In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, R ^y represents Ci- ₆ -alkyl or C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 4 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, C represents phenyl or 6- or 10-membered mono- bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S,

wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, O-Ci- ₆ -alkyl, O-halo-Ci-

₆ -alkyl, OH, CN, COOR ⁴ , 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and phenyl.

In an even more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, C represents a 10- membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S,

wherein heteroaryl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, O-Ci- ₆ -alkyl, O-halo-Ci- ₆ -alkyl, OH, CN, COOR ⁴ , 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and phenyl.

In an even more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, C is

, wherein

R ⁶ is independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , OC(O)- R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl;

q is 0, 1 , 2 ,3 or 4; and

r is 0, 1 or 2.

In most preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, C represents

In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, m is 0, 1 or 2 and n is 0 or 1.

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, m is 1 or 2 and n is 1.

In a most preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, m and n are both 1. In a preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, the compound is represented by the following formula (1 -1 )

(1-1 ) wherein A represents C3-10 cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R ^a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10- membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S;

R ^a represents halogen, CN, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, hydroxy-Ci- ₆ -alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN; C represents 6- to 10-membered mono- or bicyclic aryl or 5- to 14-membered mono-, bi- or tricyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^y , 0-R ^y , 0C(0)-R ^y , S-R ^y , S(0) ₂ -R ^y , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^y , C(0)N(R ¹ ) ₂ , C(0)0-R ^y , C(0)-R ^y , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl; Ci- ₆ - cycloalkyl, and halo C-i- ₆ -alkyl, or

two substituents on the aryl or heteroaryl ring systems together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S,

wherein the heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C-i- ₆ -alkyl, halo-Ci- ₆ -alkyl, CN and oxo;

R ^y represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN;

Y is hydrogen, OR ⁴ , halogen, Ci- ₆ -alkyl or halo-Ci- ₆ -alkyl;

R ² is halogen, Ci- ₆ alkyl, C3-6-cycloalkyl, halo-Ci- ₆

-alkyl, OR ⁴ , S(0) ₂ N(R ¹ ) ₂ , S(0) ₂ -Ci _-6 -alkyl, S(0) ₂ -C _3-6 -cycloalkyl, S(0) ₂ -halo-Ci _-6 -alkyl, S(0) ₂ N(R ¹ ) ₂ , C(0)N(R ¹ ) ₂ , CN, C(0)0R ⁴ or oxo, or

two R ² on the same carbon atom form together with the carbon atom to which they are attached a C _3-10 cycloalkyl group, or

two R ² at different carbon atoms form together a -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, CH ₂ - CH(CH ₃ )-, -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ - group; and

o is 0-4. In an even more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, C represents a 10- membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S,

wherein heteroaryl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, O-Ci- ₆ -alkyl, O-halo-Ci- ₆ -alkyl, OH, CN, COOR ⁴ , 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and phenyl.

In a more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, the compound is represented by the following formula (1 -2)

wherein

R ⁵ is independently selected from hydrogen, halogen and Ci- ₆ -alkyl;

R ⁶ is independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , OC(O)- R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN;

X is hydrogen, halogen, Ci- ₆ -alkyl, O-Ci- ₆ -alkyl, S-Ci- ₆ -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ or CN;

U is N or CR ⁵ ;

p is 0, 1 , 2 or 3;

q is 0, 1 , 2, 3 or 4; and

r is 0, 1 or 2.

In an even more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, the compound is represented by the following formula (1 -2)

wherein

R ⁵ is independently selected from hydrogen, halogen and Ci- ₆ -alkyl;

R ⁶ is independently selected from the group consisting of halogen, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN;

X is hydrogen, halogen, Ci- ₆ -alkyl, O-Ci- ₆ -alkyl, S-Ci- ₆ -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ or CN; U is N or CR ⁵ ;

p is 0, 1 , 2 or 3;

q is 0, 1 , 2, 3 or 4; and

r is 0, 1 or 2.

In a further more preferred embodiment of the compounds according to Formula (1 ) in combination with any of the above and below embodiments, U is CR ⁵ , in particular CH.

In a most preferred embodiment of the componds according to Formula (1 ), the compound is selected from



WO 2019/115586 25

In an uppermost preferred embodiment of the compounds according to Formula (1 ) in combination any of the above and below embodiments, the compound is selected from 29 PCT/EP2018/084483

30

In a further uppermost preferred embodiment of the compounds according to Formula (1 ) in combination any of the above and below embodiments, the compound is selected from

In a preferred embodiment in combination with any of the above and below embodiments, the compound is represented by Formula (2).

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents C3-10 cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R ^a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOFI, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S and wherein the (hetero)cyclic ring may be unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl or oxo;

R ^a represents halogen, CN, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, hydroxy-Ci- ₆ -alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents C3-10 cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R ^a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono ©(^cyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S and wherein the (hetero)cyclic ring may be unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl or oxo;

R ^a represents halogen, CN, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, hydroxy-Ci- ₆ -alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a further preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents C3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S and wherein the (hetero)cyclic ring may be unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl or oxo; and

R ^x represents Ci- ₆ -alkyl or C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, R ^x represents Ci- ₆ -alkyl or C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 4 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

In a more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents 6- to 10- membered mono or bicyclic aryl or 5- to 10-membered cyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein aryl and heteroaryl are substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OH, CN and COOFI.

In a more preferred embodiment of the compounds according to Formula (1 ) in

combination with any of the above and below embodiments, A’ is , wherein

X is hydrogen, halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, O-Ci- ₆ -alkyl, S-Ci- ₆ -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN;

R ⁵ is independently selected from hydrogen, halogen and Ci- ₆ -alkyl;

U is N or CR ⁵ ; and

p is 0, 1 , 2, or 3.

In an even more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents

In a further more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents phenyl which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6- membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, and R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN.

In a most preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents

In a further more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, A’ represents

In a further preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, B represents a bond.

In a further preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, R ¹ is hydrogen. In an equally preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, R ¹ is C-i- ₆ alkyl.

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, R ² is halogen, Ci- ₆ alkyl, C3-6-cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ , CN, oxo or two R ² on the same carbon atom form together with the carbon atom to which they are attached a C3-io-cycloalkyl group, or two R ² at different carbon atoms form together a -CFI2-, -CFI(CFl3)-, -C(CFl3)2-, CFl2-CFI(CFl3)-, -CFI2-CFI2- or -CFI2-CFI2-CFI2- and o is 0, 1 or 2.

In a more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, o is 0.

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, Z represents -C2-3-alkylene-, -O-C1-2- alkylene-, -C-i-2-alkylene-O-, -NR ³ C(0)-Co-i-alkylene-, -C(0)NR ³ -Co-i-alkylene-, -C0-1- alkylene-NR ³ C(0)-, -Co-1-alkylene C(0)NR ³ , -NR ⁹ -Ci-2-alkylene- or -C-i-2-alkylene-NR ⁹ -, wherein alkylene is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of OR ⁴ , Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl; and

R ⁹ is hydrogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl.

In a more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, Z represents -C2-3-alkylene- , -O-Ci-2-alkylene-, -C-i-2-alkylene-O-, -NR ³ C(0)-Co-i-alkylene-, -C(0)NR ³ -Ci-alkylene-, - Co-i-alkylene-NR ³ C(0)-, -Ci-alkylene-C(0)NR ³ , -NR ⁹ -Ci-2-alkylene- or -C-i-2-alkylene- NR ⁹ -,

wherein alkylene is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of OR ⁴ , Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl; and

R ⁹ is hydrogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl.

In a more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, Z represents -C2-3-alkylene- , -O-Ci-2-alkylene- or -C-i-2-alkylene-O-,

wherein alkylene is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl.

In a most preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, Z represents -CFI2-CFI2-, - O-CH2- or -CH2-O-. In an uppermost preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, Z represents -O-CH2-.

In a further uppermost preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, Z represents -CFI2-O-.

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, D represents 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^z , 0-R ^z , 0C(0)-R ^z , S-R ^z , N(R ¹ ) ₂ , NR ¹ C(0)R ^z , C(0)N(R ¹ ) ₂ , C(0)0-R ^z , C(0)-R ^z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo Ci- ₆ -alkyl, or

two substituents on the aryl or heteroaryl ring systems together with the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S,

wherein the heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, CN and oxo; and

R ^z represents Ci- ₆ -alkyl or C3-6-cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ and CN.

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, R ^z represents Ci- ₆ -alkyl or C3-6-cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 4 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ and CN.

In a more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, D represents phenyl or 5- or 6-membered mono- or bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S,

wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, halo-Ci- ₆ -alkyl, O-Ci- ₆ -alkyl, OH, and N(R ¹ )2.

In a preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, m is 0, 1 or 2 and n is 0 or 1.

In a more preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, m is 1 or 2 and n is 1.

In a most preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, m and n are both 1.

In a further preferred embodiment in combination with any of the above and below embodiments, the compound is represented by Formula (2-1 ) or (2-2)

wherein A’ represents C3-10 cycloalkyl, which may be optionally fused with a phenyl ring, 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

two substituents on the same carbon atom or on two different carbon atoms form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, wherein optionally one carbon atom in the cycloalkyl ring may be replaced by a heteroatom selected from O, N and S;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN;

D represents 6- to 10-membered mono- or bicyclic aryl or 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, OH, R ^z , 0-R ^z , 0C(0)-R ^z , S-R ^z , S(0) ₂ -R ^z , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^z , C(0)N(R ¹ ) ₂ , C(0)0-R ^z , C(0)-R ^z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl; C3-6- cycloalkyl, and halo-Ci- ₆ -alkyl, or

two substituents on the aryl or heteroaryl ring systems together with the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S,

wherein the heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, CN and oxo;

R ^z represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN;

V is O or CR ⁷ R ⁸ ;

R ² is halogen, Ci- ₆ alkyl, C3-6 cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ , S(0) ₂ N(R ¹ ) ₂ , S(0) ₂ -Ci- ₆ - alkyl, S(0) ₂ -C _3-6 -cycloalkyl, S(0) ₂ -halo-Ci- ₆ -alkyl, S(0) ₂ N(R ¹ ) ₂ , C(0)N(R ¹ ) ₂ , CN, C(0)0R ⁴ or oxo, or two R ² on the same carbon atom form together with the carbon atom to which they are attached a C _3-10 cycloalkyl group, or

two R ² at different carbon atoms form together a -CH2-, -CH(CH3)-, -C(CH3)2-, CH2- CH(CH ₃ )-, -CH2-CH2- or -CH2-CH2-CH2- group;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, halo-Ci- ₆ -alkyl and OR ⁴ ;

o is 0-4; and

k is 1 or 2.

In a more preferred embodiment in combination with any of the above and below embodiments, the compound is represented by the following Formulae (2-3) and (2-4)

wherein

X is hydrogen, halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, O-Ci- ₆ -alkyl, S-Ci- ₆ -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN;

R ⁵ is independently selected from hydrogen, halogen and Ci- ₆ -alkyl;

R ⁶ is independently selected from halogen, OH, R ^z , 0-R ^z , 0C(0)-R ^z , S-R ^z , S(0) ₂ -R ^z , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^z , C(0)N(R ¹ ) ₂ , C(0)0-R ^z , C(0)-R ^z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl; C3-6- cycloalkyl, and halo-Ci- ₆ -alkyl,

R ^z represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo- Ci- ₆ -alkyl, OR ¹ and CN;

U is N or CR ⁵ ;

V is O or CR ⁷ R ⁸ ;

p is 0, 1 , 2 or 3; and

q is 0, 1 , 2, 3 or 4.

In a further more preferred embodiment of the compounds according to Formulae (2-3) and (2-4) in combination with any of the above and below embodiments, U is CR ⁵ , in particular CH.

In a further more preferred embodiment of the compounds according to Formulae (2-3) and (2-4) in combination with any of the above and below embodiments, V is -O- and R ⁷ and R ⁸ both represent hydrogen.

In a most preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, the compounds according to Formula (2) are selected from

44 PCT/EP2018/084483

In an uppermost preferred embodiment of the compounds according to Formula (2) in combination with any of the above and below embodiments, the compound according to Formula (2) is selected from

In the context of the present invention "Ci- ₆ -alkyl" means a saturated alkyl chain having 1 , 2, 3, 4, 5, or 6 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, ferf-butyl, n-pentyl, isopentyl, neopentyl and hexyl.

The term "halo-Ci- ₆ -alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen atom which may be the same or different. Preferred example thereof include CHF2, CF3, CFI2CFI2CI, and CFI2CF3.

A“C _x-y -alkylene” means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. X is an integer selected from 0, 1 , and 2 and y is an integer selected from 0, 1 , 2, and 3. Moreover, in the context of the present invention,“Co-alkylene” is meant to represent a bond. An alkylene group may be straight chained or branched.

A C3-io-cycloalkyl group or C3-io-carbocycle means a saturated or partially unsaturated mono-, bi-, spiro-, or multicyclic ring system comprising 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, adamantyl, spiro[3.3]heptane and pentacyclo[4.2.0.0 ² ' ⁵ .0 ³ ' ⁸ .0 ⁴ ' ⁷ ]octyl. As an example, a C3-6-cycloalkyl group means a cycloalkyl ring having 3, 4, 5 or 6 carbon atoms. The C3-io-cycloalkyl group can be connected to the remainder of the molecule via a bond or the cycloalkyl group may share a carbon at the attachment point with the remainder of the molecule. Illustrative examples of the attachment possibilities are shown below:

A 3- to 10-membered heterocycloalkyl group means a saturated or partially unsaturated mono-, bi-, tri-, spiro or multicyclic ring system having 3, 4, 5, 6, 7, 8, 9 or 10 ring members. Similarly, a 3- to 6-membered heterocycloalkyl group means a saturated or partially unsaturated mono-, bi-, spiro or multicyclic ring system having 3, 4, 5 or 6 ring members. The heterocycloalkyl comprises up to 5 heteroatoms, such as 1 , 2, 3, 4 or 5 heteroatoms, preferably 1 , 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms and most preferably 1 heteroatom, wherein the heteroatoms are independently selected from N, O, S, S(O) and S(0) ₂ , preferably N, O and S. Examples thereof include epoxidyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl tetrahydropyranyl, 1 ,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1 ,4-dihydropyridinyl, 2- azaspiro[3.3]heptane and 3,6-dihydro-2/-/-thiopyranyl. The heterocycloalkyl group can be connected to the remainder of the molecule via a carbon atom or nitrogen atom.

A 5-14-membered mono-, bi- or tricyclic heteroaromatic ring system (within the application also referred to as heteroaryl) containing up to 4 heteroatoms means a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms. Examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl, pyrazolo[1 ,5-a]pyrimidinyl and dibenzo[b,d]furanyl. The nitrogen or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-dioxide. If not stated otherwise, the heteroaryl system can be connected via a carbon or nitrogen atom. Examples for /V-linked heterocycles are

A 6-10-membered mono- or bicyclic aromatic ring system (within the application also referred to as aryl) means an aromatic carbon cycle such as phenyl or naphthyl.

Halogen is selected from fluorine, chlorine, bromine and iodine.

The compounds of the present invention are further intended to include all possible geometric isomers. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated forms. A bond in a structure diagram represented by a wavy line ” is intended to indicate that the structure represents the cis or the trans isomer, or a mixture of the cis and trans isomers in any ratio.

Compounds of the present invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.

The compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.

The compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

Further the compounds of the present invention may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol.

Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, but not limited to ² H (deuterium, D), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³⁵ S, ³⁶ CI and ¹²⁵ l. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The disclosure also includes“deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g. a human. See, for example, Foster in Trends Pharmacol. Sci. 1984:5;524. Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¹⁸ F labeled compound may be useful for PET or SPECT studies.

The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as“H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

The compounds of the present invention are useful as inhibitors of ID01. Hence, they are potential therapeutic agents for the prophylaxis and/or treatment of ID01 -mediated diseases or conditions such as cancer, viral and bacterial infections such as HIV infection, hanta virus infection, tuberculosis, leprae, depression, epilepsy, schizophrenia, neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease, trauma, age-related cataracts, organ transplantation, cardiovascular disease, endometriosis, type 2 diabetic nephropathy, chronic obstructive pulmonary disease (COPD), osteoporosis, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus.

In a preferred embodiment, the compounds are used in the prophylaxis and/or treatment of cancer.

Examples of cancer types that may be treated using the compounds and compositions described herein include but are not limited to carcinomas, sarcomas, lymphomas and leukemias, germ cell tumors and blastomas, cancer of adrenal gland, bladder, brain, breast, bone, cervix, colorectum, colon, connective tissue, endometrium, esophagus, head, liver, lung, mesothelial lining, muscle, neck, ovary, pancreas, prostate, skin, stomach, testis, thyroid, white blood cell, or glioblastoma, mesothelioma, melanoma, renal cell carcinoma, gastric carcinoma, choriocarcinoma, cutaneous basocellular carcinoma, testicular seminoma and ovarian dysgerminoma. In a recent review by Hornyak et al. examples of such cancer types are given (Hornyak et al. Front Immunol. 2018 Jan 31 ;9:151 ).

Furthermore, the present invention provides pharmaceutical compositions comprising at least one compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier. "Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable excipient.

The pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like a prodrug compound or other therapeutic agents.

Additional therapeutic agents are preferably selected from known cancer therapeutics. Examples thereof include PD-1 agent, PD-L1 agent, CTLA-4 agent as well as chemotherapeutic agents, anticancer vaccines, oncolytic viruses, cytokine therapy, TLR agonists, STING agonists, as well as other immuno oncology therapeutics. The compounds of the present invention may also be administered to a patient while the patient undergoes irradiation therapy.

Examples of PD-1 agents include, but are not limited to, Pembrolizumab, Cemiplimab and Nivolumab.

Examples of PD-L1 agents include, but are not limited to, Atezolizumab, Avelumab and Durvalumab.

Examples of CTLA-4 agents include, but are not limited to, Ipilimumab.

Examples of chemotherapeutic agents include, but are not limited to, Cyclophosphamide, Busulfan, Carmustin, Temozolimide, Procarbazin,Trabectedin, Cisplatin, Carboplatin, Methotrexat, Pemetrexed, 6-Mercatopurine, 6-Thioguanine, Cladibine, Clofarabine, Nelarabine, Pentostatine, 5-Fluorouracil, Cytarabine, Gemcitabine, Azacitidine,

Vincristine, Vinblastine, Vindesine, Paclitaxel, Docetaxel, Cabazitaxel, Ixabepilone, Eribulin, Estramustine phosphate, Topotecan, Irinotecan, Etoposide, Teniposide, Dactinomycin, Bleomycin, Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Mitoxantron, all-trans retinoic acid, Bexarotene, AS2O3, Imatinib, Nilotinib, Dasatinib, Bosutinib, Ponatinib, Erlotinib, Gefitinib, Afatinib, Osimertinib, Lapatinib, Crizotinib, Ceritinib, Axitinib, Cabozantinib, Lanvatinib, Nintedanib, Pazopanib, Regorafenib, Sorafenib, Sunitinib, Ruxolitinib, Dovitinib, Ibrutinib, Idelalisib, Vemurafenib, Dabrafenib, Trametinib, Cobimetinib, Palbociclib, Temsirolismus, Everolimus, Bortezomib, Carfilzomib, Vismodegib, Panobinostat, Olaparib, Venetoclax, Rituximab, Trastuzumab, Pertuzumab, Cetuximab, Panitumumab, Necitumumab, Bevacizumab, Ramucirumab, Olaratumab, Mifamurtide, Elotuzumab, Catumaxomab, Blinatumomab, Rituximab, Daratumumab, Alemtuzumab, Prednisone, Buserelin, Goserelin, Leuprorelin, Histrelin, Triptorelin, Degarelix, Abarelix, Flutamide, Bicalutmide, Enzalutamide, Arbiraterone, Tamoxifen, Toremifen, Exemestane, Letrozole, Anastrozole, Fulvestrant, Thalidomide, Lenalidomide, Pomalidomide,

Examples of anticancer vaccines include, but are not limited to, Flepa-VAC-101 and Sipuleucel-T.

Examples of oncolytic viruses include, but are not limited to, H101 , Talimogene laherparepvec.

Examples of Toll like receptor agonists include, but are not limited to, Imiquimod, Resiquimod, monophosphoryl lipid A, BCG , CpG ODNs, Motolimod, GSK1795091 and Telratolimod.

Examples of STING agonists include, but are not limited to, ADU-S100 and MK-1454.

Examples of cytokine therapy include, but are not limited to, IL-2, GM-CSF, IL-12 and IL- 10.

Examples of other Immune-Oncology therapeutics that can be used in combination with the compounds of the present invention include, but are not limited to Chimeric antigen receptor, or CAR T-cell therapy, such as Tisagenlecleucel, Axicabtagen Ciloleucel, agents targeting T cell co-stimulatory (e.g. 0X40) or co-inhibitory (e.g. LAG3) molecules and immune response modifying enzymes such as Asparaginase or Kynureninase.

The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, emulsions and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non- aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

The compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of the present invention are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing IDO mediated conditions for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

Abbreviations

Herein and throughout the application, the following abbreviations may be used.

Ac acetyl

AIBN 2,2'-(diazene-1 ,2-diyl)bis(2-methylpropanenitrile) br broad

CDI 1 , 1 '-carbonyldiimidazole

d doublet

DAST diethylaminosulfur trifluoride

DCE 1 ,2-dichloroethane

DCM dichloromethane

DEAD diethyl diazene-1 ,2-dicarboxylate

DIBAL-H diisobutylaluminum hydride

DIPEA A/,/V-diisopropylethylamine

DMF A/,/V-dimethylformamide

DMSO dimethyl sulfoxide

DPPA Diphenylphosphoryl azide

EDC 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et ₂ 0 diethyl ether

EtOAc ethyl acetate

HATU 0-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate

HOBt 1 -hydroxybenzotriazole

HPLC high performance liquid chromatography

/-PrOH isopropyl alcohol

LDA lithium diisopropylamide

m multiplet

mCPBA 3-chloroperoxybenzoic acid

Ms methanesulfonyl

NCS /V-chlorosuccinimide

PE petroleum ether

prep preparative

rt room temperature SFC supercritical fluid chromatography

t triplet

TEA triethylamine

TFA trifluoroacetic acid

TFAA trifluoroacetic acid anhydride

THF tetrahydrofurane

General Schemes

The compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in schemes 1-4 below. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.

Scheme 1 shows the synthesis of intermediates of structure A-4. A Suzuki coupling of boronic acid or boronic acid ester A-1 with halogen A-2 or alternatively enol triflate A-1 with boronic acid or boronic acid ester A-2 affords the cyclic olefin A-3. A sequence of hydrogenation and deprotection gives intermediates of structure A-4 where Y is a hydrogen. Alternatively aryl or heteroaryl halides A-5 can be metallated with e.g. n-BuLi followed by reaction with ketones of structure A-6 to give cyclic hydroxy compounds A-7. Deprotection or a sequence of transformation of the hydroxy group with e.g. DAST followed by deprotection gives intermediates of structure A-4.

1 H /Pd(C)

,

boronic acid ester boronic acid,

or OTf boronic acid ester

T = halogen

Scheme 1

Scheme 2 shows the synthesis of compounds of structure B-3 and B-5 of the present invention. Amine B-1 undergoes amide formation with methyl 2-chloro-2-oxoacetate to give oxalamide ester intermediates of structure B-2. Direct ester aminolysis with cyclic amines A-4 or B-4 gives compounds of structure B-3 or B-5. Alternatively B-2 is saponified to the corresponding carboxylic acid which can be converted to B-3 or B-5 by amide coupling reaction using e.g. HATU.

Scheme 3 shows an alternative synthesis of compounds of structure B-3. Cyclic amine A-4 undergoes amide formation with methyl 2-chloro-2-oxoacetate to give oxalamide ester intermediates of structure C-1. Direct ester aminolysis with B-1 or alternatively ester saponification followed by amide coupling reaction affords compounds of structure B-3.

A-4 C-1 B-3

Scheme 3

Scheme 4 shows the synthesis of intermediates of structure B-4. Pyridine C-1 can be N- alkylated with (chloromethyl)benzene at elevated temperatures. The pyridinium intermediate C-2 can be partially reduced with NaBH ₄ to give the tetrahydropyridine C-3, which can be transformed into ether intermediate C-4 via Mitsunobu reaction. Radical cyclization of C-4 using n-Bu3SnH and AIBN affords the corresponding spirocyclic intermediate C-5. Deprotection of C-5 with 1 -chloroethyl carbonylchloridate leads to intermediates of structure B-4.

Scheme 4 Intermediate 1 : 4-(Difluoromethyl)aniline (Int 1 )

Int 1a Int 1 b Int 1

Stepl : 1-(Difluoromethyl)-4-nitrobenzene (Int 1 b)

To a mixture of 4-nitrobenzaldehyde (5.00 g, 33.10 mmol) in DCM (75 ml_) diethylaminosulfur trifluoride (6.40 g, 39.70 mmol) was added dropwise at -70 °C. The mixture was stirred at the same temperature for 10 min. The cooling bath was removed and the mixture was stirred overnight. Concentrated aqueous NaHCC solution was added slowly to the mixture and the mixture was extracted with DCM (3 x 50 ml_). The combined organic layers were dried over anhydrous Na2S0 _4, filtered and concentrated to dryness. The residue was purified by column chromatography (PE) to provide the title compound.

Step 2: 4-(Difluoromethyl)aniline (Int 1)

To a mixture of 1 -(difluoromethyl)-4-nitrobenzene (Int 1 b) (3.50 g, 20.20 mmol) in THF (50 ml_) was added NH ₄ CI (10.8 g, 202 mmol) and iron powder (1 1.3 g, 202 mmol) and the mixture was stirred at rt overnight. The mixture was filtered and water was added. The mixture was extracted with EtOAc (3 x 50 ml_) and the combined organic layers were dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow oil.

Intermediate 2: 4-Bromo-2-(difluoromethoxy)quinoline (Int 2)

To a solution of 4-bromo-4a,8a-dihydroquinolin-2(1 /-/)-one (672 mg, 3.00 mmol) in DMF (20 ml_) was added sodium 2-chloro-2,2-difluoroacetate (684 mg, 4.50 mmol), and Na ₂ C0 ₃ (636 mg, 6.00 mmol) and the mixture was stirred at 80 °C for 2 h under N2. It was cooled to rt and diluted with FI2O (20 ml_). It was extracted with EtOAc (3 x 20 ml_). The combined organic layers were washed with brine (40 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (4:1 ) to give the title compound as a yellow solid.

Intermediate 3: 4-Fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-amine hydrochloride (Int 3)

Int 3a Int 3b Int 3

Step 1 : ferf-Butyl (4-fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)carbamate (Int 3b)

To a solution of 4-fluorobicyclo[4.2.0]octa-1 (6),2,4-triene-7-carboxylic acid (Int 3a) (0.488 g, 3.0 mol) and TEA (0.613 ml_, 4.4 mmol) was added DPPA (970 mg, 3.5 mmol) and the mixture was stirred at 85 °C for 4 h. After cooling to rt the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (EtOAc/Cyclohexane) to afford the title compound as a white solid.

Step 2: 4-Fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-amine hydrochloride (Int 3)

To a solution of ferf-butyl (4-fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)carbamate (Int 3b) (400 mg, 1.7 mmol) in EtOAc (4 ml_) was added HOI in 1 ,4-dioxane (2.0 ml_, 4 M, 8 mmol) and the mixture was stirred at rt for 2 h. The mixture was concentrated to dryness to afford the title compound as a white solid.

Intermediate 10: Methyl 2-((3-chloro-4-fluorophenyl)amino)-2-oxoacetate (Int 10)

Int 10a Int 10

To a mixture of 3-chloro-4-fluoroaniline (1.00 g, 6.87 mmol) and TEA (1.43 ml, 10.31 mmol) in DCM (25 ml_) was added methyl 2-chloro-2-oxoacetate (890 mg, 7.20 mmol). The mixture was stirred at rt overnight. The mixture was filtered and the residue was extracted with EtOAc (20 ml). The combined organic layers were concentrated to dryness to give the title compound as a white solid. Intermediates 10/1 to 10/29

The following Intermediates were prepared similar as described for Intermediate 10 using the appropriate amine building blocks.

Intermediate 11: Lithium 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (Int 11)

Int 10/3 Int 11

A mixture of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (Int 10/3) (1.0 g, 4.7 mmol, 1.0 eq.) and LiOI-M-hO (216 mg, 5.1 mmol, 1.1 eq.) in THF/H2O (12 ml_:3 ml_) was stirred at rt for 3 h. The mixture was concentrated in vacuo to afford a white solid. Hexane (20 mL) was added to the white solid and stirred at rt for 2 h. The mixture was filtered. The solid residue was collected and dried. Acetonitrile (10 mL) was added to the residue and stirred at rt for 1 h. The residue was collected by filtration, washed with EtOAc (5 mL) and then dried to afford the title compound as a white solid.

Intermediates 11/1 to 11/2

The following Intermediates were prepared similar as described for Intermediate 11 using the appropriate building blocks.

Intermediate 12: Lithium 2-((5-chloropyridin-2-yl)(methyl)amino)-2-oxoacetate (Int 12)

Int 10/3 Int 12a Int 12

Step 1 : Methyl 2-((5-chloropyridin-2-yl)(methyl)amino)-2-oxoacetate (Int 12a)

To a solution of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (Int 11 b) (214 mg, 1.0 mmol) in DMF (4 ml) was added NaH (48 mg, 1.2 mmol, 1.2 eq.) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Methyliodide (156 mg, 1.1 mmol) was added and the mixture was stirred at rt for 2 h. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 4:1 ) to give the title compound as a yellow oil.

Step 2: Lithium 2-((5-chloropyridin-2-yl)(methyl)amino)-2-oxoacetate (Int 12)

To a solution of methyl 2-((5-chloropyridin-2-yl)(methyl)amino)-2-oxoacetate (Int 12a) (180 mg, 0.79 mmol) in THF (2 mL) and H2O (0.5 mL) was added LiOH H ₂ 0 (33 mg, 0.79 mmol). The mixture was stirred at rt for 3 h. The mixture was concentrated to dryness. Hexane (10 mL) was added and the suspension was stirred at rt for 1 h. The mixture was filtered and the residue was collected and dried. Acetonitrile (10 mL) was added to the residue and the suspension was stirred at rt for 1 h. The residue was collected by filtration, extracted with EtOAc (5 mL) and dried to give the title compound as a white solid.

Intermediate 13: 2-((5-Chloropyridin-2-yl)amino)-2-oxoacetic acid (Int 13)

Int 10/3 Int 13

To a solution of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (Int 10/3) (0.50 g, 2.30 mmol) in THF (8 mL), MeOH (5 mL) and H ₂ 0 (5 mL) was added LiOH H ₂ 0 (289 mg, 6.90 mmol). The mixture was stirred at rt for 3 h. It was concentrated and the residue was diluted with H2O (10 mL). It was acidified with 1 N HCI solution to pH = 6-7 and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S0 ₄ , filtered and concentrated to give the title compound as a yellow solid.

Intermediate 13/1 : 2-((4-Chlorophenyl)amino)-2-oxoacetic acid (Int 13/1 )

The title compound was prepared similar as described for intermediate 13 using methyl 2-((4-chlorophenyl)amino)-2-oxoacetate (Int 10/1) in place of methyl 2-((5-chloropyridin- 2-yl)amino)-2-oxoacetate (Int 10/3). Intermediate 20: 6-Fluoro-4-(piperidin-4-yl)quinoline (Int 20)

Int 20a Int 20b Int 20c Step 3

Int 20

Step 1 : ferf-Butyl 4-(6-fluoroquinolin-4-yl)-5,6-dihydropyridine-1 (2/-/)-carboxylate (Int 20b)

To a solution of 4-chloro-6-fluoroquinoline (Int 20a) (2.00 g, 1 1.0 mmol) in dioxane (40 mL) and H2O (5 ml_) was added ferf-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 5,6-dihydropyridine-1 (2/-/)-carboxylate (4.43 g, 14.0 mmol), Pd(dppf)2Cl2 (450 mg, 0.55 mmol) and CS2CO3 (7.18 g, 22.00 mmol). The mixture was stirred at 90 °C for 16 h. The mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (PE: EtOAc = 4:1 ) to give the title compound as a pale yellow solid.

Step 2: ferf-Butyl 4-(6-fluoroquinolin-4-yl)piperidine-1-carboxylate (Int 20c)

To a solution of ferf-butyl 4-(6-fluoroquinolin-4-yl)-5,6-dihydropyridine-1 (2/-/)-carboxylate (Int 20b) (3.40 g, 10.30 mmol) in EtOH (35 mL) was added Pd/C (0.68 g). The mixture was stirred under H2 atmosphere at rt for 16 h. The mixture was filtered and the residue was washed with EtOH (15 mL). The combined organic layers were concentrated to dryness to give the title compound as a brown oil.

Step 3: 6-Fluoro-4-(piperidin-4-yl)quinoline (Int 20)

To a solution of ferf-butyl 4-(6-fluoroquinolin-4-yl)piperidine-1-carboxylate (Int 20c) (3.20 g, 9.69 mmol) in DCM (20 mL) was added HCI/dioxane (4M, 15 mL). The mixture was stirred at rt for 3 h. The mixture was concentrated and the residue was diluted with H2O (15 mL). The pH was adjusted with saturated aqueous NaHC0 ₃ to pH = 8-9. The mixture was extracted with DCM/i-PrOH (3/1 ,3 x 30 mL). The combined organic layers were washed with brine (30 ml_), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow solid.

Intermediates 20/1 to 20/17

The following Intermediates were prepared similar as described for Intermediate 20 using the appropriate building blocks.

Intermediate 21 : 4-(Quinolin-4-yl)piperidin-4-ol hydrochloride (Int 21 )

Int 21a Int 21 b Int 21

Step 1 : ferf-Butyl 4-hydroxy-4-(quinolin-4-yl)piperidine-1-carboxylate (Int 21 b)

To a solution of 4-bromoquinoline (500 mg, 2.42 mmol) in THF (10 ml_) was added n- BuLi (1.5 ml_, 2.5N in THF) at -78 °C and the mixture was stirred at this temperature for 1 h. Then tert- butyl 4-oxopiperidine-1-carboxylate (578 mg, 2.90 mmol) dissolved in THF (10 ml_) was added and the mixture was stirred at rt for 3h. Aqueous NH ₄ CI (30 ml_) was added and the mixture was extracted with EtOAc (2 x 30 ml_). The combined organic layers were washed with brine (30 ml_), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography (EtOAc/PE = 1 : 4) to give the title compound as a yellow solid.

Step 2: 4-(Quinolin-4-yl)piperidin-4-ol hydrochloride (Int 21 )

To a solution of tert- butyl 4-hydroxy-4-(quinolin-4-yl)piperidine-1 -carboxylate (Int 21 b) (174 mg, 0.53 mmol) in 1 ,4-dioxane (2 ml_) was added HCI/1 ,4-dioxane (2 ml_, 4M) at rt. The mixture was stirred for 1 h and concentrated to dryness to give the title compound as a white solid. Intermediate 22: 4-(4-Fluoropiperidin-4-yl)quinoline hydrochloride (Int 22)

Step 1 : ferf-Butyl 4-fluoro-4-(quinolin-4-yl)piperidine-1 -carboxylate (Int 22a)

To a solution of ferf-butyl 4-hydroxy-4-(quinolin-4-yl)piperidine-1 -carboxylate (Int 21 b) (781 mg, 2.38 mmol) in DCM (20 ml_) was added DAST (575 mg, 3.57 mmol) at 0 °C. The mixture was stirred at rt overnight. Then the mixture was diluted with water (30 ml_) and extracted with DCM (3 x 30 ml_). The combined organic layers were washed with brine (30 ml_), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by prep-TLC (PE/EtOAc, 4:1 , v/v) to give the title compound as a brown solid.

Step 2: 4-(4-Fluoropiperidin-4-yl)quinoline hydrochloride (Int 22)

A mixture of ferf-butyl 4-fluoro-4-(quinolin-4-yl)piperidine-1-carboxylate (Int 22a) (163 mg, 0.49 mmol) in 1 ,4-dioxane (3 ml_) and HCI/1 ,4-dioxane (2 ml_) was stirred at rt for 3 h. It was then concentrated to give the title compound as a yellow solid.

Intermediate 23: 4-(8-Azabicyclo[3.2.1]octan-3-yl)quinoline hydrochloride (Int 23)

Int 23 Int 23d Step 1 : ferf-Butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-3- ene-8- carboxylate (Int 23b)

To a solution of ferf-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Int 23a) (1.00 g, 4.33 mmol) in THF (10 mL) was added LDA (2 N, 3.3 mL) at -78 °C and the mixture was stirred for 10 min at the same temperature. A solution of N- phenylbis(trifluoromethanesulfonimide) (1.75 g, 4.88 mmol) in THF (8 mL) was added. The mixture was stirred at -78 °C for 30 min. The cooling bath was removed and the mixture was stirred for 1.5 h. Saturated aqueous NH ₄ CI (30 mL) was added and stirring was continued for 5 min. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (EtOAc/PE = 1 :2) to give the title compound as a yellow oil.

Step 2: ferf-Butyl 3-(quinolin-4-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (Int 23c)

To a mixture of ferf-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-3- ene- 8-carboxylate (Int 23b) (1.10 g, 3.08 mmol), quinolin-4-ylboronic acid (533 mg, 3.08 mmol) and CS2CO3 (2.00 g, 6.16 mmol) in 1 ,4-dioxane (15 mL) was added dppfPdCh (120 mg) and the mixture was stirred at 100 °C overnight. Water (30 mL) was added and the mixture was extracted with EtOAc (1 x 30 mL). The organic layer was washed with brine (1 x 30 mL), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography (EtOAc/PE = 1 : 10) to give the title compound as a white solid.

Step 3: ferf-Butyl 3-(quinolin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Int 23d)

To a solution of ferf-butyl 3-(quinolin-4-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (Int 23c) (419 mg, 1.25 mmol) in MeOH (5 ml_) was added Pd/C (150 mg) and the mixture was stirred at rt under hydrogen atmosphere for 4 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography (EA: PE = 1 : 8) to give the title compound as a white solid.

Step 4: 4-(8-Azabicyclo[3.2.1]octan-3-yl)quinoline hydrochloride (Int 23)

To a solution of ferf-butyl 3-(quinolin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Int 23d) (316 mg, 0.93 mmol) in 1 ,4-dioxane (2 mL) was added HCI/1 ,4-dioxane (2 ml_, 4M) at rt. The mixture was stirred at rt for 1 h. The mixture was concentrated to dryness to give the title compound as a white solid. Intermediate 23/1 : 4-(2,2-Dimethylpiperidin-4-yl)quinoline hydrochloride (Int 23/1)

The title compound was prepared similar as described for intermediate 23 using in step 1 tert- butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate in place of tert- butyl 3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate (Int 23a).

Intermediate 23/2: 4-(3,3-Dimethylpiperidin-4-yl)-6-fluoroquinoline trifluoroacetic acid salt (Int 23/2)

Int 23/2a Int 23/2b Int 23/2

Steps 1 -3: tert- Butyl 4-(6-fluoroquinoline-4-yl)-3,3-dimethylpiperidine-1 -carboxylate (Int 23/2b)

The title compound was prepared similar as described for intermediate 23 using in step 1 tert- butyl 3,3-dimethyl-4-oxopiperidine-1 -carboxylate (Int 23/2a) in place of tert- butyl 3- oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Int 23a).

Step 4: 4-(3,3-Dimethylpiperidin-4-yl)-6-fluoroquinoline trifluoroacetic acid salt (Int 23/2)

To a solution of tert- butyl 4-(6-fluoroquinolin-4-yl)-3,3-dimethylpiperidine-1-carboxyla te (Int 23/2b) (79 mg, 0.22 mmol) in DCM (5 ml_) was added TFA (1 ml_) and the mixture was stirred at rt for 2 h. The mixture was concentrated to dryness to give the title compound as a yellow solid.

Intermediate 24: 2-(4-(Piperidin-4-yl)quinoline-6-yl)propan-2-ol trifluoroacetic acid salt

(Int 24)

Int 24a Int 24b Int 24c Int 24d

Int 24 Int 24e

Step 1 : Methyl 4-(1 -(ferf-butoxycarbonyl)-1 ,2,3,6-tetrahydropyridin-4-yl)quinoline-6- carboxylate (Int 24c)

To a solution of methyl 4-bromoquinoline-6-carboxylate (Int 24a) (2.00 g, 7.50 mmol) in dioxane (20 ml_) and H2O (2 ml_) was added tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate (Int 24b) (2.78 g, 9.00 mmol), Pd(dppf)2Cl2 (200 mg, 0.26 mmol) and K2CO3 (2.07 g, 15.00 mmol). The mixture was stirred at 90 °C for 16 h. The mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 4:1 ) to give the title compound as a pale yellow solid.

Step 2: Methyl 4-(1 -(ferf-butoxycarbonyl)piperidin-4-yl)quinoline-6-carboxylate (Int 24d)

To a solution of methyl 4-(1-(ferf-butoxycarbonyl)-1 ,2,3,6-tetrahydropyridin-4- yl)quinoline-6-carboxylate (Int 24c) (2.60 g, 7.06 mmol) in EtOH (25 ml_) was added Pd/C (0.30 g). The mixture was stirred at rt for 16 h under H2. The mixture was filtered and washed with EtOH (10 ml_). The filtrate was concentrated to dryness to give the title compound as a brown oil.

Step 3: tert- Butyl 4-(6-(2-hydroxypropan-2-yl)quinoline-4-yl)piperidine-1-carbo xylate (Int 24e)

To a solution of methyl 4-(1-(ferf-butoxycarbonyl)piperidin-4-yl)quinoline-6-carboxy late (Int 24d) (330 mg, 0.89 mmol) in THF (4 ml_) was added 2M MeMgBr/THF (1.2 ml_, 3.56 mmol) dropwise at 0 °C. The mixture was stirred at rt for 14 h. The mixture was diluted with H2O (30 mL), extracted with EtOAc (3 x 20 ml_) and washed with brine (20 ml_). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by preparative TLC (PE/EtOAc = 3: 1 ) to give the title compound as a white solid.

Step 4: 2-(4-(Piperidin-4-yl)quinoline-6-yl)propan-2-ol trifluoroacetic acid salt (Int 24)

To a solution of ferf-butyl 4-(6-(2-hydroxypropan-2-yl)quinoline-4-yl)piperidine-1- carboxylate (Int 24e) (180 mg, 0.48 mmol) in DCM (5 ml_) was added TFA (5 ml_). The mixture was stirred at rt for 3 h. The mixture was concentrated to dryness to give the title compound as a yellow solid.

Int 25: 4-(Piperidin-4-yl)quinoline-6-carboxamide hydrochloride (Int 25)

Int 25

Step 1 : 4-(1-(ferf-Butoxycarbonyl)piperidin-4-yl)quinoline-6-carboxy lic acid (Int 25a)

To a solution of methyl 4-(1-(ferf-butoxycarbonyl)piperidin-4-yl)quinoline-6-carboxy late (Int 24d) (444 mg, 1.20 mmol) in EtOH (5 ml_)/THF (5 ml_) was added aqueous LiOH (2M, 5 ml_) and the mixture was stirred at rt for 2 h. The mixture was diluted with FI2O (30 ml_) and acidified to pH = 4-5 using 2M HCI. The mixture was extracted with EtOAc (3 x 20 ml_). The combined organic layers were washed with brine (30 ml_), dried over Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a white solid.

Step 2: ferf-Butyl 4-(6-carbamoylquinolin-4-yl)piperidine-1-carboxylate (Int 25b) To a solution of 4-(1-(ferf-butoxycarbonyl)piperidin-4-yl)quinoline-6-carboxy lic acid (Int 25a) (360 mg, 1.01 mmol), HATU (768 mg, 2.02 mmol) and TEA (306 mg, 3.03 mmol) in DMF (6 ml_) was added NH ₄ CI (66 mg) and the mixture was stirred at rt overnight. The mixture was diluted with H2O (20 ml_) and extracted with EtOAc (3 x 20 ml_). The combined organic layers were washed with brine (20 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by preparative TLC to give the title compound.

Step 3: 4-(Piperidin-4-yl)quinoline-6-carboxamide hydrochloride (Int 25)

To a solution of ferf-butyl 4-(6-carbamoylquinolin-4-yl)piperidine-1-carboxylate (Int 25b) (260 mg, 0.73 mmol) in MeOH (50 ml_) was added HCI/dioxane (4M, 5 ml_). The mixture was stirred at rt for 3 h. The mixture was concentrated to dryness to give the title compound as a yellow solid.

Intermediate 26: 4-(Piperidin-4-yl)quinoline-6-carbonitrile hydrochloride (Int 26)

Int 25b Int 26a Int 26

Step 1 : ferf-Butyl 4-(6-cyanoquinolin-4-yl)piperidine-1-carboxylate (Int 26a)

To a solution of ferf-butyl 4-(6-carbamoylquinolin-4-yl)piperidine-1-carboxylate (Int 25b) (355 mg, 1.00 mmol) and triethylamine (3.03 mg, 3.00 mmol) in DCM (5 ml_) was added TFAA (1.2 ml_, 8.00 mmol) dropwise at 0 °C. The mixture was stirred at rt for 2 h. The mixture was washed with 1 M HCI solution (5 ml_), saturated NaHCOs (5 ml_) and brine (5 ml_). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by preparative TLC (PE/EtOAc = 2: 1 ) to give the tilte compound as a yellow solid.

Step 2: 4-(Piperidin-4-yl)quinoline-6-carbonitrile hydrochloride (Int 26)

To a solution of ferf-butyl 4-(6-cyanoquinolin-4-yl)piperidine-1 -carboxylate (Int 26a) (270 mg, 0.80 mmol) in MeOH (5 mL) was added HCI/dioxane (4M, 5 mL). The mixture was stirred at rt for 3 h. The mixture was concentrated to dryness to give the title compound as a yellow solid.

Intermediate 27: £rans-4-(6-Fluoroquinolin-4-yl)piperidin-3-ol trifluoroacetic acid salt (Int 27)

racemate racemate

Int 20b Int 27a Int 27

Step 1 : frans-ferf-Butyl 4-(6-fluoroquinolin-4-yl)-3-hydroxypiperidine-1-carboxylate (Int 27a)

To a solution of ferf-butyl 4-(6-fluoroquinolin-4-yl)-3,6-dihydropyridine-1 (2/-/)-carboxylate (Int 20b) (2.66 g, 8.11 mmol) in THF (30 ml_) was added BH ₃ (1 N in THF, 8 ml_) at 0 °C under N ₂ and the mixture was stirred at 40 °C overnight. The mixture was cooled to rt, NaOFI (2N, 1.6 ml_) was added. The mixture was stirred for 12 min, FI2O2 (30%, 1.3 ml_) was added at 0 °C, and the mixture was stirred at rt for 3 h. The mixture was diluted with FI2O (50 ml_) and extracted with EA (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness (EtOAc/PE = 1 : 4) to give the title compound as a yellow solid.

Step 2: frans-4-(6-Fluoroquinolin-4-yl)piperidin-3-ol trifluoroacetic acid salt (Int 27)

To a solution of ferf-butyl 4-(6-fluoroquinolin-4-yl)-3-hydroxypiperidine-1-carboxylate (Int 27a) (168 mg, 0.49 mmol) in DCM (5 ml_) TFA (1 ml_) was added and the mixture was stirred at rt for 2 h. The mixture was concentrated to dryness to give the title compound as a yellow solid.

Intermediate 28: 4-(3,3-Difluoropiperidin-4-yl)-6-fluoroquinoline trifluoroacetic acid salt

(Int 28)

Int 27a Int 28a Int 28b

Int 28

Step 1 : ferf-Butyl 4-(6-fluoroquinolin-4-yl)-3-oxopiperidine-1-carboxylate (Int 28a)

To a solution of frans-ferf-butyl 4-(6-fluoroquinolin-4-yl)-3-hydroxypiperidine-1- carboxylate (Int 27a) (332 mg, 0.96 mmol) in DCM (5 ml_) was added Dess-Martin periodinane (1.03 g, 2.40 mmol) and the mixture was stirred at rt overnight. Aqueous NaHCC (50 ml_) was added and the mixture was extracted with DCM (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness to give the title compound as a white solid.

Step 2: ferf-Butyl 3,3-difluoro-4-(6-fluoroquinolin-4-yl)piperidine-1-carboxyla te (Int 28b)

To a solution of ferf-butyl 4-(6-fluoroquinolin-4-yl)-3-oxopiperidine-1-carboxylate (Int 28a) (299 mg, 0.87 mmol) in DCM (5 ml_) was added DAST (210 mg, 1.31 mmol) at 0 °C and the mixture was stirred at rt for 1 h. Aqueous NaHC0 ₃ (50 ml_) was added and the mixture was extracted with DCM (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness to give the title compound as a brown solid.

Step 3: 4-(3,3-Difluoropiperidin-4-yl)-6-fluoroquinoline trifluoroacetic acid salt (Int 28)

To a solution of ferf-butyl 3,3-difluoro-4-(6-fluoroquinolin-4-yl)piperidine-1-carboxyla te (Int 28b) (104 mg, 0.28 mmol) in DCM (5 ml_) was added TFA (1 ml_) and the mixture was stirred at rt for 2 h. The mixture was concentrated to dryness to give the title compound as a brown solid.

Intermediate 29: c/ ^' s-4-(6-Fluoroquinolin-4-yl)piperidin-3-ol (Int 29)

racemate

Int 20b Int 29a Int 29b

racemate

Int 29

Step 1 : 4-(3-(ferf-Butoxycarbonyl)-7-oxa-3-azabicyclo[4.1 0]heptan-6-yl)-6- fluoroquinoline 1 -oxide (Int 29a)

To a solution of ferf-butyl 4-(6-fluoroquinolin-4-yl)-5,6-dihydropyridine-1 (2/-/)-carboxylate (Int 20b) (1.00 g, 3.05 mmol) in DCM (20 ml_) was added mCPBA (1.85 g, 9.15 mmol, 85%) and the mixture was stirred at rt overnight. Aqueous Na ₂ S0 ₃ (50 ml_) was added and the mixture was extracted with DCM (3 x 50 ml_). The combined organic layers were washed with aqueous NaHCC (50 ml_) and brine (50 ml_), dried over Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow solid, which was used in the next step without further purification.

Step 2: c/ ^' s-ferf-Butyl 4-(6-fluoroquinolin-4-yl)-3-hydroxypiperidine-1 -carboxylate (Int 29b)

To a solution of 4-(3-(ferf-Butoxycarbonyl)-7-oxa-3-azabicyclo[4.1.0]heptan-6 -yl)-6- fluoroquinoline 1-oxide (Int 29) (1.01 g, 2.81 mmol) in MeOH (5 ml_) was added Pd/C (1.00 g) and the mixture was stirred under H2 atmosphere at rt overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (EtOAc/PE = 1 : 1 ) to give the title compound as a yellow solid.

Step 3: c/s-4-(6-Fluoroquinolin-4-yl)piperidin-3-ol triflu oroacetic acid salt (Int 29)

To a solution of c/ ^' s-ferf-butyl 4-(6-fluoroquinolin-4-yl)-3-hydroxypiperidine-1-carboxylate (Int 29b) (242 mg, 0.70 mmol) in DCM (5 ml_) was added TFA (1 ml_) and the mixture was stirred at rt for 2 h. The mixture was concentrated to dryness to give the title compound as a yellow solid. Intermediate 29/1 : trans 6-Fluoro-4-(3-methoxypiperidin-4-yl)quinoline trifluoroacetic acid salt (Int 29/1)

racemate racemate racemate

Int 27a Int 29/1 a Int 29/1

Step 1 : trans-tert- Butyl 4-(6-fluoroquinolin-4-yl)-3-methoxypiperidine-1 -carboxylate (Int 29/1 a)

To a solution of trans-tert- butyl 4-(6-fluoroquinolin-4-yl)-3-hydroxypiperidine-1- carboxylate (Int 27a) (314 mg, 0.91 mmol) in dry DMF (5 ml_) was added NaFI (91 mg, 2.28 mmol, 60%) at 0 °C and the mixture was stirred at 0 °C for 1 h. Mel was added (194 mg, 1.37 mmol) and the mixture was stirred at rt for 3 h. Aqueous NH CI was added and the mixture was extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (30 ml_) and concentrated to dryness to give the title compound as a yellow solid.

Step 2: trans 6-Fluoro-4-(3-methoxypiperidin-4-yl)quinoline trifluoroacetic acid salt (Int 29/1 )

To a solution of trans-tert- butyl 4-(6-fluoroquinolin-4-yl)-3-methoxypiperidine-1 - carboxylate (Int 29/1 a) (265 mg, 0.74 mmol) in DCM (5 ml_) was added TFA (1 ml_) and the mixture was stirred at rt for 2 h. The mixture was concentrated to dryness to give the title compound as a yellow solid.

Intermediate 30: Methyl 2-oxo-2-(4-(quinolin-4-yl)piperidin-1 -yl)acetate (30)

Int 30

To a solution of 4-(piperidin-4-yl)quinoline hydrochloride (150 mg, 0.53 mmol, 1.0 eq.) and TEA (107 mg, 1.06 mmol, 2.0 eq.) in DCM (3 ml_) was added methyl 2-chloro-2- oxoacetate (77 mg, 0.63 mmol, 1.2 eq.) dropwise. The mixture was stirred at rt for 40 min and filtered. The filtrate was concentrated and purified by flash chromatography on silica gel (PE/EtOAc = 4:1 ) to give the title compound as a brown solid.

Intermediates 30/1 to 30/4

The following Intermediates were prepared similar as described for Intermediate 30 using the appropriate building blocks.

Intermediate 31 : Lithium 2-(4-(6-fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxoacetate (Int 31)

Int 30/1 Int 31 A mixture of methyl 2-(4-(6-fluoroquinolin-4-yl)piperidin-1-yl)-2-oxoacetate (Int 30/1) (1.10 g, 3.48 mmol, 1.0 eq.) and UOH H2O (160.9 mg, 3.83 mmol, 1.1 eq) in THF/H2O (20 ml_:5 ml_) was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo, washed with hexane and EtOAc to afford the title compound as a white solid.

Intermediate 32: 2-(4-(6-Fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxoacetic acid (Int 32)

Int 30/1 Int 32

To a mixture of methyl 2-(4-(6-fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxoacetate (Int 30/1) (500 mg, 1.58 mmol) in TFIF (15 ml_) was added NaOFI (64 mg, 1. 6 mmol dissolved in 15 ml_ FI2O) and the mixture was stirred at rt for 0.5 h. The pH was adjusted to pH = 2 with aqueous HCI. The mixture was concentrated to dryness and the residue was purified by column chromatography to give the title compound as a white solid.

Intermediate 33: Sodium 2-oxo-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidin]-1'-yl)acetate (Int 33)

Int 33a Int 33b Int 33

Step 1 : Methyl 2-oxo-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperi din]-T- yl)acetate (Int 33b)

To a mixture of 6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidine] hydrochloride (Int 33a) (200 mg, 0.681 mol) in DCM (4 ml_) TEA (0.19 ml_, 1.362 mmol) was added at rt. Methyl 2-chloro-2-oxoacetate (0.072 ml_, 0.749 mmol) was added dropwise and the mixture was stirred at rt for 4 h. Water was added (4 ml_) and the mixture was extracted with DCM (3 x 10 ml_). The combined organic layers were washed with brine, dried over anhydrous Mg ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient 12-100% EtOAc in cyclohexane) to afford the title compound as a white solid. Step 2: Sodium 2-oxo-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperi din]-T- yl)acetate (Int 33)

To a mixture of methyl 2-oxo-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperi din]-T- yl)acetate (Int 33b) (70.0 mg, 0.204 mmol) in THF (1.5 ml_) aqueous NaOFI (0.1 12 ml_, 2M, 0.224 mmol) was added. The mixture was stirred at rt for 30 min. The mixture was concentrated to dryness to afford the title compound which was used in the next step without further purification.

Intermediate 40: 5-Fluoro-6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'-pipe ridine] (Int 40)

Int 40 Int 40e Int 40d

Step 1 : 1 -Benzyl-4-(hydroxymethyl)pyridin-1-ium chloride (Int 40b)

A solution of pyridin-4-ylmethanol (Int 40a) (2.18 g, 20.00 mmol) and

(chloromethyl)benzene (2.52 g, 20.00 mmol) in CH3CN (30 ml_) was refluxed overnight. The mixture was concentrated to dryness to give the title compound as a white solid.

Step 2: (1 -Benzyl-1 ,2,3, 6-tetrahydropyridin-4-yl)methanol (Int 40c)

To a solution of 1 -benzyl-4-(hydroxymethyl)pyridin-1 -ium chloride (Int 40b) (4.70 g, 20.00 mmol) in MeOH (50 ml_) was added NaBH ₄ (1.52 g, 40 mmol) at 0 °C and the mixture was stirred for 3 h. The mixture was poured into water (100 ml_) and extracted with EtOAc (2 x 100 ml_). The combined organic layers were dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 1 : 1 ) to give the title compound as a brown solid. Step 3: 1 -Benzyl-4-((2-bromo-4-fluoro-5-(trifluoromethyl)phenoxy)meth yl)-1 ,2,3,6- tetrahydropyridine (Int 40d)

To a mixture of (1 -benzyl-1 ,2,3, 6-tetrahydropyridin-4-yl)methanol (Int 40c) (557 mg, 2.75 mmol), 2-bromo-4-fluoro-5- (trifluoromethyl)phenol (71 1 mg, 2.75 mmol) and PPh3 (721 mg, 2.75 mmol) in THF (20 ml_) was added DEAD (479 mg, 2.75 mmol) and the mixture was stirred overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (PE/EtOAc = 5:1 ) to give the title compound as a brown solid.

Step 4: T-Benzyl-5-fluoro-6-(trifluoromethyl)-2/-/-spiro[benzofuran- 3,4'-piperidine] (Int 40e)

A mixture of 1-benzyl-4-((2-bromo-4-fluoro-5-(trifluoromethyl)phenoxy)met hyl)-1 ,2,3,6- tetrahydropyridine (Int 40d) (1.47 g, 3.33 mmol), AIBN (109 mg, 0.66 mmol) and n- BusSnH (1.94 g, 6.66 mmol) in toluene (20 ml_) was refluxed overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (PE/EtOAc = 5:1 ) to give the title compound as a brown solid.

Step 5: 5-Fluoro-6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'-pipe ridine] (Int 40)

To a solution of T-benzyl-5-fluoro-6-(trifluoromethyl)-2/-/-spiro[benzofuran- 3,4'- piperidine] (Int 40e) (730 mg, 2.00 mmol) in DCE (10 ml_) was added 1 -chloroethyl carbonochloridate (429 mg, 3.00 mmol) at 0 °C and the mixture was refluxed for 2 h. After cooling to rt the mixture was concentrated to dryness. The residue was dissolved in MeOFI (10 mL) and the mixture was refluxed for 1 h. After cooling to rt, the mixture was partitioned between NaOH (20 mL, 1.0 M) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated to dryness and the residue was purified by column chromatography on silica gel (PE/EtOAc = 2:1 ) to give the title compound as a brown solid.

Intermediate 40/1 : 2/-/-Spiro[benzofuran-3,4'-piperidine]-6-carbonitrile (Int 40/1)

The title compound was prepared similar as described for intermediate 40 using in step 3 4-bromo-3-hydroxybenzonitrile in place of 2-bromo-4-fluoro-5- (trifluoromethyl)phenol. Intermediate 41 : 6-(Difluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidine] (Int 41 )

Step 1 : Methyl 3-((1 -benzyl-1 ,2,3, 6-tetrahydropyridin-4-yl)methoxy)-4-bromobenzoate

(Int 41a)

To a solution of methyl 4-bromo-3-hydroxybenzoate (1.14 g, 4.93 mmol), (1-benzyl- 1 ,2,3,6-tetrahydropyridin-4-yl)methanol (1.00 mg, 4.93 mmol) and PPh3 (1.29 g, 4.93 mmol) in THF (30 ml_) was added DEAD (858 mg, 4.93 mmol) at rt and the mixture was stirred overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (PE/EtOAc = 5:1 ) to give the title compound as a light yellow solid.

Step 2: Methyl T-benzyl-2/-/-spiro[benzofuran-3,4'-piperidine]-6-carboxylat e (Int 41c)

A mixture of methyl 3-((1 -benzyl-1 ,2,3, 6-tetrahydropyridin-4-yl)methoxy)-4- bromobenzoate (Int 41a) (1.23 g, 2.95 mmol), AIBN (97 mg, 0.59 mmol) and n-Bu3SnH (1.72 g, 5.90 mmol) in toluene (20 ml_) was refluxed overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (PE/EtOAc = 5:1 ) to give the title compound as a white solid. Step 3: (1'-Benzyl-2/-/-spiro[benzofuran-3,4'-piperidin]-6-yl)methan ol (Int 41 d)

To a solution of methyl T-benzyl-2/-/-spiro[benzofuran-3,4'-piperidine]-6-carboxylat e (Int 41c) (696 mg, 2.07 mmol) in THF (20 ml_) was added LiAIH ₄ (79 mg, 2.08 mmol) at 0 °C. The mixture was stirred for 3 h and then water (1 ml_) was added. The mixture was filtered and the organic layer was concentrated to dryness to give the title compound as white solid.

Step 4: T-Benzyl-2/-/-spiro[benzofuran-3,4'-piperidine]-6-carbaldehy de (Int 41 e)

The mixture of (T-benzyl-2/-/-spiro[benzofuran-3,4'-piperidin]-6-yl)methano l (Int 41 d) (447 mg, 1.44 mmol) and Mn0 ₂ (2.51 g, 28.8 mmol) in DCM (30 ml_) was refluxed for 3 h. The mixture was filtered and concentrated to dryness to give the title compound as a brown solid which was used in the next step without further purification.

Step 5: T-Benzyl-6-(difluoromethyl)-2/-/-spiro[benzofuran-3,4'-piper idine] (Int 41 f)

To a solution of T-benzyl-2/-/-spiro[benzofuran-3,4'-piperidine]-6-carbaldehy de (Int 41 e) (355 mg, 1.16 mmol) in DCM (20 ml_) was added DAST (934 mg, 5.80 mmol). The mixture was refluxed for 3 h. After cooling to rt, water (20 ml_) was added and the mixture was extracted with EtOAc (3 x 10 ml_). The combined organic layers were washed with brine (20 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 2:1 ) to give the title compound as a white solid.

Step 6: 6-(Difluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidine] (Int 41)

To a solution of T-benzyl-6-(difluoromethyl)-2H-spiro[benzofuran-3,4'-piperid ine] (Int 41 f) (190 mg, 0.58 mmol) in DCE (10 ml_) was added 1 -chloroethyl carbonochloridate (249 mg, 1.74 mmol) at 0 °C and the mixture was refluxed for 2 h. After cooling to rt the mixture was concentrated. The residue was dissolved in MeOH (10 ml_) and the mixture was refluxed for 1 h. After cooling to rt, the mixture was partitioned between NaOH (20 ml_, 1.0 M) and EtOAc (20 ml_). The aqueous layer was extracted with EtOAc (2 x 20 ml_). The combined organic layers were concentrated to dryness and the residue was purified by column chromatography on silica gel (PE/EtOAc = 2:1 ) to give the title compound as a brown solid.

Intermediate 42: 6'-(Trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzofuran] hydrochloride

(Int 42)

Step 1 : 1 ,4-Dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (Int 42b)

To a solution of 1 ,4-dioxaspiro[4.5]decan-8-one (Int 42a) (1.20 g, 7.69 mmol) and 1 ,1 ,1 - trifluoro-/V-phenyl-/V-((trifluoromethyl)sulfonyl)methanesul fonamide (3.57 g, 10.00 mmol) in THF (50 ml_) under N ₂ at -78 °C was added lithium bis(trimethylsilyl)amide in THF (1 M, 10.0 ml_, 10.00 mmol). The mixture was stirred at rt overnight, quenched with FI2O (50 ml_), and extracted with EtOAc (3 x 50 ml_). The combined organic layers were dried over MgS0 ₄ , filtered and concentrated to give the title compound as a brown oil, which was directly used in the next step without further purification.

Step 2: Methyl 1 ,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate (Int 42c)

A mixture of 1 ,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (Int 42b) (7.69 mmol, crude), Pd(PPfi3)2Cl2 (291 mg, 1.11 mmol), and TEA (1.14 g, 11.04 mmol) in MeOFI (20 ml_) was stirred at rt overnight under a carbon monoxide atmosphere at 5 bar pressure. The reaction mixture was quenched with FI2O (100 ml_) and extracted with EtOAc (2 x 100 ml_). The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (PE/EtOAc = 10:1 ) to give the title compound as a yellow oil. Step 3: (1 ,4-Dioxaspiro[4.5]dec-7-en-8-yl)methanol (Int 42d)

To a solution of methyl 1 ,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate (Int 42c) (1.20 g, 6.06 mmol) in dry THF (50 ml_) was added LiAIH ₄ (230 mg, 6.06 mmol) at 0 °C, and the mixture was stirred at rt for 3 h. Then 40 % aqueous NaOH solution (1 ml_) was added and the mixture was stirred at rt for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 2:1 ) to give the title compound as a light yellow oil.

Step 4: 8-((2-Bromo-5-(trifluoromethyl)phenoxy)methyl)-1 ,4-dioxaspiro[4.5]dec-7-ene

(Int 42e)

To a solution of (1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)methanol (Int 42d) (340 mg, 2.00 mmol), 2-bromo-5-(trifluoromethyl)phenol (482 mg, 2.00 mmol) and PPfi3 (786 mg, 3.00 mmol) in THF (10 ml_) was added DEAD (576 mg, 3.00 mmol) under Ar, and the mixture was stirred at rt overnight. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (PE/EtOAc = 10:1 ) to give the title compound as a yellow oil.

Step 5: 6-(Trifluoromethyl)-2/-/-dispiro[benzofuran-3,T-cyclohexane- 4',2"-[1 ,3]dioxolane]

(Int 42f)

A solution of 8-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)-1 ,4-dioxaspiro[4.5]dec-7- ene (Int 42e) (393 mg, 1.00 mmol), n-Bu3SnH (582 mg, 2.00 mmol) and AIBN (33 mg, 0.20 mmol) in toluene (10 ml_) was heated to reflux for 3 h. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (PE/EtOAc = 10:1 ) to afford the title compound as a white solid.

Step 6: 6-(Trifluoromethyl)-2/-/-spiro[benzofuran-3,T-cyclohexan]-4' -one (Int 42g)

To a solution of 6-(trifluoromethyl)-2/-/-dispiro[benzofuran-3,T-cyclohexane- 4',2"- [1 ,3]dioxolane] (Int 42f) (314 mg, 1.00 mmol) in THF (20 ml_) was added concentrated aqueous HCI (1 ml_, 12 M), and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (3 x 30 ml_). The combined organic layers were dried over MgS0 ₄ , filtered and concentrated in to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 10:1 ) to give the title compound as a yellow solid. Step 7: 2/-/-6-(Trifluoromethyl)-2/-/-spiro[benzofuran-3,T-cyclohexa n]-4'-one oxime (Int 42h)

A solution of 6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,1'-cyclohexan]-4 '-one (Int 42g) (2.70 g, 10.00 mmol), NH ₂ OH*HCI (1.38 g, 20.00 mmol) and AcONa (2.46 g, 30.00 mmol) in MeOH (50 ml_) was stirred at rt overnight. The mixture was concentrated. The residue was dissolved in water (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were concentrated to give the title compound as a white solid.

Step 8: 6'-(Trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzofuran]-7- one (Int 42i)

To a solution of 2/-/-6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,T-cyclohexa n]-4'-one oxime (Int 42h) (2.85 g, 10.00 mmol) in THF (30 ml_) was added SOCI2 (2.38 g, 20.00 mmol) at 0 °C and the mixture was stirred at rt overnight. The mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 2:1 ) to give the title compound as a brown solid.

Step 9: 1 -Benzyl-6'-(trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzof uran]-7-one (Int 42j)

To a solution of 6'-(trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzofuran]-7- one (Int 42i) (1.14 g, 4.00 mmol) in THF (20 ml_) was added NaH (320 mg, 8.00 mmol, 60 % in mineral oil) at 0 °C and the mixture was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 ml_). The combined organic layers were concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 2:1 ) to give the title compound as a brown solid.

Step 10: 1-Benzyl-6'-(trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzo furan] (Int 42k)

To a solution of 1-benzyl-6'-(trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzo furan]-7-one (Int 42 j) (1.20 g, 2.90 mmol) in THF (20 mL) was added BH _3* THF (29 mL, 29.00 mmol, 1.0 M) at 0 °C and the mixture was refluxed overnight. After cooling to rt, MeOH (1.0 mL) was added and the mixture was stirred for 2 h. Aqueous HCI (1.0 mL, 1.0 M.) was added and the mixture was refluxed for 3 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE/EtOAc = 3:1 ) to give the title compound as a white solid.

Step 11 : 6'-(Trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzofuran] hydrochloride (Int 42)

To a solution of 1-benzyl-6'-(trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzo furan] (Int 42k) (550 mg, 1.52 mmol) in DCE (50 mL) was added 1 -chloroethyl carbonochloridate (5 mL) at 0°C, and the mixture was refluxed overnight. After cooling to rt the mixture was concentrated. The residue was dissolved in MeOH (50 mL) and the mixture was refluxed for 1 h. After cooling to rt the mixture was concentrated to dryness. The residue was washed with hexane and dried to give the title compound as a gray solid.

Example 1 : /V-(4-Chloro-2-fluorophenyl)-2-(4-(6-fluoroquinolin-4-yl)pip eridin-1 -yl)-2- oxoacetamide (1)

Int 10/1 Example 1

A solution of methyl 2-((4-chlorophenyl)amino)-2-oxoacetate (Int 10/1) (166 mg, 0.78 mmol), TEA (157 mg, 1.56 mmol) and 6-fluoro-4-(piperidin-4-yl)quinoline (Int 20) (160 mg, 0.52 mmol) in MeOH (6 ml_) was stirred at 70 °C for 16 h. The mixture was concentrated and the residue was diluted with H2O (20 ml_). The mixture was extracted with EtOAc (3 x 30 ml_). The combined organic layers were washed with brine (30 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (500 MHz, DMSO- d ₆ ): d ppm 10.96 (s, 1 H), 8.84 (d, J = 4.5 Hz, 1 H), 8.15-8.10 (m, 2H), 7.72-7.68 (m, 3H), 7.47-7.42 (m, 3H), 4.54-4.51 (m, 1 H), 3.95-3.92 (m, 1 H), 3.78-3.73 (m, 1 H), 3.50-3.45 (m, 1 H), 3.1 1 -3.05 (m, 1 H), 2.00-1.93 (m, 2H), 1.79-1.67 (m, 2H). MS (ESI): m/z 412.2 [M+H] ⁺ .

Examples 1/1 to 1/48

The following Examples were prepared similar as described for Example 1 using the appropriate building blocks.

Example 2: /V-(5-Chloropyridin-2-yl)-2-(4-(6-fluoroquinolin-4-yl)piperi din-1 -yl)-2- oxoacetamide (2)

Int 11 Example 2

A mixture of lithium 2-((5-chloropyridin-2-yl)(methyl)amino)-2-oxoacetate (Int 11 ) (100 mg, 0.5 mmol), 6-fluoro-4-(piperidin-4-yl)quinoline (Int 20) (122 mg, 0.5 mmol), HATU (225 mg, 0.6 mmol) and DIPEA (194 mg, 1.5 mmol) in DMF (10 ml_) was stirred at rt overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid. ¹ H NMR ( DMSO-cfe , 400 MHz): d ppm 10.44 (br s, 1 H), 8.85 (d, J = 4.4 Hz, 1 H), 8.44 (s, 1 H), 8.16-8.10 (m, 3H), 7.98-7.96 (m, 1 H), 7.72-7.67 (m, 1 H), 7.47 (d, J = 4.4 Hz, 1 H), 4.50-4.46 (m, 1 H), 3.82- 3.71 (m, 2 H), 3.51 -3.45 (m, 1 H), 3.08-3.02 (m, 1 H), 1.97-1.72 (m, 4H). MS (ESI): m/z 413.0 [M+H] ⁺ .

Examples 2/1 to 2/6

The following Examples were prepared similar as described for Example 2 using the appropriate building blocks.

Example 3: /V-(5-Chloropyridin-2-yl)-2-oxo-2-(4-(quinolin-4-yl)piperidi n-1 -yl)acetamide

(3)

Int 10/3 Example 3

To a solution of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (Int 10/3) (200 mg, 0.93 mmol, 1.0 eq.) in THF/H2O (5 ml_, v/v = 4:1 ) was added UOH H2O (79 mg, 1.87 mmol, 2.0 eq.). The mixture was stirred at rt overnight and was evaporated to dryness to afford 300 mg of a white solid. The residue (150 mg, 0.75 mmol, 1.0 eq.) was dissolved in DMF (5 ml_). 4-(Piperidin-4-yl)quinoline hydrochloride (129 mg, 0.75 mmol, 1.0 eq.), FIATU (205 mg, 0.54 mmol, 1.2 eq.) and DIPEA (117 mg, 0.90 mmol, 2.0 eq.) were added and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-FIPLC to afford the title compound as a white solid. ¹ FI NMR (CDsOD, 400 MHz): d ppm 8.80-8.78 (m, 1 H), 8.34-8.32 (m, 2H), 8.19-8.17 (m, 1 H), 8.06-8.04 (m, 1 H), 7.83-7.77 (m, 2H), 7.70-7.66 (m, 1 H), 7.48-7.46 (m, 1 H), 4.73-4.69 (m, 1 H), 4.26-4.23 (m, 1 H), 3.89-3.83 (m, 1 H), 3.55-3.49 (m, 1 H), 3.14-3.08 (m, 1 H), 2.09- 1.90 (m, 4H). MS (ESI): m/z 395.0 [M+H] ⁺ .

Example 4: N-(( 1 r,4r)-4-Methylcyclohexyl)-2-oxo-2-(4-(quinolin-4-yl)piperidi n-1 - yl)acetamide (4)

Int 30 Example 4

To a solution of methyl 2-oxo-2-(4-(quinolin-4-yl)piperidin-1 -yl)acetate (Int 30) (460 mg of crude, 0.52 mmol, 1 .0 eq.) in THF/h O (5 ml_, v/v = 1 :1 ) was added UOH H2O (44 mg, 1 .04 mmol, 2.0 eq.). The mixture was stirred at rt overnight and was concentrated to dryness to give the crude lithium salt as a white solid. The solid was dissolved in DMF (10 ml_) and 4-(piperidin-4-yl)quinoline hydrochloride (252 mg, 1.68 mmol, 1.0 eq.), FIATU (766 mg, 1 .01 mmol, 1 .2 eq.) and DIPEA (436 mg, 3.38 mmol, 2.0 eq.) were added and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-FIPLC to give the title compound as a white solid. ¹ FI NMR (CDsOD, 400 MHz): d ppm 8.78 (d, J = 5.2 Hz, 1 H), 8.31 (d, 1 H, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.80-7.76 (m, 1 H), 7.69-7.65 (m, 1 H), 7.44 (d, J = 4.8 Hz, 1 H), 4.66-4.63 (m, 1 H), 4.07-4.04 (m, 1 H), 3.85-3.81 (m, 1 H), 3.69-3.65 (m, 1 H), 3.47-3.44 (m, 1 H), 3.05- 3.00(m, 1 H), 2.06-1 .74 (m, 8H), 1.36-1 .29 (m, 3H), 1.08-1 .04 (m, 2H), 0.93-0.90 (m, 3H). MS (ESI): m/z 380.1 [M+H] ⁺ .

Example 5: (S)-2-(4-(6-Fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxo-/V-(1 ,2,3,4-tetrahydro- naphthalen-2-yl)acetamide (5)

Int 31 Example 5

A solution of lithium 2-(4-(6-fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxoacetate (Int 31 ) (130.0 mg, 0.4 mmol, 1 .0 eq.), (S)-1 ,2,3,4-tetrahydronaphthalen-2-amine (67.6 mg, 0.5 mmol, 1 .1 eq.), HATU (197.9 mg, 0.5 mmol, 1.2 eq.) and DIPEA (162.5 mg, 1.2 mmol, 3.0eq.) in DMF (1 1 mL) was stirred at rt under N ₂ overnight. The reaction solution was concentrated in vacuo and purified by prep-HPLC to afford the title compound as a white solid. ¹ H NMR (DMSO-de, 400 MHz): d ppm 8.85-8.82 (m, 2H), 8.14-8.09 (m, 2H), 7.72-7.67 (m, 1 H), 7.44-7.43 (m, 1 H), 7.09 (s, 4H), 4.49-4.44 (m, 1 H), 4.08-4.04 (m, 1 H), 3.89-3.85 (m, 1 H), 3.72 (t, J = 10.8 Hz, 1 H), 3.41 (t, J =12.0 Hz, 1 H), 3.04-2.96 (m, 2H), 2.89-2.85 (m, 2H), 2.74-2.68 (m, 1 H), 2.02-1 .87 (m, 3H), 1 .77-1 .60 (m, 3H). MS (ESI): m/z 432.1 [M+H] ⁺ . Examples 5/1 to 5/10

The following Examples were prepared similar as described for Example 5 using the appropriate building blocks.

Example 6: /V-(5-Chloropyridin-2-yl)-2-(4-(naphthalen-1 -yl)piperidin-1 -yl)-2- oxoacetamide (6)

Int 30/2 Example 6

To a solution of 5-chloropyridin-2-amine (180 mg, 1.4 mmol) in 1 ,4-dioxane (10 ml), AIMb3 (1 M, 1.7 ml) was added, then stirred at rt for 2 h. Methyl 2-(4-(naphthalen-1 -yl)piperidin- 1 -yl)-2-oxoacetate (Int 30/2) (200 mg, 0.67 mmol) was added and the mixture was stirred at 80°C overnight. Water was added (10 ml_) and the mixture was extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with water (20 ml), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified on silica gel column (PE/EtOAc = 5/1 (v/v)) to afford the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-de): d ppm 1 1.43 (s, 1 H), 8.43 (s, 1 H), 8.27 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.4 Hz , 1 H), 7.97-7.93 (m, 2H), 7.81 (d, J = 8.0 Hz, 1 H), 7.59-7.42 (m, 4H), 4.51 (d, J = 8.4 Hz, 1 H), 3.83-3.71 (m, 2H), 3.49-3.45 (m, 1 H), 3.07-3.01 (m, 1 H), 1.99- 1.74 (m, 4H). MS-ESI: m/z 394.1 [M+H] ⁺ .

Examples 6/1 to 6/2

The following Examples were prepared similar as described for Example 6 using the appropriate building blocks.

Example 7: /V-(4-(2-Chloroethyl)phenyl)-2-(4-(6-fluoroquinolin-4-yl)pip eridin-1-yl)-2- oxoacetamide (7)

Int 32 Example 7

To a solution of 2-(4-(6-fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxoacetic acid (Int 32) (100 mg, 0.33 mmol), HATU (189 mg ,0.49 mmol) and TEA (67 mg, 0.66 mmol) in DCM (5 ml_) was added 4-(2-chloroethyl)aniline (54 mg, 0.35 mmol) at rt. After stirring overnight, the mixture was concentrated and the residue was redissolved in DCM (50 ml_) and washed with water (50 ml_) twice. The organic layer was dried over Na ₂ S0 ₄ , the combined organic layer was concentrated under vacuum, and then purified by silica gel column chromatography (EA: PE = 1 :2, v/v) to give the title compound as a white solid. ¹ H NMR (500 MHz, DMSO-de): d ppm 10.79 (s, 1 H), 8.95 (d, J=4.0 Hz, 1 H), 8.25-8.16 (m, 2H), 7.82-7.78 (m, 1 H), 7.82-7.60 (m, 3H), 7.28-7.26 (m, 2H), 4.54-4.52 (m, 1 H), 3.95-3.93 (m, 1 H), 3.84-3.79 (m, 3H), 3.50-3.45 (m, 1 H), 3.10-2.98 (m, 3H), 2.00-1.93 (m, 2H), 1.82- 1.70 (m, 2H). MS-ESI: m/z =440.2 [M+1] ⁺ .

Examples 7/1 to 7/2

The following Examples were prepared similar as described for Example 7 using the appropriate building blocks.

Example 8: 2-(4-(6-Fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxo-/V-(1 -phenylethyl)acetamide

(8)

Int 30/1 Example 8

To a mixture of methyl 2-(4-(6-fluoroquinolin-4-yl)piperidin-1 -yl)-2-oxoacetate (Int 30/1) (100 mg, 0.32 mmol) in MeOH (1 ml_) was added compound 1 -phenylethanamine (46 mg, 0.38 mmol) and the mixture was stirred at 70 °C for 5 h. The mixture was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (500 MHz, DMSO- d ₆ ): d ppm 9.26-9.21 (m, 1 H), 8.97-8.94 (m, 1 H), 8.25-8.16 (m, 2H), 7.82-7.79 (m, 1 H), 7.60-7.58 (m, 1 H), 7.37-7.22 (m, 4H), 5.04-4.98 (m, 1 H), 4.49-4.46 (m, 1 H), 3.78-3.60 (m, 2H), 3.39-3.35 (m, 1 H), 3.01 -2.95 (m, 1 H), 1.95-1.70 (m, 4H), 1.42-1.39 (m, 3H). MS (ESI): m/z 406.2 [M+H] ⁺ .

Examples 8/1 to 8/6

The following Examples were prepared similar as described for Example 8 using the appropriate building blocks.

Example 9: 4-(1-(2-((5-Chloropyridin-2-yl)amino)-2-oxoacetyl)piperidin- 4-yl)-1 -naphthoic acid (9)

Step 1 : Methyl 4-(1-(2-((5-chloropyridin-2-yl)arnino)-2-oxoacetyl)piperidin -4-yl)-1 - naphthoate (9a)

To a stirred solution of 2-((5-chloropyridin-2-yl)amino)-2-oxoacetic acid (Int 13) (160 mg, 0.80 mmol), HOBt (108 mg, 0.80 mmol), DIPEA (620 mg, 4.80 mmol), and EDCI (305 mg, 1.60 mmol) in DMF (6 ml_) was added methyl 4-(piperidin-4-yl)-1 -naphthoate (Int 20/12) (269 mg, 0.88 mmol) at rt. The mixture was stirred at rt for 16 h, diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 ml_). The combined organic layers were washed with brine (30 mL), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with PE: EtOAc = 1 :1 (v/v) to give the title compound as a white solid.

Step 2: 4-(1 -(2-((5-Chloropyridin-2-yl)amino)-2-oxoacetyl)piperidin-4-yl )-1 -naphthoic acid (9)

To a solution of methyl 4-(1 -(2-((5-chloropyridin-2-yl)amino)-2-oxoacetyl)piperidin-4-yl )- 1 -naphthoate (9a) (200 mg, 0.40 mmol) in THF (5 mL), MeOFI (5 mL) and H2O (5 mL) was added UOH H2O (60 mg, 1.20 mmol). The mixture was stirred at rt for 12 h, concentrated and the residue was diluted with FI2O (10 mL). It was neutralized with 1 N HCI solution to pH = 6-7 and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by prep-HPLC to give the title compound as a white solid. ¹ H NMR (500 MHz, CD ₃ OD): d ppm 8.96-8.95 (m, 1 H), 8.40-8.30 (m, 2H), 8.22-8.20 (m, 1 H), 8.15-8.13 (m, 1 H), 7.88-7.85 (m, 1 H), 7.66-7.57 (m, 2H), 7.51 (d, J = 7.6 Hz, 1 H), 4.74- 4.71 (m, 1 H), 4.25-4.22 (m, 1 H), 3.86 (t, J = 1 1.6 Hz, 1 H), 3.55 (t, J = 11.8 Hz, 1 H), 3.20- 3.08 (m, 1 H), 2.15-1.91 (m, 4H). MS-ESI: m/z =438.0 [M+1] ⁺ . Example 10a and 10b: frans-/V-(4-Chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)-3- hydroxypiperidin-1 -yl)-2-oxoacetamide (separated enantiomers) (10a, 10b)

Step 1 : frans-/V-(4-Chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)-3-hyd roxypiperidin-1-yl)-2- oxoacetamide (racemate) (10)

To a solution of frans-4-(6-fluoroquinolin-4-yl)piperidin-3-ol trifluoroacetic acid salt (Int 27) (114 mg, 0.33 mmol) and methyl 2-((4-chlorophenyl)amino)-2-oxoacetate (Int 10/1 ) (86 mg, 0.40 mmol) in MeOH (5 ml_) was added TEA (101 mg, 1.00 mmol) and the mixture was stirred at 80 °C overnight. The mixture was diluted with H2O (50 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow solid.

Step 2: frans-/V-(4-Chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)-3-hyd roxypiperidin-1-yl)-2- oxoacetamide (separated enantioners) (10a, 10b)

Chiral HPLC separation (IE column, n-hexane/0.1 % DEA : EtOH/0.1 % DEA = 50 : 50) of frans-N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)-3-hydr oxypiperidin-1-yl)-2- oxoacetamide (racemate) (10) (92 mg, 0.22 mmol) afforded trans-N-( 4-chlorophenyl)-2- (4-(6-fluoroquinolin-4-yl)-3-hydroxypiperidin-1 -yl)-2-oxoacetamide (10a, first eluting enantiomer with a retention time of 8.64 min) and trans-N-( 4-chlorophenyl)-2-(4-(6- fluoroquinolin-4-yl)-3-hydroxypiperidin-1 -yl)-2-oxoacetamide (10b, second eluting enantiomer with a retention time of 10.67 min).

Example 10a: ¹ H NMR (500 MHz, DMSO-d ₆ ): d ppm 11.01 (s, 0.5 H), 10.97 (s, 0.5H), 8.87-8.85 (m, 1 H), 8.20-8.01 (m, 2H), 7.79-7.61 (m, 3H), 7.58-7.50 (m, 1 H), 7.47-7.34 (m, 2H), 5.21 -5.16 (m, 1 H), 4.59-4.40 (m, 1 H), 3.99-3.82 (m, 2H), 3.68-3.60 (m, 2H), 3.45- 2.78 (m, 2H), 1.91-1.61 (m, 2H). MS-ESI: m/z = 428.2 [M+1] ⁺ .

Example 10b: ¹ H NMR (500 MHz, DMSO-d ₆ ): d ppm 1 1.01 (m, 0.5 H), 10.97 (s, 0.5 H), 8.87-8.85 (m, 1 H), 8.23-7.98 (m, 2H), 7.79-7.60 (m, 3H), 7.58-7.50 (m, 1 H), 7.47-7.37 (m, 2H), 5.21 -5.16 (m, 1 H), 4.59-4.41 (m, 1 H), 3.99-3.82 (m, 2H), 3.68-3.60 (m, 1 H), 3.41 - 2.78 (m, 2H), 1.93-1.64 (m, 2H). MS-ESI: m/z = 428.2 [M+1] ⁺ .

Examples 10/1 a, 10/1 b

The following Examples were prepared similar as described for Example 10a and 10b using the appropriate building blocks.

Examples 100 to 100/15

The following Examples were prepared similar as described for Example 1 using the appropriate building blocks.

/

Example 101 : /V-(4-Chlorophenyl)-2-(6-(difluoromethyl)-2 -/-spiro[benzofuran-3,4'- piperidin]-T-yl)-2-oxoacetamide (101)

A mixture of 6-(difluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidine] (Int 41 ) (69 mg, 0.29 mmol), 2-(4-chlorophenylamino) -2-oxoacetic acid (Int 13/1 ) (58 mg, 0.29 mmol), BOPCI (74 mg, 0.29 mmol) and DIEA (75 mg, 0.58 mmol) in DCM (10 ml_) was stirred at rt overnight. Water (20 ml_) was added and the mixture was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (400 MHz, CDCI3): d ppm 9.23 (s, 1 H), 7.63-7.51 (m, 2H), 7.39-7.30 (m, 2H), 7.18 (d, J = 7.6 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 7.05 (s, 1 H), 6.58 (t, J = 56.4 Hz, 1 H), 5.22-5.14 (m, 1 H), 4.65-4.42 (m, 3H), 3.47-3.28 (m, 1 H), 3.08-2.88 (m, 1 H), 2.19-1.80 (m, 4H). MS (ESI): m/z 421.1 [M+H] ⁺ .

Example 102: /V-(4-Chlorophenyl)-2-oxo-2-(6'-(trifluoromethyl)-2' -/-spiro[azepane-4,3'- benzofuran]-1 -yl)acetamide (102)

To a solution of 2-((4-chlorophenyl)amino)-2-oxoacetic acid (Int 13/1 ) (40 mg, 0.20 mmol), EDCI HCI (58 mg, 0.30 mmol) and HOBt (40 mg, 0.30 mmol) in CH2CI2 (10 ml_) was added /V-methylmorpholine (0.5 mL) and the mixture was stirred at rt for 30 min. 6'- (Trifluoromethyl)-2'/-/-spiro[azepane-4,3'-benzofuran] hydrochloride (Int 42) (60 mg, 0.2 mmol) was added and the mixture was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated to dryness and the residue was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): d ppm 10.96 (s, 1 H), 7.78-7.61 (m, 2H), 7.50-7.36 (m, 3H), 7.28-7.23 (m, 1 H), 7.13-7.11 (m, 1 H), 4.59-4.38 (m, 2H), 3.85-3.38 (m, 4H), 2.12-1.69 (m, 6H). MS (ESI): m/z 453.1 [M+H] ⁺ .

Example 103: /V-(4-Fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)-2-oxo-2-(6-

(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidin]-1 '-yl)acetamide (103)

Int 33 Example 103

To a mixture of sodium 2-oxo-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperi din]- 1'-yl)acetate (Int 33) (30 mg, 0.085 mmol), HATU (48.7 mg, 0.128 mmol) and TEA (0.030 mL, 0.214 mmol) in DCM (1.0 mL) 4-fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-amine hydrochloride (Int 3) (14.8 mg, 0.085 mmol) was added and the mixture was stirred at rt overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid. ¹ H NMR (DMSO-d ₆ , 300 MHz): d ppm 9.46 (d, J= 6.7 Hz, 1 H), 7.47-7.42 (m, 1 H), 7.25-7.03 (m, 5H), 5.34-5.26 (m, 1 H), 4.62-4.60 (m, 2H), 4.28-4.23 (m, 1 H), 3.84-3.74 (m, 1 H), 3.59-3.52 (m, 1 H), 3.30- 3.20 (m, 1 H), 3.11 -3.00 (m, 1 H), 2.97-2.84 (m, 1 H), 1.88-1.74 (m, 4H). MS (ESI): m/z 449.3 [M+H] ⁺ . Example 103/1 : A/-(bicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)-2-oxo-2-(6-(trifluoromethyl)- 2/-/-spiro[benzofuran-3,4'-piperidin]-T-yl)acetamide (103/1 )

The title compound was prepared similar as described for Example 103 using bicyclo[4.2.0]octa-1 (6),2,4-trien-7-amine hydrogen chloride in place of 4- fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-amine hydrochloride (Int 3). ¹ FI NMR (DMSO-d ₆ , 300 MHz): d ppm 9.43 (d, J = 7.1 Hz, 1 H), 7.44 (d, J = 7.5 Hz, 1 H), 7.34-7.20 (m, 6H), 5.35-5.31 (m, 1 H), 4.62-4.60 (m, 2H), 4.28-4.20 (m, 1 H), 3.84-3. 73 (m, 1 H), 3.61 (dd, J = 14.2, 5.3 Hz, 1 H), 3.27-3.23 (m, 1 H), 3.15-3.07 (m, 1 H), 2.95-2.85 (m, 1 H), 1.88-1.73 (m, 4H). MS (ESI): m/z 431.3 [M+H] ⁺ .

Biological Assays

SKOV-3 cellular Indoleamine 2,3-dioxygenase assay

SKOV-3 cells were obtained from the American Type Culture Collection (ATCC® HTB- 77™) and maintained in McCoy ^' s medium (Pan Biotech) supplemented with 10 % fetal bovine serum and 1 % Penicilin/Streptomycin. Cells were kept at 37° C in a humidified incubator with 5 % CO2. For assay preparation, cells were seeded at a density of 2 ^* 10 ⁵ /ml into black clear bottom 96 well plates in 100 pi medium/well supplemented with 50 ng/ml Interferon gamma (eBioscience, Thermo Fisher Scientific). After cells fully adhered to the plate, dilution series of compounds were added in medium containing additional L- Tryptophan to a final L-Tryptophan concentration of 100 mM. The cells were incubated for 24 hours. Detection of produced N-Formylkynurenin was performed by addition of 3- Methylpiperidine to a final concentration of 200 mM. The plates were sealed and heated to 65° C for 20 minutes in a water bath. After cooling the fluorescence of each well was recorded with a Victor™X4 (PerkinElmer) plate reader at an emission wavelength of 535 nm and excitation at 405 nm (Tomek et al.; Anal Bioanal Chem (2013) 405:2515-2524., Tomek et al.; Biochim Biophys Acta. 2015 Sep;1850(9):1772-80).

The IC50 values of the example compounds are shown in Table 1 below (A = IC50 < 100 nM, B = 100 nM < IC50 < 1 mM, C = IC50 > 1 mM). Table 1