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(1 1 ):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 concept! 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-Hydroxykynurenine and Kynurenic acid also serve as ligands for the Aryl Hydrocarbon Receptor (AHR) albeit with differentially reported efficacies (DiNatale et al.; Toxicol Sci. 2010; 1 15(1 ):89-97, Mezrich et al.; J Immunol· 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 Immunol· 2016;197(3):962-70) or with IL-6 as mediator (Litzenburger et al.; 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 al.; Proc Natl Acad Sci U S A. 2008 Jul 15; 105(28):9721-6, Mezrich et al.; J Immunol· 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): 1 69-74; Hanagiri et al.; J Clin Cell Immunol 2014, 5:5, Okamoto et al.; Clin Cancer Res. 2005; 1 1 (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; 1 14(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; 1 1 (3):31 -9, Hou et al.; Cancer Res. 2007 Jan 15;67(2):792-801 , Sharma et al.; Blood. 2009 Jun 1 1 ;1 13(24):6102-1 1 , 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- Hyd roxykyn u ren i ne 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.).

ID01 also seems to be involved in disorders of the central nervous system because its downstream products 3-Hydroxy kynurenine 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 and Schizophrenia (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). 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.

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, B, D, E, T, W, X, Z, R ¹ , R ² , R ⁵ , R ¹⁰ , m, o and p 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 formula (1 ) 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)

(1) (2)

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

A represents C3-io-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 , OC(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-io-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 heterocycloalkyl 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-e-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 C- _M -aikyl;

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 , OC(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-e-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 heterocyclic 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-e-cycloalkyl or 3- to 6 membered heterocycloalkyl 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;

E represents a 6-membered aryl or 6-membered heteroaryl containing 1 to 2 nitrogen atoms;

R ⁵ is independently selected from hydrogen, halogen and C-i-e-alkyl;

T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(C)-R ^X , COOH, Ci _-6 -alkyl, C _2.6 - alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocycloalkyl, 6-membered aryl-Ci- ₆ alkyl, 5- to 6-membered heteroaryl- C-i-e-alkyi, 3- to 6-membered heterocycloalkyl-Ci-e-alkyl, or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

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

R ¹⁰ represents hydrogen, Ci - ₆ -alkyl, h a lo-Ci - _b -al ky I ; or

R ¹⁰ and T form together with the carbon atom to which they are attached a 3- to 10- membered mono- or bicyclic ring system which is saturated or partially unsaturated and wherein the ring system may further contain 1 , 2 or 3 heteroatoms independently selected from N, O and S,

wherein the ring system is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, OCi-e-alkyl, oxo, Ci- ₆ -alkyl and halo-Ci- ₆ -alkyl;

W represents O, NOR ⁴ , NR ¹ , NON, or NS(0) ₂ Ci- ₆ -alkyl;

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 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, ha!o-C-i-e-alkyl, OR ¹ or CN;

Z represents -C2-3-alkylene-, -O-Oi-2-alkylene-, -Ci-2-alkylene-O-, -C(0)NR ³ -Co-i- alkylene-, -Ci-alkylene-NR ³ C(0)-, -Co-i-alkylene-C(0)NR ³ -, -S(0) _t -Ci- ₂ -alkylene-, -C1-2- alkylene-S(0)t-, -NR ⁹ -Ci-2-alkylene- or -Ci-2-alkylene-NR ⁹ -,

wherein alkylene is unsubstituted or substituted with 1 to 4 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, Ci-e-alkyl, C3-6-cycloalkyl, halo-Ci-e-alkyl, OR ⁴ , S(0) ₂ N(R ¹ ) ₂ , S(0) ₂ -Ci-e- alkyl, S(0) ₂ -C _3-6 -cycloalkyl, S(0) ₂ -halo-Ci- ₆ -alkyl, C(0)N(R ¹ ) ₂ , ON, 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 C3-10 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 ³ is hydrogen or Ci- ₆ -alkyl;

R ⁴ is hydrogen or Ci-e-alky!;

m is 1 or 2;

o is 0, 1 , 2, 3 or 4;

p is 0, 1 , 2 or 3; and

t is 0, 1 or 2,

with the proviso that 2,3-dihydro-a-methyl-A/-1 ,3,4-thiadiazol-2-yl-spiro[1 H-indene-1 ,4’- piperidine]-1’-acetamide is excluded.

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

A represents C3-io-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 , OC(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-e-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 C 3-10-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-C-i-e-alkyl and oxo;

R ^x represents Ci-6-alkyl, C _3-6 -cycloalkyl or 3- to 6-membered heterocycloalkyl 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-e-a!ky!, 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;

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 , OC(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 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 heterocyclic 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, C ₃ -e-cycloalkyl or 3- to 6 membered heterocycloalkyl 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, C-i-e-alkyl, halo-Ci- ₆ -alkyl, OR ¹ and CN;

E represents a 6-membered aryl or 6-membered heteroaryl containing 1 to 2 nitrogen atoms;

R ⁵ is independently selected from hydrogen, halogen and C-i-e-a!kyl; T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci _-6 -alkyl, C ₂ -e- alkenyl, C3-6-cycloalkyl, 6-mem bered aryl, 5- to 6-mem bered heteroaryl, 3- to 6- membered heterocycloalkyl, 6-membered aryl-C-i-e alkyl, 5- to 6-mem bered heteroaryl- Ci- ₆ -alkyl, 3- to 6-membered heterocycloalkyl-Ci- ₆ -alkyl, or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

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

R ¹⁰ represents hydrogen, Ci -b-alkyl, h a lo-Ci -b-al ky I ; or

R ¹⁰ and T form together with the carbon atom to which they are attached a 3- to 10- membered mono- or bicyclic ring system which is saturated or partially unsaturated and wherein the ring system may further contain 1 , 2 or 3 heteroatoms independently selected from N, O and S,

wherein the ring system is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, OCi- ₆ -alkyl, oxo, Ci- ₆ -alkyl and halo-Ci- ₆ -alkyl;

W represents O, NOR ⁴ , NR ¹ , NON, or NS(0) ₂ Ci- ₆ -alkyl;

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 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, halo-Ci-e-alkyl, OR ¹ and CN;

Z represents -C2-3-alkylene-, -O-Ci-2-alkylene-, -Ci-2-alkylene-O-, -C(0)NR ³ -Co-i- alkylene-, -Ci-alkylene-NR ³ C(0)-, -Co-i-alkylene-C(0)NR ³ -, -S(0) _t -Ci- ₂ -alkylene-, -C1-2- alkylene-S(0) _t -, -NR ⁹ -Ci-2-alkylene- or -Ci-2-alkylene-NR ⁹ -,

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

R ⁹ is hydrogen, Ci-e-alkyi, halo-Ci-e-alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl; R ¹ is hydrogen or Ci-e-alkyl;

R ² is Ci- ₆ -alkyi, C3-6-cycioalkyl, halo-Ci-e-alkyl, OR ⁴ , S(0) ₂ N(R ¹ ) ₂ , S(0) ₂ -Ci- ₆ -alkyl, S(0) ₂ -C _3-6 -cycloaikyl, S(0) ₂ -halo-Ci- ₆ -alkyi, C(0)N(R ¹ ) ₂ , ON, 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 ³ is hydrogen or Ci-e-alkyl;

R ⁴ is hydrogen or Ci- ₆ -alkyl;

m is 1 or 2;

o is 0, 1 , 2, 3 or 4;

p is 0, 1 , 2 or 3; and

t is 0, 1 or 2,

with the proviso that 2,3-dihydro-a-methyl-A/-1 ,3,4-thiadiazol-2-yl-spiro[1 H-indene-1 ,4’- piperidine]-1’-acetamide is excluded.

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

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*, 0-R ^x , OC(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-e-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, C ₁ - ₆ -alkyl, halo-Ci- ₆ -alkyl, hydroxy-Ci- ₆ -alkyl, C _3-6 -cycloalkyl or halo-C _3-6 -cycloalkyl;

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl 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 , OC(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-e-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-e-alkyl, C3-e-cycloalkyl or 3- to 6-membered heterocycloalkyl 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, C-i-e-alkyi, halo-Ci- ₆ -alkyl, OR ¹ and CN;

V is O or CR ⁷ R ⁸ ;

R ² is C1-6 alkyl, C3-6 cycloalkyl, halo-Ci-e-alkyl, OR ⁴ , S(0)2N(R ¹ )2, S(0)2-Ci-e-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)OR ⁴ or oxo, or

two R ² on the same carbon atom form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, or

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

T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci _-6 -alky, IC2-6- alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocycloalkyl, 6-membered aryl-C-i-6 alkyl, 5- to 6-membered heteroaryl- Ci- ₆ -alkyl, 3- to 6-membered heterocycloalkyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyl-

Ci- ₆ -alkyl,

wherein alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- ₆ -alkylene-OH, -Co- ₆ -alkylene-R ^x , -Co- ₆ -al ky len e-O- R ^x , - Co-6-alkylene-OC(0)-R ^x , -Co-6-alkylene-S-R ^x , -Co-6-alkylene-S(0)2-R ^x , -Co-6-alkylene- S(0) ₂ N(R ¹ ) ₂ , -Co-6-alkylene-N(R ¹ ) ₂ , -Co-6-alkylene-NR ¹ C(0)R ^x , -Co-e-alkylene- C(0)N(R ¹ ) ₂ , -Co- ₆ -a I ky I e n e-C (O )0- R ^x , -Co- ₆ -alkylene-C(0)-R ^x , -Co- ₆ -alkylene-CN, -Co-e- alkylene-COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and 6-membered aryl;

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

m is 1 or 2.

In a preferred embodiment in combination with any of the embodiments above and below, the compound is represented by the following formulae (1 -3) and (1 -4) wherein

X is hydrogen, halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, O-Ci- ₆ -alkyl, S-Ci-e-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 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-a!kyl, halo-Ci-e-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 , OC(0)-R ^z , S-R ^z , S(0) ₂ -R ^z , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) _2I 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 , C-i-e-alkyl; C3-6- cycloalkyl, and halo-Ci- ₆ -alkyl,

R ^z represents Ci-e-alkyl, C3-e-cycloalkyl or 3- to 6 membered heterocycloalkyl 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;

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 ;

T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(C)-R ^X , COOH, Ci _-6 -alkyl, halo- Ci- ₆ -aikyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-Ci- ₆ alkyl, 5- to 6-membered heteroaryl-Ci- ₆ -alkyl, 3- to 6-membered heterocyclyl-C-i-e-alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e-alkylene-OH, -Co- ₆ -alkylene-R*, -Co- ₆ -alkylene-0-R ^x , -Co- ₆ -alkylene- 0C(0)-R ^x , -Co-6-alkylene-S-R ^x , -Co-6-alkylene-S(0)2-R ^x , -Co-6-alkylene-S(0)2N(R ¹ )2, -Co- 6-alkylene-N(R ¹ )2, -Co-6-alkylene-NR ¹ C(0)R ^x , -Co-6-alkylene-C(0)N(R ¹ )2, -Co-6-alkylene- C(0)0-R ^x , -Co- ₆ -alkylene-C(0)-R ^x , -Co-e-alkylene-CN, -Co-e-alkylene-COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl;

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 preferred embodiment in combination with any of the embodiments above and below, the compound is represented by the following formula (1 -5)

wherein

X is hydrogen, halogen, Ci-e-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 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alky!, halo-Ci- ₆ -alkyl, OR ¹ or CN;

R ⁵ is independently selected from hydrogen, halogen and C-i-e-alkyl;

R ⁶ is independently selected from halogen, OH, R ^z , 0-R ^z , OC(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 ) _2I 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-e-alkyl; C3-6- cycloalkyl, and halo-Ci- ₆ -alkyl,

R ^z represents Ci-e-a!kyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl 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, C-i-e-alkyl, halo-Ci- ₆ -alkyl, OR ¹ and CN;

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

T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(C)-R ^X , COOH, Ci-e-alkyl, halo- Ci- ₆ -alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-Ci-6 alkyl, 5- to 6-membered heteroaryl-Ci- ₆ -alkyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

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

U is N or CR ⁵ ;

p is 0, 1 , 2 or 3; and

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

In a preferred embodiment in combination with any of the embodiments above and below, the compound is represented by the following formula (1 -6)

wherein X is hydrogen, halogen, Ci-e-alkyl, C ₃ -e-cycioalkyl, O-Ci- ₆ -alkyl, S-Ci-e-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 1 to 4 substituents independently selected from the group consisting of 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 , OC(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, C _3-6 -cycloalkyl or 3- to 6 membered heterocycloalkyl 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;

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

T represents hydrogen, CN, C(C)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci-e-alkyl, halo- Ci-6-alkyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i- ₆ alkyl, 5- to 6-membered heteroaryl-Ci-6-alkyl, 3- to 6-membered heterocyclyl-Ci-6-alkyl or 3- to 6-membered cycloalkyl-Ci-6-alkyl,

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

p is 0, 1 , 2 or 3; and

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

In a further preferred embodiment in combination with any of the embodiments above and below, the compound is represented by the following formula (1 -7)

wherein

Q is OR ⁴ or CN;

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 1 to 4 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN;

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

R ⁶ is independently selected from halogen, OH, R ^z , 0-R ^z , OC(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, C _3-6 -cycloalkyl or 3- to 6 membered heterocycloalkyl 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;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, halo-Ci- ₆ -alkyl and OR ⁴ ; T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci _-6 -alkyl, halo- Ci-e-alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i- ₆ alkyl, 5- to 6-membered heteroaryl-Ci- ₆ -alkyl, 3- to 6-membered heterocyclyl-Ci-e-alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

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

U is N or CR ⁵ ;

p is 0, 1 , 2 or 3; and

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

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

wherein

X is hydrogen, halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, O-Ci- ₆ -alkyl, S-Ci-e-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 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN;

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

T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci-6-alkyl, halo- Ci-e-alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-Ci- ₆ alkyl, 5- to 6-membered heteroaryl-Ci- ₆ -alkyl, 3- to 6-membered heterocyclyl-Ci-e-alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

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

R ^x represents Ci-e-alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl 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, C-i-e-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 , OC(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 heterocyclic 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-e-alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl 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 Ci- ₆ alkyl, C _3.6 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 -io 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;

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

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

m is 1 or 2.

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

wherein

X is hydrogen, halogen, Ci-e-alkyl, C _3-6 -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 1 to 4 substituents independently selected from the group consisting of halogen, C-i-e-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 , C-R ^z , OC(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-e-alkyl; C3-6- cycloalkyl, and halo-Ci- ₆ -alkyl,

R ^z represents Ci-e-alkyl, C3-e-cycloalkyl or 3- to 6 membered heterocycloalkyl 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;

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 ;

T represents hydrogen, CN, C(0)N(R ¹ )2, C(0)0-R ^x , C(0)-R ^x , COOH, Ci-6-alkyl, halo- Ci- ₆ -alkyi, C2-e-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i-e alkyl, 5- to 6-membered heteroaryl-C-i- ₆ -alkyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

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

U is N or OR 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 preferred embodiment in combination with any embodiment above and below, the compound is represented by the following formula (2-5)

wherein

X is hydrogen, halogen, Ci-e-alkyl, C3-6-cycloalkyl, O-Ci-e-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 1 to 4 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN;

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

R ⁶ is independently selected from halogen, OH, R ^z , 0-R ^z , OC(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 heterocycloalkyl 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;

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

T represents hydrogen, CN, C(0)N(R ¹ ) ₂ , C(C)0-R ^x , C(0)-R ^x , COOH, Ci-e-alkyl, halo- Ci- ₆ -alkyl, C ₂ -e-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i- ₆ alkyl, 5- to 6-membered heteroaryl-Ci- ₆ -alkyl, 3- to 6-membered heterocyclyl-C-i-e-alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

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

U is N or CR ⁵ ;

p is 0, 1 , 2 or 3; and

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

In a preferred embodiment in combination with any of the embodiments above and below, T represents hydrogen, halogen, CN, Ci - ₆ -alkyl, halo-Ci- ₆ -alkyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, 6- membered aryl-Ci-e alkyl, 5- to 6-membered heteroaryl-Ci-e-alkyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl,

wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e-alkylene-OH, -Co-e-alkylene-CN, -Co- ₆ -alkylene-R ^x and -Co- ₆ -alkylene-O- R ^x .

In a more preferred embodiment in combination with any of the embodiments above and below, T represents hydrogen, Ci- ₆ -alkyl, halo-Ci-e-alkyl, C3-6-cycloalkyl, 3- to 6 membered cycloalkyl-Ci- ₆ -alkyl,

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

In a further more preferred embodiment in combination with any of the embodiments above and below, T represents Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C3-6-cycloalkyl, 3- to 6 membered cycloalkyl-Ci- ₆ -alkyl,

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

In a preferred embodiment in combination with any of the embodiments above and below, the compound 2, 3-dihydro-N-(1 -methyl-1 H-pyazol-3-yl)-spiro[1 H-indene-1 ,4’- piperidine]-1’-acetamide is excluded. In a further 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 embodiments above and below, A represents C3-io-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 , OC(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.

In a more preferred embodiment of the compounds according to formula (1 ) in combination with any of the embodiments above and below, A represents C3-6- cycloalkyl, which may be optionally fused with a phenyl ring, 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, N and S, 6- or 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 4 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , OC(0)-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.

In an even more preferred embodiment of the compounds according to formula (1 ) in combination with any of the embodiments above and below, A represents phenyl or 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S, wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R ^x , O- R ^x , C(0)0-R ^x , C(0)-R ^x , CN and COOH. In a most preferred embodiment of the compounds according to formula (1 ) in combination with any of the embodiments above and below, 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 , C(0)0-R ^x , C(0)-R ^x , CN and COOH.

In a further preferred embodiment of the compounds according to formula (1 ) in combination with any of the embodiments above and below, R ^x represents Ci- ₆ -alkyl or C _3-6 -cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, C-i- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ and CN.

Also preferred is an embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, wherein A represents C 3-6- cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or

substituted 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-e-alkyl;

U is N or CR ⁵ ;

p is 0, 1 , 2 or 3; and

R ^a represents halogen, CN, C1 - ₆ -alkyl, halo-Ci-e-alkyl, hydroxy-Ci-e-alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl.

In a more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, A represents 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, C1- 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 (1 ) in combination with any of the above and below embodiments, A represents wherein

X is halogen, Ci- ₆ -alkyl, C _3-6 -cycloalkyl, or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci-6-alkyl;

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

U is N or CR ⁵ ; and

p is 0, 1 , 2 or 3.

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

X is halogen, Ci- ₆ -alkyl, C _3-6 -cycloalkyl, or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci- ₆ -alkyl;

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 preferred embodiment in combination with any of the above and below embodiments, U is N.

In a further preferred embodiment in combination with any of the above and below embodiments, U is CR ⁵ and R ⁵ is independently selected from hydrogen, halogen and

Ci-e-alkyl.

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

X is halogen, Ci- ₆ -alkyl, C _3-6 -cycloalkyl, or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci- ₆ -alkyl. In an equally most preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, A represents wherein

X is halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci- ₆ -alkyl.

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

In a preferred embodiment of the compounds according to formula (1 ) in combination with any of the embodiments above and below, W represents O, NCN or NOR ⁴ , more preferably W represents O.

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

In a further 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

In an equally 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 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

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

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

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

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

In a preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, R ⁶ is independently selected from halogen and R ^z ; wherein R ^z represents Ci- ₆ -alkyl, 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.

More preferably, R ⁶ is halo-Ci- ₆ -alkyl.

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

In am equally 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

In an equally 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

In an alternatively 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

In an equally 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 In a further 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

In a preferred embodiment of the compounds according to formula (2) in combination with any of the embodiments above and below, E represents a 6-membered aryl.

In a preferred embodiment of the compounds according to formula (2) in combination with any of the embodiments above and below, X represents hydrogen, halogen, C-i-e- alkyl, C _3-6 -cycloalkyl, O-Ci-6-alkyl or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C-i- ₆ -alkyl, haio-Ci-6-alkyl, OR ¹ or CN.

In a more preferred embodiment of the compounds according to formula (2) in combination with any of the embodiments above and below, X represents halogen, Ci- ₆ -alkyl or CN, wherein alkyl is unsubstituted or substituted with 1 to 4 halogen atoms.

In an even more preferred embodiment of the compounds according to formula (2) in combination with any of the embodiments above and below, X is halogen, most preferably, X is Cl.

In a preferred embodiment of the compounds according to formula (2) in combination with any of the embodiments above and below, R ⁵ represents hydrogen, halogen or Ci- ₆ -alkyl, more preferably hydrogen or Ci-e-alkyl, most preferably hydrogen.

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

following formula

In a preferred embodiment of the compounds according to formula (2) in combination with any of the above and below embodiments, R ⁶ is independently selected from halogen and R ^z ; wherein R ^z represents Ci-6-alkyl, C _3-6 -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. More preferably, R ⁶ is halo-Ci-e-alkyl.

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

In a preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, D represents phenyl or 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S, wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R ^z , O- R ^z , OC(0)-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 , ON, 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-e-alkyl, C3-6-cycloalkyl and halo-Ci- ₆ -alkyl, or two substituents on the phenyl 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 heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci - ₆ -alkyl, halo-Ci-e-alkyl, CN and oxo.

In a preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, R ^z represents Ci- ₆ -alkyl or C3-6-cycioalkyl, 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 (1 ) or (2) in combination with any of the embodiments above and below, T represents CN, C(0)N(R ¹ ) ₂ , C(0)C-R ^x , C(C)-R ^x , COOH, Ci -e-alkyl, C _2.6 -alkenyl, C _3.6 -cycloalkyl, 6- membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6- membered aryl-C-i-e alkyl, 5- to 6-membered heteroaryl-Ci- ₆ -alkyl, 3- to 6-membered heterocycloalkyl-Ci- ₆ -alkyl, or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl, wherein alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, - Co- ₆ -alkylene-OH, -Co- ₆ -aikylene-R ^x , -Co- ₆ -alkylene-0-R ^x , -Co- ₆ -alkylene-OC(0)-R ^x , -Co- ₆ - alkylene-S-R ^x , -Co-6-alkylene-S(0)2-R ^x , -Co-6-alkylene-S(0)2N(R ¹ )2, -Co-6-alkylene- N(R ¹ ) ₂ , -C _0-6 -alkylene-NR ¹ C(O)R ^x , -Co- ₆ -alkylene-C(0)N(R ¹ ) ₂ , -C _0-6 -alkylene-C(O)O-R ^x , -Co- ₆ -a I ky I e n e-C (O )- R ^x , -Co- ₆ -alkylene-CN, -Co-e-alkylene-COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and 6-membered aryl.

In a more preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, T represents CN, C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci- ₆ -alkyl, C _3.6 -cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocycloalkyl, wherein alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e- alkylene-OH, -Co- ₆ -alkylene-R ^x , -Co- ₆ -alkylene-0-R ^x , -Co- ₆ -alkylene-OC(0)-R ^x , -Co- ₆ - alkylene-S-R ^x , -Co-6-alkylene-S(0)2-R ^x , -Co-6-alkylene-S(0)2N(R ¹ )2, -Co-6-alkylene- N(R ¹ ) ₂ , -Co- ₆ -alkylene-NR ¹ C(0)R ^x , -Co- ₆ -alkylene-C(0)N(R ¹ ) ₂ , -C ₀ -e-alkylene-C(O)O-R ^x , -Co- ₆ -a I ky I e n e-C (O )- R ^x , -Co- ₆ -alkylene-CN, -Co-e-alkylene-COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and 6-membered aryl.

In a most preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, T represents CN, C(0)N(R ¹ )2, C(0)0-R ^x , C(0)-R ^x , COOH, Ci-6-alkyl, or Cs-e-cycloalkyl, wherein alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, - Co- ₆ -alkylene-OH, -Co- ₆ -alkylene-R ^x , -Co- ₆ -alkylene-0-R ^x , -Co- ₆ -alkylene-OC(0)-R ^x , -Co- ₆ - alkylene-S-R ^x , -Co-6-alkylene-S(0)2-R ^x , -C _o-6 -alkylene-S(0)2N(R ¹ )2, -Co-6-alkylene- N(R ¹ ) ₂ , -Co _-6 -alkylene-NR ¹ C(0)R ^x , -Co- ₆ -alkylene-C(0)N(R ¹ ) ₂ , -C _0-6 -alkylene-C(O)O-R ^x , -Co-6-a I ky I e n e-C (O )- R ^x , -Co-e-alkylene-CN, -Co-6-alkylene-COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and 6-membered aryl.

In a further preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, T is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- ₆ -alkylene-OH, and -Co- ₆ -alkylene-CN. In a most preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, T is Ci-e-alkyl.

In a preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, Z represents -C2-3- alkylene-, -O-Ci- ₂ -alkylene-, -Ci-2-alkylene-O-, -C(0)NR ³ -Co-i-aikylene-, -Ci-alkylene- NR ³ C(0)-, -Co-i-alkylene-C(0)NR ³ -, -S(0)t-Ci- ₂ -aikylene-, -Ci- ₂ -alkyiene-S(0)t-, -NR ⁹ - Ci-2-alkylene- or -Ci- ₂ -alkylene-NR ⁹ -, wherein alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of O-C _1-6 - alkyl, Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl.

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

In an even more preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, Z represents -C2-3- alkylene-, -O-Ci-2-alkylene-, -Ci-2-alkylene-O-, -NR ⁹ -Ci-2-alkylene- or -Ci-2-alkylene- NR ⁹ -, wherein alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of O-Ci- ₆ -alkyl, Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl.

In a more preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, Z represents -ethylene-, -O-methylene-, or methylene-O-, with methylene-O- being more preferred,

wherein methylene and ethylene are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of O-Ci- ₆ -alkyl, Ci-e-a!kyl, halogen and halo-Ci- ₆ -alkyl.

In a most preferred embodiment of the compounds according to formula (1 ) or (2) of the compounds according to formula (1 ) in combination with any of the above and below embodiments, Z represents an ethylene group which is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of O-Ci- ₆ -alkyl, Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl. In an utmost most preferred embodiment of the compounds according to formula (1 ) or (2) of the compounds according to formula (1 ) in combination with any of the above and below embodiments, Z represents -CH2-O-.

In a preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, R ⁹ is hydrogen.

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

In an equally preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, m is 2.

In a preferred embodiment of the compounds according to formula (1 ) or (2) in combination with any of the embodiments above and below, o is 0, 1 or 2, more preferably, o is 0 or 1 and most preferred, o is 0.

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

 

and their tautomers or pharmaceutically acceptable salts thereof.

In a more preferred embodiment in combination with any of the embodiments above and below, the compound according to formula (1 ) is selected from

 42

and their pharmaceutically acceptable salts thereof.

In an even more preferred embodiment in combination with any of the embodiments above and below, the compound according to formula (1 ) is selected from

and their pharmaceutically acceptable salts thereof.

In an equally more preferred embodiment in combination with any of the embodiments above and below, the compound according to formula (1 ) is selected from

and their pharmaceutically acceptable salts thereof.

In an even more preferred embodiment in combination with any of the embodiments above and below, the compound according to formula (1 ) is selected from

their pharmaceutically acceptable salts thereof.

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

and its enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof.

The invention further relates to a compound according to formulae (1 ) or (2) for use as medicament.

The compound according to formulae (1 ) or (2) is further useful in the prophylaxis and/or treatment of a disease or condition mediated by indoleamine 2,3-dioxygenase.

In a preferred embodiment in combination with any of the embodiments above and below, the disease or condition is selected from the group consisting of cancer, viral and bacterial infections such as HIV infection, hanta virus infection, tuberculosis, leprae, depression, epilepsy, neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, trauma, age-related cataracts, organ transplantation, cardiovascular disease, endometriosis, type-2 diabetic nephropathy, chronic obstructive pulmonary disease (CORD), osteoporosis, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus.

In a more preferred embodiment in combination with any of the embodiments above and below, the disease or condition is cancer.

In a further preferred embodiment in combination with any of the embodiments above and below, the compound according to formulae (1 ) or (2) is administered with one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, AhR modulator, chemotherapeutic agent, anticancer vaccine, onolytic viruses, TLR agonists, STING agonists, and cytokine therapy as well as other immuno oncology, or wherein the compound is administered under irradiation therapy.

The invention further relates to a pharmaceutical composition comprising a compound according to formulae (1 ) or (2) and pharmaceutically acceptable excipients.

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 -alkyi" 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, CH2CH2CI, and CH2CF3.

A“Cx-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-cycioalkyl 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, pyrrol id iny I, tetrahydrofuranyl, piperidinyl, piperazinyl tetrahydro-pyranyl, 1 ,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1 ,4-dihydropyridinyl, 2- azaspiro [3.3]heptane and 3,6-dihydro-2H-thiopyranyl. The heterocycloalkyl group can be connected to the remainder of the molecule via a carbon atom or nitrogen atom. A 5-14-mem bered 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 A/-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 A/-linked heterocycles are

A 6-10-mem bered 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“ww” 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.

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 Ή” 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 can be in the form of a prodrug compound. "Prodrug compound" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of the prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated. These compounds can be produced from compounds of the present invention according to well-known methods. Other examples of the prodrug are compounds, wherein the carboxylate in a compound of the present invention is, for example, converted into an alkyl-, aryl-, choline-, amino, acyloxymethylester, linolenoylester.

Metabolites of compounds of the present invention are also within the scope of the present invention.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of the present invention or their prodrugs may occur, the individual forms, like e.g. the keto and enol form, are each within the scope of the invention as well as their mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.

If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials. Another way to obtain pure enantiomers from racemic mixtures would use enantioselective crystallization with chiral counterions.

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.

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 I D01 -mediated diseases or conditions such as cancer, viral and bacterial infections such as HIV infection, hanta virus infection, tuberculosis, leprae, depression, epilepsy, neurodegenerative diseases such as Parkinson’s disease, 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, AhR modulators, CTLA-4 agent as well as chemotherapeutic agents, anticancer vaccines, onolytic viruses, TLR agonists, STING agonists, cytokine therapy and other immuno oncology. 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, Estra mu stine 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, Hepa-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. LAG 3) 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

br broad

GDI 1 ,1 '-carbonyldiimidazole

d doublet

DAST diethylaminosulfur trifluoride

DCM dichloromethane

DEAD diethyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

DIPEA A/,/\/-diisopropylethylamine

DMF A/,A/-dimethylformamide

DMSO dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et ₂ 0 diethyl ether

EtOAc ethyl acetate

HBTU 2-(1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate

HATU 0-(7-azabenzotriazol-1-yl)-N,N,N’,A/-tetramethyluronium hexafluorophosphate

HOBt 1 -hydroxybenzotriazole

HPLC high performance liquid chromatography

/- PrOH isopropyl alcohol

LDA lithium diisopropylamide

LiHMDS lithium bis(trimethylsilyl)amide m multiplet

MCPBA 3-chloroperoxybenzoic acid

Ms methanesulfonyl

NBS /V-bromosuccinimide

NCS A/-chlorosuccinimide

PE petroleum ether

prep preparative

PPTS pyridinium p-toluenesulfonate

rt room temperature

RT retention time

SFC supercritical fluid chromatography

t triplet

TEA triethylamine

TFA trifluoroacetic acid

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 and 2 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 the present invention of structure A- 6. Treatment of ketone intermediates of structure A-1 with NaBH ₄ leads to hydroxy intermediates of structure A-2. Under treatment with pyridinium p-toluenesulfonate intermediate A-2 undergoes elimination reaction to the corresponding double bond intermediate A-3. T reatment with lithium bis(trimethylsilyl)amide followed by ferf-butyl bis(2-chloroethyl)carbamate affords the corresponding spirocyclic intermediate A-4. Double bond reduction with, for example, hydrogen and Pd catalysis affords intermediates A-5 which can be deprotected with TFA to give intermediates of structure A-6.

A-6 A-5 A-4

z = -CH ₂ CH ₂ - m = 1 , o = 0

Scheme 1

Scheme 2 shows the synthesis of example compounds of the present invention of structure B-5. Treatment of intermediates A-6 with a-chloro ester intermediate B-1 affords intermediates of structure B-2. Saponification with NaOH gives the corresponding carboxylic acid intermediates B-3 which can undergo amide coupling with B-4 and, for example, HATU to afford compounds of structure B-5. In an alternative synthesis route B-6 is first amide coupled with B-4 and, for example, EDC/HOBt to give intermediates B-7. /V-Alkylation reaction of intermediates A-6 with B- 7 affords compounds of structure B-5.

Scheme 2

Intermediate 1 : 5-Fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine] trifluoroacetate salt

(Int 1 )

Step 1 : 6-Fluoro-2,3-dihydro-1 H-inden-1-ol (Int 1 b)

To a solution of 6-f!uoro-2,3-dihydro-1 H-inden-1-one (Int 1a) (2.00 g, 13.33 mmol) in methanol (20 mL) and DCM (10 mL) was added NaBH ₄ (507 mg, 13.33 mmol) and the mixture was stirred at 0 °C for 15 min and then at rt for 1 h. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (DCM) to give the title compound as a yellow oil. Step 2: 5-Fluoro-1 H-indene (Int 1c)

A mixture of 6-fluoro-2,3-dihydro-1 H-inden-1-ol (Int 1 b) (1.50 g, 9.86 mmol) and pyridinium p-toluenesulfonate (7.43 g, 29.60 mmol) in toluene (12 mL) was stirred at 1 10 °C overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness to give the title compound as a brown oil.

Step 3: ferf-Butyl 5-fluorospiro[indene-1 ,4'-piperidine]-1 '-carboxylate (Int 1d)

Lithium bis(trimethylsilyl)amide (21 mL, 1 M solution in THF) was added dropwise to a cooled solution of 5-fluoro-1 H-indene (Int 1c) (1.30 g, 9.70 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at 0 °C under N ₂ for 1 h. ferf-Butyl bis(2- chloroethyl)carbamate (2.34 g, 9.70 mmol) dissolved in THF (2 mL) was added dropwise at 0 °C and the mixture was stirred at the same temperature for 10 min. The mixture was stirred at rt overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to dryness and the residue was purified by silica gel chromatography (gradient 0-50% DCM in PE) to give the title compound as a yellow solid.

Step 4: ferf-Butyl 5-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate (Int 1e)

A mixture of ferf-butyl 5-fluorospiro[indene-1 ,4'-piperidine]-1 '-carboxylate (Int 1d) (2.00 g, 6.60 mmol) and 10% Pd/C (190 mg) in ethanol (15 mL) was stirred at rt under hydrogen atmosphere for 3 h. The mixture was filtered and the residue was concentrated to dryness to give a colorless oil, which was purified by preparative HPLC to give the title compound.

Step 5: 5-Fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine] trifluoroacetate salt (Int 1 ) To a solution of ferf-butyl 5-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '- carboxylate (Int 1e) (1 18 mg, 0.38 mmol) in DCM (6 mL) was added TFA (1 mL) and the mixture was stirred at rt for 1 h. The mixture was concentrated to dryness to give the title compound as a yellow oil, which was used in the next step directly.

Intermediates 2c, 2d: ferf-Butyl 5,7-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '- carboxylate (Int 2c), ferf-butyl 4,6-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '- carboxylate (Int 2d)

Steps 1-3: Mixture of regioisomers ferf-butyl 5,7-difluorospiro[indene-1 ,4'-piperidine]-1 carboxylate and ferf-butyl 4,6-difluorospiro[indene-1 ,4'-piperidine]-1 '-carboxylate (Int 2b)

The title compound was prepared similar as described for Intermediate i d, steps 1-3 using in step 1 4,6-difluoro-2,3-dihydro-1 H-inden-1-one (Int 2a) in place of 6-fluoro-2,3- dihydro-1 H-inden-1-one.

Step 4: ferf-Butyl 5,7-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate (Int 2c) and ferf-butyl 4,6-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '- carboxylate (Int 2d)

The mixture of regioisomers ferf-butyl 5,7-difluorospiro[indene-1 ,4'-piperidine]-1 '- carboxylate and ferf-butyl 4,6-difluorospiro[indene-1 ,4'-piperidine]-T-carboxylate (Int 2b) (348 mg, 1.08 mmol) and 10% Pd/C (133 mg) in ethanol (15 ml_) was stirred at rt under hydrogen atmosphere for 3 h. The mixture was filtered and concentrated to dryness. The residue was purified by preparative chiral HPLC (AD-H, column 4.6 x 250 mm, 5 pm, 0.1 % diethylamine in n-hexane/0.1 % diethylamine in EtOH = 95:5, flow rate 1 .0 mL/min) to afford the two separated regioisomers. First eluting isomer ferf-butyl 5,7- difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '-carboxylate (Int 2c) with RT = 4.286 min and second eluting isomer ferf-butyl 4,6-difluoro-2,3-dihydrospiro[indene-1 ,4'- piperidine]-1 '-carboxylate (Int 2d) with RT = 4.818 min.

Intermediate 3: 5,7-Difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine] trifluoroacetate salt (Int 3)

Int 3 The title compound was prepared similar as described for Intermediate 1 , step 5 using ferf-butyl 5,7-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate (Int 2c), in place of ferf-butyl 5-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate.

Intermediate 4: 4,6-Difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine] trifluoroacetate salt (Int 4)

Int 4

The title compound was prepared similar as described for Intermediate 1 , step 5 using ferf-butyl 4,6-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate (Int 2d) in place of ferf-butyl 5-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate.

Intermediate 5: 6-Fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine] trifluoroacetate salt

(Int 5)

The title compound was prepared similar as described for Intermediate 1 , step 5 using commercially available ferf-butyl 6-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T- carboxylate in place of ferf-butyl 5-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '- carboxylate.

Intermediate 6: 6-(Trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-2'-o ne (Int 6)

Step 1 : ferf-Butyl 6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidine]-1 '-carboxylate

(Int 6b)

To a solution of 6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine] (Int 6a) (300 mg, 1.21 mmol), TEA (360 mg, 3.63 mmol) in THE (5 mL) and DCM (5 mL) was added di-ferf-butyl dicarbonate (310 mg, 1.62 mmol). The mixture was stirred at rt overnight. Brine (50 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow solid.

Step 2: ferf-Butyl 2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidi ne]-T- carboxylate (Int 6c)

To a mixture of Nal0 ₄ (958 mg, 4.42 mmol), RuCh (46 mg, 0.22 mmol) in water (20 mL) was added a solution of ferf-buty! 6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidine]-1 '-carboxy!ate (Int 6b) (400 mg, 1.11 mmol) in EtOAc (20 mL) and the mixture was stirred at rt overnight. Brine (30 mL) was added and the mixture was extracted with EtOAc (3 x 20 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 = 5: 1 ) to give the title compound as a white solid.

Step 3: 6-(Trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine]-2'- one (Int 6)

A mixture of fe/ -butyl 2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidi ne]-T- carboxylate (Int 6c) (700 mg, 1.92 mmol) in HCI (4M in dioxane, 8 mL) was stirred at 0 °C for 3 h. The mixture was concentrated to dryness to give the title compound as a white solid.

Intermediate 7: 7-(Trifluoromethyl)spiro[chromane-4,4'-piperidine] (Int 7)

Step 1 : 1-Benzyl-4-(2-hydroxyethyl)pyridin-1-ium bromide (Int 7c)

To a solution of 2-(pyridin-4-yl)ethan-1-ol (Int 7a) (2.00 g, 16.30 mmol) in ChhCN (20 mL) was added (bromomethyl)benzene (Int 7b) (3.32 g, 19.60 mmol). The mixture was refluxed for 3 h. The solution was concentrated to dryness to give the title compound as a yellow solid.

Step 2: 2-(1 -Benzyl-1 ,2,3, 6-tetrahydropyridin-4-yl)ethan-1-ol (Int 7d)

To a solution of 1 -benzyl-4-(2-hydroxyethyl)pyridin-1 -ium bromide (Int 7c) (2.50 g, 8.53 mmol) in MeOH (30 mL) was added NaBhU (648 mg, 17.10 mmol) at -20 °C, and the mixture was stirred at this temperature for 0.5 h. The mixture was poured into water (30 mL) and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed by brine (2 x 30 mL), dried over Na2S0 ₄ , and concentrated to dryness. The residue was purified by column chromatography on silica gel (EtOAc) to give the title compound as a yellow oil.

Step 3: 1-Benzyl-4-(2-(2-bromo-5-(trifluoromethyl)phenoxy)ethyl)-1 ,2,3,6-tetrahydro- pyridine (Int 7e)

To a solution of 2-(1 -benzyl-1 ,2,3,6-tetrahydropyridin-4-yl)ethan-1-ol (Int 7d) (800 mg, 3.69 mmol), 2-bromo-5-(trifluoromethyl)phenol (885 mg, 3.69 mmol) and PPfb (1.45 g, 5.54 mmol) in THF (20 mL) was added DEAD (962 mg, 5.54 mmol) under Ar. The mixture was stirred at rt overnight. The mixture was concentrated to dryness 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 4: 1 '-Benzyl-7-(trifluoromethyl)spiro[chromane-4,4'-piperidine] (Int 7f)

A solution of 1-benzyl-4-(2-(2-bromo-5-(trifluoromethyl)phenoxy)ethyl)-1 ,2,3,6- tetrahydropyridine (Int 7e) (1.00 g, 2.28 mmol), n-Bu3SnH (1.33 g, 4.56 mmol) and AIBN (75 mg, 0.46 mmol) in toluene (20 mL) was refluxed for 3 h. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (PE:EtOAc = 15: 1 ) to give the title compound as a yellow solid.

Step 5: 7-(Trifluoromethyl)spiro[chromane-4,4'-piperidine] (Int 7)

To a solution of T-benzyl-7-(trifluoromethyl)spiro[chromane-4,4'-piperidine] (Int 7f) (600 mg, 1.66 mmol) in 1 ,2-dichloroethane (10 mL) was added 1-chloroethyl carbonochloridate (1.18 g, 8.30 mmol) under Ar and the mixture was refluxed overnight. The mixture was concentrated. MeOH (10 mL) was added and the mixture was refluxed for 3 h. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (PE:EtOAc = 4:1 ) to give the title compound as a yellow solid.

Intermediate 8: 6-(T rifluoromethyl)-2H-spiro[benzo[b]thiophene-3,4'-piperidine] hydrogen chloride (Int 8)

Step 1 : 4-(((2-Bromo-5-(trifluoromethyl)phenyl)thio)methyl)pyridine (Int 8c)

A mixture of 2-bromo-5-(trifluoromethyl)benzenethiol (Int 8b) (2.06 g, 8.00 mmol), 4- (chloromethyl)pyridine hydrochloride (Int 8a) (1.32 g, 8.00 mmol) and K ₂ CO ₃ (3.32 g, 24.00 mmol) in DMF (50 mL) was stirred at rt overnight. The mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (4 x 100 mL) and brine (100 ml_), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness to give the title compound as a brown oil.

Step 2: 4-(((2-Bromo-5-(trifluoromethyl)phenyl)thio)methyl)-1-(4-met hoxybenzyl) pyridin-1 -ium chloride (Int 8d)

A mixture of 4-(((2-bromo-5-(trifluoromethyl)phenyl)thio)methyl)pyridine (Int 8c) (2.30 g, 6.62 mmol) and 4-methoxybenzyl chloride (2.07 g, 13.24 mmol) in 1 ,2-dichloroethane (50 mL) was heated to reflux overnight. After cooling to rt the mixture was concentrated to dryness. The residue was washed with petrol ether and dried to give the title compound as a brown semi-solid.

Step 3: 4-(((2-Bromo-5-(trifluoromethyl)phenyl)thio)methyl)-1 -(4-methoxybenzyl)-

1 ,2,3,6-tetrahydropyridine (Int 8e)

To a solution of 4-(((2-bromo-5-(trifluoromethyl)phenyl)thio)methyl)-1-(4-met hoxy- benzyl)pyridin-1-ium chloride (Int 8d) (3.33 g, 6.60 mmol) in MeOH (100 mL) was added NaBH ₄ (750 mg, 19.80 mmol) at -10 °C, and the mixture was allowed to warm to rt slowly and stirred overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (PE:EtOAc = 4: 1 ) to give the title compound as a slight yellow oil.

Step 4: 1 '-(4-Methoxybenzyl)-6-(trifluoromethyl)-2/-/-spiro[benzo[b]t hiophene-3,4'- piperidine] (Int 8f)

A solution of 4-(((2-bromo-5-(trifluoromethyl)phenyl)thio)methyl)-1 -(4-methoxybenzyl)- 1 ,2,3,6-tetrahydropyridine (Int 8e) (1.35 g, 2.86 mmol), n-Bu SnH (2 mL) and AIBN (150 mg) in toluene (50 mL) was refluxed overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (0.25% Et N in PE:EtOAc = 4:1 - 3:1 ) to give the title compound as a yellow oil.

Step 5: 6-(Trifluoromethyl)-2H-spiro[benzo[b]thiophene-3,4'-piperidi ne] hydrogen chloride (Int 8)

To a solution of T-(4-methoxybenzyl)-6-(trifluoromethyl)-2H-spiro[benzo[b]thi ophene-

3,4'-piperidine] (Int 8f) (610 mg, 1.55 mmol) in 1 ,2-dichloroethane (50 mL) was added 1 -chloroethyl carbonochloridate (2.65 g, 18.50 mmol) under Ar. The mixture was refluxed overnight. The mixture was concentrated to dryness and the residue was dissolved in MeOH (50 mL). The mixture was refluxed for 3 h and concentrated to dryness. The residue was triturated with hexane to give the title compound as a yellow solid. Intermediate 9: 6'-(Trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofuran] hydrochloride (Int 9)

Int 91 Int 9J Int 9k Int 9 Step 1 : 1 ,4-Dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (Int 9b)

To a solution of 1 ,4-dioxaspiro[4.5]decan-8-one (Int 9a) (1.20 g, 7.69 mmol) and 1 ,1 , 1- trifluoro-A/-phenyl-A/-((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 H2O (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSC , 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 9c)

A mixture of 1 ,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (Int 9b) (7.69 mmol, crude), Pd(PPh3)2Cl2 (291 mg, 1 .1 1 mmol), and TEA (1.14 g, 1 1.04 mmol) in MeOH (20 mL) was stirred at rt overnight under a carbon monoxide atmosphere at 5 bar pressure. The reaction mixture was quenched with H2O (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 9d)

To a solution of methyl 1 ,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate (Int 9c) (1.20 g, 6.06 mmol) in dry THE (50 m!_) was added UAIH4 (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 9e)

To a solution of (1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)methanol (Int 9d) (340 mg, 2.00 mmol), 2-bromo-5-(trifluoromethyl)phenol (482 mg, 2.00 mmol) and PPh ₃ (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-(T rifluoromethyl)-2H-dispiro[benzofuran-3, 1 '-cyclohexane-4', 2"-

[1 ,3]dioxolane] (Int 9f)

A solution of 8-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)-1 ,4-dioxaspiro[4.5]dec-7- ene (Int 8e) (393 mg, 1.00 mmol), n-Bu ₃ SnH (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)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-one (Int 9g)

To a solution of 6-(trifluoromethyl)-2H-dispiro[benzofuran-3,1 '-cyclohexane-4', 2"- [1 ,3]dioxolane] (Int 9f) (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 MgSC , filtered and concentrated 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: 2H-6-(Trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-one oxime (Int 9h)

A solution of 6-(trifluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'-one (Int 9g) (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'H-spiro[azepane-4,3'-benzofuran]-7-on e (Int 9i)

To a solution of 2H-6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '-one oxime (Int 9h) (2.85 g, 10.00 mmol) in THF (30 mL) was added SOCh (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'H-spiro[azepane-4,3'-benzofu ran]-7-one (Int 9j)

To a solution of 6'-(trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofuran]-7-on e (Int 9i)

(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'H-spiro[azepane-4,3'-benzofu ran] (Int 9k)

To a solution of 1-benzyl-6'-(trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofu ran]-7-one

(Int 9j) (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 HOI (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'H-spiro[azepane-4,3'-benzofuran] hydrochloride (Int 9)

To a solution of 1-benzyl-6'-(trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofu ran] (Int 9k)

(550 mg, 1.52 mmol) in 1 ,2-dichloroethane (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 grey solid.

Intermediate 10: 2-(2,3-Dihydrospiro[indene-1 ,4'-piperidine]-T-yl)acetic acid (Int 10)

Int 10a Int 10b Int 10

Step 1 : ferf-Butyl 2-(2,3-dihydrospiro[indene-1 ,4'-piperidin]-1 '-yl)acetate (Int 10b)

To a mixture of 2,3-dihydrospiro[indene-1 ,4'-piperidine] (Int 10a) (100 mg, 0.55 mmol) and ferf-butyl 2-bromoacetate (129 mg, 0.66 mmol) in DCM (5 mL) was added TEA (139 mg, 1.38 mmol) and the mixture was stirred at rt for 2 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness to give the title compound as a white solid.

Step 2: 2-(2,3-Dihydrospiro[indene-1 ,4'-piperidine]-T-yl)acetic acid (Int 10)

To a mixture of ferf-buty! 2-(2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-yl)acetate (Int

10b) (92 mg, 0.31 mmol) in DCM (5 mL) was added TEA (2 mL) and the mixture was stirred at rt for 30 min. The mixture was concentrated to dryness to give the title compound as a brown oil.

Intermediate 11 : 2-(2,3-Dihydrospiro[indene-1 ,4'-piperidine]-1 '-yl)propanoic acid (Int 11 )

Int 10a Int 11b Int 11 Stepl : Methyl 2-(2,3-dihydrospiro[indene-1 ,4'-piperidin]-1 '-yl)propanoate (Int 11 b)

To a mixture of 2,3-dihydrospiro[indene-1 ,4'-piperidine] (Int 10a) (100 mg, 0.55 mmol) and methyl 2-bromopropanoate (1 10 mg, 0.66 mmol) in DCM (5 mL) was added TEA (139 mg, 1.38 mmol) and the mixture was stirred at rt for 2 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2S0 ₄ and concentrated to dryness to give the title compound as a white solid.

Step 2: 2-(2,3-Dihydrospiro[indene-1 ,4'-piperidine]-1 '-yl)propanoic acid (Int 11 )

To a mixture of methyl 2-(2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-yl)propanoate (Int 11 b) (85 mg, 0.31 mmol) in MeOH (2 mL) was added aqueous NaOH (2M, 1 mL) and the mixture was stirred at rt for 3 h. The mixture was concentrated and the pH was adjusted to pH < 4 with 2M HCI. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SC>3, filtered and concentrated to dryness to give the title compound as a brown oil.

Intermediate 12: 2-(2'-Oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piper idine]-1 '- yl)propanoic acid (Int 12)

Step 1 : Methyl 2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piper idine]-T-yl) propanoate (Int 12a)

To a mixture of 6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine]-2'- one (Int 6)

(300 mg, 1.12 mmol) in dry THE (20 mL) was added NaH (60%, 260 mg, 6.72mmol) and the mixture was stirred at rt for 10 min. Methyl 2-bromopropanoate (540 mg, 6.62 mmol) was added and the mixture was stirred under reflux overnight. Brine (30 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow oil. Step 2: 2-(2'-Oxo-6-(trifluoromethyi)-2H-spiro[benzofuran-3,4'-piper idine]-T-yl) propanoic acid (Int 12)

To a mixture of methyl 2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidine]-T-yl)propanoate (Int 12a) (630 mg) in a mixture of MeOH and THF (6 mL, 1 :1 ), was added LiOH (3 mL, 1.5M solution in water). The mixture was stirred at rt overnight. The pH of the mixture was adjusted to pH = 5-6 with 1 M aqueous HCI and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na ₂ S0 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 white solid.

Intermediate 13: 2-Methyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-pip eridine]-

1 '-yl)propanoic acid (Int 13)

Int 6a Int 13

A solution of 6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine] (Int 6a) (200 mg, 0.78 mmol), 2-bromo-2-methylpropanoic acid (130 mg, 0.78 mmol) and DIPEA (302 mg, 2.34 mmol) in Ch CN (20 mL) was stirred at 80 °C overnight. After cooling to rt the mixture was concentrated to dryness to give the title compound as a yellow oil which was used in the next step without further purification.

Intermediates 13/1 -13/3

The following Intermediates were prepared similar as described for Intermediate 13 using the appropriate building blocks.

Intermediate 14: 4-Amino-4-oxo-2-(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3 ,4'- piperidin]-1 '-yl)butanoic acid (Int 14)

Step 1 : 4-Amino-2-bromo-4-oxobutanoic acid (Int 14b)

To a solution of D,L-asparagine (3.00 g, 20.00 mmol) and KBr (3.57 g, 30.00 mmol) in 2N aqueous H ₂ SO ₄ (50 mL) was added NaN0 ₂ (2.76 g, 40.00 mmol) in portions at -10 °C. The mixture was allowed to warm to rt slowly and stirred overnight. The mixture was diluted with water (30 mL) and extracted with a mixture of THF/EtOAc (4:1 , 3 x 50 mL). The combined organic layers were concentrated to give a residue, which was stirred with EtOAc (50 mL) and filtered. The filtrate was concentrated to dryness to give the title compound as a yellow solid. Step 2: 4-Amino-4-oxo-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4 '-piperidin]-1 yl)butanoic acid (Int 14)

To a mixture of 4-amino-2-bromo-4-oxobutanoic acid (Int 14b) (196 mg, 1.00 mmol), and 6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine] hydrochloride (293 mg, 5 1 .00 mmol) in acetonitrile (20 ml_) was added DIPEA (2 ml_). The mixture was stirred at

80 °C overnight. The mixture was concentrated to dryness to give the title compound as a yellow solid, which was used in the next step without further purification.

Intermediate 15: 2-Bromo-A/-(4-chlorophenyl)-3-cyclopropylpropanamide (Int 15)

^■ \ Q Int 15 Int 15g Int 15f Int 15e

Step 1 : Ethyl 2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxylate (Int 15b)

A solution of ethyl 1 ,3-dithiane-2-carboxylate (10.00 g, 52.00 mmol) and (bromom ethyl )cyclopropane (7.02 g, 52.00 mmol) in dry DMF (20 ml_ ) was added dropwise over a period of 20 min to an ice cooled suspension of NaH (60% oil

15 dispension, 4.20 g, 104.00 mmol) in toluene (60 ml_). The mixture was stirred at rt overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (2 x 50 ml_). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to give the title compound as a yellow oil.

20 Step 2: 2-(Cyclopropylmethyl)-1 , 3-d ith ia ne-2-ca rboxyl ic acid (Int 15c)

To a solution of ethyl 2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxylate (Int 15b) (2.00 g, 8.12 mmol) in EtOH (30 mL) was added 2 M NaOH (10 mL), and the mixture was stirred at 50 °C for 4 h. After cooling, the solution was adjusted to pH = 3-4 with 1 M HCI, and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a white solid.

Step 3 : A/-(4-Chlorophenyl)-2-(cyc!opropylmethyl)-1 ,3-dithiane-2-carboxamide (Int 15d)

A mixture of 2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxylic acid (Int 15c) (1.70 g, 7.78 mmol), 4-chloroaniline (1.00 g, 7.78 mmol), HATU (4.43 g, 1 1 .67 mmol) and DIPEA (3.00 g, 23.34 mmol) in DMF (30 mL) was stirred at rt overnight. Water (50 ml_) was added and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5: 1 ) to give the title compound as a yellow solid.

Step 4: N-(4-Chlorophenyl)-2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxamide (Int 15e)

To a solution of A/-(4-chlorophenyl)-2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxamide (Int 15d) (2.00 g, 6.10 mmol) in acetone (24 mL ) and H2O (6 mL) was added NBS (1.63 g, 9.10 mmol) at 0 °C. The mixture was stirred at rt overnight. The mixture was concentrated and the residue was mixed with EtOAc (30 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 2:1 ) to give the title compound as a white solid.

Step 5: /V-(4-Chlorophenyl)-3-cyclopropyl-2-hydroxypropanamide (Int 15f)

To a solution of A/-(4-chlorophenyl)-2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxamide (Int 15e) (420 mg, 1 .77 mmol) in EtOH (20 mL) was added NaBH ₄ (100 mg, 2.65 mmol) at 0 °C, and the mixture was stirred at rt for 4 h. The mixture was concentrated and the residue was mixed with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL), and the combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 1 :1 ) to give the title compound as a white solid.

Step 6: 1-((4-Chlorophenyl)amino)-3-cyclopropyl-1-oxopropan-2-yl methanesulfonate

(Int 15g)

To a solution of A/-(4-chlorophenyl)-3-cyclopropyl-2-hydroxypropanamide (Int 15f) (380 mg, 1.58 mmol) and DIPEA (613 mg, 4.76 mmol) in DOM (20 mL) was added MsCI (2 mL) at 0 °C, and the mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 ml_). The combined organic layers were washed with brine, dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow solid.

Step 7: 2-Bromo-A/-(4-chlorophenyl)-3-cyclopropylpropanamide (Int 15)

A mixture of 1-((4-chlorophenyl)amino)-3-cyclopropyl-1-oxopropan-2-yl methane- sulfonate (Int 15g) (420 mg, 1.32 mmol) and LiBr (574 mg, 6.60 mmol) in acetone (20 mL) was stirred at 50 °C overnight. The mixture was concentrated and the residue was mixed with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL), and 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 = 2:1 ) to give the title compound as a white solid.

Intermediate 16: 3-(4-Fluorophenyl)-2-(6-(trifluoromethyl)-2/-/-spiro[benzofu ran-3,4'- piperidin]-T-yl)propanoic acid (Int 16)

Step 1 : Methyl 3-(4-fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofura n-3,4'- piperidin]-T-yl)propanoate (Int 16b)

To a solution of Methyl 2-bromo-3-(4-fluorophenyl)propanoate (Int 16a) (586 mg, 2.00 mmol), 6-(trifluoromethyl)- 2H-spiro[benzofuran-3,4'-piperidine] hydrochloride (624 mg, 2.40 mmol) in acetonitrile (10 mL) was added DIPEA (645 mg, 5.00 mmol) and the mixture was stirred at 80 °C overnight. Water was added and the mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over Na2S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography (PE: EtOAc = 10:1 ) to give the title compound as a yellow solid.

Step 2: 3-(4-Fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofura n-3,4'-piperidin]-T- yl)propanoic acid (Int 16) To a solution of methyl 3-(4-fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofura n- 3,4'-piperidin]-T-yl)propanoate (Int 16b) (480 mg, 1.10 mmol) in MeOH (10 mL) was added aqueous NaOH (2M, 2 mL) and the mixture was stirred at 70 ⁰ C overnight. The mixture was concentrated and water (5 mL) was added. The pH was adjusted to pH = 4 with aqueous HCI (2M). The precipitated solid was filtered and the filter residue was dried to give the title compound as a white solid.

Intermediates 16/1 -16/2

The following Intermediates were prepared similar as described for Intermediate 16 using the appropriate building blocks.

Intermediate 17: 1-Bromo-N-(4-chlorophenyl)cyclobutane-1 -carboxamide (Int 17)

Int 17a Int 17b Int 17

Step 1 : 1 -Bromocyclobutane-1 -carboxylic acid (Int 17b)

To a solution of methyl 1 -bromocyclobutane-1 -carboxylate (192 mg, 1.00 mmol) in MeOH (4 mL) was added aqueous NaOH (2M, 1 mL) at rt and the mixture was stirred for 2 h. Water (20 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ S0 ₄ , filtered and concentrated to to dryness to give the title compound as a yellow solid. Step 2: 1-Bromo-/V-(4-chlorophenyl)cyclobutane-1 -carboxamide (Int 17) To a solution of 1 -bromocyclobutane-1 -carboxylic acid (Int 17b) (1 15 mg, 0.65 mmol) in DCM (5 ml_) was added SOCI2 (190 mg, 1.62 mmol) and the mixture was stirred at 40 0 C for 1 h. The mixture was concentrated and the residue was dissolved in DCM (20 ml_). EbN (131 mg, 1.30 mmol) and 4-chloroaniline (99 mg, 0.78 mmol) were added and the mixture was stirred at rt overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography (PE:EtOAc = 10:1 ) to give the title compound as a white solid.

Intermediates 17/1-17/2

The following Intermediates were prepared similar as described for Intermediate 17 using the appropriate building blocks.

Intermediate 20: 2-Chloro-/\/-(4-chlorophenyl)propanamide (Int 20)

Int 20a Int 20

To a solution of 4-chloroaniline (2.00 g, 15.75 mmol) (Int 20a) in DCM (20 ml_) was added 2-chloropropanoic acid (3.40 g, 31.49 mmol), EDC (3.93 g, 20.47 mmol), DIPEA (6.09 g, 47.24 mmol) and HOBt (2.76 g, 20.47 mmol). The mixture was stirred at rt overnight. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (gradient 0-50% DCM in PE) to give the title compound. Intermediate 21 : 2-Bromo-A/-(4-chlorophenyl)propanamide (Int 21 )

Int 20a Int 21

To a solution of 2-bromopropanoic acid (3.06 g, 20.00 mmol) in DCM (15 mL) was added oxalyl dichloride (6 mL, 70.00 mmol) followed by 2 drops of DMF. The mixture was stirred at rt for 30 min. The mixture was concentrated and the residue was added to a solution of 4-chloroaniline (1.95 g, 15.3 mmol) (Int 20a) and TEA (5.67 g, 56.20 mmol) in dry DCM (15 mL) at 0 °C. The mixture was stirred for 18 h at rt. The mixture was poured into ice-water and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a solid.

Intermediate 21/1 : 2-Bromo-N-(4-chlorophenyl)butanamide (Int 21/1 )

Int 21/1

The title compound was prepared similar as described for Intermediate 21 , using 2- bromobutanoic acid in place of 2-bromopropanoic acid.

Example 1 : A/-(4-Chlorophenyl)-2-(2,3-dihydrospiro[indene-1 ,4'-piperidin]-1 '- yl)acetamide (1 )

Int 10 Example 1 A mixture of 2-(2,3-dihydrospiro[indene-1 ,4'-piperidin]-T-yl)acetic acid (Int 10) (65 mg, 0.27 mmol), HATU (154 mg, 0.41 mmol) and DIPEA (87 mg, 0.68 mmol) in DMF (5 mL) was stirred at rt for 1 h. 4-Chloroaniline (41 mg, 0.32 mmol) was added and the mixture was stirred overnight at rt. Water (20 ml_) was added and the mixture was extracted with EtOAc (3 x 20 ml_). The combined organic layers were washed with brine (20 mL), dried over anhydrous 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-de): d ppm 9.89 (s, 1 H), 7.73 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.26-7.12 (m, 4H), 3.17 (s, 2H), 2.86-2.82 (m, 4H), 2.38-2.34 (m, 2H), 1 .97-1.92 (m, 4H), 1.46-1 .30 (m, 2H). MS (ESI): m/z 355.2 [M+H] ⁺ .

Examples 1/1 to 1/10

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

Example 1 /3a: Stereoselective route for (S)-A/-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-

2H-spiro[benzofuran-3,4'-piperidin]-1 '-yl)butanamide (1/3a)

Step 1 : Methyl (R)-2-((methylsulfonyl)oxy)butanoate (Int 1/3b)

To a solution of methyl (R)-2-hyd roxy buta noate (1 18 mg, 1.00 mmol) in DCM (5 ml_) was added MsCI (171 mg, 1.50 mmol) and TEA (253 mg, 2.50 mmol) at 0 °C and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM (20 mL). The combined organic layers were washed with brine (20 ml_), dried over Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a colorless oil.

Step 2: Methyl (S)-2-(6-(trifluorom ethyl )-2/- -spiro[benzofuran-3,4'-piperidin]-T· yl)butanoate (Int 1/3c) To a solution of methyl (R)-2-((methylsulfonyl)oxy)butanoate (Int 1/3b) (141 mg, 0.72 mmol) in DMF (20 mL) was added K ₂ CO ₃ (199 mg, 1.44 mmol) and 6-(trifluoromethyl)- 2H-spiro[benzofuran-3,4'-piperidine] hydrochloride (253 mg, 0.86 mmol). The mixture was stirred at 50 °C overnight. Water was added and the mixture was extracted with EtOAc (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 column chromatography (PE: EtOAc = 10:1 ) to give the title compound as a yellow solid.

Step 3: (S)-2-(6-(Trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidi n]-1 '-yl)butanoic acid (Int 1/3d)

To a solution of methyl (S)-2-(6-(trifluoromethyl)-2F/-spiro[benzofuran-3,4'-piperid in]-T- yl)butanoate (Int 1/3c) (88 mg, 0.25 mmol) in MeOH (2 mL) was added aqueous KOH (2M, 2 mL) and the mixture was stirred at rt overnight. The mixture was concentrated, water (2 mL) was added and the pH was adjusted to pH = 4 with aqueous HCI (2M). The precipitated solid was filtered and the residue was dried to give the title compound as a white solid.

Step 4: (S)-/V-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benz ofuran-3,4'- piperidin]-T-yl)butanamide (1/3a)

To a solution of (S)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidi n]-T- yl)butanoic acid (Int 1/3d) (59 mg, 0.17 mmol) in DMF (3 mL) was added HATU (97 mg, 0.26 mmol) and DIPEA (55 mg, 0.43 mmol). The mixture was stirred at rt for 1 h. 4- Chloroaniline (26 mg, 0.20 mmol) was added and the mixture was stirred at rt overnight. Water (20 mL) was added and the mixture was 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 column chromatography (PE: EtOAc = 2:1 ) to give the title compound as a white solid. ¹ H NMR (500 MHz, DMSO-de): d ppm 10.03 (s, 1 H), 7.70-7.67 (m, 2H), 7.45 (d, 8.0 Hz, 1 H), 7.39-7.36 (m, 2H), 7.21 (d, J = 7.1 Hz, 1 H), 7.09 (s, 1 H), 4.44 (s, 2H), 3.14-3.1 1 (m, 1 H), 3.94-2.87 (m, 2H), 2.41 -2.37 (m, 1 H), 2.30-2.26 (m, 1 H), 1.92-1.64 (m, 6H), 0.89 (t, J = 7.4 Hz, 3H). MS (ESI): 453.0 [M+H] ⁺ .

Example 1/3b: (R)-N-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzo furan-3,4'· piperidin]-1 '-yl)butanamide (1/3b) prepared by chiral separation

A/-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofur an-3,4'-piperidin]-T- yl)butanamide (1/3) was subjected to separation by chiral SFC (AD-H, 4.6 x 100 mm, C0 ₂ /Me0H 80/20) to afford (R)-A/-(4-chlorophenyl)-2-(6-(trifluoromethyi)-2H- spiro[benzofuran-3,4'-piperidin]-1 '-yl)butanamide (1/3b) as the first eluting enantiomer. The absolute configuration of Example 1/3 b was assigned by chiral HPLC comparison with Example 1/3a. ¹ H NMR (500 MHz, DMSO-de): d ppm 10.03 (s, 1 H), 7.69 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 7.7 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1 H), 7.09 (s, 1 H), 4.44 (s, 2H), 3.14-3.1 1 (m, 1 H), 2.95-2.87 (m, 2H), 2.41 -2.36 (m, 1 H), 2.31-2.25 (m, 1 H), 1.93-1.64 (m, 6H), 0.89 (t, J = 7.4 Hz, 3H). MS (ESI): 453.0 [M+H] ⁺ .

Example 2: A/-(4-Chlorophenyl)-2-(6-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidin]-1 '- yl)propanamide (2)

F To a solution of 6-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine] trifluoroacetate salt (Int 5) (67 mg, 0.21 mmol) in DMF (3 mL) was added 2-chloro-A/-(4- chlorophenyl)propanamide (Int 20) (71 mg, 0.33 mmol), K2CO3 (90 mg, 0.65 mmol) and Kl (109 mg, 0.65 mmol). The mixture was stirred at 90 °C under microwave irradiation for 1.5 h. The mixture was concentrated to dryness and the residue was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (500 MHz, DMSO-de): d ppm 9.94 (s, 1 H), 7.72 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.20- 7.18 (m, 1 H), 7.10-7.08 (m, 1 H), 6.96-6.90 (m, 1 H), 3.34-3.30 (m, 2H), 2.83- 2.72 (m, 4H), 2.35-2.31 (m, 1 H), 2.01 -1.86 (m, 4H), 1.49-1.46 (m, 2H), 1.21 (d, J = 6.9 Hz, 3H). MS (ESI): 387.1 [M+H] ⁺ . Examples 2/1 to 2/3

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

Example 3: 2-(5-Chloro-3H-spiro[isobenzofuran-1 ,4'-piperidin]-1 '-yl)-A/-(4-chlorophenyl) propanamide (3)

A mixture of NaH (36 mg, 1.50 mmol) and 5-chloro-3H-spiro[isobenzofuran-1 ,4'- piperidine] hydrochloride (130 mg, 0.50 mmol) in DMF (3 ml_) was stirred at 0°C for 20 min. A solution of 2-bromo-/V-(4-chlorophenyl)propanamide (Int 21 ) in DMF was added dropwise at 0°C and the mixture was stirred at rt overnight. The mixture was diluted with water (20 ml_) 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 to dryness. The residue was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (500 MHz, DMSO-de): d ppm 9.97 (s, 1 H), 7.73-7.71 (m, 2H), 7.39- 7.31 (m, 5H), 4.94 (s, 2H), 3.38-3.33 (m, 1 H), 2.78-2.64 (m, 3H), 2.54-2.51 (m, 1 H), 1 .99-1.95 (m, 2H), 1.65-1.62 (m, 2H), 1.21 (d, J = 6.9 Hz, 3H). MS (ESI): 405.2 [M+H] ⁺ .

Example 3/1

The following Example was prepared similar as described for Example 3 using the appropriate building blocks.

Examples 10b, 10c, 10d, 10e: Separate isomers of N- (4-chlorophenyl)-2-(2'-oxo-6- (trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T-yl)p ropanamide (10b, 10c, 10d, 10e)

Examples 10b, 10c, IQd, 10@ configurations not assigned

Step 1 : N-(4-Chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[be nzofuran-3,4'- piperidin]-1 '-yl)propanamide, mixture of isomers (10a)

To a solution of 2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piper idine]-T- yl)propanoic acid (200 mg, 0.58 mmol) (Int 12), HBTU (330 mg, 0.87 mmol) and 4- chloroaniline (147 mg, 1.16 mmol) in DMF (15 mL) 4-methylmorpholine (175 mg, 1.74 mmol) was added. The mixture was stirred at rt for 3 h. Brine (30 mL) was added and the mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous 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.

Step 2: Separate isomers A/-(4-Chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidin]-T-yl)propanamide (10b, 10c, 10d, 10e)

The mixture of isomers A/-(4-chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidin]-1 '-yl)propanamide (10a) was separated by preparative TLC (silica gel plate, PE/EtOAc = 4:5) to afford a faster eluting fraction A (single diastereomer, racemate) and a slower eluting fraction B (single diastereomer, racemate).

Fraction A was further separated by preparative chiral-SFC (stationary phase CHIRALCEL OD (Daicel), mobile phase CCte/MeOH) to afford two separate enantiomers of A/-(4-chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[b enzofuran- 3,4'-piperidin]-T-yl)propanamide (10b and 10c).

First eluting enantiomer of A-(4-chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidin]-T-yl)propanamide from fraction A (10b), (RT of 2.77 min with the following analytical SFC-conditions: column OD-H (4.6 x 100 mm, 5 pm), mobile phase 80% CO2 / 20% MeOH, flow rate 2 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, CD3OD): d ppm d 7.60-7.50 (m, 2H), 7.36 (d, J = 7.8 Hz, 1 H), 7.33-

7.26 (m, 2H), 7.23 (d, J = 7.8 Hz, 1 H), 7.05 (s, 1 H), 5.14 (q, J = 7.4 Hz, 1 H), 4.53 (d, J

= 9.2 Hz, 1 H), 4.40 (d, J = 9.2 Hz, 1 H), 3.68-3.51 (m, 2H), 2.74-2.61 (m, 2H), 2.30-2.20 (m, 1 H), 2.17-2.01 (m, 1 H), 1.55 (d, J = 7.4 Hz, 3H). MS (ESI): 475.1 [M+Na] ⁺ .

Second eluting enantiomer of A/-(4-chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidin]-T-yl)propanamide from fraction A (10c), (RT of 3.17 min with the following analytical SFC-conditions: column OD-H (4.6 x 100 mm, 5 pm), mobile phase 80% CO2 / 20% MeOH, flow rate 2 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, CD3OD): d ppm 7.61-7.50 (m, 2H), 7.36 (d, J = 7.8 Hz, 1 H), 7.34-

7.27 (m, 2H), 7.23 (d, J = 7.8 Hz, 1 H), 7.05 (s, 1 H), 5.14 (q, J = 7.4 Hz, 1 H), 4.53 (d, J

= 9.2 Hz, 1 H), 4.40 (d, J = 9.2 Hz, 1 H), 3.66-3.51 (m, 2H), 2.74-2.61 (m, 2H), 2.30-2.20 (m, 1 H), 2.17-2.04 (m, 1 H), 1.55 (d, J = 7.4 Hz, 3H). MS (ESI): 453.1 [M+H] ⁺ .

Fraction B was separated by preparative chiral-SFC (stationary phase CHIRALCEL OD (Daicel), mobile phase C02/MeOH) to afford two separate enantiomers of N-(4- chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofu ran-3,4'-piperidine]-T- yl)propanamide (10d and 10e). First eluting enantiomer of A/-(4-chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidine]-T-yl)propanamide from fraction B (10d), (RT of 2.48 min with the following analytical SFC-conditions: column OD-H (4.6 x 100 mm, 5 pm), mobile phase 80% CO2 / 20% MeOH, flow rate 2 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, CD ₃ OD): d ppm 7.63-7.49 (m, 3H), 7.39-7.24 (m, 2H), 7.16 (d, J = 7.8 Hz, 1 H), 7.03 (s, 1 H), 5.15 (q, J = 7.4 Hz, 1 H), 4.52 (d, J = 9.1 Hz, 1 H), 4.35 (d, J = 9.1 Hz, 1 H), 3.73-3.50 (m, 2H), 2.68 (s, 2H), 2.32-2.14 (m, 1 H), 2.14-1.99 (m, 1 H), 1.53 (d, J = 7.4 Hz, 3H). MS (ESI): 453.1 [M+H] ⁺ .

Second eluting enantiomer of A/-(4-chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidine]-T-yl)propanamide from fraction B (10e), (RT of 3.12 min with the following analytical SFC-conditions: column OD-H (4.6 x 100 mm, 5 pm), mobile phase 80% CO2 / 20% MeOH, flow rate 2 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, CD3OD): d ppm 7.63-7.47 (m, 3H), 7.36-7.27 (m, 2H), 7.16 (d, J = 7.6 Hz, 1 H), 7.03 (s, 1 H), 5.15 (q, J = 7.4 Hz, 1 H), 4.52 (d, J = 9.1 Hz, 1 H), 4.35 (d, J = 9.1 Hz, 1 H), 3.71 -3.50 (m, 2H), 2.68 (s, 2H), 2.30-2.16 (m, 1 H), 2.16-2.00 (m, 1 H), 1.53 (d, J = 7.4 Hz, 3H). MS (ESI): 453.1 [M+H] ⁺ .

Example 20: A/-(4-chlorophenyl)-4-hydroxy-2-(6-(trifluoromethyl)-2H-spir o[benzofuran- 3,4'-piperidin]-1 '-yl)butanamide (20)

Step 1 : 3-(6-(T rifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T-yl)dih ydrofuran-

2(3H)-one (20b)

To a mixture of 3-bromodihydrofuran-2(3H)-one (20a) (330 mg, 2.00 mmol) and 6- (trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine] hydrochloride (586 mg, 2.00 mmol) in CH3CN (20 mL) was added DIPEA (2 mL), and the mixture was stirred at 80 °C overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (EtOAc) to give the title compound as a slight yellow solid. Step 2: A/-(4-Chlorophenyl)-4-hydroxy-2-(6-(trifluoromethyl)-2H-spir o[benzofuran-3,4'- piperidin]-1 '-yl)butanamide (20)

To a solution of 4-chloroaniline (1 10 mg, 0.87 mmol) in dry DCM (15 mL) was added AIMe3 (0.45 mL, 0.87 mmol, 2.0 mol/L in toluene) dropwise at 0 °C. After 30 min at rt, a solution of 3-(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidin] -T-yl)dihydrofuran- 2(3H)-one (20b) (100 mg, 0.29 mmol) in dry DCM (2.5 mL) was added dropwise at 0°C. The mixture was warmed to rt and stirred overnight. The mixture was diluted with 1 M HCI (20 mL) and extracted with DCM (2 x 25 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 preparative HPLC to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-de): d ppm 10.7 (s, 1 H), 7.71-7.68 (m, 2H), 7.45 (d, J = 7.6 Hz, 1 H), 7.39-7.35 (m, 2H), 7.21 (d, J = 8.0 Hz, 1 H), 4.55-4.44 (m, 1 H), 4.43 (s, 2H), 3.56-3.38 (m, 3H), 2.42-2.27 (m, 2H), 1.91-1.78 (m, 4H), 1.72-1.66 (m, 2H). MS (ESI): 469.1 [M+H] ⁺ .

Example 21 : W-(4-Chlorophenyl)-3-cyclopropyl-2-(6-(irifluoromeihyl)-2/-/ -spiro

[benzofuran-3,4'-piperidin]-1 '-yl)propanamide (21 )

A mixture of 2-bromo-A/-(4-chlorophenyl)-3-cyclopropylpropanamide (Int 15) (280 mg, 0.93 mmol), 6-(trifluoromethyl)- 2H-spiro[benzofuran-3,4'-piperidine] hydrochloride (714 mg, 2.78 mmol), K ₂ CO ₃ (385 mg, 2.78 mmol) and DIPEA (360 mg, 2.78 mmol) in CH3CN (30 mL) was stirred at 80 °C for 3 d. The mixture was concentrated to dryness and the residue was mixed with EtOAc (20 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous 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, DMSO-de): d ppm 10.09 (s, 1 H), 7.71-7.67 (m, 2H), 7.44 (d, J = 8.0 Hz, 1 H), 7.39-7.36 (m, 2H), 7.21 (d, J = 7.6 Hz, 1 H), 7.09 (s, 1 H), 2.95-2.87 (m, 2H), 4.43 (s, 2H), 3.32- 3.30 (m, 1 H) 2.43-2.38 (m, 1 H), 2.29-2.24 (m, 1 H), 1.95-1.83 (m, 2H), 1.72-1.65 (m, 3H), 1.55-1 .48 (m, 1 H), 0.71-0.66 (m, 1 H), 0.42-0.35 (m, 2H), 0.08-0.06 (m, 2H). MS (ESI): 479.3 [M+H] ⁺ .

Stereoselective route for (S)-N-(4-Chlorophenyl)-3-cyclopropyl-2-(6-(trifluoromethyl)- 2H-spiro[benzofuran-3,4'-piperidin]-1 '-yl)propamamide (21 e)

Step 1 : Methyl (R)-3-cyclopropyl-2-((methylsulfonyl)oxy)propanoate (21 b)

To a solution of methyl (R)-3-cyclopropyl-2-hydroxypropanoate (21a) (720 mg, 5.00 mmol) in DCM (10 ml_) was added MsCI (855 mg, 7.50 mmol) and TEA (1.26 g, 12.50 mmol) at 0 °C and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM (20 ml_). The combined organic layers were washed with brine (20 ml_), dried over Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a colorless oil.

Step 2: Methyl (S)-3-cyclopropyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran -3,4'- piperidin]-T-yl)propanoate (21c)

To a solution of methyl (R)-3-cyclopropyl-2-((methylsulfonyl)oxy)propanoate (21 b) (724 mg, 3.26 mmol) in DMF (10 ml_) was added K ₂ CO ₃ (900 mg, 6.52 mmol), 6- (trifluoromethyl)- 2H-spiro[benzofuran-3,4'-piperidine] hydrochloride (1.15 g, 3.91 mmol), and the mixture was stirred at 50 °C overnight. Water was added and the mixture was extracted with EtOAc (20 mL), washed with brine (20 mL), dried over

Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography (PE: EtOAc = 10:1 ) to give the title compound as a yellow solid.

Step 3: (S)-3-Cyclopropyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran -3,4'-piperidin]-T- yl)propanoic acid (21 d) To a solution of methyl (S)-3-cyclopropyi-2-(6-(trifluoromethyl)-2H-spiro[benzofuran -

3,4'-piperidin]-T-yl)propanoate (21c) (41 mg, 0.1 1 mmol) in THF/MeOH (1 :1 , 2 mL) was added LiOH (2M aqueous solution, 2 mL) and the mixture was stirred at rt overnight. The mixture was concentrated and water (2 mL) was added. The pH was adjusted to pH = 4 with aqueous HCI (2M) and the mixture was filtered. The precipitated solid was filtered and the filter residue was dried to give the title compound as a white solid.

Step 4: (S)-A/-(4-chlorophenyl)-3-cyclopropyl-2-(6-(trifluoromethyl) -2 -/-spiro[benzo- furan-3,4'-piperidin]-T-yl)propanamide (21 e)

To a solution of (S)-3-cyclopropyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran -3,4'- piperidin]-T-yl)propanoic acid (21 d) (20 mg, 0.05 mmol) in DMF (3 mL) was added HATU (29 mg, 0.08 mmol) and DIPEA (16 mg, 0.13 mmol). The mixture was stirred at rt for 1 h. 4-Chloroaniline (8.0 mg, 0.06 mmol) was added and the mixture was stirred overnight. Water (20 mL) was added and the mixture was 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 column chromatography on silica gel (PE: EtOAc = 2:1 ) to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-de): d ppm 10.09 (s, 1 H), 7.71 -7.67 (m, 2H), 7.44 (d, 3 = 7.8 Hz, 1 H), 7.39-7.35 (m, 2H), 7.21 (d, J = 7.0 Hz, 1 H), 7.09 (s, 1 H), 4.43 (s, 2H), 3.32-3.30 (m, 1 H), 2.95-2.87 (m, 2H), 2.43-2.24 (m, 2H), 1.95-83 (m, 2H), 1.70-1.64 (m, 3H), 1.55-1 .49 (m, 1 H), 0.71-0.67 (m, 1 H), 0.42-0.37 (m, 2H), 0.08-0.06 (m, 2H). MS (ESI): 479.2 [M+H] ⁺ .

Example 21 f: (R)-A/-(4-Chlorophenyl)-3-cyclopropyl-2-(6-(irifluoromethyl) -2H- spiro[benzofuran-3,4'-piperidin]-1 '-yl)propanamide (21 f) prepared by chiral separation

N-(4-Chlorophenyl)-3-cyclopropyl-2-(6-(trifluoromethyl)-2H-s piro [benzofuran-3,4'- piperidin]-T-yl)propanamide (21 ) was subjected to separation by chiral SFC (OJ20, 20 x 250 mm, C0 ₂ /MeOH 80/20) to afford (R)-A/-(4-chlorophenyl)-3-cyclopropy!-2-(6-

(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T-y l)propanamide (21 f) as the second eluting enantiomer. The absolute configuration of Example 21 f was assigned by chiral HPLC comparison with Example 21e. ¹ H NMR (400 MHz, DMSO-de): d ppm 10.09 (s, 1 H), 7.70-7.67 (m, 2H), 7.44 (d, J = 7.8 Hz, 1 H), 7.38-7.36 (m, 2H), 7.20 (d, J = 8.3 Hz, 1 H), 7.09 (s, 1 H), 4.43 (s, 2H), 3.33-3.31 (m, 1 H), 2.95-2.87 (m, 2H), 2.43- 2.24 (m, 2H), 1.94-1.83 (m, 2H), 1 .70-1.64 (m, 3H), 1.55-1.49 (m, 1 H), 0.71-0.67 (m,

1 H), 0.42-0.37 (m, 2H), 0.08-0.06 (m, 2H). MS (ESI): 479.1 [M+H] ⁺ .

Example 22: 1 '-(1-(5-Chloro-1 /-/-benzo[d]imidazol-2-yl)propyl)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidine] (22)

A solution of 2-(6-(tr!fluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T -yl)butanoic acid (lnt 13/1 ) (344 mg, 1.00 mmol), 4-chlorobenzene-1 ,2-diamine (142 mg, 1.00 mmol), HATU (570 mg, 1.50 mmol) and DIPEA (0.52 mL, 3.00 mmol) in DMF (20 mL) was stirred at rt overnight. Water (25 mL) was added and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (3 x 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) to give the intermediate aniline as a yellow solid. The solid was dissolved in AcOH (20 mL) and the mixture was heated to reflux overnight. After cooling to rt the mixture was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound as slight yellow solid. ¹ H NMR (400 MHz, DMSO-de): d ppm 12.49-12.41 (m, 1 H), 7.65-7.48 (m, 2H), 7.40 (d, J = 7.6 Hz, 1 H), 7.21 -7.15 (m, 2H), 7.07 (s, 1 H), 4.32 (s, 2H), 3.74-3.70 (m, 1 H), 2.95-2.85 (m, 2H), 2.17-1 .83 (m, 6H), 1.69-1.66 (m, 2H), 0.86-0.82 (m, 3H). MS (ESI): 450.2 [M+H] ⁺ .

Example 23: A/-(4-Chlorophenyl)-1-(6-(trifluoromethyl)-2H-spiro[benzofur an-3,4'- piperidin]-T-yl)cyclobutane-1 -carboxamide

To a solution of 1 -bromo-A/-(4-chlorophenyl)cyclobutane-1 -carboxamide (Int 17) (93 mg, 0.33 mmol) in toluene (5 ml_) 6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidine] hydrochloride (1 16 mg, 0.40 mmol), K3PO4 (175 mg, 0.83 mmol), PPh3 (87 mg, 0.33 mmol) and CullVfeS (10 mg) were added and the mixture was stirred at 100 °C overnight. Water was added and the mixture was extracted with EtOAc (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 HPLC to give the title compound as a white solid. ¹ H NMR (500 MHz, DMSO-de): d ppm 9.59 (s, 1 H), 7.77-7.74 (m, 2H), 7.46 (d, J = 7.7 Hz, 1 H), 7.41 -7.33 (m, 2H), 7.23 (d, J = 8.4 Hz, 1 H),

7.10 (s, 1 H), 4.46 (s, 2H), 2.86-2.81 (m, 2H), 2.30-2.26 (m, 4H), 2.19-2.13 (m, 2H), 2.00-1.93 (m, 2H), 1.75-1.70 (m, 4H). MS (ESI): 465.2 [M+H] ⁺ .

Examples 23/1-23/2

The following Examples were prepared similar as described for Example 23 using the appropriate building blocks.

Example 24: A/-(4-Chlorophenyl)-2-(1 ,1-dioxido-6-(trifluoromethyl)-2/-/- spiro[benzo[b]thiophene-3,4'-piperidin]-1 '-yl)butanamide (24)

Step 1 : 1 '-(1-((4-Chlorophenyl)amino)-1-oxobutan-2-yl)-6-(trifluorome thyl)-2H- spiro[benzo[b]thiophene-3,4'-piperidine] 1 '-oxide 1 ,1 -dioxide (24a)

To a solution of A/-(4-chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzo[b] thiophene-

3,4'-piperidin]-1 '-yl)butanamide (Example 1/8) (80 mg, 0.17 mmol) in AcOH (10 ml_) was added H2O2 (20 ml_, 33% (w/w) in water) and the mixture was stirred at 100 °C for

3 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc (2 x

25 mL). The combined organic layers were washed by brine (50 ml_), dried over anhydrous Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a yellow oil which was used in the next step without further purification.

Step 2: A/-(4-Chlorophenyl)-2-(1 , 1-dioxido-6-(trifluoromethyl)-2H-spiro[benzo[b] thiophene-3, 4'-piperidin]-1 '-yl)butanamide (24)

To a solution of T-(1-((4-chlorophenyl)amino)-1-oxobutan-2-yl)-6-(trifluorome thyl)-2H- spiro[benzo[b]thiophene-3,4'-piperidine] T-oxide 1 ,1 -dioxide (24a) (88 mg, 0.17 mmol) in AcOH (10 mL) was added Zn powder (444 mg, 6.84 mmol) and the mixture was stirred at rt overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-de): d ppm 10.02 (s, 1 H), 8.18 (s, 1 H), 8.10 (d, J = 8.5 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.73 -7.67 (m, 2H), 7.40-7.35 (m, 2H), 3.79-3.63 (m, 2H), 3.15-3.12 (m, 1 H), 2.97-2.89 (m, 2H), 2.58-2.53 (m, 1 H), 2.46-2.39 (m, 1 H), 2.14-2.04 (m, 2H), 1.80-1.64 (m, 4H), 0.90 (t, J = 7.3 Hz, 3H). MS (ESI): 501 .2 [M+H] ⁺ .

Examples 25b, 25c, 25d, 25e: Separate isomers of A/-(4-Chlorophenyl)-2-(6'- (frifluoromethyi)-2'H-spiro[azepane-4,3'-benzofuran]-1 -yl)butanamide (25b, 25c, 25d, 25e)

Step 1 : A/-(4-Chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[azepan e-4,3'-benzofuran]- 1 -yl)butanamide (25a)

A mixture of 6'-(trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofuran] hydrochloride (Int 9) (100 mg, 0.32 mmol), 2-bromo-N-(4-chlorophenyl)butanamide (Int 21/1 ) (90 mg,

0.32 mmol), K2CO3 (135 mg, 0.96 mmol) and DIPEA (126 mg, 0.96 mmol) in CH3CN (30 mL) was stirred at 80 °C overnight. The mixture was concentrated to dryness. Water (30 mL), and EtOAc (20 mL) were added and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous 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.

Step 2: Separate isomers of A/-(4-Chlorophenyl)-2-(6'-(trifluoromethyl)-2'H- spiro[azepane-4,3'-benzofuran]-1-yl)butanamide (25b, 25c, 25d, 25e)

A/-(4-Chlorophenyl )-2-(6'-(trifluorom ethyl )-2'H-spiro[azepane-4,3'-benzofuran]-1- yl)butanamide (25a) was subjected to a separation via chiral SFC, using the following chiral-SFC conditions: stationary phase CHIRALPAK AS-3 (Daicel), mobile phase C0 ₂ /isopropanol (0.2% diethylamine), 84/15 to afford the four isomers:

First eluting isomer of A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[azepan e-4,3'- benzofuran]-1 -yl)butanamide (25b): ¹ H NMR (400 MHz, DMSO-cfe): d ppm 9.98 (s, 1 H), 7.67 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 7.7 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 2H), 7.18 (d, J =

8.3 Hz, 1 H), 7.07 (s, 1 H), 4.44-4.36 (m, 2H), 3.24-3.20 (m, 1 H), 2.92-2.70 (m, 4H),

1 .95-1.51 (m, 8H), 0.91 (t, J = 7.2 Hz, 3H). MS (ESI): 467.2 [M+H] ⁺ .

Second eluting isomer of A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'/-/-spiro[azep ane-

4,3'-benzofuran]-1-yl)butanamide (25c) ¹ H NMR (400 MHz, DMSO-cfe) d 9.98 (s, 1 H), 7.67 (d, J = 6.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 6.8 Hz, 2H), 7.19 (d, J =

7.8 Hz, 1 H), 7.07 (s, 1 H), 4.44-4.38 (m, 2H), 3.21-3.17 (m, 1 H), 2.98-2.84 (m, 2H),

2.77-2.69 (m, 2H), 2.00-1.53 (m, 8H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI): 467.2 [M+H] ⁺ .

Third eluting isomer of A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[azepan e- 4,3'-benzofuran]-1-yl)butanamide (25d) ¹ H NMR (400 MHz, DMSO-cfe): d ppm 9.98 (s, 1 H), 7.67 (d, J = 6.8 Hz, 2H), 7.42 (d, J = 7.7 Hz, 1 H), 7.36 (d, J = 9.2 Hz, 2H), 7.19 (d,

J = 7.8 Hz, 1 H), 7.07 (s, 1 H), 4.44-4.38 (m, 2H), 3.21-3.17 (m, 1 H), 2.96-2.84 (m, 2H),

2.77-2.70 (m, 2H), 1.99-1.50 (m, 8H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI): 467.2 [M+H] ⁺ .

Fourth eluting isomer of A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[azepan e- 4,3'-benzofuran]-1-yl)butanamide (25e) ¹ H NMR (400 MHz, DMSO-cfe) d ppm 9.98 (s, 1 H), 7.67 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 2H), 7.18 (d,

J = 7.7 Hz, 1 H), 7.07 (s, 1 H), 4.44-4.36 (m, 2H), 3.24-3.20 (m, 1 H), 2.90-2.71 (m, 4H),

1 .96-1.52 (m, 8H), 0.91 (t, J = 7.2 Hz, 3H).

Example 30: /\/-(4-Chloropheny!)- V-hydroxy-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidin]-1 '-yl)butanimidamide (30)

Step 1 : A/-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofur an-3,4'-piperidin]-1 yl)butanethioamide (30a)

A/-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofur an-3,4'-piperidin]-1 '- yl)butanamide (Example 1/3) (1.00 g, 2.21 mmol) was suspended in toluene (10 mL) and P2S5 (982 mg, 4.42 mmol) was added to the mixture. The mixture was heated at 120 °C overnight. The mixture was concentrated and the residue was disssolved in EtOAc (20 mL). The organic layer was washed with water (2 x 20 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to give the title compound as a yellow solid.

Step 2: 4-Chloro-A/-(1-(methylthio)-2-(6-(trifluoromethyl)-2H-spiro[ benzofuran-3,4'- piperidin]-T-yl)but-1-en-1-yl)aniline (30b)

To a solution of N-(4-chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofura n-3,4'- piperidin]-T-yl)butanethioamide (30a) (500 mg, 1.06 mmol) in anhydrous DCM (10 mL) under nitrogen was added DIPEA (0.5 mL). Methyl trifluoromethanesulfonate (174 mg, 1 .06 mmol) was added dropwise and the mixture was stirred for 2 h at rt. DCM (15 mL) was added and the mixture was washed with water (2 x 20 mL). The combined organic layers were dried over Na2S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 10: 1 ) to give the title compound as a white solid.

Step 3: A/-(4-Chlorophenyl)-/V-hydroxy-2-(6-(trifluoromethyl)-2/-/-s piro[benzofuran-3,4'- piperidin]-T-yl)butanimidamide (30) To a solution of 4-chloro-A/-(1-(methylthio)-2-(6-(trifluoromethyl)-2H-spiro[ benzofuran- 3,4'-piperidin]-T-yl)but-1-en-1-yl)aniline (30b) (1 10 mg, 0.23 mmol) in EtOH (1.5 ml_) was added a 50% solution (w/w) of NH2OH in water (0.5 ml_) at 70 °C and the mixture was stirred at 70 °C overnight. EtOAc (10 ml_) was added and the organic layer was washed with water (2 x 10 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-de): d ppm 10.74-10.51 (m, 1 H), 9.77 (br s, 0.5 H), 8.42 (br s, 0.5 H), 7.57-7.54 (m, 1 H), 7.34-7.28 (m, 4H), 7.17 (s, 1 H), 6.95-6.89 (m, 1 H), 4.64-4.53 (m, 2H), 4.03-3.00 (m, 5H), 2.18-1.91 (m, 6H), 0.92 (t, J = 7.2 Hz, 3H). MS (ESI): 468.0 [M+H] ⁺ .

Examples 30/1 -30/2

The following Examples were prepared similar as described for Example 30 using the appropriate building blocks.

If one were to use similar procedures as that desdribed above the following compounds including their enantiomers and diastereomers would be obtained:

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 % CO ₂ . 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 pM. 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 = IC ₅₀ < 50 nM, B = 50 nM £ IC50 £ 1 pM, C = IC50 > 1 pM). Table 1