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-Formyl kynurenine 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): 1269-74; 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):312-9, 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-Hydroxykynurenine in this process and it is therefore hypothesized that patients with HIV may benefit from ID01 inhibition together with antiretroviral therapy (Favre et al.; Sci Transl Med. 2010 May 19;2(32):32ra36.).

ID01 also seems to be involved in disorders of the central nervous system because its downstream products 3-Hydroxykynurenine and quinolinic acid act as neurotoxins (Okuda et al.; J Neurochem. 1998;70(1 ):299-307, Schwarcz et al.; Science. 1983;219(4582):316-8). Thereby, ID01 is also implicated in the disease development of Huntington ^' s disease, Amyotrophic lateral sclerosis, Alzheimer ^' s disease, Parkinson ^' s disease 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.; I nt 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, Y, Z, R ² , R ⁵ , R ¹⁰ , m, n, 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 C3-10 cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R ^a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10- membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci-e-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 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, C _3-6 -cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci-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 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 ) _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 C-i-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 heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, halo-Ci- ₆ -alkyl, CN and oxo;

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

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

T represents hydrogen, halogen, CN, OH, OR ^x , OC(C)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(C)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(C)-R ^x , COOH, Ci-e-alkyl, halo-Ci-e-alkyl, C ₂ -e-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocyclyl, 6-mem bered aryl-C-i-e alkyl, 5- to 6-mem bered heteroaryl-Ci-6- alkyl, 3- to 6-membered heterocyclyl-Ci-e-alkyl, or 3- to 6-mem bered 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-e-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-e-alkylene-C(0)N(R ¹ )2, -Co-6-alkylene- C(0)0-R ^x , -Co- ₆ -alkylene-C(0)-R ^x , -Co- ₆ -a!ky!ene-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, halogen, Ci- ₆ -alkyl, halo-Ci-e-a!ky!; or

R ¹⁰ and T form together 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, O-Ci- 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-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 halogen, C-i-e-alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN;

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

Z represents -C2-3-alkylene-, -O-Oi-2-alkylene-, -Ci-2-alkylene-O-, -NR ³ C(0)-Co-i- alkylene-, -C(0)NR ³ -Co-i-aikylene-, -Co-i-aikylene-NR ³ C(0)-, -Co-i-alkylene C(0)NR ³ -, -S(0) _t -Ci- ₂ -alkylene-, -Ci- ₂ -alkylene-S(0) _t -, -NR ⁹ -Ci-2-alkylene- or -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-e-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-e-alkyl;

R ² is halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ , S(0) ₂ N(R ¹ ) ₂ , S (0) ₂ -01 - ₆ - alkyl, S(0) ₂ -C _3-6 -cycloalkyl, S(0) ₂ -halo-Ci- ₆ -alkyi, 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(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 0, 1 or 2;

n is 0, 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.

In a preferred embodiment in combination with any of the embodiments above and below, the compound is represented by the following formulae (1 ) and (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, 3- to 10- membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-mem bered 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-e-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-Ci- ₆ -alkyl or oxo;

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

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci-e-alky!, 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-e-alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

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

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

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

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 Ci- ₆ -alkyl;

T represents hydrogen, halogen, CN, OH, OR ^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 , COOH, Ci- ₆ -alkyl, halo-Ci _-6 -alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocyclyl, 6-membered aryl-Ci-6 alkyl, 5- to 6-membered heteroaryl-C-i-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-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) ₂ N(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-a I ky I e n e-C (O )0- R ^x , -Co-e-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;

R ¹⁰ represents hydrogen, halogen, Ci- ₆ -aikyl, halo-Ci- ₆ -alkyl; 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-e-alkyl and halo-Ci- ₆ -alkyl;

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

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 halogen, Ci-e-alkyl, halo-Ci- ₆ -alkyl, OR ¹ or CN;

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

Z represents -C2-3-alkylene-, -O-Ci-2-alkylene-, -Ci-2-alkylene-O-, -NR ³ C(0)-Co-i- alkylene-, -C(O)NR ³ -C ₀ -i-alkylene-, -Co-i-alkylene-NR ³ C(0)-, -C ₀ -i-alkylene C(0)NR ³ -, -S(0)t-Ci-2-alkylene-, -Ci-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-e-alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl;

R ¹ is hydrogen or Ci- ₆ -alkyl;

R ² is Ci -6-alkyl, Cs-e-cycloalkyl, halo-Ci-e-alkyl, OR ⁴ , S(0) ₂ N(R ¹ ) ₂ , S(0) ₂ -Ci- ₆ -alkyl, S(0) ₂ - C3-6-cycloalkyl, S(0) ₂ -halo-Ci- ₆ -alkyl, 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 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 ³ is hydrogen or Ci- ₆ -alkyl;

R ⁴ is hydrogen or Ci-e-alkyl;

m is 0, 1 or 2;

n is 0, 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.

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

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

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

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, 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 , 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 ) _2I NR ¹ C(C)R ^z , C(0)N(R ¹ ) ₂ , C(0)0-R ^z , C(C)-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, haio-C-i-e-alkyl, CN and oxo;

R ^z represents Ci- ₆ -alkyl, C _3-6 -cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

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

V is O or CR ⁷ R ⁸ ;

R ² is C1-6 alkyl, C _3-6 cycloalkyl, halo-Ci _-6 -alkyl, OR ⁴ , S(C) ₂ N(R ¹ ) ₂ , S(C) ₂ -Ci- ₆ -alkyl, S(0) ₂ - Cs-e-cycloalkyl, S(0) ₂ -halo-Ci _-6 -alkyl, S(0) ₂ N(R ¹ ) ₂ , C(C)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 C3-10 cycloalkyl group, or

two R ² at different carbon atoms form together a -CH ₂ -, -CH(CH3)-, -C(CH3) 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, C1-6 alkyl, halo-Ci-6-alkyl and OR ⁴ ;

T represents hydrogen, halogen, CN, OH, OR ^x , OC(C)-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 , COOH, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C ₂ -e-alkenyl, C _3-6 -cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocyclyl, 6-membered aryl-Ci-6 alkyl, 5- to 6-membered heteroaryl-Ci-e- alkyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalky!-Ci-e-aSkyl, 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- OC(0)-R ^x , -Co-6-alkylene-S-R ^x , -Co-6-alkylene-S(C) ₂ -R ^x , -Co-6-alkylene-S(C) ₂ N(R ¹ ) ₂ , -Co- ₆ -alkylene-N(R ¹ ) ₂ , -Co-6-alkylene-NR ¹ C(C)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-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;

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

k 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-e-a!kyl, 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;

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

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

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

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

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, halogen, CN, OH, OR ^x , 0C(0)-R ^x , S-R ^x , S(0)2-R ^x , S(0)2N(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 , COOH, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-mem bered heteroaryl, 3- to 6- membered heterocyclyl, 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-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-e-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-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 of the embodiments above and below, the compound is represented by the following formula (1 -5)

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

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

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

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

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, halogen, CN, OH, OR ^x , OC(0)-R ^x , S-R ^x , S(0)2-R ^x , S(0)2N(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 , COOH, Ci- ₆ -alkyl, halo-Ci _-6 -alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocyclyl, 6-membered aryl-Ci-6 alkyl, 5- to 6-membered heteroaryl-Ci-e- 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-alky!ene-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-aikylene-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-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 OR ⁵ ;

p is 0, 1 , 2 or 3; and

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

In an equally further 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- ₆ -alkyl, C3-6-cycloalkyl, O-Ci- ₆ -alkyl, S-Ci-e-a!kyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

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

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

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

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

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

wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- ₆ -alkyl, halo-Ci-e-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, halogen, CN, OH, OR ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , 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 heterocyclyl, 6-membered aryl-Ci-6 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-e-a!ky!, 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- 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-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 -7)

wherein

X is hydrogen, halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, O-Ci- ₆ -alkyl, S-Ci-e-a!kyl, 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 ³ is hydrogen or C-i-e-alkyl;

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 ) 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-6-alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, C-i-e-alkyl, halo-Ci-e-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, halogen, CN, OH, OR ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci- ₆ -alkyl, halo-Ci _-6 -alkyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-mem bered heteroaryl, 3- to 6- membered heterocyclyl, 6-membered ary!-Ci-e alkyl, 5- to 6-membered heteroaryl-C-i-e- alkyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyl-Ci-e-a!ky!, 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) 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-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 ;

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-e-alky!, 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-e-alkyl, OR ¹ or CN; R ⁵ is independently selected from hydrogen, halogen and Ci-e-alkyl;

T represents hydrogen, halogen, CN, OH, OR ^x , OC(0)-R ^x , S-R ^x , S(0)2-R ^x , S(0)2N(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 , COOH, Ci-e-alkyl, halo-Ci _-6 -alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-mem bered heteroaryl, 3- to 6- membered heterocyclyl, 6-membered aryl-Ci-6 alkyl, 5- to 6-membered heteroaryl-Ci-e- alkyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyS-Ci-e-a!kyl, 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-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-e-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;

R ^x represents Ci-e-alkyl, C3-e-cycloalkyl or 3- to 6 mem be red 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-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 ) _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 , Ci- ₆ -alkyl; C3-6- cycloalkyl, and halo-Ci- ₆ -alkyl, or

two substituents on the aryl or heteroaryl ring systems together with the carbon atom to which they are attached form a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S, wherein the heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C-i-e-alkyl, halo-Ci- ₆ -alkyl, CN and oxo;

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

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

V is O or CR ⁷ R ⁸ ;

R ² is C _1-6 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-i o 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, C1-6 alkyl, halo-Ci-e-alkyl and OR ⁴ ;

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

k 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, C-i- ₆ -alkyl, C _3-6 -cycloalkyl, O-Ci-e-alkyl, S-Ci-e-alky!, 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, C-i-e-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 , 0C(0)-R ^z , S-R ^z , S(0)2-R ^z , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^z , C(0)N(R ¹ ) ₂ , C(0)0-R ^z , C(0)-R ^z , 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,

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

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

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, halogen, CN, OH, OR ^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 , COOH, Ci-6-alkyl, halo-Ci-e-alkyl, C _2-6 -alkenyl, 0 _3-6 -cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocyclyl, 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-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) ₂ N(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;

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 more preferred embodiment in combination with any of the above and below embodiments, the compound is represented by the following formula (2-5)

wherein

X is hydrogen, halogen, Ci- ₆ -alkyl, C _3-6 -cycloalkyl, O-Ci- ₆ -alkyl, S-Ci-e-a!kyl, 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-e-a!ky!, 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 , 0C(0)-R ^z , S-R ^z , S(0) ₂ -R ^z , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^z , C(0)N(R ¹ ) ₂ , C(0)0-R ^z , C(0)-R ^z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

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

R ^z represents Ci- ₆ -alkyl, C _3-6 -cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S,

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

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, halogen, CN, OH, OR ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci-6-alkyl, halo-Ci-e-alkyl, C _2-6 -alkenyl, C3-e-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocyclyl, 6-membered aryl-C-i-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-6-alkylene-OH, -Co-6-alkylene-R ^x , -Co-e-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-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;

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 above and below embodiments, 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- 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-e-alkylene-OH, -Co- ₆ -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-e-alkyl, halo-Ci- ₆ -alkyl, C3-e-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 C1 - ₆ -alkyl, halo-Ci- ₆ -alkyl, C3-6- cycloalkyl, halogen, CN, OH and O-Ci- ₆ -alkyl.

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 above and below embodiments, A represents C3-6-cycloalkyl, 3- to 7- membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-mem bered 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-mem bered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR ¹ , Ci- ₆ -alkyl, C3-6- cycloalkyl and halo-Ci- ₆ -alkyl, or

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

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

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

In a more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, A represents 6- to 10- membered mono or bicyclic aryl or 5- to 10-mem bered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , 0-R ^x , OC(0)-R ^x , S-R ^x , N(R ¹ )2, NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,

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

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, Ci- ₆ -alkyl, halo Ci- ₆ -alkyl, OR ¹ and CN.

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

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

R ^x represents Ci-e-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, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, OR ¹ and CN.

In a more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, A represents phenyl which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R ^x , C-R ^x , OC(0)-R ^x , S-R ^x , S(C) ₂ -R ^X , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ )2, NR ¹ C(C)R ^x , C(0)N(R ¹ )2, C(0)0-R ^x , C(C)-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 haio-Ci- ₆ -aikyl, and

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O, N and S, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci-e-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, C _3-6 -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 halogen, C1-6- alkyl, halo-Ci-e-alkyl, OR ¹ or CN;

R ⁵ is independently selected from hydrogen, halogen and Ci- ₆ -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- ₆ -alkyl, hydroxy-Ci- ₆ -alkyl, C _3-6 -cycloalkyl or halo-C _3-6 -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, 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 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- ₆ -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, C3-6-cycloalkyl, or CN

wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or C-i-e-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- ₆ -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, C3-6-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-e-alkyl, Ce-e-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 an utmost preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, A represents

In an equally utmost 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 above and below embodiments, R ^a represents halogen, CN, Ci - ₆ -alkyl, halo-Ci- ₆ -alkyl, or hydroxy-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, R ^a represents halogen, CN, or Ci- ₆ -alkyl.

In a most preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, R ^a represents F or Cl, more preferably F.

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

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

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

In an equally preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, R ¹ is C1-6 alkyl.

In a preferred embodiment of the compounds according to formula (1 ) in combination with any of the embodiments above and below, T represents halogen, CN, OH, OR ^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 , COOH, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, 6-membered aryl-Ci- ₆ alkyl, 5- to 6-membered heteroaryl-C-i- 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- 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) ₂ N(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.

In an equally preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, T is hydrogen, halogen, CN, OH, OR ^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 , COOH, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl

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

In a more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, T is hydrogen, halogen, CN, OH, OR ^x , S-R ^x , Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C _2-6 -alkenyl, C _3-6 -cycloalkyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci- ₆ -alkyl or 3- to 6-membered cycloalkyl-

Ci- ₆ -alkyl,

wherein alkyl, cycloalkyl and heterocycloalkyl, are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , O- R ^x , S-R ^x , CN and COOH.

In an even more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, T is hydrogen, Ci- ₆ -alkyl, halo-Ci-6-alkyl, C3-6-cycloalkyl, 3- to 6-membered heterocyclyl or 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 halogen, OH, Ci-e-alkyl, halo-C-i-e- alkyl, C3-6-cycloalkyl and O-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, T is hydrogen, Ci- ₆ -alkyl, or halo-Ci- ₆ -alkyl, more preferably Ci-e-alky!, or halo-Ci- ₆ -alkyl, most preferably Ci- ₆ -alkyl.

In a preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, R ² is C _1-6 alkyl, C3-6 cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ , CN, oxo or two R ² on the same carbon atom form together with the carbon atom to which they are attached a C _3-6 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 - and o is 0, 1 or 2.

In a more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, R ² is C-i-e-alkyl, C3-6- cycloalkyl, halo-Ci- ₆ -alkyl, OR ⁴ or oxo 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 - and o is 0, 1 or 2.

In a preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, Z represents -ethylene-, -O-methylene-, -methylene-O-, -NR ³ C(0)-, -C(0)NR ³ -, -NR ³ C(0)-, -C(0)NR ³ -, -S(0)t-methylene-, - methylene-S(0) _t -, -NR ⁹ -methylene- or -methylene-NR ⁹ -,

wherein methylene and ethylene are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of OR ⁴ , Ci-e-alky!, halogen and 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, Z represents an ethylene group which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of OR ⁴ , Ci-e-aiky!, halogen and halo-Ci- ₆ -alkyl.

In an equally more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, Z represents -CR ⁷ R ⁸ 0-, wherein 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 .

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

In a preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, W represents O or NR ¹ .

In a more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, W represents O.

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

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

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

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

wherein V represents -Co-2-alkylene-, -O-Co-i-alkylene-, -Co-i-alkylene-O-, -NR ³ C(0)-, -C(0)NR ³ -, -NR ³ C(0)-, -C(0)NR ³ -, -S(O) _t -C ₀ -i-alkylene-, -C ₀ -i-alkylene-S(O) _t -, -NR ⁹ -C ₀ - i-alkylene- or -Co-1-alkylene-NR ⁹ -,

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

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

R ⁹ is hydrogen, Ci- ₆ -alkyl, halo-Ci-e-alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl and k is 1 or 2.

In a more preferred embodiment of the compounds according to formulae (1-1 ) or (1-2) in combination with any of the above and below embodiments, V represents -CR ⁷ R ⁸ -, -O-Co-1-alkylene-, -Co-i-alkylene-O-, -NR ⁹ -Co-i-alkylene- or -Co-1-alkylene-NR ⁹ -, wherein alkylene is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of OR ⁴ , Ci- ₆ -alkyl, halogen and halo-Ci- ₆ -alkyl;

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

R ⁹ is hydrogen, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl; and k is 1 or 2.

In an even more preferred embodiment of the compounds according to formulae (1-1 ) or (1-2) in combination with any of the above and below embodiments, V represents - CR ⁷ R ⁸ - or -0-;

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 ; and

k is 1 or 2.

In a most preferred embodiment of the compounds according to formulae (1 -1 ) or (1-2) in combination with any of the above and below embodiments, V represents -CR ⁷ R ⁸ -;

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 ; and

k is 1 or 2. In an equally most preferred embodiment of the compounds according to formulae (1 -1 ) or (1 -2) in combination with any of the above and below embodiments, V represents -0-;

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 ; and

k is 1 or 2.

In a preferred embodiment of the compounds according to formulae (1-1 ) or (1-2) in combination with any of the above and below embodiments, A represents C3-10 cycloalkyl, which may be optionally fused with a phenyl ring, 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 , ON, 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, ON, OR ¹ , Ci-e-alky!, C3-6- cycloalkyl and haio-Ci- ₆ -alkyl, or

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

R ^x represents Ci- ₆ -alkyl, C3-6-cycloalkyl or 3- to 6 mem be red 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 ON.

In a more preferred embodiment of the compounds according to formulae (1-1 ) or (1-2) in combination with any of the above and below embodiments, A represents C3-10 cycloalkyl, 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, 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 , S-R ^x , S(0)2-R ^x , N(R ¹ ) _2I CN, COOH, 5- or 6-mem bered 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 formulae (1-1 ) or (1-2) in combination with any of the above and below embodiments, the compound is represented by formulae (1 -3) or (1-4)

wherein U is N or CR ⁵ ;

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

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

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

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

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

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 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 further 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 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 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 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 even more preferred embodiment of the compounds according to formula (1 ) in combination with any of the above and below embodiments, the compound is

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

represented by the following formula

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 compound according to formula (2) in combination with any of the above and below embodiments, the compound is represented by formulae (2- 1 ) or (2-2)

wherein V represents -Co-2-alkylene-, -O-Co-i-alkylene-, -Co-i-alkyiene-O-, -NR ³ C(0)-, - C(0)NR ³ -, -NR ³ C(0)-, -C(0)NR ³ -, -S(O) _t -C _0-i -alkylene-, -C ₀ -i-alkylene-S(O) _t -, -NR ⁹ -C ₀ -i- alkylene- or -Co-1-alkylene-NR ⁹ -,

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

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 ;

R ⁹ is hydrogen, Ci- ₆ -alkyl, halo-Ci-e-alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl and k is 1 or 2.

In a more preferred embodiment of the compounds according to formulae (2-1 ) or (2-2) in combination with any of the above and below embodiments, V represents -CR ⁷ R ⁸ - - O-Co-i-alkylene-, -Co-i-alkylene-O-, -NR ⁹ -Co-i-alkylene- or -Co-1 -a I ky I e n e- N R ⁹ - , wherein alkylene is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of OR ⁴ , Ci-e-alkyl, halogen and halo-Ci- ₆ -alkyl;

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

R ⁹ is hydrogen, Ci- ₆ -alkyl, halo-Ci-e-alkyl, C(0)-Ci- ₆ -alkyl, or C(0)-halo-Ci- ₆ -alkyl; and k is 1 or 2.

In an even more preferred embodiment of the compounds according to Formulae (2-1 ) or (2-2) in combination with any of the above and below embodiments, V represents -CR ⁷ R ⁸ - or -0-;

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

k is 1 or 2. In a most preferred embodiment of the compounds according to formulae (2-1 ) or (2-2) in combination with any of the above and below embodiments, V represents -CR ⁷ R ⁸ -;

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 ; and

k is 1 or 2.

In a more preferred embodiment of the compound according to formulae (2-1 ) or (2-2) in combination with any of the above and below embodiments, the compound is represented by formulae (2-3) or (2-4)

In a more preferred embodiment of the compound according to formulae (2-1 ), (2-2) (2- 3) or (2-4) in combination with any of the above and below embodiments, X is halogen, Ci- ₆ -alkyl, C3-6-cycloalkyl, or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci-e-alkyl; and

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

In a preferred embodiment of the compounds according to formula (2) in combination with any of the embodiments above and below, T represents halogen, CN, OH, OR ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) _2I C(0)0-R ^x , C(0)-R ^x , COOH, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, 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-e-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- 0C(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- 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. In an equally preferred embodiment of the compounds according to formula (2) in combination with any of the above and below embodiments, T is hydrogen, halogen, CN,

OH, OR ^x , 0C(0)-R ^x , S-R ^x , S(0) ₂ -R ^x , S(0) ₂ N(R ¹ ) ₂ , N(R ¹ ) ₂ , NR ¹ C(0)R ^x , C(0)N(R ¹ ) ₂ , C(0)0-R ^x , C(0)-R ^x , COOH, Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 3- to

6-membered heterocyclyl, 3- to 6-mem bered heterocyclyl-C-i-e-alkyl or 3- to 6-membered cycloalkyl-Ci- ₆ -alkyl

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

In a more preferred embodiment of the compounds according to formula (2) in combination with any of the above and below embodiments, T is hydrogen, halogen, CN, OH, OR ^x , S-R ^x , Ci- ₆ -alkyl, halo-Ci- ₆ -alkyl, C _2-6 -alkenyl, C3-6-cycloalkyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-6-alkyl or 3- to 6-membered cycloalkyl-

Ci- ₆ -alkyl,

wherein alkyl, cycloalkyl and heterocycloalkyl, are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R ^x , O- R ^x , S-R ^x , CN and COOH.

In an even more preferred embodiment of the compounds according to formula (2) in combination with any of the above and below embodiments, T is hydrogen, Ci- ₆ -alkyl, halo-Ci-6-alkyl, C3-6-cycloalkyl, 3- to 6-membered heterocyclyl or 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 halogen, OH, Ci- ₆ -alkyl, halo-Ci- ₆ - alkyl, C3-6-cycloalkyl and O-Ci- ₆ -alkyl.

In a most preferred embodiment of the compounds according to formula (2) in combination with any of the above and below embodiments, T is hydrogen, Ci- ₆ -alkyl or halo-Ci- ₆ -alkyl, more preferably Ci-e-alkyl or halo-Ci- ₆ -alkyl, most preferably Ci- ₆ -alkyl. 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 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 further preferred embodiment of the compound according to formula (1 ), the compound is selected from

and their pharmaceutically acceptable salts thereof.

In a more preferred embodiment of the compound according to formula (1 ), the compound is selected from

and their pharmaceutically acceptable salts thereof.

In a further more preferred embodiment of the compound according to formula (1 ), the compound is selected from

and their pharmaceutically acceptable salts thereof.

In a further more preferred embodiment of the compound according to formula (1 ), the compound is selected from

and their pharmaceutically acceptable salts thereof.

In a further preferred embodiment of the compound according to formula (2), the 5 compound is selected from

and their pharmaceutically acceptable salts thereof.

The present invention further relates to the use of the compounds according to formulae (1 ) or (2) as medicament.

The compounds according to formulae (1 ) or (2) are 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 above and below embodiments, the disease or condition mediated by indoleamine 2,3-dioxygenase is selected from the group consisting of cancer, viral and bacterial infections such as HIV infection, hanta virus infection, tuberculosis, leprae, depression, epilepsy, schizophrenia, 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 above and below embodiments, the disease or condition mediated by indoleamine 2,3-dioxygenase is cancer.

In a further preferred embodiment in combination with any of the above and below embodiments, the compound according to formulae (1 ) or (2) can be 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 furthermore relates to 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 -alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen atom which may be the same or different. Preferred example thereof include CH F2, CF3, CH2CH2CI, and CH2CF3.

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

A C3-io-cycloalkyl group or C3-io-carbocycle means a saturated or partially unsaturated mono-, bi-, spiro-, or multicyclic ring system comprising 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, adamantyl, spiro[3.3]heptane and pentacyclo[4.2.0.0 ² ' ⁵ .0 ³ _’ ⁸ .0 ⁴ _’ ⁷ ]octyl. As an example, a C3-6-cycloalkyl group means a cycloalkyl ring having 3, 4, 5 or 6 carbon atoms. The C _3-10 -cycloalkyl group can be connected to the remainder of the molecule via a bond or the cycloalkyl group may share a carbon at the attachment point with the remainder of the molecule. Illustrative examples of the attachment possibilities are shown below:

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

A 5-14-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 /V-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“ ^Ά/W ” j _s 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“H” or“hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

The compounds of the present invention 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, schizophrenia, 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 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 agents, PD-L1 agents, CTLA-4 agents, AhR modulators, chemotherapeutic agents, anticancer vaccines, onolytic viruses, TLR agonists, STING agonists, and cytokine therapy as well as other immuno oncology, or wherein the compound is administered under 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- ercatopurine, 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, AS ₂ O ₃ , 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

AIBN 2,2'-azobis(2-methylpropionitrile)

br broad

CAN cerium(IV) ammonium nitrate

GDI 1 ,1 '-carbonyldiimidazole

d doublet

DAST diethylaminosulfur trifluoride

DEAD diethyl azodicarboxylate DCM dichloromethane

DIBAL-H diisobutylaluminum hydride

DIPEA A ,A/-diisopropylethylamine

DMF A/,N-dimethylformamide

DMSO dimethyl sulfoxide

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

Et ethyl

Et ₂ 0 diethyl ether

EtOAc ethyl acetate

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

HOBt 1 -hydroxybenzotriazole

HPLC high performance liquid chromatography

/- PrOH isopropyl alcohol

LDA lithium diisopropylamide

LHMDS lithium bis(trimethylsilyl)amide

m multiplet

Me methyl

MCPBA 3-chloroperoxybenzoic acid

Ms methanesulfonyl

NCS /V-chlorosuccinimide

PE petroleum ether

prep preparative

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 scheme 1 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 Examples of structure A-5. T reatment of intermediates of structure A-1 with n-Bu3SnH leads to spirocyclic intermediates of structure A-2. Deprotection with for example hydrochloric acid followed by Horner Wadsworth Emmons reaction of the corresponding ketone leads to intermediates of structure A-3. Double bond reduction with for example hydrogen and Pd catalysis affords ester intermediates of structure A-4. A sequence of ester saponification and amide coupling with the corresponding amines using for example EDCI/HOBt leads to compounds of structure

A-5.

Intermediate 1 : 6-(T rifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-one (Int 1)

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

To a solution of 1 ,4-dioxaspiro[4.5]decan-8-one (Int 1a) (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 MgS0 ₄ , filtered and concentrated to give the title compound as a brown oil, which was directly used in the next step without purification.

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

A mixture of 1 ,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (Int 1 b) (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 1d)

To a solution of methyl 1 ,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate (Int 1c) (1.20 g, 6.06 mmol) in dry THF (50 mL) was added L1AIH4 (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 resulting 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 1e)

To a solution of (1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)methanol (Int 1d) (340 mg, 2.00 mmol), 2-bromo-5-(trifluoromethyl)phenol (482 mg, 2.00 mmol) and PPh3 (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 1f)

A solution of 8-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)-1 ,4-dioxaspiro[4.5]dec-7- ene (Int 1e) (393 mg, 1.00 mmol), n-BusSnH (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-(T rifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-one (Int 1)

To a solution of 6-(trifluoromethyl)-2H-dispiro[benzofuran-3,T-cyclohexane-4' ,2"- [1 ,3]dioxolane] (Int 1f) (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 resulting mixture was extracted with EtOAc (3 x 30 mL), the combined organic layers were dried over MgS0 ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE: EtOAc = 10: 1 ) to give the title compound as a yellow solid.

Intermediate 1/1 : 6-(Difluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-one (Int 1/1 )

Int 1/1 The title compound was prepared similar as described for intermediate 1 , steps 1-6, using in step 4 2-bromo-5-(difluoromethyl)phenol in place of 2-bromo-5- (trifluoromethyl)phenol.

Intermediate 2: 2-(6-(Difluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4' -yl)acetic acid (Int 2)

Int 2

Step 1 : Ethyl 2-(6-(difluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4' - ylidene)acetate (Int 2a)

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.40 g, 6.20 mmol) in dry THE (50 ml_) was added NaH (384 mg, 9.60 mmol, 60% in oil) at 0 °C, and the mixture was stirred for 1 h. 6-(Difluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'-one (Int 1/1 , 1 .20 g, 4.80 mmol) was added and the mixture was stirred at rt for 3 h. The mixture was poured into saturated N H4CI solution (100 ml_) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were 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 colorless oil.

Step 2: Ethyl 2-(6-(difluoromethyl)-2/-/-spiro[benzofuran-3,T-cyclohexan]- 4'-yl)acetate

(Int 2b)

To a solution of ethyl 2-(6-(difluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'- ylidene)acetate (Int 2a) (1.30 g, 4.00 mmol) and NiCte^hbO (2.00 g, 8.00 mmol) in MeOH (50 mL) was added NaBhU (1 .50 g, 40.00 mmol) at 0 °C, and the mixture was stirred for 3 h. The mixture was poured into water (100 mL) and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2S0 ₄ and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 ) to give the title compound as a colorless oil.

Step 3: 2-(6-(Difluoromethyl)-2/-/-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)acetic acid (Int 2)

A solution of ethyl 2-(6-(difluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'- yl)acetate (Int 2b) (1.20 g, 3.70 mmol) and LiOH (10 ml_, 2 M in water) in THF/MeOH (20 ml_, 10:1 ) was refluxed for 2 h. After cooling to rt, the mixture was concentrated. HCI (1.0 ml_, 1.0 M) was added. The precipitated solid was filtered and the filter residue was dried in vacuum to give the title compound as white solid.

Intermediate 10: 2-(2',3'-Dihydrospiro[cyclohexane-1 ,1 '-inden]-4-yl)acetic acid (Int 10)

Stepl : ferf-Butyl 2-(2',3'-dihydrospiro[cyclohexane-1 , 1 '-inden]-4-ylidene)acetate (Int 10b)

To a solution of terf-butyl 2-(diethoxyphosphoryl)acetate (151 mg, 0.60 mmol) in THE (10 mL) was added 60% sodium hydride in mineral oil (24 mg, 0.60 mmol). The mixture was stirred at rt for 30 min. A solution of 2',3'-dihydrospiro[cyclohexane-1 ,T-inden]-4-one (Int 10a) (100 mg, 0.50 mmol) in THE (5 mL) was added and the mixture was stirred at rt for 1 h. Saturated brine (15 mL) was added and the mixture was extracted with EtOAc (2 x

20 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness to give a brown oil. The crude product was triturated with isohexane to give the title compound as a white solid. Step 2: ferf-Butyi 2-(2',3'-dihydrospiro[cyclohexane-1 , 1 '-inden]-4-yl)acetate (Int 10c)

A mixture of terf-butyl 2-(2',3'-dihydrospiro[cyclohexane-1 ,1 '-inden]-4-ylidene)acefate (Snt 10b) (155 mg, 0.52 mmol) and Pd/C (20 mg) in MeOH (30 mL) was stirred under H2 atmosphere at rt for 2 h. The mixture was filtered and concentrated to dryness to give the title compound as a white solid.

Step 3: 2-(2',3'-Dihydrospiro[cyclohexane-1 , 1 '-inden]-4-yl)acetic acid (Int 10)

To a mixture of ferf-butyl 2-(2',3'-dihydrospiro[cyclohexane-1 ,T-inden]-4-yl)acetate (Int

10c) (140 mg, 0.47 mmol) in DCM (5 mL) was added TFA (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[cyclohexane-1 ,T-inden]-4-yl)propanoic acid (Int 11 )

Ini 11

Step 1 : Ethyl 2-(2',3'-dihydrospiro[cyclohexane-1 ,T-inden]-4-ylidene)propanoate (Int 11 b)

To the solution of ethyl 2-(diethoxyphosphoryl)propanoate (1.40 g, 6.00 mmol) in THF (20 mL) was added NaH (180 mg, 7.50 mol) at 0 °C and the mixture was stirred at rt for 1 h. 2',3'-Dihydrospiro[cyclohexane-1 , 1 '-inden]-4-one (Int 10a) (1 .00 g, 5.00 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was poured into saturated NH ₄ CI solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were concentrated to dryness and the residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 ) to give the title compound as a colorless oil. Step 2: Ethyl 2-(2',3'-dihydrospiro[cyclohexane-1 ,1 '-inden]-4-yl)propanoate (Int 11c)

A mixture of ethyl 2-(2',3'-dihydrospiro[cyclohexane-1 ,1 '-inden]-4-ylidene)propanoate (racemate) (Int 11 b) (1.10 g, 3.80 mmol), Pd/C (82 mg, 0.80 mmol) and HCOONH ₄ (178 mg, 3.80 mmol) in methanol (50 ml_) was stirred at rt overnight. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as a colorless oil.

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

A mixture of ethyl 2-(2',3'-dihydrospiro[cyclohexane-1 , 1 '-inden]-4-yl)propanoate (Int 11 c)

(978 mg, 3.40 mmol) and NaOH (273 mg, 6.80 mmol) in methanol (20 mL) was stirred at rt overnight. The mixture was concentrated to dryness and the residue was dissolved in water. The pH of the mixture was adjusted to pH 1 -2 using aqueous HCI (1.0 M). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to dryness to give the title compound as a yellow solid.

Intermediate 12: 2-(6-(Trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- yl)propanoic acid (Int 12)

Step 1 : Ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- ylidene)propanoate (Int 12a)

To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (285 mg, 1.20 mmol) in dry THE (10 mL) was added NaH (60 mg, 1.50 mmol, 60% in mineral oil) at 0 °C, and the mixture was stirred for 1 h at this temperature. Then 6-(trifluoromethyl)-2H-spiro[benzofuran-3,T- cyclohexan]-4'-one (Int 1 ) (270 mg, 1 .00 mmol) was added and the mixture was stirred at rt for 3 h. The mixture was poured into saturated NH4CI solution (10 ml_) and extracted by EtOAc (3 x 20 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 colorless oil.

Step 2: Ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- yl)propanoate (Int 12b)

To a solution of ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- ylidene)propanoate (Int 12a) (340 mg, 1.00 mmol) and NiCl _2* 6H ₂ 0 (237 mg, 1.00 mmol) in MeOH (20 mL) was added NaBhU (190 mg, 5.00 mmol) at 0 °C, and the mixture was stirred for 3 h. The mixture was poured into water (30 mL) and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2S0 ₄ , and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 ) to give the title compound as a colorless oil.

Step 3: 2-(6-(T rifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)propanoic acid

(Int 12)

A solution of ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'- yl)propanoate (Int 12b) (342 mg, 1.00 mmol) and LiOH (120 mg, 5.00 mmol) in a mixture of THF/MeOH (10 mL, 1 : 1 ) was heated to reflux for 2 h. After cooling to rt, aqueous HOI (1 mL, 1 M) was added. The formed solid was filtered off and dried under vacuum to give the title compound as a white solid.

Intermediate 13: 2-Methyl-2-(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3, T-cyclohexan]- 4'-yl)propanoic acid (Int 13)

Stepi : Ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, 1’-cyclohexan]-4'- ylidene)acetate (Int 13a)

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (2.69 g, 12.00 mmol) in dry THF (100 ml_) was added NaH (600 mg, 15.00 mmol, 60% in mineral oil) at 0 °C, and the mixture was stirred for 1 h at 0 °C. Then 6-(trifluoromethyl)-2H-spiro[benzofuran-3,T- cyclohexan]-4'-one (Int 1 ) (2.70 g, 10.00 mmol) was added and the mixture was stirred at rt for 3 h. The mixture was poured into saturated NH4CI solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated to dryness and the residue was purified by column chromatography on silica gel (PE: EtOAc = 10:1 ) to give the title compound as colorless oil.

Step 2: Ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '-yl)acetate

(Int 13b)

To a solution of ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- ylidene)acetate (Int 13a) (2.90 g, 8.50 mmol) and NiCl ₂ 6H ₂ 0 (2.00 g, 8.50 mmol) in MeOH (100 mL) was added NaBhU (1.50 g, 40.00 mmol) at 0 °C, and the mixture was stirred for 3 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2S0 ₄ , filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EA = 20:1 ) to give the title compound as a colorless oil.

Step 3: Ethyl 2-methyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cycl ohexan]-4'- yl)propanoate (Int 13c)

To a solution of ethyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- yl)acetate (Int 13b) (1.00 g, 2.90 mmol) in THF (20 mL) was added LHMDS (6.4 mL, 1 M in THF) at -78 °C and the mixture was stirred at -78 °C for 1 h. lodomethane (1.00 g, 7.20 mmol) was added and the mixture was allowed to warm up to rt and stirred overnight. Water (100 mL) was added 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 , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 20: 1 ) to give the title compound as a colorless oil.

Step 4: 2-Methyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'- yl)propanoic acid (Int 13)

A solution of ethyl 2-methyl-2-(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3, 1 '-cyclohexan]- 4'-yl)propanoate (Int 13c) (370 mg, 1.00 mmol) and LiOH H2O (84 mg, 2.00 mmol) in a mixture of THF and MeOH (70 mL, 1 :1 ) was heated to reflux for 2 h. After cooling to rt, HCI (25 mL, 1 M) was added and the mixture was filtered. The filter cake was dried under high vacuum to give the title compound as a white solid.

Intermediate 14: 5'-(Trifluoromethyl)-2'H-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4- one (Int 14)

Step 1 : 2-((1 ,4-Dioxaspiro[4.5]dec-7-en-8-yl)methoxy)-5-bromo-3-iodopyrid ine (Int 14a)

To a solution of (1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)methanol (Int 1 d) (6.80 g, 40.00 mmol) in DMF (70 mL) was added NaH (3.20 g, 80.00 mmol, 60 % in oil) at 0 °C and the mixture was stirred at 0 °C for 1 h. 5-Bromo-2-fluoro-3-iodopyridine (12.00 g, 40.00 mmol) was added and stirring was continued at rt for 2 h. The mixture was poured into water (1 L) and extracted by EtOAc (3 x 100 ml_). The combined organic layers were washed with brine (100 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid.

Step 2: 5-Bromo-2H-dispiro[furo[2,3-b]pyridine-3, 1 '-cyclohexane-4', 2"-[1 ,3]dioxolane]

(Int 14b)

A solution of 2-((1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)methoxy)-5-bromo-3-iodopyrid ine (Int 14a, 16.1 g, 35.7 mmol), n-Bu3SnH (10.4 g, 35.7 mmol) and AIBN (590 mg, 3.6 mmol) in toluene (320 mL) was heated to reflux overnight. After cooling to rt the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid.

Step 3: 5-lodo-2H-dispiro[furo[2,3-b]pyridine-3,1 '-cyclohexane-4', 2"-[1 ,3]dioxolane] (Int 14c)

To a solution of 5-bromo-2H-dispiro[furo[2,3-b]pyridine-3,T-cyclohexane-4',2" -

[1 ,3]dioxolane] (Int 14b, 4.50 g, 13.80 mmol) in 1 ,4-dioxane (20 mL) was added Kl (4.60 g, 27.60 mmol), Cul (266.00 mg, 1 .40 mmol) and N ¹ ,N ² -dimethylethane-1 ,2-diamine (123 mg, 1.40 mmol). The mixture was heated to reflux overnight under N ₂ . Then the mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid.

Step 4: 5-(Trifluoromethyl)-2H-dispiro[furo[2,3-b]pyridine-3,T-cyclo hexane-4',2"-

[1 ,3]dioxolane] (Int 14d)

KF (1.50 g, 25.90 mmol) and Cul (4.90 g, 25.90 mmol) were placed in a flask and were flame-heated under gentle shaking and high vacuum until a greenish color appeared. After cooling to rt a solution of 5-iodo-2H-dispiro[furo[2,3-b]pyridine-3,T-cyclohexane- 4',2"-[1 ,3]dioxolane] (Int 14c, 3.70 g, 10.00 mmol) and (trifluoromethyl)trimethylsilane (3.70 g, 25.90 mmol) in DMF (50 mL) was added and the mixture was stirred at 80 °C for 2 h. The mixture was poured into water (500 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid. Step 5: 5'-(Trifluoromethyl)-2'H-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-one (Int 14)

To a solution of 5-(trifluoromethyl)-2/-/-dispiro[furo[2,3-b]pyridine-3,T-cyc lohexane-4',2"- [1 ,3]dioxolane] (Int 14d, 630 mg, 2.00 mmol) in THF (10 mL) was added concentrated aqueous HCI solution (2 mL, 12 N), and the mixture was stirred at rt overnight. Water (30 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid.

Intermediate 15: 6'-(Trifluoromethyl)-2'H-spiro[cyclohexane-1 , 3'-f u ro[2 , 3-b] pyrid i n]-4- one (Int 15)

Step 1 : 2-((1 ,4-Dioxaspiro[4.5]dec-7-en-8-yl)methoxy)-6-bromo-3-iodopyrid ine (Int 15a)

To a solution of (1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)methanol (Int 1 d, 6.80 g, 40.00 mmol) in DMF (70 mL) was added NaH (3.20 g, 80.00 mmol, 60 % in oil) at 0 °C and the mixture was stirred at 0 °C for 1 h, then 6-bromo-2-fluoro-3-iodopyridine (12.00 g, 40.00 mmol) was added and stirring was continued at rt for 2 h. The mixture was poured into water (1 L) and extracted by EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid. Step 2: 6-Bromo-2H-dispiro[furo[2,3-b]pyridine-3, 1 '-cyclohexane-4', 2"-[1 ,3]dioxolane]

(Int 15b)

A solution of 2-((1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)methoxy)-6-bromo-3-iodopyrid ine (Int 15a, 16.1 g, 35.7 mmol), n-Bu3SnH (10.4 g, 35.7 mmol) and AIBN (590 mg, 3.6 mmol) in toluene (320 mL) was heated to reflux overnight. After cooling to rt the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE:EtOAc = 5:1 ) to afford the title compound as a white solid.

Step 3: 6-(Trifluoromethyl)-2H-dispiro[furo[2,3-b]pyridine-3,1 '-cyclohexane-4',2"-

[1 ,3]dioxolane] (Int 15c)

KF (1.50 g, 25.90 mmol) and Cul (4.90 g, 25.90 mmol) were placed in a flask and were flame-heated under gentle shaking and high vacuum until a greenish color appeared. After cooling to rt a solution of 5-iodo-2H-dispiro[furo[2,3-b]pyridine-3,1 '-cyclohexane- 4',2"-[1 ,3]dioxolane] (Int 14c, 3.70 g, 10.00 mmol) and (trifluoromethyl)trimethylsilane (3.70 g, 25.90 mmol) in DMF (50 mL) was added and the mixture was stirred at 80 °C for 2 h. The mixture was poured into water (500 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid.

Step 4: 6'-(Trifluoromethyl)-2'/-/-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-one (Int 15)

To the solution of 6-(trifluoromethyl)-2H-dispiro[furo[2,3-b]pyridine-3, T-cyclohexane- 4',2"-[1 ,3]dioxolane] (Int 15c, 1.00 g, 3.10 mmol) in DMF (10 mL) was added Cul (4.90 g, 25.90 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.20 g, 6.20 mmol). The mixture was stirred at 100 °C for 1 h under microwave irradiation. The mixture was poured into water (100 mL) and extracted by EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1 ) to afford the title compound as a white solid.

intermediate 16: 2-(5'-(Trifluoromethyl)-2'/-/-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]- 4-yl)propanoic acid (Int 16)

2-(5'-(T rifluoromethyl)-2'H-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanoic acid

(Int 16) was prepared from 5'-(trifluoromefhyl)-2'H-spiro[cyclohexane-1 ,3'-furo[2,3- b]pyridin]-4-one (Int 14) using a similar procedure as described for 2-(6-(trifluoromethyl)- 2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)propanoic acid (Int 12).

Intermediate 17: 2-(6'-(Trifluoromethyl)-2'H-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-

4-yl)propanoic acid (Int 17)

2-(6'-(T rifluoromethyl)-2'/-/-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanoic acid

(Int 17) was prepared from 6'-(trifluoromethyl)-2'H-spiro[cyclohexane-1 ,3'-furo[2,3- b]pyridin]-4-one (Int 15) using a similar procedure as described for 2-(6-(trifluoromethyl)- 2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)propanoic acid (Int 12).

Intermediate 18: 2'-Methyl-5'-(trifluoromethyl)spiro[cyclohexane-1 , 1 '-isoindoline]-3',4- dione (Int 18)

Step 1 : N-(4-Methoxybenzyl)-1 ,4-dioxaspiro[4.5]dec-7-en-8-amine (Int 18a)

A mixture of 1 ,4-dioxaspiro[4.5]decan-8-one (2.90 g, 18.60 mmol), (4- methoxyphenyl)methanamine (2.55 mg, 18.60 mmol) and 4A molecular sieves (20.00 g) in DCM (150 mL) was refluxed overnight. The mixture was used directly in the next step.

Step 2: 2-Bromo-A-(4-methoxybenzyl)-A/-(1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-

(trifluoromethyl)benzamide (Int 18b)

To a mixture of crude A -(4-methoxybenzyl)-1 ,4-dioxaspiro[4.5]dec-7-en-8-amine (Int

18a, 18.60 mmol) above was added 2-bromo-5-(trifluoromethyl)benzoyl chloride (5.35 g, 18.60 mmol) and DIPEA (4.80 g, 37.2 mmol) in DCM at 0 °C. The mixture was stirred overnight and then filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (PE:EtOAc = 5:1 ) to give the title compound as a yellow oil.

Step 3: 2-(4-Methoxybenzyl)-5-(trifluoromethyl)dispiro[isoindoline-1 ,T-cyclohexane- 4',2"-[1 ,3]dioxolan]-3-one (Int 18c)

A mixture of 2-bromo-A/-(4-methoxybenzyl)-A/-(1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-

(trifluoromethyl)benzamide (Int 18b, 4.90 g, 9.32 mmol), n-Bu3SnH (5.40 g, 18.64 mmol) and AIBN (305 mg, 1.86 mmol) in toluene (20 mL) was refluxed overnight. The resulting mixture was concentrated. 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: 5-(T rifluoromethyl)dispiro[isoindoline-1 , 1 '-cyclohexane-4', 2"-[1 ,3]dioxolan]-3- one (Int 18d)

To a solution of 2-(4-methoxybenzyl)-5-(trifluoromethyl)dispiro[isoindoline-1 ,1 '- cyclohexane-4',2"-[1 ,3]dioxolan]-3-one (Int 18c, 4.47 g, 10.00 mmol) in acetonitrile (50 mL) was added CAN (16.50 g, 30.00 mmol) in water (20 mL) at 0 °C. The mixture was stirred for 3 h and water (100 mL) was added. The mixture was filtered and the filtrate was extracted with EtOAc (3 x 100 mL). The organic phase was concentrated and the residue was purified by column chromatography on silica gel (PE: EtOAc = 3:1 ) to afford the title compound as a yellow solid.

Step 5: 2-Methyl-5-(trifluoromethyl)dispiro[isoindoline-1 ,T-cyclohexane-4',2"-

[1 ,3]dioxolan]-3-one (Int 18e)

To a solution of 5-(trifluoromethyl)dispiro[isoindoline-1 , 1 '-cyclohexane-4', 2"- [1 ,3]dioxolan]-3-one (Int 18d, 981 mg, 3.00 mmol) in THE (20 mL) was added NaH (180 mg, 4.5 mmol, 60 % dispersed in mineral oil) at 0 °C and then the mixture was stirred for 1 h. To the mixture above was added Mel (852 mg, 6.0 mmol) and the mixture was stirred at rt overnight. The mixture was poured into water (20 mL) and then extracted with EtOAc (3 x 20 mL). The organic phase was concentrated and the residue was purified by column chromatography on silica gel (PE: EtOAc = 3:1 ) to afford the title compound as a light yellow solid.

Step 6: 2'-Methyl-5'-(trifluoromethyl)spiro[cyclohexane-1 ,T-isoindoline]-3',4-dione (Int 18)

To a solution of HCIO4 (10 mL, 70% aqueous) was added 2-methyl-5- (trifluoromethyl)dispiro[isoindoline-1 ,T-cyclohexane-4',2"-[1 ,3]dioxolan]-3-one (Int 18e, 716 mg, 2.10 mmol) at 0 °C and then the mixture was stirred for 3 h. The mixture was added to a solution of NaHC0 ₃ (30 mL) and extracted with EtOAc (3 x 30 mL). The organic phase was concentrated and the residue was purified by column chromatography on silica gel (PE: EtOAc = 3:1 ) to afford the title compound as a white solid.

intermediate 19: 2-(2'-Methyl-3'-oxo-5'-(trifluoromethyl)spiro[cyclohexane-1 , 1 isoindo!in]-4-yl)propanoic acid (Int 19) C

lot 19

2-(2'-Meihyl-3'-oxo-5'-(trifluoromethyl)spiro[cyclohexane -1 , 1 '-isoindolin]-4-yl)propanoic acid (Int 19) was prepared from 2'-methyl-5'-(trifluoromethyl)spiro[cyclohexane-1 ,1 '- isoindoline]-3',4-dione (Int 18) using a similar procedure as described for 2-(6- (trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanoic acid (Int 12).

Intermediate 20: 2-(6-(Trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'- yl)butanoic acid (Int 20)

O

CF ₃ 2-(6-(Trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)butanoic acid (Int 20) was prepared from 6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-one (Int

1 ) by a similar procedure as described for 2-(6-(trifluorom ethyl )-2H-spiro[benzofuran-

3,1 '-cyclohexan]-4'-yl)propanoic acid (Int 12), using ethyl 2- (diethoxyphosphoryl)butanoate instead of ethyl 2-(diethoxyphosphoryl)propanoate.

Examples 1 b, 1c: Separate isomers of A/-(4-chlorophenyl)-2-(2',3'· dihydrospiro[cyclohexane-1 ,1 '-inden]-4-yl)acetamide (Examples 1 b, 1c)

Examples lb, lc, configurations not assigned

Step 1 : 2-(2',3'-Dihydrospiro[cyclohexane-1 ,1 '-inden]-4-yl)acetyl chloride (mixture of isomers) (1a)

A mixture of 2-(2',3'-dihydrospiro[cyclohexane-1 ,1 '-inden]-4-yl)acetic acid (Int 1 ) (1 14 mg, 0.47 mmol) in SOCh (5 mL) was stirred at rt for 2 h. 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.

Step 2: Separate isomers of A/-(4-chlorophenyl)-2-(2',3'-dihydrospiro[cyclohexane-1 , 1 inden]-4-yl)acetamide (1 b, 1c)

To a mixture of 2-(2',3'-dihydrospiro[cyclohexane-1 ,T-inden]-4-yl)acetyl chloride (mixture of isomers) (1a) (122 mg, 0.46 mmol) in DCM (5 mL) and 4-chloroaniline (71 mg, 0.56 mmol), TEA (70 mg, 0.69 mmol) were added. The mixture was stirred at 70 °C for 5 h. The mixture was concentrated to dryness and the residue was purified by preparative HPLC (ODS C18, column 21 .2 x 250 mm, 10 pm, 0.05% TEA in water/acetonitrile with gradient 65-95% acetonitrile, flow rate 30 mL/min) to afford the two cis/trans isomers of A/-(4-chlorophenyl)-2-(2',3'-dihydrospiro[cyclohexane-1 , 1 '-inden]-4-yl)acetamide as white solids.

First eluting isomer of A/-(4-chlorophenyl)-2-(2',3'-dihydrospiro[cyclohexane-1 , 1 -inden]- 4-yl)acetamide (Example 1 b) (RT of 2.60 min with the following analytical HPLC conditions: column X-Bridge C18 (4.6 x 50 mm, 3.5 pm), mobile phase gradient 5% - 95% acetonitrile in 10 mM aqueous NH4HCO3, flow rate 2.0 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 10.04 (s, 1 H), 7.65-7.63 (m, 2H), 7.35-7.33 (m, 2H), 7.18-7.09 (m, 4H), 2.84-2.81 (m, 2H), 2.26-2.25 (m, 2H), 1.94-1.84 (m, 3H), 1 .70-1.68 (m, 2H), 1.64-1.58 (m, 2H), 1.50-1.48 (m, 2H), 1.26-1.18 (m, 2H). MS (ESI): m/z 354.2 [M+H] ⁺ . Second eluting isomer of A/-(4-chlorophenyl)-2-(2',3'-dihydrospiro[cyclohexane-1 , 1 inden]-4-yl)acetamide (Example 1c) (RT of 2.62 min with the following analytical HPLC conditions: column X-Bridge C18 (4.6 x 50 mm, 3.5 pm), mobile phase gradient 5% - 95% acetonitrile in 10 mM aqueous NH4HCO3, flow rate 2.0 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 10.08 (s, 1 H), 7.65-7.63 (m, 2H), 7.38-7.34

(m, 3H), 7.20-7.1 1 (m, 3H), 2.83-2.80 (m, 2H), 2.48-2.46 (m, 2H), 2.17-2.13 (m, 1 H), 1 .92-1.89 (m, 2H), 1 .79-1.66 (m, 4H), 1.52-1.48 (m, 2H), 1 .40-1.36 (m, 2H). MS 354.0 (ESI): m/z [M+H] ⁺ .

Examples 1/1 a, 1/1 b: Separate isomers of A/-(4-ch!oro-2-fluorophenyl)-2-methyl-2-(6-

(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4'- yl)propanamide (1/1 a, 1/1 b)

Examples 1/1 a, 1/1 b, configurations not assigned

The title compounds were prepared simlar as described for Examples 1 b and 1c, steps 1 and 2, using in step 1 2-methyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T- cyclohexan]-4'-yl)propanoic acid (Int 13) in place of 2-(2',3'-dihydrospiro[cyclohexane- 1 ,T-inden]-4-yl)acetic acid (Int 1 ).

First eluting isomer of A/-(4-chloro-2-fluorophenyl)-2-methyl-2-(6-(trifluoromethyl) -2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (Example 1/1 a) (RT of 0.96 min with the following SFC conditions: column AD (Daicel) (20 x 250 mm), mobile phase CO2/0.2% N H3 in Methanol 50:50, flow rate 80 mL/min, column temperature 35°C): ¹ H

NMR (500 MHz, DMSO-de): d ppm 9.15 (s, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.48 (dd, J = 10.2, 2.3 Hz, 1 H), 7.44 (t, J = 8.5 Hz, 1 H), 7.27 (dd, J1 = 8.6, J ₂ =1.5 Hz, 1 H), 7.22 (d, J = 7.8 Hz, 1 H), 7.12 (s, 1 H), 4.25 (s, 2H), 1.95-1.76 (m, 3H), 1 .67-1.49 (m, 6H), 1.23 (s, 6H). MS (ESI): m/z 468.1 [M-H]-. Second eluting isomer of A/-(4-chloro-2-fluorophenyl)-2-methyl-2-(6-(trifluoromethyl) -2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide (Example 1/1 b) (RT of 1.54 min with the following SFC conditions: column AD (Daicel) (20 x 250 mm), mobile phase CO ₂ /0.2% N H3 in Methanol 50:50, flow rate 80 mL/min, column temperature 35°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 9.13 (s, 1 H), 7.47 (dd, J1 = 10.2, J ₂ = 2.2 Hz, 1 H), 7.43 (t, J = 8.4 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1 H), 7.26 (dd, Ji = 8.6, J ₂ = 1.4 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.08 (s, 1 H), 4.46 (s, 2H), 1.90-1.75 (m, 3H), 1.74-1.59 (m, 4H), 1.25- 1 .10 (m, 8H). MS (ESI): m/z 468.1 [M-H]\

Examples 2a, 2b: Separate racemic cis/trans isomers of A/-(4-chlorophenyl)-2-(2',3'- dihydrospiro[cyclohexane-1 ,1 '-inden]-4-yl)propanamide (2a, 2b)

Examples 2a, 2b, racemates, cls/trans configurations not assigned

A mixture of 2-(2',3'-dihydrospiro[cyclohexane-1 ,1 '-inden]-4-yl)propanoic acid (mixture of cis/trans isomers, racemates) (Int 11 ) (789 mg, 3.00 mmol), 4-chloroaniline (466 mg, 3.60 mmol), HATU (1.70 g, 4.50 mmol) and DIPEA (774 mg, 6.00 mmol) in DMF (10 mL) was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to dryness and the residue was purified by column chromatography on silica gel (PE: EtOAc = 10: 1 ) followed by preparative chiral-SFC (CHIRALCEL OD, column 30 x 250 mm, 5 pm, C0 ₂ /MeOH- EtOH 1 :1 , flow rate 45 mL/min) to afford the two racemic cis/trans isomers of A/-(4- Chlorophenyl)-2-(2',3'-dihydrospiro[cyclohexane-1 , 1 '-inden]-4-yl)propanamide.

First eluting racemic cis/trans isomer of A/-(4-chlorophenyi)-2-(2',3'- dihydrospiro[cyclohexane-1 ,T-inden]-4-yl)acetamide (Example 2a) with RT = 3.87 min and 4.12 min, collected in one fraction. ¹ H NMR (400 MHz, DMSO-de): d ppm 10.07 (s, 1 H), 7.67-7.64 (m, 2H), 7.42-7.40 (m, 1 H), 7.36-7.33 (m, 2H), 7.19-7.12 (m, 3 H), 2.82-

2.78 (m, 2H), 2.71 -2.67 (m, 1 H), 1.91 -1.79 (m, 3H), 1.75-1.67 (m, 3H), 1.60-1.49 (m, 3H), 1 .40-1.33 (m, 2H), 1.12 (d, J = 6.8 Hz, 3H). MS (ESI): 368.1 [M+H] ⁺ .

Second eluting racemic cis/trans isomer of -(4-chlorophenyl)-2-(2',3'- dihydrospiro[cyclohexane-1 ,T-inden]-4-yl)acetamide (Example 2b) with RT = 4.78 min and 5.99 min, collected in one fraction. ¹ H NMR (400 MHz, DMSO-d6): d ppm 9.99 (s, 1 H), 7.67-7.64 (m, 2H), 7.35-7.32 (m, 2H), 7.17-7.07 (m, 4H), 2.83-2.79 (m, 2H), 2.28- 2.24 (m, 1 H), 1.92-1.88 (m, 2H), 1.83-1.79 (m, 1 H), 1.59-1.46 (m, 6H), 1.30-1.23 (m, 2H), 1 .10-1.15 (m, 3H). MS (ESI): 368.3 [M+H] ⁺ . Examples 3b, 3c, 3d, 3e: Separate isomers of A/-(4-chlorophenyl)-2-(6-(trifluoromethyl)-

2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)propanamide (3a), (3b, 3c, 3d, 3e)

Examples 3b _y 3C 3d 3e

Step 1 : A/-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofur an-3, 1 '-cyclohexan]- 4'-yl)propanamide, mixture of isomers (3a)

A mixture of 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanoic acid (Int 12) (328 mg, 1 .00 mmol), 4-chloroaniline (127 mg, 1.00 mmol), EDCI (384 mg, 2.00 mmol), HOBt (270 mg, 2.00 mmol) and DIPEA (516 mg, 4.00 mmol) in DMF (10 m!_) was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with DCM (3 x 20 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 white solid.

Step 2: Separate isomers of A/-(4-chlorophenyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide (Examples 3b, 3c, 3d, 3e) The mixture of isomers /V-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofur an-

3,T-cyclohexan]-4'-yl)propanamide (3a) was separated by preparative chiral-SFC (stationary phase CHIRALCEL AD (Daicel), mobile phase CC MeOH) to afford the four separated isomers of A/-(4-chlorophenyl)-2-(6-(trifluorom ethyl )-2H-spiro[benzofuran-

3,1 '-cyclohexan]-4'-yl)propanamide (Examples 3b, 3c, 3d, 3e).

(S)-/V-(4-Chlorophenyl)-2-((3S,4'r)-6-(trifluoromethyl)-2 H-spiro[benzofuran-3,T- cyclohexan]-4'-yl)propanamide (Example 3b), (first eluting isomer of the mixture 3a, RT of 1.37 min with the following analytical SFC-Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 70% CO2 / 30% MeOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.1 (s, 1 H), 7.68-7.63 (m, 2H), 7.60-7.57 (m, 1 H), 7.38-7.32 (m, 2H), 7.25-7.21 (m, 1 H), 7.1 1 (s, 1 H), 4.37-4.29 (m,

2H), 2.64-2.57 (m, 1 H), 1 .90-1.67 (m, 4H), 1.61-1.47 (m, 5H), 1.14 (d, J=6.8 Hz, 3H). MS

(ESI): 438.1 [M+H] ⁺ .

(R)-A/-(4-Rhlorophenyl)-2-((3R,4'r)-6-(trifluoromethyl)-2 H-spiro[benzofuran-3,r- cyclohexan]-4'-yl)propanamide (Example 3c), (second eluting isomer of the mixture 3a, RT of 1.90 min with the following analytical SFC-Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 70% CO2 / 30% MeOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.1 (s, 1 H), 7.67-7.64 (m, 2H), 7.60-7.57 (m, 1 H), 7.37-7.33 (m, 2H), 7.25-7.21 (m, 1 H), 7.1 1 (s, 1 H), 4.37-4.29 (m,

2H), 2.64-2.58 (m, 1 H), 1 .90-1.68 (m, 4H), 1.61-1.48 (m, 5H), 1.14 (d, J=6.8 Hz, 3H). MS

(ESI): 438.1 [M+H] ⁺ .

(S)-A/-(4-Chlorophenyl)-2-((3R,4's)-6-(trifluoromethyl)-2 H-spiro[benzofuran-3,T- cyclohexan]-4'-yl)propanamide (Example 3d), (third eluting isomer of the mixture 3a, RT of 2.18 min with the following analytical SFC-Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 70% CO2 / 30% MeOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.0 (s, 1 H), 7.67-7.63 (m, 2H), 7.42-7.39 (m, 1 H), 7.36-7.32 (m, 2H), 7.22-7.18 (m, 1 H), 7.07 (s, 1 H), 4.48-4.41 (m, 2H), 2.27-2.22 (m, 1 H), 1.87-1.82 (m, 1 H), 1.75-1.58 (m, 6H), 1.18-0.97 (m, 5H). MS (ESI): 438.2 [M+H] ⁺ .

(R)-W-(4-chlorophenyl)-2-((3S,4's)-6-(trifluoromethyl)-2H -spiro[benzofuran-3,T- cyclohexan]-4'-yl)propanamide (Example 3e), (fourth eluting isomer of the mixture 3a, RT of 2.72 min with the following analytical SFC-Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 70% CO2 / 30% MeOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.0 (s, 1 H), 7.67-7.63 (m, 2H), 7.42-7.39 (m, 1 H), 7.36-7.33 (m, 2H), 7.22-7.18 (m, 1 H), 7.07 (s, 1 H), 4.48-4.41 (m, 2H), 2.28-2.22 (m, 1 H), 1.87-1.82 (m, 1 H), 1.75-1.57 (m, 6H), 1.18-0.98 (m, 5H). MS (ESI): 438.2 [M+H] ⁺ . The absolute configuration of Example 3e was determined by X- ray diffraction analysis.

Stereoselective route for (S)-/V-(4-Chlorophenyl)-2-((3R,4's)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (Example 3d) and (S)-A/-(4- ChlorophenyI)-2-((3S,4'r)-6-(trifluoromethyl)-2H-spiro[benzo furan-3,1 '-cyclohexan]-4'- yl)propanamide (Example 3b)

Example 3d: (S)-A/-(4-Chlorophenyl)-2-((3f?,4's)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide (3d)

Step 1 : Methyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- ylidene)acetate (Int 21a)

To a solution of 6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-one (Int 1 , 1 .35 g, 5.00 mmol) in dry THF (25 mL) was added NaH (300 mg, 15.00 mmol, 60 % dispersion in mineral oil) at 0 °C, and the mixture was stirred for 1 h. Then methyl 2- (diethoxyphosphoryl)acetate (1.76 g, 12.00 mmol) was added and the mixture was stirred at rt for 3 h. The mixture was poured into saturated N H4CI solution (50 mL) and extracted with EtOAc (3 x 50 ml_). The combined organic phase was concentrated and the residue was purified by column chromatography on silica gel (PE: EtOAc = 10: 1 ) to afford the title compound as a colorless oil.

Step 2: Methyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '-yl)acetate

(Int 21 b)

To a solution of methyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'- ylidene)acetate (Int 21a, 1.68 g, 5.00 mmol) and NiCh-ehbO (1.18 g, 5.00 mmol) in MeOH (30 mL) was added NaBFU (950 mg, 25.00 mmol) at 0 °C, and the mixture was stirred for 3 h. Then it was poured into water (30 mL) and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed by brine (2 x 30 mL), dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 ) to afford the title compound as a colorless oil.

Step 3: 2-(6-(Trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)acetic acid (Int 21c)

A solution of methyl 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'- yl)acetate (Int 21 b, 1 .64 g, 5.00 mmol) and LiOH (600 mg, 25.00 mmol) in a mixture of THF/MeOH (30 mL, 10:1 ) was refluxed for 2 h. After cooling to rt, aqueous HOI (1.0 mL, 1 .0 N) was added, the formed solid was filtered and dried under vacuum to afford the title compound as a white solid.

Step 4: (S)-4-Phenyl-3-(2-((3R,4's)-6-(trifluoromethyl)-2H-spiro[ben zofuran-3, 1 cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (Int 21d-1 ) and (S)-4-phenyl-3-(2-((3S,4'r)-6- (trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4'-yl) acetyl)oxazolidin-2-one

(21d-2)

A mixture of 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '-yl)acetic acid (Int 21c, 1 .35 g, 4.30 mmol), EEDQ (1.06 g, 4.30 mmol), (S)-4-phenyloxazolidin-2-one (701 mg, 4.30 mmol) and LiCI (180 mg, 4.30 mmol) in EA (20 mL) was stirred and heated to reflux overnight. After cooling to rt the mixture was poured into aqueous HOI (20 mL, 1 .0 N) and extracted by EtOAc (3 x 20 mL). The combined organic phase was concentrated and the residue was purified by column chromatography on silica gel (PE: EtOAc = 10: 1 ) to afford the title compounds as a white solid. This mixture was subjected to separation by chiral SFC (CHIRALCEL OD, C0 ₂ /MeOH, 60/40%) to afford (S)-4- phenyl-3-(2-((3R,4's)-6-(trifluoromethyl)-2H-spiro[benzofura n-3,T-cyclohexan]-4'- yl)acetyl)oxazolidin-2-one (Int 21 d-1 , second eluting isomer) and (S)-4-phenyl-3-(2- ((3S,4'r)-6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'- yl)acetyl)oxazolidin-2-one (Int 21d-2, first eluting isomer).

Step 5: (S)-4-Phenyl-3-((S)-2-((3R,4's)-6-(trifluoromethyl)-2H-spiro [benzofuran-3,1 '- cyclohexan]-4'-yl)propanoyl)oxazolidin-2-one (Int 21e)

To a solution of (S)-4-phenyl-3-(2-((3R,4's)-6-(trifluoromethyl)-2H-spiro[ben zofuran-3,1 '- cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (Int 21 d-1 , 502 mg, 1.09 mmol) in dry THF (15 ml_) was added LHMDS (1.6 ml_, 1.61 mmol, 1.0 M in THF) at -40 °C and the mixture was stirred for 0.5 h. Mel (774 mg, 5.45 mmol) was added and the mixture was stirred for further 2 h at -40 °C. Saturated aqueous NH ₄ CI solution (3.0 mL) was added at -40 °C and the mixture was concentrated. 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: (S)-2-((3R,4's)-6-(T rifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexanj-4'- yl)propanoic acid (Int 21 )

To a mixture of (S)-4-phenyl-3-((S)-2-((3R,4's)-6-(trifluoromethyl)-2H-spiro [benzofuran-

3,T-cyclohexan]-4'-yl)propanoyl)oxazolidin-2-one (Int 21e, 206 mg, 0.44 mmol) and LiOH (36 mg, 0.88 mmol) in THF (10 mL) was added H ₂ 0 ₂ (1.0 mL, 30 % in H ₂ 0). The mixture was stirred at 0 °C for 2 h and then poured into saturated aqueous NaHSC solution. The resulting mixture was extracted by EtOAc (3 x 10 mL) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by prep-HPLC to give the title compound as a white solid

Step 7: (S)-/V-(4-Chlorophenyl)-2-((3R,4's)-6-(trifluoromethyl)-2H-s piro[benzofuran-3,T- cyclohexan]-4'-yl)propanamide (Example 3d)

A mixture of (S)-2-((3R,4's)-6-(trifluoromethyl)-2/-/-spiro[benzofuran-3, 1 '-cyclohexan]-4'- yl)propanoic acid (Int 21 , 40 mg, 0.12 mmol), 4-chloroaniline (15 mg, 0.12 mmol), EDCI (29 mg, 0.15 mmol), HOBt (20 mg, 0.15 mmol) and DIEA (28 mg, 0.22 mmol) in DMF (10 mL) was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic phase was concentrated and the residue was purified by prep-HPLC to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-de): d ppm 10.0 (s, 1 H), 7.69-7.61 (m, 2H), 7.42-7.40 (m, 1 H), 7.37 - 7.30 (m, 2H), 7.22-7.18 (m, 1 H), 7.07 (s, 1 H), 4.48-4.41 (m, 2H), 2.27-2.21 (m, 1 H), 1.87- 1 .82 (m, 1 H), 1.75-1.58 (m, 6H), 1.18-0.95 (m, 5H). MS (ESI): 438.2 [M+H] ⁺ .

Example 3b: (S)-N-(4-Chlorophenyl)-2-((3S,4'r)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (3b)

Starting from (S)-4-phenyl-3-(2-((3S,4Y)-6-(trifluoromethyl)-2H-spiro[benz ofuran-3,1 '- cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (21 d-2), (S)-A/-(4-chlorophenyl)-2-((3S,4'r)-6- (trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (Example 3b) was obtained following a similar procedure as described for (S)-/V-(4-chlorophenyl)-2- ((3R,4's)-6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (Example 3d). ¹ H NMR (400 MHz, DMSO-de): d ppm 10.1 (s, 1 H), 7.70-7.62 (m, 2H), 7.60-7.57 (m, 1 H), 7.40-7.30 (m, 2H), 7.25-7.21 (m, 1 H), 7.1 1 (s, 1 H), 4.37-4.29 (m, 2H), 2.65-2.55 (m, 1 H), 1.90-1.67 (m, 4H), 1.62-1.47 (m, 5H), 1.14 (d, J = 6.8 Hz, 3H). MS (ESI): 438.1 [M+H] ⁺ .

Stereoselective route for Examples 3e and 3c

3e 3c

Step 1 : (R)-4-Phenyl-3-(2-((3R,4's)-6-(trifluoromethyl)-2/-/-spiro[b enzofuran-3, 1 '- cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (Int 21d-3) and (R)-4-phenyi-3-(2-((3S,4'r)-6- (trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (Int 21d-4) (R)-4-Phenyl-3-(2-((3R,4's)-6-(trifluoromethyl)-2H-spiro[ben zofuran-3,1 '-cyclohexan]-4'- yl)acetyl)oxazolidin-2-one (Int 13d-3) and (R)-4-phenyl-3-(2-((3S,4'r)-6-(trifluoromethyl)- 2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (Int 21d-4) were obtained from 2-(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)acetic acid (Int 21c) following the procedure described for (S)-4-phenyl-3-(2-((3R,4's)-6- (trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (Int 21 d-1 ) and (S)-4-phenyl-3-(2-((3S,4'r)-6-(trifluoromethyl)-2H-spiro[ben zofuran-3, 1 cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (21d-2), using (R)-4-phenyloxazolidin-2-one in place of (S)-4-phenyloxazolidin-2-one. (R)-4-Phenyl-3-(2-((3R,4's)-6-(trifluoromethyl)- 2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (Int 21 d-3) was the second eluting isomer and (R)-4-phenyl-3-(2-((3S,4'r)-6-(trifluoromethyl)-2/-/- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (21d-4) was the first eluting isomer. The structure of (R)-4-phenyl-3-(2-((3S,4'r)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)acetyl)oxazolidin-2-o ne (21d-4) was confirmed by X-ray diffraction analysis.

Example 3e: (R)-A/-(4-Chlorophenyl)-2-((3S,4's)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide (3e)

Starting from (R)-4-phenyl-3-(2-((3S,4's)-6-(trifluoromethyl)-2/-/-spiro[b enzofuran-3,1 '- cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (21d-3), (R)-A -(4-chlorophenyl)-2-((3S,4's)-6- (trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (Example 3e) was obtained following a similar procedure as described for (S)-A-(4-chlorophenyl)-2- ((3R,4's)-6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (Example 3d). ¹ H NMR (400 MHz, DMSO-de): d ppm 10.0 (s, 1 H), 7.70-7.59 (m, 2H), 7.42-7.39 (m, 1 H), 7.38-7.28 (m, 2H), 7.22-7.18 (m, 1 H), 7.07 (s, 1 H), 4.48-4.41 (m, 2H),

2.28-2.22 (m, 1 H), 1.89-1.77 (m, 1 H), 1.75-1.57 (m, 6H), 1.25-0.95 (m, 5H). MS (ESI): 438.2 [M+H] ⁺ .

Example 3c: (R)-A/-(4-Chlorophenyl)-2-((3R,4'r)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (3c)

Starting from (R)-4-phenyl-3-(2-((3R,4'r)-6-(trifluoromethyl)-2H-spiro[ben zofuran-3, 1 '- cyclohexan]-4'-yl)acetyl)oxazolidin-2-one (21 d-4), (R)-A -(4-chiorophenyl)-2-((3R,4'r)-6- (trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)propanamide (Example 3c) was obtained following a similar procedure as described for (S)-A/-(4-chlorophenyl)-2- ((3R,4's)-6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (Example 3d). ¹ H NMR (400 MHz, DMSO-de): d ppm 10.1 (s, 1 H), 7.67-7.64 (m, 2H), 7.60-7.57 (m, 1 H), 7.38-7.31 (m, 2H), 7.25-7.21 (m, 1 H), 7.1 1 (s, 1 H), 4.37-4.29 (m, 2H),

2.65-2.56 (m, 1 H), 1 .90-1.68 (m, 4H), 1.62-1.46 (m, 5H), 1.14 (d, J=6.8 Hz, 3H). MS (ESI): 438.1 [M+H] ⁺ .

Examples 4b, 4c, 4d, 4e: Separate isomers of A/-(4-chlorophenyl)-2-(5'-(trifluoromethyl)- 2'H-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (4a), (4b, 4c, 4d, 4e)

Examples 4b, 4c, 4d, 4e, configurations not assigned

Step 1 : N-(4-chlorophenyl)-2-(5'-(trifluoromethyl)-2'H-spiro[cyclohe xane-1 ,3'-furo[2,3- b]pyridin]-4-yl)propanamide (4a)

A/-(4-chlorophenyl)-2-(5'-(trifluoromethyl)-2'H-spiro[cyc lohexane-1 ,3'-furo[2,3-b]pyridin]- 4-yl)propanamide (4a) was obtained from 2-(5'-(trifluoromethyl)-2'H-spiro[cyclohexane-

1 ,3'-furo[2,3-b]pyridin]-4-yl)propanoic acid (Int 16) following a similar procedure as described for A/-(4-chlorophenyl)-2-(6-(trifluoromeihyl)-2H-spiro[benzofur an-3,1 '- cyclohexan]-4'-yl)propanamide (3a).

Step 2: Separate isomers of A/-(4-chlorophenyl)-2-(5'-(trifluoromethyl)-2'H- spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (4a), (Examples 4a, 4b, 4c,

4d)

The separate isomers of A -(4-chlorophenyl)-2-(5'-(trifiuoromethyl)-2'H- spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (4a), (4b, 4c, 4d, 4e) were prepared following a similar procedure as described for the separate isomers of N-( 4- chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'- yl)propanamide (3a), (3b, 3c, 3d, 3e), using the following preparative chiral-SFC conditions: stationary phase CHIRALCEL OD (Daicel), mobile phase C0 ₂ /MeOH (0.2% ammonia, 7N in MeOH), 80/20.

First eluting isomer of A/-(4-chlorophenyl)-2-(5'-(trifluoromethyl)-2'H-spiro[cycloh exane-

1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (Example 4b), (RT of 3.38 min with the following analytical SFC-Conditions: column CHIRALPAK OD-H (4.6 x 100 mm, 5pm), mobile phase 90% CO2/ 10% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.04 (s, 1 H), 8.40 (s, 1 H), 7.96 (d, J = 2.0 Hz, 1 H), 7.66 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 4.45-4.37 (m, 2H), 2.73-2.57 (m, 1 H), 2.02-1.77 (m, 2H), 1.75-1.41 (m, 7H), 1 .14 (d, J = 6.8 Hz, 3H).. MS (ESI): 439.2 [M+H] ⁺ .

Second eluting isomer of A/-(4-chlorophenyl)-2-(5'-(trifluoromethyl)-2'H- spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (Example 4c), (RT of 4.20 min with the following analytical SFC-Conditions: column CHIRALPAK OD-H (4.6 x 100 mm, 5pm), mobile phase 90% CO2/ 10% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.04 (s, 1 H), 8.40 (s, 1 H), 7.96 (d, J = 2.0 Hz, 1 H), 7.66 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 4.45-4.37 (m, 2H), 2.73-2.57 (m, 1 H), 2.02-1.77 (m, 2H), 1.75-1.41 (m, 7H), 1.14 (d, J = 6.8 Hz, 3H). MS (ESI): 439.2 [M+H] ⁺ .

Third eluting isomer of A/-(4-chlorophenyl)-2-(5'-(trifluoromethyl)-2'H-spiro[cycloh exane-

1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (Example 4d), (RT of 4.67 min with the following analytical SFC-Conditions: column CHIRALPAK OD-H (4.6 x 100 mm, 5pm), mobile phase 90% CO2/ 10% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.01 (s, 1 H), 8.35 (s, 1 H), 8.06 (d, J = 2.2 Hz, 1 H), 7.65 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 4.55-4.49 (m, 2H), 2.29-2.17 (m, 1 H), 1.90-1.51 (m, 7H), 1.19-0.99 (m, 5H). MS (ESI): 439.1

[M+H] ⁺ .

Fourth eluting isomer of A -(4-chlorophenyl)-2-(5'-(trifluoromethyl)-2'H- spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (Example 4e), (RT of 6.08 min with the following analytical SFC-Conditions: column CHIRALPAK OD-H (4.6 x 100 mm, 5pm), mobile phase 90% CO2 / 10% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-d ₆ ): d ppm 10.01 (s, 1 H), 8.35 (s, 1 H), 8.06 (d, J = 2.2 Hz, 1 H), 7.65 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 4.55-4.49 (m, 2H), 2.29-2.17 (m, 1 H), 1.90-1.51 (m, 7H), 1.19-0.99 (m, 5H). MS (ESI):

439.2 [M+H] ⁺ .

Examples 5b, 5c, 5d, 5e: Separate isomers of A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-

2'H-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (5a), (5b, 5c, 5d, 5e)

Examples 5b, 5c, 5d, 5e, configurations not assigned Step 1 : A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[cycloh exane-1 ,3'-furo[2,3- b]pyridin]-4-yl)propanamide (5a)

A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[cyc lohexane-1 ,3'-furo[2,3-b]pyridin]- 4-yl)propanamide (5a) was obtained from 2-(5'-(trifluoromethyl)-2'H-spiro[cyclohexane-

1 ,3'-furo[2,3-b]pyridin]-4-yl)propanoic acid (Int 17) following a similar procedure as described for A/-(4-chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofur an-3,T- cyclohexan]-4'-yl)propanamide (3a).

Step 2: Separate isomers of A/-(4-chlorophenyl)-2-(6'-(trifluoromethyi)-2'H- spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (5a), (Examples 5b, 5c, 5d,

5e)

/V-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[cyc lohexane-1 ,3'-furo[2,3-b]pyridin]- 4-yl)propanamide (5a) was subjected to a separation via chiral SFC, using the following preparative chiral-SFC conditions: stationary phase CHIRALCEL AD (Daicel), mobile phase CCfe/MeOH (0.2% ammonia, 7N in MeOH), 40/60. Two fractions were separated. The first eluted fraction (from prep chiral SFC) was concentrated to dryness and subjected to a second separation via chiral HPLC, using the following conditions: stationary phase (S, S) WHELK, mobile phase n-Hexane (0.1 %DEA)/EtOH(0.1 %DEA), 75:25, giving rise to two separate isomers of N-(4-chlorophenyl)-2-(6'-(trifluoromethyl)- 2'H-spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (Example 5b, first eluting and Example 5c, second eluting from prep chiral HPLC). The second eluting fraction (from prep chiral SFC) was concentrated to dryness and subjected to a second separation via chiral SFC, using the following conditions: stationary phase CHIRALPAK AY (Daicel), mobile phase C0 ₂ /EtOH (0.5% ammonia, 7N in MeOH), 70/30, giving rise to two separate isomers of N-(4-chlorophenyl)-2-(6 -(trifluoromethyl)-2'H- spiro[cyclohexane-1 ,3'-furo[2,3-b]pyridin]-4-yl)propanamide (Example 5d, first eluting and Example 5e, second eluting from prep chiral SFC).

A/-(4-chiorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[cyc lohexane-1 , 3'-f u ro[ , 3-b] py rid i nj-

4-yl)propanamide (Example 5b), (RT of 1.29 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 80% CO2 / 20% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.02 (s, 1 H), 7.97 (d, J = 7.5 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 2H), 4.39.4.33 (m, 2H), 2.60-2.52 (m, 1 H), 1.93-1.44 (m, 9H), 1.14 (d, J = 6.8 Hz, 3H). MS (ESI): 438.9 [M+H] ⁺ . A/-(4-chlorophenyl)-2-(6'-(irifluoromethyl)-2'H-spiro[cycloh exane-1 , 3'-f u ro[2 , 3-b] py rid i n]-

4-yl)propanamide (Example 5c), (RT of 1.50 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 80% CO2 / 20% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.02 (s, 1 H), 7.97 (d, J = 7.5 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 2H), 4.39.4.33 (m, 2H), 2.60-2.52 (m, 1 H), 1.93-1.44 (m, 9H), 1.14 (d, J = 6.8 Hz, 3H). MS (ESI): 438.9 [M+H] ⁺ .

A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[cyc lohexane-1 , 3'-f u ro[2 , 3-b] py rid i n]- 4-yl)propanamide (Example 5d), (RT of 2.28 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 80% CO2 / 20% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.00 (s, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1 H), 7.34 (d, J = 8.9 Hz, 2H), 4.55-4.47 (m, 2H), 2.27-2.22 (m, 1 H), 1.92-1.53 (m, 7H), 1.22-0.96 (m, 5H). MS (ESI): 439.1 [M+H] ⁺ .

A/-(4-chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[cyc lohexane-1 ,3'-furo[2,3-b]pyridin]- 4-yl)propanamide (Example 5e), (RT of 2.48 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 80% CO2 / 20% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 10.00 (s, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1 H), 7.34 (d, J = 8.9 Hz, 2H), 4.55-4.47 (m, 2H), 2.27-2.22 (m, 1 H), 1.92-1.53 (m, 7H), 1.22-0.96 (m, 5H). MS (ESI): 439.1 [M+H] ⁺ .

Examples 6b, 6c, 6d, 6e: Separate isomers of W-(4-chlorophenyl)-2-(2'-methyl-3'-oxo-

5'-(trifluoromethyl)spiro[cyclohexane-1 ,T-isoindolin]-4-yl)propanamide (6a), (6b, 6c, 6d, 6e)

Examples 6b, 6c, 6d, 6e, configurations not assigned

Step 1 : A/-(4-chlorophenyl)-2-(2'-methyl-3'-oxo-5'-(trifluoromethyl) spiro[cyclohexane- 1 ,1 '-isoindolin]-4-yl)propanamide (6a)

A/-(4-chlorophenyl)-2-(2'-methyl-3'-oxo-5'-(trifluorometh yl)spiro[cyclohexane-1 , 1 isoindolin]-4-yl)propanamide (6a) was obtained from 2-(2'-methyl-3'-oxo-5'-

(trifluoromethyl)spiro[cyclohexane-1 , 1 '-isoindolin]-4-yl)propanoic acid (Int 19) following a similar procedure as described for A/-(4-chlorophenyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (3a).

Step 2: Separate isomers of A/-(4-chlorophenyl)-2-(2'-methyl-3'-oxo-5'- (trifluoromethyl)spiro[cyclohexane-1 , 1 '-isoindolin]-4-yl)propanamide (6a), (Examples 6a, 6b, 6c, 6d)

N-(4-Chiorophenyl)-2-(2'-methyl-3'-oxo-5'-(trifluoromethy l)spiro[cyclohexane-1 , 1 isoindolin]-4-yl)propanamide (6a) was subjected to a separation via chiral SFC, using the following preparative chiral-SFC conditions: stationary phase CHIRALCEL AD-3 (Daicel), mobile phase C0 ₂ //-Pr0H, 75/25. Three fractions were separated. The first eluted fraction (from prep chiral SFC) was concentrated to dryness and afforded the single isomer 6b. The second eluted fraction was concentrated to dryness and afforded the single isomer 6c. The third eluted fraction was concentrated to dryness and subjected to a second separation via chiral SFC, using the following conditions: stationary phase CHIRALCEL AD-3 (Daicel), mobile phase C0 ₂ /MeOH, 60/40, giving rise to two separate isomers, 6d, first eluting and 6e, second eluting.

A/-(4-Chlorophenyl)-2-(2'-methyl-3'-oxo-5'-(trifluorometh yl)spiro[cyclohexane-1 , 1 isoindolin]-4-yl)propanamide (6b), (RT of 2.00 min with the following analytical SFC- Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 75% CO2 / 25% /-PrOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO- d ₆ ): 5 ppm 10.08 (s, 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.98-7.95 (m, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 2.97 (s, 3H), 2.53-2.51 (m, 1 H), 2.22-2.03 (m, 2H), 2.00- 1 .96 (m, 1 H), 1.84-1.61 (m, 4H), 1.40-1.33 (m, 2H), 1 .20 (d, J = 6.8 Hz, 3H). MS (ESI): 465.1 [M+H] ⁺ .

A/-(4-Chlorophenyl)-2-(2'-methyl-3'-oxo-5'-(trifluorometh yl)spiro[cyclohexane-1 , 1 '- isoindolin]-4-yl)propanamide (6c), (RT of 3.28 min with the following analytical SFC- Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 75% CO2 / 25% /-PrOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO- d ₆ ): d ppm 10.14 (s, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.91 (s, 1 H), 7.66 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 3.19 (s, 3H), 2.69-2.65 (m, 1 H), 2.1 1 - 1 .81 (m, 5H), 1.76-1.68 (m, 4H), 1.17 (d, J = 6.7 Hz, 3H). MS (ESI): 465.2 [M+H] ⁺ .

A/-(4-Chlorophenyl)-2-(2'-methyl-3'-oxo-5'-(trifluorometh yl)spiro[cyclohexane-1 , 1 '- isoindolin]-4-yl)propanamide (6d), (RT of 3.81 min with the following analytical SFC- Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 75% CO2 / 25% /-PrOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO- d ₆ ): d ppm 10.07 (s, 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.98-7.95 (m, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 2.96 (s, 3H), 2.53-2.51 (m, 1 H), 2.22-2.06 (m, 2H), 1.99- 1 .96 (m, 1 H), 1.84-1.61 (m, 4H), 1.40-1.33 (m, 2H), 1 .20 (d, J = 6.8 Hz, 3H). MS (ESI): 465.3 [M+H] ⁺ .

A/-(4-Chlorophenyl)-2-(2'-methyl-3'-oxo-5'-(trifluorometh yl)spiro[cyclohexane-1 , 1 '- isoindolin]-4-yl)propanamide (6e), (RT of 4.29 min with the following analytical SFC- Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 75% CO2 / 25% /-PrOH, flow rate 2 mL/min, column temperature 35°C): ¹ H NMR (400 MHz, DMSO- d ₆ ): d ppm 10.14 (s, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.92 (s, 1 H), 7.66 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 3.19 (s, 3H), 2.69-2.65 (m, 1 H), 2.1 1 - 1 .81 (m, 5H), 1.76-1.68 (m, 4H), 1.17 (d, J = 6.7 Hz, 3H). MS (ESI): 465.1 [M+H] ⁺ . Examples 7b, 7c, 7d, 7e: Separate isomers of A/-(4-chloro-2-fluorophenyl)-2-(6- (trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)propanamide (7a),

(Examples 7b, 7c, 7d, 7e)

Examples 7b, 7c, 7d, 7e, configurations not assigned Step 1 : A/-(4-Chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro [benzofuran-3,1 '- cyclohexan]-4'-yl)propanamide (7a)

To a mixture of 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'- yl)propanoic acid (Int 12) (328 mg, 1.00 mmol) in DCM (10 mL) was added SOC (1 mL) and the mixture was stirred at rt for 2 h. The mixture was concentrated to give crude acyl chloride intermediate. The residue was redissolved in DCM (10 mL), 4-chioro-2- fluoroaniline (145 mg, 1.00 mmol) and TEA (303 mg, 3.00 mmol) were added and the mixture was stirred at rt for 2 h. The mixture was poured into water (30 mL) and the resulting mixture was extracted with DCM (3 x 30 mL). The combined organic phase was washed by brine (2 x 30 mL), dried over Na2S0 ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc = 5: 1 ) to afford the title compound as a colorless oil. Step 2: Separate isomers of A/-(4-chioro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (7a), (Examples 7b, 7c, 7d, 7e)

A/-(4-Chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-sp iro[benzofuran-3,1 '- cyclohexan]-4'-yl)propanamide (7a) was subjected to a separation via chiral SFC, using the following conditions: stationary phase (S, S) WHELK (Daicel), mobile phase C0 ₂ /MeOH (0.2% ammonia, 7N in MeOH), 75/25. Two fractions were separated. The first eluted fraction was concentrated to dryness and subjected to a second separation via chiral SFC, using the following conditions: stationary phase CHIRALPAK AD, mobile phase C0 ₂ /MeOH (0.2% ammonia, 7N in MeOH), 65/35, giving rise to two separate isomers of /\/-(4-chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-spir o[benzofuran-3,T- cyclohexan]-4'-yl)propanamide: Example 7b, first eluting and Example 7c, second eluting. The second fraction of the first chiral SFC separation was also concentrated to dryness and subjected to a second separation via chiral SFC, using the following conditions: stationary phase CHIRALCEL AD, mobile phase C0 ₂ /MeOH (0.2% ammonia, 7N in MeOH), 65/35, giving rise to two separate isomers of A/-(4-chloro-2- fluorophenyl)-2-(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3 ,T-cyclohexan]-4'- yl)propanamide: Example 7d, first eluting and Example 7e, second eluting.

/\/-(4-Chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-s piro[benzofuran-3,T- cyclohexan]-4'-yl)propanamide (Example 7b), (RT of 0.92 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% C0 ₂ / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 9.81 (s, 1 H), 7.89 (t, J = 8.6 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.49 (dd, J = 10.6, 2.3 Hz, 1 H), 7.25 (t, J = 9.1 Hz, 2H), 7.1 1 (s, 1 H), 4.38-4.31 (m, 2H), 2.91-2.78 (m, 1 H), 1.96-1.86 (m, 1 H), 1.84-1.63 (m, 3H), 1 .62-1.47 (m, 5H), 1.13 (d, J = 6.8 Hz, 3H). MS (ESI): 456.1 [M+H] ⁺ .

A/-(4-Chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-sp iro[benzofuran-3,T- cyclohexan]-4'-yl)propanamide (Example 7c), (RT of 1.81 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% C0 ₂ / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 9.74 (s, 1 H), 7.87 (t, J = 8.6 Hz, 1 H), 7.48 (dd, J = 10.6, 2.3 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 1 H), 7.25 (d, J = 8.6 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 4.48-4.42 (m, 2H), 2.47-2.40 (m, 1 H), 1.92- 1 .50 (m, 7H), 1.28-0.93 (m, 5H). MS (ESI): 456.0 [M+H] ⁺ . A/-(4-Chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro [benzofuran-3,1 '- cyclohexan]-4'-yl)propanamide (Example 7d), (RT of 1.37 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% C0 ₂ / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 9.81 (s, 1 H), 7.89 (t, J = 8.6 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.49 (dd, J = 10.6, 2.3 Hz, 1 H), 7.25 (t, J = 9.1 Hz, 2H), 7.1 1 (s, 1 H), 4.38-4.31 (m, 2H), 2.91-2.78 (m, 1 H), 1.96-1.86 (m, 1 H), 1.84-1.63 (m, 3H), 1 .62-1.47 (m, 5H), 1.13 (d, J = 6.8 Hz, 3H). MS (ESI): 456.0 [M+H] ⁺ .

A/-(4-Chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-sp iro[benzofuran-3,1 '- cyclohexan]-4'-yl)propanamide (Example 7e), (RT of 1.83 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% CO2 / 25% MeOH(0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (400 MHz, DMSO-de): d ppm 9.74 (s, 1 H), 7.87 (t, J = 8.6 Hz, 1 H), 7.48 (dd, J = 10.6, 2.3 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 1 H), 7.25 (d, J = 8.6 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 4.48-4.42 (m, 2H), 2.47-2.40 (m, 1 H), 1.92-

1 .50 (m, 7H), 1.28-0.93 (m, 5H). MS (ESI): 456.1 [M+H] ⁺ .

Examples 8b, 8c, 8d, 8e: Separate isomers of A/-(p-tolyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (8a), (Examples 8b, 8c, 8d, 8e)

Examples 8b, 8c, 8d, 8e, configurations not assigned

Step 1 : A/-(p-Tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'- yl)propanamide (8a)

A/-(p-Tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3 , 1 '-cyclohexan]-4'- yl)propanamide (8a) was obtained from 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T- cyclohexan]-4'-yl)propanoic acid (Int 12) following a similar procedure as described for A/-(4-chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro [benzofuran-3,T-cyclohexan]-

4'-yl)propanamide (7a).

Step 2: Separate isomers of A/-(p-tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, 1 cyclohexan]-4'-yl)propanamide (8a), (Examples 8b, 8c, 8d, 8e)

A/-(p-Tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3 , 1 '-cyclohexan]-4'- yl)propanamide (8a) was subjected to a separation via chiral SFC, using the following conditions: stationary phase (S, S) WHELK (Daicel), mobile phase C0 ₂ /MeOH (0.2% ammonia, 7N in MeOH), 65/35. Two fractions were separated. The first eluted fraction was concentrated to dryness and subjected to a second separation via chiral SFC, using the following conditions: stationary phase CHIRALPAK AD, mobile phase CC /MeOH (0.2% ammonia, 7N in MeOH), 65/35, giving rise to two separate isomers of N-(p- tolyl)- 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide:

Example 8b, first eluting and Example 8c, second eluting isomer. The second fraction of the first chiral SFC separation was also concentrated to dryness and subjected to a second separation via chiral SFC, using the following conditions: stationary phase CHIRALCEL AD, mobile phase CC MeOH (0.2% ammonia, 7N in MeOH), 65/35, giving rise to two separate isomers of /V-(p-tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran- 3,T-cyclohexan]-4'-yl)propanamide: Example 8d, first eluting and Example 8e, second eluting.

A/-(p-Tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3 , T-cyclohexan]-4'- yl)propanamide (Example 8b): (RT of 0.92 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% CO2 / 25% MeOH(0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 9.82 (s, 1 H), 7.60 (d, J = 7.7 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1 H), 7.10-7.07 (m, 3H), 4.36-4.30 (m, 2H), 2.63- 2.58 (m, 1 H), 2.24 (s, 3H), 1.93-1.84 (m, 1 H), 1.83-1.63 (m, 3H), 1.62-1.46 (m, 5H), 1.13 (d, J = 6.8 Hz, 3H). MS (ESI): 418.1 [M+H] ⁺ .

A/-(p-Tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3 , T-cyclohexan]-4'- yl)propanamide (Example 8c), (RT of 1.69 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% CO2 / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 9.75 (s, 1 H), 7.49 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.7 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.09-7.07 (m, 3H), 4.47-4.42 (m, 2H), 2.29- 2.17 (m, 4H), 1.91 -1.51 (m, 7H), 1.21-0.95 (m, 5H). MS (ESI): 418.1 [M+H] ⁺ .

A-(p-Tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, T-cyclohexan]-4'- yl)propanamide (Example 8d), (RT of 1.04 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% CO2 / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 9.83 (s, 1 H), 7.60 (d, J = 7.7 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1 H), 7.10-7.07 (m, 3H), 4.36-4.30 (m, 2H), 2.63- 2.58 (m, 1 H), 2.24 (s, 3H), 1.93-1.84 (m, 1 H), 1.83-1.63 (m, 3H), 1.62-1.46 (m, 5H), 1.13 (d, J = 6.8 Hz, 3H).. MS (ESI): 418.1 [M+H] ⁺ . A/-(p-Tolyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'- yl)propanamide (Example 8e), (RT of 1.75 min with the following analytical SFC- Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% CO2 / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 9.75 (s, 1 H), 7.49 (d, J = 8.4 Hz, 2H), 7.41

(d, J = 7.7 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.09-7.07 (m, 3H), 4.47-4.42 (m, 2H), 2.29- 2.17 (m, 4H), 1.91 -1.51 (m, 7H), 1.21 -0.95 (m, 5H). MS (ESI): 418.1 [M+H] ⁺ .

Examples 9b, 9c, 9d, 9e: Separate isomers of A/-((1 r,4r)-4-methylcyclohexyl)-2-(6- (trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)propanamide (9a),

(Examples 9b, 9c, 9d, Be)

Examples 9b, 9c, 9d, 9e, configurations not assigned

Step 1 : A/-((1 r,4r)-4-Methylcyclohexyl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran-3,1 '- cyclohexan]-4'-yl)propanamide (9a) L/-((1 r,4r)-4-Methylcyclohexyl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran-3, 1 cyclohexan]-4'-yl)propanamide (9a) was obtained from 2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanoic acid (Int 12) following a similar procedure as described for A/-(4-chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (7a).

Step 2: Separate isomers of A/-((1 r,4r)-4-Methylcyclohexyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide (9a), (Examples 9b, 9c, 9d, 9e)

L/-((1 r,4r)-4-Methylcyclohexyl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran-3, 1 cyclohexan]-4'-yl)propanamide (9a) was subjected to a separation via chiral SFC, using the following conditions: stationary phase CHIRALPAK AD (Daicel), mobile phase CC MeOH (1 % ammonia, 7N in MeOH), 75/25. Three fractions were separated. The first eluted fraction was concentrated to afford the single isomer Example 9b. The second fraction was concentrated to dryness and subjected to a second separation via chiral HPLC, using the following conditions: stationary phase CHIRALCEL AD, mobile phase n-hexane(0.1 % DEA):EtOH (0.1 % DEA), 75/25, giving rise to two separate isomers of A/-((1 r,4r)-4-methylcyclohexyl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran- 3,T-cyclohexan]-4'-yl)propanamide: Example 9c, first eluting and Example 9d, second eluting isomer. The third fraction of the first chiral SFC separation was also concentrated to dryness to afford the single isomer of -((1 r,4r)-4-methylcyclohexyl)-2-(6- (trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanamide: Example 9e.

L/-((1 r,4r)-4-Methylcyclohexyl)-2-(6-(trifluoromethyl)-2/-/-spiro[ benzofuran-3, 1 cyclohexan]-4'-yl)propanamide (Example 9b): (RT of 1.34 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% C0 ₂ / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 7.66 (d, J = 7.9 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 7.10 (s, 1 H), 4.36-4.29 (m, 2H), 3.56-3.41 (m, 1 H), 2.38-2.34 (m, 1 H), 1.93-1.82 (m, 1 H), 1.80-1.39 (m, 12H), 1.35-1.24 (m, 1 H), 1 .23-1.05 (m, 2H), 1.03-0.89 (m, 5H), 0.85 (d, J = 6.5 Hz, 3H). MS (ESI): 424.3 [M+H] ⁺ .

A/-((1 r,4r)-4-Methylcyclohexyl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran-3, 1 cyclohexan]-4'-yl)propanamide (Example 9c), (RT of 2.77 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% C0 ₂ / 25% MeOH (0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 7.58 (d, J = 7.9 Hz, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.20 (d, J = 7.9 Hz, 1 H), 7.07 (s, 1 H), 4.45-4.38 (m, 2H), 3.51-3.39 (m, 1 H), 2.00-1.89 (m, 1 H), 1.84-1 .40 (m, 1 1 H), 1.35-0.89 (m, 10H), 0.85 (d, J = 6.5 Hz, 3H). MS (ESI): 424.3 [M+H] ⁺ .

A/-((1 r,4r)-4-Meihylcyclohexyl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran-3, 1 '- cyclohexan]-4'-yl)propanamide (Example 9d), (RT of 2.92 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% CO2 / 25% MeOH(0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 7.58 (d, J = 7.9 Hz, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.20 (d, J = 7.9 Hz, 1 H), 7.07 (s, 1 H), 4.45-4.38 (m, 2H), 3.51-3.39 (m, 1 H), 2.00-1.89 (m, 1 H), 1.84-1 .40 (m, 1 1 H), 1.35-0.89 (m, 10H), 0.85 (d, J = 6.5 Hz,

3H). MS (ESI): 424.3 [M+H] ⁺ .

A/-((1 r,4r)-4-Methylcyclohexyl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran-3, 1 '- cyclohexan]-4'-yl)propanamide (Example 9e), (RT of 3.81 min with the following analytical SFC-Conditions: column CHIRALPAK AD-H (4.6 x 100 mm, 5pm), mobile phase 75% CO2 / 25% MeOH(0.2% ammonia, 7N in MeOH), flow rate 4 mL/min, column temperature 40°C): ¹ H NMR (500 MHz, DMSO-de): d ppm 7.67 (d, J = 7.9 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 7.10 (s, 1 H), 4.36-4.29 (m, 2H), 3.56-3.41 (m, 1 H), 2.38-2.34 (m, 1 H), 1.93-1.82 (m, 1 H), 1.80-1.39 (m, 12H), 1.35-1.24 (m, 1 H), 1 .23-1.05 (m, 2H), 1.03-0.89 (m, 5H), 0.85 (d, J = 6.5 Hz, 3H). MS (ESI): 424.3 [M+H] ⁺ .

Examples 10b, 10c, 10d, 10e: A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)butanamide (10a), (Examples 10b, 10c, 10d, 10e)

Examples 10b, 10c, !Od, lOe, configurations not assigned

Step 1 : /V-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran-3,T- cyclohexan]-4'-yl)butanamide (10a)

/V-(5-chloropyridin-2-yl)-2-(6-(trifluoromeihyl)-2/-/-spi ro[benzofuran-3,1 '-cyclohexan]-4'- yl)butanamide (10a) was obtained from 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T- cyclohexan]-4'-yl)butanoic acid (Int 20) following a similar procedure as described for N-

(4-chloro-2-f!uorophenyl)-2-(6-(trifluoromethyl)-2H-spiro [benzofuran-3,1 '-cyclohexan]-4'- yl)propanamide (7a).

Step 2: Separate isomers of A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)butanamide (10a), (Examples 10b, 10c, 10d, 10e)

A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2H-spiro [benzofuran-3,1 '-cyclohexan]-4'- yl)butanamide (10a) was subjected to a separation via column chromatography on silica gel (PE:EtOAc, 2:1 ). Two fractions were obtained. The first eluted fraction was concentrated to dryness and subjected to a separation via chiral SFC, using the following conditions: stationary phase CHIRALCEL AD, CC MeOH, 70/30, giving rise to two separate isomers of A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2H-spiro[be nzofuran- 3,1 '-cyclohexan]-4'-yl)butanamide: Example 10b, first eluting and Example 10c, second eluting isomer. The second fraction of the separation on silica gel was also concentrated to dryness and subjected to a separation via chiral SFC, using the following conditions: stationary phase CHIRALCEL AS, CC^MeOH, 90/210, giving rise to two separate isomers of A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyi)-2H-spiro[be nzofuran-3,T- cyclohexan]-4'-yl)butanamide: Example 10d, first eluting and Example 10e, second eluting isomer.

A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2H-spiro [benzofuran-3,1 '-cyclohexan]-4'- yljbutanamide (Example 10b): (RT of 1.79 min with the following analytical SFC- Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 65% CCh/MeOH 35%, flow rate 2 mL/min, column temperature 35°C) ¹ H NMR (400 MHz, DMSO-de): d ppm 10.74 (s, 1 H), 8.35 (s, 1 H), 8.19 (d, J = 8.9 Hz, 1 H), 7.88 (d, J = 8.9, 1 H), 7.60 (d, J = 7.2 Hz, 1 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.08 (s, 1 H), 4.35-4.28 (m, 2H), 2.85-2.61 (m, 1 H), 2.00-1.84 (m, 1 H), 1.79-1.59 (m, 4H), 1.57-1.36 (m, 6H), 0.84 (t, J = 7.3 Hz, 3H). MS (ESI): 453.1 [M+H] ⁺ .

A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2H-spiro [benzofuran-3,1 '-cyclohexan]-4'- yl)butanamide (Example 10c): (RT of 2.54 min with the following analytical SFC- Conditions: column CHIRALPAK AD-3 (4.6 x 100 mm, 3pm), mobile phase 65% CC /MeOH 35%, flow rate 2 mL/min, column temperature 35°C) ¹ H NMR (400 MHz, DMSO-de): d ppm 10.76 (s, 1 H), 8.35 (s, 1 H), 8.19 (d, J = 8.9 Hz, 1 H), 7.88 (d, J = 8.9, 1 H), 7.60 (d, J = 7.2 Hz, 1 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.10 (s, 1 H), 4.37-4.30 (m, 2H), 2.85-2.61 (m, 1 H), 2.00-1.84 (m, 1 H), 1.79-1.59 (m, 4H), 1.57-1.36 (m, 6H), 0.87 (t, J = 7.3 Hz, 3H). MS (ESI): 453.1 [M+H] ⁺ .

A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2/-/-spi ro[benzofuran-3,T-cyclohexan]-4'- yl)butanamide (Example 10d): (RT of 1.31 min with the following analytical SFC- Conditions: column CHIRALPAK AS-3 (4.6 x 100 mm, 3pm), mobile phase 90% C0 ₂ /MeOH 10%, flow rate 2 mL/min, column temperature 35°C) ¹ H NMR (400 MHz, DMSO-de): d ppm 10.66 (s, 1 H), 8.37 (s, 1 H), 8.20 (d, J = 9.1 Hz, 1 H), 7.88 (d, J = 9.1 Hz, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.20 (d, J = 7.7 Hz, 1 H), 7.07 (s, 1 H), 4.46-4.40 (m, 2H), 2.41-2.28 (m, 1 H), 1.89-1.78 (m, 1 H), 1.75-1.64 (m, 4H), 1.62-1.53 (m, 4H), 1.24- 1 .09 (m, 1 H), 1.09-0.93 (m, 1 H), 0.83 (t, J = 7.3 Hz, 3H). MS (ESI): 453.1 [M+H] ⁺ . A/-(5-chloropyridin-2-yl)-2-(6-(trifluoromethyl)-2/-/-spiro[ benzofuran-3,1 '-cyclohexan]-4'- yl)butanamide (Example 10e): (RT of 1.77 min with the following analytical SFC- Conditions: column CHIRALPAK AS-3 (4.6 x 100 mm, 3pm), mobile phase 90% CCte/MeOH 10%, flow rate 2 mL/min, column temperature 35°C) ¹ H NMR (400 MHz, DMSO-de): d ppm 10.66 (s, 1 H), 8.37 (s, 1 H), 8.20 (d, J = 9.1 Hz, 1 H), 7.88 (d, 3 = 9.1 Hz, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.20 (d, J = 7.7 Hz, 1 H), 7.07 (s, 1 H), 4.46-4.40 (m, 2H), 2.41-2.28 (m, 1 H), 1.89-1.78 (m, 1 H), 1.75-1.64 (m, 4H), 1.62-1.53 (m, 4H), 1.24- 1 .09 (m, 1 H), 1.09-0.93 (m, 1 H), 0.83 (t, J = 7.3 Hz, 3H). MS (ESI): 453.1 [M+H] ⁺ .

Examples 11 b, 11c, 11 d, 11e: 5-Chloro-2-(1-(6-(trifluoromethyl)-2H-spiro[benzofuran- 3,1 '-cyclohexan]-4'-yl)ethyl)-1 H-benzo[d]imidazole (11a), (Examples 11 b, 11c, 11 d, 11e)

Examples 11b, 11c, 11 d, 11 e, configurations not assigned

Step 1 : 5-Chloro-2-(1 -(6-(trifluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'- yl)ethyl)-1 H-benzo[d]imidazoie (11 a) A mixture of 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)propanoic acid (Int 12, 328 mg, 1 .00 mmol), 4-chloroaniline (142 mg, 1.00 mmol), HATU (380 mg, 1 .OOmmol) and DIPEA (387 mg, 3.00 mmol) in DMF (10 mL) was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic phase was concentrated and the residue was purified by column chromatography on silica gel (PE:EtOAc = 2:1 ) to give the intermediate anilide as a brown solid. The solid was dissolved in HO Ac (20 mL) and was heated to reflux overnight. The mixture was poured into saturated NaHC0 ₃ solution (50 mL) and extracted with DCM (3 x 50 mL). The organic phase was concentrated and the residue was purified by column chromatography on silica gel (PE:EtOAc = 5: 1 ) to give the title compound as a white solid.

5-Chloro-2-(1 -(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4' -yl)ethyl)-1 H- benzo[c/]imidazole (11a) was subjected to a separation via preparative chiral SFC, using the following conditions: stationary phase CHIRALCEL OZ (Daicel), mobile phase C02:MeOH, 85/15. Three fractions were obtained. The first eluted fraction was concentrated to dryness and subjected to a second separation via chiral SFC, using the following conditions: stationary phase CHIRALCEL AD, CC2:EtOH (0.3% ammonia), 85/15, giving rise to two separate isomers of 5-chloro-2-(1-(6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)ethyl)-1 H-benzo[cfjimidazole: Example 11 b, first eluting and Example 11c, second eluting isomer. The second and the third fraction of the first separation on chiral SFC were concentrated to dryness to afford two isomers of 5-chloro-2-(1-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-c yclohexan]-4'-yl)ethyl)-1 H- benzo[cfjimidazole: Example 11 d, second fraction and Example 11 e, third fraction.

5-Chloro-2-(1 -(6-(trifiuoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4' -yl)ethyl)-1 H- benzo[c/jimidazole (Example 11 b): (RT of 7.20 min with the following analytical SFC- Conditions: column CHIRALCEL OZ-3 (4.6 x 100 mm, 3pm), mobile phase CO2 (95- 90%)/MeCH (5-10%) ¹ H NMR (400 MHz, DMSO-de): d ppm 12.39 (d, J = 15.8 Hz, 1 H), 7.64-7.51 (m, 2H), 7.49-7.43 (m, 1 H), 7.21 -7.04 (m, 3H), 4.34-4.27 (m, 2H), 3.21-3.17 (m, 1 H), 1.88-1.81 (m, 3H), 1.78-1 .29 (m, 9H). MS (ESI): 435.3 [M+H] ⁺ .

5-Chloro-2-(1 -(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4' -yl)ethyl)-1 H- benzo[c/]imidazole (Example 11c): (RT of 7.69 min with the following analytical SFC- Conditions: column CHIRALCEL OZ-3 (4.6 x 100 mm, 3pm), mobile phase CO2 (95- 90%)/MeOH (5-10%) ¹ H NMR (400 MHz, DMSO-de): d ppm 12.39 (d, J = 15.8 Hz, 1 H), 7.64-7.51 (m, 2H), 7.49-7.43 (m, 1 H), 7.21 -7.04 (m, 3H), 4.34-4.27 (m, 2H), 3.21-3.17 (m, 1 H), 1.88-1.81 (m, 3H), 1.78-1 .29 (m, 9H). MS (ESI): 435.4 [M+H] ⁺ . 5-Chloro-2-(1 -(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,T-cyclohexan]- 4'-yl)ethyl)-1 /-/- benzo[c/]imidazole (Example 11 d): (RT of 8.38 min with the following analytical SFC- Conditions: column CHIRALCEL OZ-3 (4.6 x 100 mm, 3pm), mobile phase CO ₂ (95- 90%)/MeOH (5-10%), flow rate 2 mL/min, column temperature 35°C) ¹ H NMR (400 MHz, DMSO-de): d ppm 12.36 (d, J = 14.9 Hz, 1 H), 7.61 -7.34 (m, 3H), 7.23-7.03 (m, 3H), 4.45- 4.38 (m, 2H), 2.90-2.81 (m, 1 H), 1.91 -1.54 (m, 6H), 1.41-1.26 (m, 4H), 1.16-1.10 (m, 2H). MS (ESI): 435.3 [M+H] ⁺ .

5-Chloro-2-(1 -(6-(trifluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'-yl)ethyl)-1 H- benzo[c/]imidazole (Example 11e): (RT of 10.25 min with the following analytical SFC- Conditions: column CHIRALCEL OZ-3 (4.6 x 100 mm, 3pm), mobile phase C0 ₂ (95- 90%)/MeOH (5-10%), flow rate 2 mL/min, column temperature 35°C) ¹ H NMR (400 MHz, DMSO-de): d ppm 12.36 (d, J = 14.9 Hz, 1 H), 7.61 -7.34 (m, 3H), 7.23-7.03 (m, 3H), 4.45- 4.38 (m, 2H), 2.90-2.81 (m, 1 H), 1.91 -1.54 (m, 6H), 1.41-1.26 (m, 4H), 1.16-1.10 (m, 2H). MS (ESI): 435.3 [M+H] ⁺ . Examples 12a and 12b: Separate isomers of (2S)-A/-(4-fluorobicyclo[4.2.0]octa-

1 (6),2,4-trien-7-yl)-2-((3R,4's)-6-(tnfluoromethyl)-2H-spiro[ benzofuran-3, 1 -cyclohexan]- 4'-yl)propanamide (Examples 12a, 12b)

Examples 12a, 12b

absolute configuration at this carbon not assigned

A mixture of (S)-2-((3R,4's)-6-(trifluoromethyl)-2H-spiro[benzofuran-3,T- cyclohexan]-4'- yl)propanoic acid (Int 21 , 38 mg, 0.1 15 mmol), 4-fluorobicyclo[4.2.0]octa-1 ,3,5-trien-7- aminium chloride (20.0 mg, 0.1 15 mmol), HATU (65.7 mg, 0.173 mmol) and DIPEA (0.080 mL, 0.461 mmol) in DMF (1.0 mL) were stirred overnight at rt. The mixture was diluted with EtOAc (20mL), washed with 1 N aq. NH ₄ CI and brine. The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The residue was purified by silicagel flash chromatography (cyclohexane/EtOAc, gradient from 10-90% EtOAc in 10 column volumes). Two separate product fractions were obtained, pooled, concentrated to dryness and lyophilized from water/acetonitrile to obtain the separate title compounds: (2S)-A/-(4-fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)-2-((3f?,4's)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide Example 12a, first eluting on silica gel column, Example 12b, second eluting on silica gel column.

(2S)-A/-(4-fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)-2-((3R,4's)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide (Example 12a): ¹ H-NMR (300 MHz, DMSO): d ppm 8.54 (d, J=6.9 Hz, 1 H), 7.44-7.39 (m, 1 H), 7.23-7.00 (m, 5H), 5.24 (s, 1 H), 4.48-4.38 (m, 2H), 3.53 (dd, J=4.8, 14.0 Hz, 1 H), 2.91 (d, J=14.0 Hz, 1 H), 2.1 1- 1 .97 (m, 1 H), 1.87-145 (m, 7H), 1.17-0.89 (m, 5H). MS (ESI): 448.3 [M+H] ⁺ .

2S)-N-(4-fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)-2-((3R,4's)-6-(trifluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide (Example 12b): ¹ H-NMR (300 MHz, DMSO): d ppm 8.52 (d, J=7.3 Hz, 1 H), 7.41 (d, J=7.6 Hz, 1 H), 7.23-6.95 (m, 5H), 5.24 (s, br, 1 H), 4.44-4.41 (m, 2H), 3.51 (dd, J=4.9, 13.6 Hz, 1 H), 2.95 (d, J=14.0 Hz,

1 H), 2.09-1 .99 (m, 1 H), 1.88-1.46 (m, 7H), 1.16-0.89 (m, 5H). MS (ESI): 448.3 [M+H] ⁺ .

Example 13: (S)-/V-(4-chlorophenyl)-2-((3R,4's)-6-(difluoromethyl)-2H- spiro[benzofuran-3,T-cyclohexan]-4'-yl)propanamide (13)

Step 1 : (S)-3-(2-((3R,4's)-6-(difluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'- yl)acetyl)-4-phenyloxazolidin-2-one (Int 22a)

A solution of (S)-4-phenyloxazolidin-2-one (603 mg, 3.70 mmol) and LiCI (155 mg, 3.70 mmol) in EtOAc (20 ml_) was heated at reflux overnight. The mixture was poured into HCI (50 mL, 1 M.) and extracted by 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 = 10: 1 ) to give a white solid. The solid was submitted to chiral-HPLC separation to give the title compound which is the second eluting isomer of (S)-3-(2-(6- (difluoromethyl)-2H-spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)acetyl)-4-phenyloxazolidin- 2 -one (Int 22a) (RT of 2.92 min with the following SFC conditions: column OD (Chiralcel) (20 x 250 mm), mobile phase 00 ₂ /0.2% NH ₃ in Methanol 60:40, flow rate 45 mL/min).

Step 2: (S)-3-((S)-2-((3R,4's)-6-(difluoromethyl)-2H-spiro[benzofura n-3, 1 -cyclohexan]-

4'-yl)propanoyl)-4-phenyloxazolidin-2-one (Int 22b) To a solution of Int 22a (500 mg, 1.10 mmol) in THF (20 mL) was added LHMDS (1.6 mL, 1.60 mmol, 1 M in THF) at -40 °C and the mixture was stirred for 0.5 h. Mel (315 mg, 2.20 mmol) was added and the mixture was stirred for 2 h at -40 °C. Saturated NH4CI solution (10 mL) was added at -40 °C and the mixture was concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 ) to give the title compound as a white solid.

Step 3: (S)-2-((3R,4's)-6-(difluoromethyl)-2H-spiro[benzofuran-3,1 '-cyclohexan]-4'- yl)propanoic acid (Int 22c) To a mixture of Int 22b (200 mg, 0.44 mmol) and UOITI-I2O (37 mg, 0.88 mmol) in THF (10 mL) was added H2O2 (1 mL, 30% in water). The mixture was stirred at 0 °C for 2 h. The mixture was poured into saturated NaHS0 ₃ solution. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed by brine, 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 white solid.

Step 4: (S)-A/-(4-chlorophenyl)-2-((3R,4's)-6-(difluoromethyl)-2H-sp iro[benzofuran-3,T- cyclohexan]-4'-yl)propanamide (13)

To a mixture of Int 22c (100 mg, 0.32 mmol) in DCM (10 mL) was added SOCI2 (1 mL) and the mixture was stirred at rt for 2h. The mixture was concentrated to dryness to give a solid whisch was dissolved in DCM (10 mL). 4-Chloroaniline (61 mg, 0.48 mmol) and TEA (65 mg, 0.64 mmol) were added and the mixture was stirred at rt overnight. The mixture was poured into water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were concentrated to dryness and the residue was purified by preparative HPLC to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): d ppm 9.99 (s, 1 H), 7.71-7.60 (m, 2H), 7.42-7.26 (m, 3H), 7.07 - 6.77 (m, 3H), 4.44- 4.36 (m, 2H), 2.28-2.20 (m, 1 H), 1.88-1.55 (m, 7H), 1 .20-0.94 (m, 5H). MS (ESI): m/z 420.1 [M+H] ⁺ .

Examples 14a, 14b: Separate isomers of A/-(4-chloro-2-fluorophenyl)-2-(6-

(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4'- yl)acetamide (14a, 14b)

Examples 14a, 1 b, configurations not assigned The title compounds were prepared simlar as described for Examples 1 b and 1c, steps

1 and 2, using in step 1 2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,T-cyclohexan]-4 '- yl)acetic acid (Int 21c, step 3 in Examples 3b and 3d) in place of 2-(2',3'- dihydrospiro[cyclohexane-1 ,T-inden]-4-yl)acetic acid (Int 1 ).

First eluting isomer of A-(4-chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)acetamide (Example 14a) (RT of 1.98 min with the following SFC conditions: column AD (Daicel) (20 x 250 mm), mobile phase CO2/I % NH ₃ in Ethanol 70:30, flow rate 80 mL/min): ¹ H NMR (500 MHz, DMSO-de): d ppm 9.80 (s, 1 H), 7.93 (dd, J1 = J ₂ = 8.6 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.48 (dd, J1 = 10.7, J ₂ = 2.3 Hz, 1 H), 7.28-7.21 (m, 2H), 7.1 1 (s, 1 H), 4.36 (s, 2H), 2.54 (d, J = 7.4 Hz, 2H), 2.10- 2.02 (m, 1 H), 1.91-1.78 (m, 2H), 1.72-1.62 (m, 2H), 1 .62-1.47 (m, 4H). MS (ESI): m/z 442.0 [M+H] ⁺ .

Second eluting isomer of A/-(4-chloro-2-fluorophenyl)-2-(6-(trifluoromethyl)-2H- spiro[benzofuran-3, 1 '-cyclohexan]-4'-yl)acetamide (Example 14b) (RT of 2.58 min with the following SFC conditions: column AD (Daicel) (20 x 250 mm), mobile phase C0 ₂ /1 % NH ₃ in Ethanol 70:30, flow rate 80 mL/min): ¹ H NMR (500 MHz, DMSO-de): d ppm 9.77 (s, 1 H), 7.90 (dd, J1 = J ₂ = 8.6 Hz, 1 H), 7.47 (dd, J1 = 10.7, J ₂ = 2.3 Hz, 1 H), 7.43 (d, J = 7.7 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 1 H), 7.21 (d, J = 7.4 Hz, 1 H), 7.08 (s, 1 H), 4.46 (s, 2H), 2.32 (d, J = 7.1 Hz, 2H), 1.91 -1.84 (m, 1 H), 1.81 -1.62 (m, 6H), 1 .18-1.05 (m, 2H). MS (ESI): m/z 442.0 [M+H] ⁺ .

If one were to use similar procedures as that desdribed for Example 13, steps 1 -4 using in step 1 either (S)-4-phenyloxazolidin-2-one or (R)-4-phenyloxazolidin-2-one and in step

2 either the first or the second eluting diastereomer the following compounds, next to Example 13, 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 % Penicillin/Streptomycin. Cells were kept at 37° C in a humidified incubator with 5 % CO2. For assay preparation, cells were seeded at a density of 2 ^* 10 ⁵ /ml into black clear bottom 96 well plates in 100 pi medium/well supplemented with 50 ng/ml Interferon gamma (eBioscience, Thermo Fisher Scientific). After cells fully adhered to the plate, dilution series of compounds were added in medium containing additional L- Tryptophan to a final L-Tryptophan concentration of 100 mM. The cells were incubated for 24 hours. Detection of produced N-Formylkynurenin was performed by addition of 3- Methylpiperidine to a final concentration of 200 mM. The plates were sealed and heated to 65° C for 20 minutes in a water bath. After cooling the fluorescence of each well was recorded with a Victor™ X4 (PerkinElmer) plate reader at an emission wavelength of 535 nm and excitation at 405 nm (Tomek et al. ; Anal Bioanal Chem (2013) 405:2515-2524., Tomek et al.; Biochim Biophys Acta. 2015 Sep; 1850(9): 1772-80).

The IC50 values of the example compounds are shown in Table 1 below (A = I C50 < 50 nM, B = 50 nM < IC50 £ 1 pM, C = IC50 > 1 pM).