New benzimidazole derivatives

Abstract

The invention relates to a compound of formula (I) wherein A and R1 to R7 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P60080

[0003] New benzimidazole derivatives

[0004] The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to compounds that are TMEM175 enhancers. The compound of formula (I) is particularly useful in the treatment or prophylaxis of neurodegenerative diseases, fibrotic disorders or inflammatory disorders, more specifically, synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis and lysosomal storage disorders.

[0005] The invention relates in particular to a compound of formula (I)

[0006]

[0007] wherein

[0008] A is nitrogen or -CH-;

[0009] one of R1and R2is hydrogen, haloalkoxy, haloalkyl, haloalkylsulfanyl, halophenyl or alkoxy and the other one is hydrogen, halogen or alkyl;

[0010] one of R3and R4is hydrogen and the other one is hydrogen, haloalkyl, halogen, alkyl or alkoxycarbonylalkyl;

[0011] R5is hydroxyalkyl, hydroxycycloalkyl, halohydroxyalkyl or aminocarbonylalkyl;

[0012] R6is hydrogen; and

[0013] DP / 04.03.26R7is cycloalkylalkyl, halocycloalkylalkyl, haloalkylcycloalkyl, haloalkyl, cycloalkylcycloalkyl, cycloalkyl, alkynylphenyl, alkylcycloalkyl or haloalkylcycloalkylalkyl;

[0014] or R6and R7, together with the carbonyl and nitrogen atom to which they are attached, form azaspiro[2.4]heptan-4-one and R5is as defined above; or R5and R6, together with the carbon and nitrogen atoms to which they are attached, form hydroxypyrrolidinyl and R7is as defined above;

[0015] or a pharmaceutically acceptable salt thereof;

[0016] provided that

[0017] 2-chloro-N-[2-hydroxy-l-(6-methyl-lH-benzimidazol-2-yl)ethyl]-acetamide; 2-chloro-N-[l-(5,7-difluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; N-[2-hydroxy-l-(6-methyl-lH-benzimidazol-2-yl)propyl]-2-methyl-cyclopropanecarboxamide;

[0018] 2-chloro-N-[1-(5-fluoro-7-methyl-1H-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;

[0019] 2-chloro-N-[l-(6-chloro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[2-hydroxy-l-(6-methoxy-5-methyl-lH-benzimidazol-2-yl)ethyl]-acetamide;

[0020] N-[l-(7-fluoro-lH-benzimidazol-2-yl)-2-hydroxypropyl]-2-methyl-cyclopropanecarboxamide;

[0021] 2-chloro-N-[l-(5,7-dimethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; N-[2-hydroxy-l-(7-methyl-lH-benzimidazol-2-yl)propyl]-2-methyl-cyclopropanecarboxamide;

[0022] 2-chloro-N-[l-(7-chloro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[l-(6,7-dimethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[l-(6-fluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;2-chloro-N-[l-(6-fluoro-7-methyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]- acetamide;

[0023] N-[l-(6-fluoro-lH-benzimidazol-2-yl)-2-hydroxypropyl]-2-methyl- cyclopropanecarboxamide;

[0024] 2-chloro-N-[l-(6-ethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;

[0025] 2-chloro-N-[l-(7-fluoro-5-methyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]- acetamide;

[0026] 2-chloro-N-[2-hydroxy-l-[6-(l-methylethyl)-lH-benzimidazol-2-yl]ethyl]- acetamide;

[0027] 2-chloro-N-[2-hydroxy-l-(7-methoxy-lH-benzimidazol-2-yl)ethyl]-acetamide;

[0028] 2-chloro-N-[l-(6,7-difluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;

[0029] 2-chloro-N-[2-hydroxy-l-(6-methoxy-lH-benzimidazol-2-yl)ethyl]-acetamide;

[0030] 2-chloro-N-[l-(7-fluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;

[0031] 2-chloro-N-[l-(4,7-dimethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;

[0032] 2-chloro-N-[2-hydroxy-l-(7-methyl-lH-benzimidazol-2-yl)ethyl]-acetamide; and

[0033] 2-chloro-N-[l-(6-fluoro-5-methyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]- acetamide;

[0034] are excluded.

[0035] TMEM175, or Transmembrane Protein 175, is a cation-selective lysosomal ion channel shown to conduct both potassium and proton currents (Hu M, Li P, Wang C, Feng X, Geng Q, Chen W, Marthi M, Zhang W, Gao C, Reid W, Swanson J, Du W, Hume RI, Xu H. Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes. Cell 185: 2292-2308. e20, 2022). TMEM175 contributes to maintenance of the lysosomal membrane potential and stabilization of the lysosomal pH gradient both of which are crucial for proper lysosomal function (Cang, C.; Aranda, K.; Seo, Y.-J.; Gasnier, B.; Ren, D. TMEM175 Is an Organelle K+Channel Regulating Lysosomal Function. Cell 2015, 162, 1101-1112). Lysosomal catabolic activity is dependent upon a variety of enzymes confined to the lysosomal lumen. The majority of these enzymes exhibit pH dependent activity and are optimally functional at an acidic pH between 4.5 to 5.0 (Mellman I. Organelles observed: lysosomes. Science 244: 853-854, 1989. doi:10.1126 / science.244.4906.853). TMEM175 acts as a proton-activated channel that will preferentially expel protons from the lysosomal lumen at pH <4.5. At pH > 5.0, protondependent activation is reduced and the proton flux from the lumen to the cytosol is decreased, helping to maintain the optimal pH range for normal lysosomal function (Hu et al 2022, op. cit.). In mice, knockout of TMEM175 has been shown to reduce the enzymatic degradation of BSA and more specifically, the pH dependent activity of cathepsins B and D are reduced (Wie J, Liu Z, Song H, Tropea TF, Yang L, Wang H, Liang Y, Cang C, Aranda K, Lohmann J, Yang J, Lu B, Chen-Plotkin AS, Luk KC, Ren D. A growth-factor-activated lysosomal K+channel regulates Parkinson’s pathology. Nature 591: 431-437, 2021. doi: 10.1038 / s41586-021-03185-z).

[0036] TMEM175 has been identified as a novel lysosomal ‘leak-like’ potassium channel representing the major K+permeability of lysosomes (Cang et al., 2015, op. cit.).

[0037] TMEM175 is unique among other canonical potassium channels for several reasons: (1) no sequence homology with other tetrameric potassium channels, (2) it possesses a unique structure (Lee C, Guo J, Zeng W, Kim S, She J, Cang C, Ren D, Jiang Y. The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature. 2017 Jul 27;547(7664):472-475; Oh S, Paknejad N, Hite RK. Gating and selectivity mechanisms for the lysosomal K+channel TMEM175. Elife. 2020 Mar 31;9:e53430) and assembles as a homodimer of 2 homologous copies of a six-transmembrane helix domain, where (3) the transmembrane helix 1 and 7 serve as the pore forming helix and (4) it is localized at lysosomal and endosomal membranes. Furthermore, TMEM175 is not blocked by cesium (Cs+) as are the majority of potassium channels, but instead can conduct Cs+with a similar permeability as K+. It has been shown to be blocked by 4-AP. Interestingly, TMEM175 is activated by growth factors via AKT in a kinase independent fashion (Wie et al., 2021, op. cit.).

[0038] In knockout studies, it has been shown that TMEM175 regulates lysosomal membrane potential, pH stability, and organelle fusion via potassium conductance on lysosomal and endosomal membranes (Cang et al, 2015, op. cit.).

[0039] TMEM175 with the M393T risk mutation is thought to be a (partial) loss of function mutation because measured currents are reduced (Wie et al., 2021, op. cit.) and the effect on lysosomal pH resembles that of knockout cells with a more alkaline pH during starvation. Furthermore, lysosomal localization of TMEM175 M393T might be reduced as compared to wildtype TMEM175 (Jinn S, Blauwendraat C, Toolan D, Gretzula CA, Drolet RE, Smith S, Nalls MA, Marcus J, Singleton AB, Stone DJ. Functionalization of the TMEM175 p. M393T variant as a risk factor for Parkinson disease. Hum Mol Genet. 2019Oct l;28(19):3244-3254). In contrast to wildtype TMEM175, M393T overexpression does not reduce PFF-induced phospho a-synuclein (Jinn et al., 2019, op. cit.).

[0040] The Q65P variant is considered as a gain-of-function mutation under stress. When cells are starved, it leads to a reduction in TMEM175 current that is dependent and gated by AKT. In the Q65P mutant, the starvation-induced reduction in K+ current is delayed and early during starvation, the Q65P TMEM175 lysosomes carry a higher current than wildtype TMEM175. Taken together, these data suggest that the Q65P mutation represents a gain-of-function mutation under stress (Wie et al., 2021, op. cit.).

[0041] Dysfunction in lysosomal activities is linked to various neurodegenerative diseases, including Parkinson's disease, suggesting a potential role for TMEM175 in neurodegenerative disorders (Bahr B. A., Bendiske J. The neuropathogenic contributions of lysosomal dysfunction. J. Neurochem. 2002;83:481-489). Consistent with this hypothesis, TMEM175 has been identified by genome-wide association studies as a genetic risk factor for Parkinson’s disease (PD) (Hopfner F, Mueller SH, Szymczak S, Junge O, Tittmann L, May S, Lohmann K, Grallert H, Lieb W, Strauch K, Miiller-Nurasyid M, Berger K, Schormair B, Winkelmann J, Mollenhauer B, Trenkwalder C, Maetzler W, Berg D, Kasten M, Klein C, Hbglinger GU, Gasser T, Deuschi G, Franke A, Krawczak M, Dempfle A, Kuhlenbaumer G. Rare variants in specific lysosomal genes are associated with Parkinson’s disease. Mov Disord 35: 1245-1248, 2020. doi: 10.1002 / mds.28037), Rapid-eye-movement (REM) sleep behavior disorder (RBD) (Krohn L, et al. Genetic, structural, and functional evidence link TMEM175 to synucleinopathies. Ann. Neurol. 2020;87:139-153. doi: 10.1002 / ana.25629) and Dementia with Lewy Bodies (Chia R, Sabir MS, Bandres-Ciga S, et al.; American Genome Center. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021;53(3):294-303). Multiple coding variants of TMEM175 have been identified and one variant, TMEM175 M393T, is associated with an increased risk and earlier onset of Parkinson’s disease (Blauwendraat C., Heilbron K., Vallerga C. L., Bandres-Ciga S., von Coelln R., Pihlstrom L., Simon-Sanchez J., Schulte C., Sharma M., Krohn L. et al. (2019) Parkinson's disease age at onset genome-wide association study: defining heritability, genetic loci, and alpha-synuclein mechanisms. Mov. Disord., 34, 866-875). Functional analysis of M393T indicated that M393T is a partial loss of function allele, suggesting that enhancement of TMEM175 activity could provide a therapeutic benefit in Parkinson’s disease (Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, Voleti B, Vassileva G, Disa J, Tadin-Strapps M, Stone DJ. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases alpha-synuclein aggregation. Proc Natl Acad Sci USA 114: 2389-2394, 2017. doi:

[0042] 10.1073 / pnas.1616332114).TMEM175 has also been identified as a comorbid gene between Amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (Tian Y, Ma G, Li H, Zeng Y, Zhou S, Wang X, Shan S, Xu Y, Xiong J, Cheng G. Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease. Mov Disord. 2023 Oct;38(10):1813-1821. doi: 10.1002 / mds.29572. Epub 2023 Aug 3) and as a shared genetic risk loci among Alzheimer’s disease related dementias, Parkinson’s disease and Amyotrophic lateral sclerosis (Wainberg, M., Andrews, S. J. & Tripathy, S. J. Shared genetic risk loci between Alzheimer’s disease and related dementias, Parkinson’s disease, and amyotrophic lateral sclerosis. Alz Res Therapy 15, 113 (2023)). Further, in a proteome-wide association study (PWAS) for Amyotrophic lateral sclerosis, TMEM175 was identified (Ma, Y., Jia, T., Qin, F. et al. Abnormal Brain Protein Abundance and Cross-tissue mRNA Expression in Amyotrophic Lateral Sclerosis. Mol Neurobiol 61, 510-518 (2024)) and lysosomal dysfunction is an important pathogenic disease mechanism in ALS (Root J, Merino P, Nuckols A, Johnson M, Kukar T. Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.

[0043] Neurobiol Dis. 2021 Jul;154:105360). Therefore, TMEM175 enhancers may address the underlying disease biology in ALS.

[0044] Lysosomal storage disorders (Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Publisher Correction: Lysosomal storage diseases. Nat Rev Dis Primers. 2019 May 17;5( 1 ): 34) are characterized by accumulation of substrates in excess in lysosomes, often resulting from defects in lysosomal function. Since TMEM175 knockout leads to a reduced lysosomal hydrolysis activity and degradation activity (Hu et al 2022, op. cit.), a TMEM175 enhancer may increase lysosomal degradation capacity and thereby reduce pathological storage in lysosomal storage disorders.

[0045] In the present description the term “alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straightchain and branched-chain C1-C8alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls. Particular examples of “alkyl” are methyl, ethyl, propyl, the isomeric butyls and the isomeric pentyls.

[0046] The term “cycloalkyl”, alone or in combination, signifies a monocyclic or bicyclic, including spiro bicyclic, cycloalkyl ring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and bicyclo[l.l.l]pentanyl.Particular “cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentanyl and spiro[3.3]heptanyl.

[0047] The term “oxy”, alone or in combination, signifies the -O- group.

[0048] The term “alkyloxy” or “alkoxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert. butoxy. A particular example of “alkyloxy” or “alkoxy” is methoxy.

[0049] The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens, i.e. one, two or three halogens. A particular halogen is fluorine.

[0050] The term “haloalkyl”, alone or in combination, denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. Particular “haloalkyl” are trifluoromethyl, trifluoroethyl, difluoromethyl, difluoromethyl, trifluoropropyl, fluorobutyl and trifluoropentyl.

[0051] The term “halocycloalkyl”, alone or in combination, denotes a cycloalkyl group substituted with at least one halogen, particularly substituted with one, two or three halogens. Particular “haloalkyl” are fluorocyclobutyl difluorocyclobutyl, difluorocyclopentyl and 3-fluorobicyclo[l.l.l]pentan-l-yl.

[0052] The term “haloalkoxy” or haloalkyloxy”, alone or in combination, denotes an alkoxy group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. Particular “haloalkoxy” are trifluoromethoxy and difluoromethoxy

[0053] The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.

[0054] The term “alkynyl”, alone or in combination, signifies a monovalent linear or branched saturated hydrocarbon group of 2 to 7 carbon atoms, in particular from 2 to 4 carbon atoms, and comprising one, two or three triple bonds. Examples of alkynyl include ethynyl, propynyl, prop-2-ynyl, isopropynyl, n-butynyl, and iso-butynyl. A particular example of “alkynyl” is ethynyl.The term “carbonyl”, alone or in combination, signifies the -C(O)- group.

[0055] The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

[0056] The term “sulfanyl”, alone or in combination, signifies the -S- group.

[0057] The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition these salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

[0058] If one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethyl silyl ethyl carbamate (Teoc), carbobenzyl oxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0059] The compound of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, forexample, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0060] The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration.

[0061] The invention further relates to a compound of formula (I)

[0062]

[0063] wherein

[0064] A is nitrogen or -CH-;

[0065] one of R1and R2is hydrogen, haloalkoxy, fluoroalkyl, haloalkylsulfanyl, halophenyl or alkoxy and the other one is hydrogen, halogen or alkyl;

[0066] one of R3and R4is hydrogen and the other one is hydrogen, haloalkyl, halogen, alkyl or alkoxycarbonylalkyl;

[0067] R5is hydroxyalkyl, hydroxycycloalkyl, halohydroxyalkyl or aminocarbonylalkyl;

[0068] R6is hydrogen; and

[0069] R7is cycloalkylalkyl, halocycloalkylalkyl, haloalkylcycloalkyl, haloalkyl, cycloalkylcycloalkyl, cycloalkyl, alkynylphenyl, dialkylcycloalkyl or haloalkylcycloalkylalkyl;

[0070] or R6and R7, together with the carbonyl and nitrogen atom to which they are attached, form azaspiro[2.4]heptan-4-one and R5is as defined above;

[0071] or R5and R6, together with the carbon and nitrogen atoms to which they are attached, form hydroxypyrrolidinyl and R7is as defined above;

[0072] or a pharmaceutically acceptable salt thereof.

[0073] The invention also relates to a compound of formula (I) wherein A is nitrogen.The invention thus relates in particular to a compound of formula (I) which is of formula (I-a)

[0074]

[0075] wherein R1to R7are as defined above.

[0076] The invention further relates to:

[0077] A compound of formula (I) wherein one of R1and R2is haloalkoxy and the other one is hydrogen or halogen, in particular hydrogen;

[0078] A compound of formula (I) wherein one of R1and R2is trifluoromethoxy and the other one is hydrogen or fluoro, in particular hydrogen;

[0079] A compound of formula (I) wherein one of R3and R4is hydrogen and the other one is hydrogen or halogen;

[0080] A compound of formula (I) wherein one of R3and R4is hydrogen and the other one is hydrogen or fluorine;

[0081] A compound of formula (I) wherein R3and R4are both hydrogen at the same time;

[0082] A compound of formula (I) wherein R5is hydroxyalkyl, hydroxycycloalkyl or halohydroxy alkyl;

[0083] A compound of formula (I) wherein R5is hydroxy ethyl, hydroxypropyl, hydroxy cyclopropyl or (trifluoro)(hydroxy)ethyl;

[0084] A compound of formula (I) wherein R5is hydroxy ethyl;

[0085] A compound of formula (I) wherein R7is cycloalkylalkyl, halocycloalkylalkyl, haloalkyl, cycloalkyl or haloalkylcycloalkylalkyl;

[0086] A compound of formula (I) wherein R7is cyclobutylmethyl, difluorocyclobutymethyl, trifluoropentyl, 3 -fluorobicyclofl.1. l]pentan-l-yl, spiro[3.3]heptanyl or trifluoromethylcyclopropylmethyl; andA compound of formula (I) wherein R7is difluorocyclobutymethyl or 3-fluorobicyclo[1.1.1]pentan-1-yl.

[0087] In the definition of R7, the cycloalkyl is advantageously a spiroalkyl, like for example spiro[3.3]heptanyl.

[0088] The invention further relates in particular to a compound of formula (I-a) wherein: one of R1and R2is haloalkoxy and the other one is hydrogen or halogen, in particular hydrogen;

[0089] one of R3and R4is hydrogen and the other one is hydrogen or halogen;

[0090] R5is hydroxyalkyl, hydroxycycloalkyl or halohydroxyalkyl;

[0091] R6is hydrogen; and

[0092] R7is cycloalkylalkyl, halocycloalkylalkyl, haloalkyl, cycloalkyl or haloalkylcycloalkylalkyl.

[0093] The invention further relates in particular to a compound of formula (I-a) wherein: one of R1and R2is trifluoromethoxy and the other one is hydrogen or fluoro, in particular hydrogen;

[0094] one of R3and R4is hydrogen and the other one is hydrogen or fluorine;

[0095] R5is hydroxyethyl, hydroxypropyl, hydroxycyclopropyl or

[0096] (trifluoro)(hy droxy)ethyl;

[0097] R6is hydrogen; and

[0098] R7is cyclobutylmethyl, difluorocyclobutymethyl, trifluoropentyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, spiro[3.3]heptanyl or

[0099] trifluoromethylcyclopropylmethyl.

[0100] The invention further relates to a compound of formula (I) selected from

[0101] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0102] 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-(3,3-difluorocyclobutyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0103] 2-cyclobutyl-N-[(lS,2S)-l-[5-(difluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propy 1 ] acetami de;

[0104] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[7-(trifluoromethyl)-lH-benzimidazol-2-yl]propyl]acetamide;

[0105] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]propyl]acetamide;

[0106] 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]propyl]acetamide;

[0107] 2-cyclobutyl-N-[(lR*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;

[0108] 2-cyclobutyl-N-[(lS*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;

[0109] trans-(lR*,2R*)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-2-(trifluoromethyl)cyclopropanecarboxamide;

[0110] 2-(3,3-difluorocyclopentyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0111] 2-cyclobutyl-l-[(2S,3R)-3-hydroxy-2-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]pyrrolidin- 1 -yl]ethenone;

[0112] 4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl ]butanami de;

[0113] 2-cyclobutyl-N-[(lS*,2S)-l-[4-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;

[0114] 2-cyclobutyl-N-[(lS*,2R)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0115] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-indol-2-yl]propyl]acetamide;3-fluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-3-methyl-butanamide;

[0116] 4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-3,3-dimethyl-butanamide;

[0117] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide;

[0118] 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide;

[0119] 2-(l-fluorocyclobutyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-y 1 ] propyl ] acetami de;

[0120] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(2,2,2-trifluoroethyl)-lH-benzimidazol-2-yl]propyl]acetamide;

[0121] 2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((1S*,2S)-2-hydroxy-1-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)propyl)acetamide;

[0122] 2-(3-fluorocyclobutyl)-N-((lS*,2S)-2-hydroxy-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propyl)acetamide;

[0123] N-[(lS*,2S)-l-[5-(difluoromethylsulfanyl)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]-2-(l-fluorocyclobutyl)acetamide;

[0124] (S)-2-cyclobutyl-N-[(l-hydroxycyclopropyl)-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]methyl]acetamide;

[0125] 2-cyclobutyl-N-[(lS,2S)-l-[5-(2,2-difluoroethyl)-lH-benzimidazol-2-yl]-2-hydroxy-propy 1 ] acetami de;

[0126] rac-(lS,2R)-2-cyclopropyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]cyclopropanecarboxamide;

[0127] (2S)-2-(l-bicyclo[l.l.l]pentanyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]propenamide;

[0128] 3-ethynyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]benzamide;(2R)-2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]propenamide;

[0129] 2-cyclopentyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0130] 2-cyclopropyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]cyclopropanecarboxamide;

[0131] 2-(l-methylcyclopropyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0132] N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]spiro[3.3]heptane-2-carboxamide;

[0133] 3,3-dimethyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl ] cy cl obutanecarb oxami de;

[0134] N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-2-[l-(trifluoromethyl)cyclopropyl]acetamide;

[0135] 2-cyclobutyl-N-[(lR*,2R)-3, 3, 3-trifluoro-2-hydroxy-l-[5-(tri fluoromethoxy)- 1H-benzimidazol-2-yl]propyl]acetamide;

[0136] 2-cyclobutyl-N-[(2S)-2-hydroxy- l-[4-methyl-5-(tri fluoromethoxy)- lH-benzimidazol-2-yl]propyl]acetamide;

[0137] 2-cyclobutyl-N-[(lS*,2R)-3,3,3-trifluoro-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0138] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-methyl-5-(trifluoromethoxy)-lH-benzimidazol-2-y 1 ] propyl ] acetami de;

[0139] (2S*,3R*)-3-[(2-cyclobutylacetyl)amino]-2-methyl-3-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propenamide;

[0140] N-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butanamide;

[0141] 2-(3,3-difluorocyclobutyl)-N-[3-hydroxy-2-methyl-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;5-[(2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-5-azaspiro[2.4]heptan-4-one;

[0142] 2-(3,3-difluorocyclobutyl)-N-[(lS*,2S)-l-[6-(3-fluorophenyl)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide; and

[0143] methyl 2-[2-[(lS*,2S)-l-[[2-(3,3-difluorocyclobutyl)acetyl]amino]-2-hydroxy-propyl]-6-methoxy-lH-benzimidazol-4-yl]acetate;

[0144] or a pharmaceutically acceptable salt thereof.

[0145] The invention also relates in particular to a compound of formula (I) selected from: 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0146] 2-(3,3-difluorocyclobutyl)-N-[(1S*,2S)-2-hydroxy-1-[5-(trifluoromethoxy)-1H-benzimidazol-2-yl]propyl]acetamide;

[0147] 2-cyclobutyl-N-[(1S*,2S)-1-[6-fluoro-5-(trifluoromethoxy)-1H-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;

[0148] 2-cyclobutyl-N-[(1S*,2S)-1-[4-fluoro-5-(trifluoromethoxy)-1H-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;

[0149] 2-cyclobutyl-N-[(lS*,2R)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;

[0150] 4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-3,3-dimethyl-butanamide;

[0151] 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide;

[0152] 2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-((1S*,2S)-2-hydroxy-1-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)propyl)acetamide;

[0153] (S)-2-cyclobutyl-N-[(l-hydroxycyclopropyl)-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]methyl]acetamide;

[0154] N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]spiro[3.3]heptane-2-carboxamide;N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-2-[l-(trifluoromethyl)cyclopropyl]acetamide;

[0155] 2-cyclobutyl-N-[(lS*,2R)-3,3,3-trifluoro-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimi dazol -2-y 1 ] propyl ] acetami de; and

[0156] N-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butanamide;

[0157] or a pharmaceutically acceptable salt thereof.

[0158] The following abbreviations are used in the present description.

[0159] ACN / MeCN is acetonitrile

[0160] Bn is benzyl

[0161] DCM is dichloromethane

[0162] DIPEA is diisopropylethylamine

[0163] DMAC is dimethylacetamide

[0164] DMAP is dimethylaminopyridine

[0165] DMF is dimethylformamide

[0166] DMSO is dimethyl sulfoxide

[0167] EA / EtOAc is ethyl acetate

[0168] HATU is Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium

[0169] HO Ac is acetic acid

[0170] LAH is lithium aluminiumhydride

[0171] LDA is lithium diisopropylamide

[0172] NMI is N-methyl imidazole

[0173] NMM is N-methyl morpholine

[0174] Pd(dppf)Cl₂ is 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)PE is petroleum ether

[0175] RT is room temperature

[0176] TBDPS is tert-butyldiphenylsilyl

[0177] TCFH is tetramethylchloroformamidinium hexafluorophosphate

[0178] TEA is tri ethylamine

[0179] TFA is trifluoroacetic acid

[0180] THF is tetrahydrofuran

[0181] TLC thin layer chromatography

[0182] Ts is tosyl

[0183] The compound of the invention, having formula (II), (III) or (IV), all encompassed by formula (I), can be prepared according to the following process.

[0184] R7HO TCFH, NMI

[0185]

[0186] Scheme 1: Synthesis of the compound of formula (II)

[0187] To benzene- 1,2-diamine 1 was coupled amino-acid 2 using either TCFH and NMI in acetonitrile or DMF, or with HATU and NMM or DIPEA in dimethylacetamide or DMF, at RT for 1 to 2 hours, to provide amide intermediate 3. Treatment with acetic acid at 80C for 3 hours resulted in cyclization to the corresponding benzimidazole 4. In most cases, racemization was found to occur during the cyclization, especially if R5 contains an unprotected hydroxyl group but it could be significantly suppressed in case R5 contains a tert-butyldiphenylsilyl ether group. In some examples, separation of the diastereomerscould be achieved at this stage. Treatment with TFA in DCM at OC, or with HC1 in dioxane, and stirring at RT for 1.5 hour afforded the free amine intermediate 5, which could then be coupled to a carboxylic acid using TCFH and NMI, in acetonitrile or DMF, at RT for 1-2 hour, to yield final benzimidazoles of Formula (II). Separation of the diastereomers could also take place after the final coupling using any suitable separation or purification procedure such as, for example, reverse-phase or normal-phase chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, supercritical fluid chromatography or a combination of these procedures

[0188] AcOH TCFH, NMI 80°C

[0189] TFA / DCM TCFH, NMI

[0190]

[0191] 9 (HI) Scheme 2: Synthesis of the compound of formula (III)

[0192] Compounds of formula (III) can be prepared by a variation of the synthesis described for compounds of formula (II) by reacting (2R,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid with benzene- 1,2-diamine 1 using TCFH in the presence of a suitable base, like NMI, to yield the amide intermediate 7. Subsequent treatment with acetic acid at 80C for 1 hour resulted in cyclization to the corresponding benzimidazole 8. Boc deprotection can be carried out by treatment with TFA in DCM at OC to RT, or with HC1 in dioxane. Coupling with a carboxylic acid using TCFH and NMI, in acetonitrile or DMF, at RT for 1-2 hour, leads to the desired benzimidazole of Formula (III).

[0193]

[0194] Scheme 3: Synthesis of the compound of formula (IV)

[0195] Compounds of formula (IV) can be prepared by a variation of the synthesis described for compounds of formula (II) by reacting benzimidazole intermediate 5 with 1-[2-(benzyloxy)ethyl]cyclopropane-l -carboxylic acid using TCFH in the presence of a suitable base, like NMI, to yield the amide intermediate 11. Hydrogenation in presence of Pd / C in MeOH at RT for 24hrs led to formation of alcohol 12, which can then be reacted with tosyl chloride in DCM at OC in presence of base, such as TEA, to afford the tosylated intermediate 13. Cyclization by treatment with sodium hydride in THF at OC for 30min leads to the desired benzimidazole of Formula (IV).

[0196] The invention thus relates also to a process for the preparation of a compound of formula (I) comprising one of the following steps:

[0197] (a) the reaction of a compound of formula (A)

[0198]

[0199] in the presence of R7COOH, a carboxylic acid activating agent and a base;(b) the reaction of a compound of formula (B)

[0200]

[0201] in the presence of R7COOH, a carboxylic acid activating agent and a base; or

[0202] (c) the reaction of a compound of formula (C)

[0203]

[0204] in the presence of a base;

[0205] wherein A and R1to R5are as defined above and X is a leaving group.

[0206] In the process of the invention, the carboxylic acid activating agent can be for example TCFH or HATU.

[0207] The base of steps (a) and (b) can be for example NMI or NMM.

[0208] The base of step (c) can be for example NaH;

[0209] In step (c), the leaving group can be OTs, OMs or halogen like iodine, bromine, or chlorine, more particularly OTs.

[0210] The steps (a) and (b) can be carried out in acetonitrile or DMF. It can be done at RT for 1-2 hour. Step (c) can be carried out in THF or DMF at 0C to RT.

[0211] The process according to the invention can be followed by a separation step of the diastereomers of formula (I), in particular by reversed-phase chromatography.

[0212] The invention further relates to:

[0213] A compound of formula (I), when manufactured according to a process of the invention;A compound of formula (I) for use as therapeutically active substance;

[0214] A pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier;

[0215] The use of a compound of formula (I) for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders;

[0216] The use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders;

[0217] A compound of formula (I) for use in the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders; and

[0218] A method for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders, which method comprises administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0219] Another embodiment of the invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0220] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factors known to medical practitioners.

[0221] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0222] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0223] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0224] The invention will now be illustrated by the following examples which have no limiting character.Examples

[0225] Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, reversed- and normal-phase chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, supercritical fluid chromatography or a combination of these procedures. However, other equivalent separation or isolation procedures could, of course, also be used. Mixture of chiral compounds of formula (I) or intermediates can be separated using the following conditions, either as an intermediate in the synthesis or after the final step in the synthesis:

[0226] Example Purification conditions Stage of Peak #

[0227] purification

[0228] 1 purified by reverse phase separation column Final step First peak [Mobile Phase A: Water (0.3% NH4HCO3), (amide

[0229] Mobile Phase B: acetonitrile; Gradient: 0% coupling)

[0230] B to 70% B in 30 min]; first peak (7.8%

[0231] yield)

[0232] 2 purified by reverse phase separation column Final step Second peak [Mobile Phase A: Water (0.3% NH4HCO3), (amide

[0233] Mobile Phase B: acetonitrile; Gradient: 0% coupling)

[0234] B to 70% B in 30 min]; first peak (6.5%

[0235] yield)

[0236] 3 purified by prep.-TLC eluting with 3% Final step Second peak MeOH in EtOAc; second fraction (4.7% (amide

[0237] yield) coupling)

[0238] 4 N. A. (no racemization)

[0239] 5 purified by silica gel column Boc-amino First peak chromatography, eluted with EA: PE (1:1); Benzimidazole

[0240] first fraction (29.4% yield) intermediate

[0241]

[0242] purified by reversed-phase flash Boc-amino First peak chromatography with the following Benzimidazole conditions: column, Cl 8 silica gel; mobile intermediate

[0243] phase, MeCN in Water (lOmmol / L

[0244] NH4HCO3), 30% to 50% gradient in 10

[0245] min; detector, UV 254 nm; first peak

[0246] (31.5% yield)

[0247] purified by reversed-phase flash Boc-amino Second peak chromatography with the following Benzimidazole conditions: column, Cl 8 silica gel; mobile intermediate

[0248] phase, MeCN in Water (lOmmol / L

[0249] NH4HCO3), 30% to 50% gradient in 10

[0250] min; detector, UV 254 nm; second peak

[0251] (12% yield)

[0252] purified by reversed-phase flash Final step Second peak chromatography with the following (TBDPS ether conditions: column, Cl 8 silica gel; mobile deprotection)

[0253] phase, MeCN in Water (lOmmol / L

[0254] NH4HCO3), 30% to 50% gradient in 10

[0255] min; detector, UV 254 nm. RT2 ( 8.5%

[0256] yield).

[0257] purified by reversed-phase flash Final step First peak chromatography with the following (TBDPS ether conditions: column, Cl 8 silica gel; mobile deprotection)

[0258] phase, MeCN in Water (lOmmol / L

[0259] NH4HCO3), 30% to 50% gradient in 10

[0260] min; detector, UV 254 nm. RT1 ( 41.0%

[0261] yield).

[0262] purified by Prep-HPLC: Column: Sunfire Final step First peak prep C18 column 30*150 mm, 5pm; Mobile (TBDPS

[0263] Phase A: Water (0.1% FA), Mobile Phase deprotection)

[0264] B: ACN; Flow rate: 60mL / min; Gradient

[0265] (B%): 22% B to 40% B in 9 min; Wave

[0266] Length: 254nm / 220nm; RTl=10.13min

[0267] (5.6% yield)

[0268]

[0269] purified by reverse phase separation column Final step Second peak [Mobile Phase A: Water (0.3% NH4CO3), (amide

[0270] Mobile Phase B: acetonitrile; Gradient: coupling)

[0271] 0%B to 70% B in 30 min]; second peak

[0272] (12.3% yield)

[0273] Mixture of 2 diastereomers

[0274] purified by reverse phase separation column Final step Second peak [Mobile Phase A: Water (0.3% NH4CO3), (amide

[0275] Mobile Phase B: acetonitrile; Gradient: coupling)

[0276] 0%B to 70% B in 30 min]; second peak

[0277] (13.2% yield)

[0278] purified by reverse phase separation column Final step First peak [Mobile Phase A: Water (0.3% NH4CO3), (amide

[0279] Mobile Phase B: acetonitrile; Gradient: coupling)

[0280] 0%B to 70% B in 30 min]; first peak

[0281] (23.9% yield)

[0282] purified by reverse phase separation column Final step First peak [Mobile Phase A: Water (0.3% NH4CO3), (amide

[0283] Mobile Phase B: acetonitrile; Gradient: coupling)

[0284] 0%B to 70% B in 30 min]; first peak

[0285] (12.5% yield)

[0286] purified by Prep.-TLC, eluted with PE / EA Benzimidazole Second peak (1:1); second fraction (15.9% yield) intermediate

[0287] purified by reversed-phase flash Final step Second peak chromatography with the following (amide

[0288] conditions: column, Cl 8 silica gel; mobile coupling)

[0289] phase, MeCN in Water (0.1% FA), 10% to

[0290] 50% gradient in 20 min; detector, UV 254

[0291] nm; second peak (7.8% yield)

[0292] purified by reversed-phase flash Final step Second peak chromatography with the following (amide

[0293] conditions: column, Cl 8 silica gel; mobile coupling)

[0294]

[0295] phase, MeCN in Water (0.1% FA), 10% to50% gradient in 20 min; detector, UV 254

[0296] nm; second peak (6.5% yield)

[0297] purified by reverse phase separation column Final step First peak [Mobile Phase A: Water (0.3% NH4HCO3), (ester

[0298] Mobile Phase B: acetonitrile; Gradient: 0% hydrolysis)

[0299] B to 70% B in 30 min]; first peak (4.92%

[0300] yield)

[0301] purified by reverse phase separation column Final step Second peak [Mobile Phase A: Water (0.3% NH4HCO3), (ester

[0302] Mobile Phase B: acetonitrile; Gradient: 0% hydrolysis)

[0303] B to 70% B in 30 min]; first peak (7.79%

[0304] yield)

[0305] Prep-HPLC with the following conditions Final step Second peak (Column: XSelect CSH Prep Cl 8 OBD (amide

[0306] Column, 30*150 mm, 5m; Mobile Phase A: coupling)

[0307] Water(0.1% FA), Mobile Phase B: ACN;

[0308] Flow rate: 60mL / min; Gradient: 20% B to

[0309] 36% B in 9 min; Wave Length:

[0310] 254nm / 220nm; RT2=10.40min (8.93%

[0311] yield)

[0312] reversed-phase flash chromatography with Final step Second peak the following conditions: column, C18 (amide

[0313] silica gel; mobile phase, MeCN in water (10 coupling)

[0314] mmol / L NH4HCO3), 30% to 50% gradient

[0315] in 10 min; detector, UV 254 nm (39.9%

[0316] yield)

[0317] purified by reverse phase separation column Final step First peak [Mobile Phase A: Water (0.3% FA), Mobile (amide

[0318] Phase B: acetonitrile; Gradient: 0%B to coupling)

[0319] 70% B in 30 min] (12.3% yield)

[0320] reversed-phase flash chromatography with Final step Second peak the following conditions: column, C18 (amide

[0321] silica gel; mobile phase, MeCN in Water coupling)

[0322]

[0323] (0.1% FA), 10% to 90% gradient in 60 min;

[0324] detector, UV 254 nm. (8.6% yield)

[0325] purified by Prep-HPLC with the following Final step Second peak conditions (Column: XSelect CSH Prep (amide

[0326] C18 OBD Column, 30*150 mm, 5m; coupling)

[0327] Mobile Phase A: Water(0.1% FA), Mobile

[0328] Phase B: ACN; Flow rate: 60mL / min;

[0329] Gradient: 12% B to 32% B in 9 min; Wave

[0330] Length: 254nm / 220nm; RT2=11.18min

[0331] (30.9% yield)

[0332] No separation (e.r.=3:l)

[0333] N. A. (no racemization)

[0334] purified by HP -Flash with the following Boc-amino Second peak condition Column: YMC-Triant perpC 18-S, Benzimidazole 50*250 nm, 10 pm; Mobile Phase A: Water intermediate

[0335] (0.1% FA), Mobile Phase B: ACN; Flow

[0336] rate: 100 mL / min; Gradient: 15%-45% in 30

[0337] min; Wave Length: 220 / 254 nm;

[0338] RT2=28.5min

[0339] Same intermediate as in example 28

[0340] Same intermediate as in example 28

[0341] Same intermediate as in example 28

[0342] Same intermediate as in example 28

[0343] Same intermediate as in example 28

[0344] Same intermediate as in example 28

[0345] Same intermediate as in example 28

[0346] Same intermediate as in example 28

[0347] Same intermediate as in example 28

[0348]

[0349] purified by Prep-HPLC with the following Boc-amino First peak conditions MeCN in Water (0.1% FA) Benzimidazole intermediate

[0350] No separation (mixture of two

[0351] diastereoisomers, dr= 1:2

[0352] purified by Prep-HPLC with the following Boc-amino Second peak conditions ( MeCN in Water (0.1% FA) Benzimidazole intermediate

[0353] purified by Prep-HPLC with the following Boc-amino First peak conditions (Column: XSelect CSH Prep Benzimidazole C18 OBD Column, 30*150 mm, 5pm; intermediate

[0354] Mobile Phase A: Water(0.1% FA), Mobile

[0355] Phase B: ACN; Flow rate: 60mL / min;

[0356] Gradient (B%): 23% B to 39% B in 9 min;

[0357] Wave Length: 254nm / 220nm;

[0358] RTl=7.57min (57.5% yield)

[0359] First purification: purified by Column: Final step Second peak Torus Diol OBD, 3*25 cm, 5 pm; Mobile (amide

[0360] Phase A: CO2, Mobile Phase B: MEOH(1% coupling)

[0361] 2M NH3-MEOH); Flow rate: 100 mL / min;

[0362] Gradient: isocratic 15% B; Column

[0363] Temperature (°C): 35; Back Pressure(bar):

[0364] 100; Wave Length: 220 nm; RT2: 4.65min

[0365] Second purification: purified by Column:

[0366] First peak Enantiocel- A4-5, 3.0*25CM, 5um; Mobile

[0367] Phase A: Hex(10 mM NH3-MeOH), Mobile

[0368] Phase B: ETOH; Flow rate: 40 mL / min;

[0369] Gradient (B%): isocratic 20; Wave Length:

[0370] 212 / 254 nm; RTl=7.0min (38.2% yield)

[0371] No separation (racemate)

[0372] No good conditions for chiral separation

[0373] found. Mixture of 4 diastereomers.

[0374]

[0375] 45 purified by Prep-HPLC with the following Final step mix. of conditions (Column: Xselect CSH Prep (alkylation) diastereomers C18, 30*150mm 5pm; Mobile Phase A:

[0376] Water (0.1% FA), Mobile Phase B: ACN;

[0377] Flow rate: 60 mL / min; Gradient (B%):

[0378] isocratic 25% to 38% B in 10 min; Wave

[0379] Length: 254 / 220 nm; RTl(min): 12.22 min

[0380] (24.9% yield)

[0381] 46 purified by Prep-HPLC with the following Boc-amino Second peak conditions (Column: XSelect CSH Fluoro Benzimidazole

[0382] Phenyl 30*150 mm, 5pm; Mobile Phase A: intermediate Water(0.1%FA), Mobile Phase B: MeOH;

[0383] Flow rate: 60 mL / min; Gradient (B%): 22%

[0384] B to 38% B in 15 min; Wave Length:

[0385] 254nm / 220 nm; RT2=11.3 min (52% yield)

[0386] 47 purified by Prep-HPLC with the following Final step First peak conditions (Column: XBridge Shield RP18 (amide

[0387] OBD Column 30*150 mm, 5pm; Mobile coupling)

[0388] Phase A: Water(0.1%FA), Mobile Phase B:

[0389] MeOH— HPLC; Flow rate: 60 mL / min;

[0390] Gradient (B%): 24% B to 34% B in 8 min;

[0391] Wave Length: 254nm / 220 nm; RTl(min):

[0392] 7.885 min (22.4% yield)

[0393]

[0394] Example 1: 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] acetamide

[0395]

[0396] a) tert-butyl ((2A,35)-l-((2-amino-5-(trifluoromethoxy) phenyl) amino)-3 -hydroxy- 1-oxobutan-2-yl) carbamate

[0397] A solution of 4-(trifluorom ethoxy) benzene- 1,2-diamine (5g, 5.205 mmol, 1 equiv) and (tert-butoxycarbonyl)-D-threonine (0.91 g, 4.164 mmol, 0.8 equiv) in ACN (10 mL) wastreated with TCFH (2.19 g, 7.808 mmol, 1.5 equiv) at 0 °C under nitrogen atmosphere followed by the addition of NMI (2.14 g, 26.025 mmol, 5 equiv) dropwise at 0 °C. The mixture was stirred for 2 hours at RT. The residue was purified by reverse phase separation column [Mobile Phase A: Water (0.3% NH4CO3), Mobile Phase B: acetonitrile; Gradient: 0%B to 70% B in 30 min] to give tert-butyl ((2R,3S)-l-((2-amino-5 -(trifluoromethoxy) phenyl) amino)-3 -hydroxy- l-oxobutan-2-yl) carbamate (1.3 g, 63.50% yield) as a yellow solid. LC-MS (ESI, m / z): [M+ H] +: 394.1.

[0398] b) tert-butyl ((2S)-2-hydroxy-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl) propyl) carbamate

[0399] A solution of tert-butyl ((2R,3S)-l-((2-amino-5-(trifluoromethoxy) phenyl) amino)-3-hydroxy-l-oxobutan-2-yl) carbamate (1 g, 2.542 mmol, 1 equiv) in HOAc (10 mL) was stirred for 3 hours at 80 °C. The residue was purified by reverse phase separation column [Mobile Phase A: Water (0.3% NH4CO3), Mobile Phase B: acetonitrile; Gradient: 0%B to 70% B in 30 min] to give tert-butyl ((2 S)-2-hydroxy-l -(5 -(trifluoromethoxy)- 1H-benzo[d]imidazol-2-yl) propyl) carbamate (600 mg, 62.88% yield) as a white solid. LC-MS (ESI, m / z): [M+ H] +: 376.1

[0400] c) (2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol

[0401] A solution of tert-butyl ((2S)-2-hydroxy-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl) propyl) carbamate (600 mg, 1.599 mmol, 1 equiv) in DCM (5 mL) was treated with TFA (1.2 mL) at 0 °C. The mixture was stirred for 1.5 hours at RT. After concentration under reduced pressure, the residue was purified by reverse phase separation column [Mobile Phase A: Water (0.3% NH4CO3), Mobile Phase B: acetonitrile; Gradient: 0%B to 70% B in 30 min] to afford (2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl) propan-2-ol (400 mg, 90.92% yield) as a colorless oil. LC-MS (ESI, m / z): [M+ H] +: 276.1

[0402] d) 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0403] A solution of (2S)-l-amino-l-[5-(trifluoromethoxy)-lH-l,3-benzodiazol-2-yl] propan-2-ol (160 mg, 0.581 mmol, 1 equiv) and cyclobutylacetic acid (53.06 mg, 0.4649 mmol, 0.8 equiv) in ACN (2 mL) was treated with NMI (238.54 mg, 2.909 mmol, 5 equiv) at 0 °C followed by the addition of TCFH (244.36 mg, 0.872 mmol, 1.5 equiv) dropwise at 0 °C. The mixture was stirred for 2 hours at RT. The residue was purified by reverse phase separation column [Mobile Phase A: Water (0.3% NH4HCO3), Mobile Phase B: acetonitrile; Gradient: 0% B to 70% B in 30 min] to afford the title product 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide (15.9 mg, 7.82% yield, first peak) as a white solid and the diastereomer 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide (13.4 mg, 6.53% yield, second peak) as a white solid. LC-MS (ESI, m / z): [M+ H] +:

[0404] 372.15. 1HNMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.06 (t, J = 8.6, 4.2 Hz, 1H), 4.90 (dd, J = 8.6, 4.2 Hz, 1H), 4.05 (d, J = 5.1 Hz, 1H), 2.60 (h, J = 7.7 Hz, 1H), 2.43 (dd, J = 13.9, 7.8 Hz, 1H), 2.32 (dd, J= 13.9, 7.3 Hz, 1H), 2.01 (tdt, J = 7.8, 5.1, 3.0 Hz, 2H), 1.87 - 1.61 (m, 4H), 1.05 (d, J = 6.3 Hz, 3H).

[0405] Example 2: 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] acetamide

[0406] H /

[0407] N HN^K

[0408] } — (0

[0409] N >-0H

[0410]

[0411] The title compound is the second eluting peak obtained from the purification of 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide (Example 1) as a white solid (6.5% yield). LC-MS (ESI, m / z): [M+ H] +: 372.15. 1HNMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.01 (dd, J = 8.6, 4.2 Hz, 2H), 4.16 (d, J = 5.1 Hz, 1H), 2.60 (h, J = 7.7 Hz, 1H), 2.43 (dd, J = 13.9, 7.8 Hz, 1H), 2.32 (dd, J = 13.9, 7.3 Hz, 1H), 2.01 (tdt, J = 7.8, 5.1, 3.0 Hz, 2H), 1.87 - 1.61 (m, 4H), 1.05 (d, J = 6.3 Hz, 3H).

[0412] Example 3: 2-(3,3-difluorocyclobutyl)-N-[(lS*,2S)-2-hydroxy-l-[5- (trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0413] H /

[0414] N HN—

[0415] } — \0

[0416] N >— OH

[0417]

[0418] The title compound was obtained in analogy to Example 1 (6.7% yield) using (2S)-1-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and (3,3-difluorocyclobutyl) acetic acid. LC-MS (ESI, m / z): [M+ H]+: 408.10,'H NMR (400 MHz, DMSO-d6) δ 12.43 – 12.37 (m, 1H), 8.23 (dd, J = 8.5, 4.8 Hz, 1H), 7.64 – 7.56 (d, J = 8.8 Hz, 2H), 7.46 (s, 1H), 7.15 (dd, J = 12.5, 9.5 Hz, 1H), 5.04 (ddd, J = 15.1, 7.7, 4.3 Hz,2H), 4.18 (q, J= 5.5 Hz, 1H), 2.65 (tdd, J= 14.6, 7.1, 4.5 Hz, 2H), 2.59 -2.52 (m, 1H), 2.51 - 2.25 (m, 3H), 1.06 (d, J= 6.3 Hz, 3H).

[0419] Example 4: 2-cyclobutyl-N-[(lS,2S)-l-[5-(difluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyljacetamide

[0420] O OH

[0421]

[0422] a) M[(LS',26')-2-[( / c77-butyldiphenylsilyl) oxy]-l-[5-(difluoromethoxy)-U / -l,3-benzodiazol-2-yl] propyl]-2-cyclobutylacetamide

[0423] The title compound was obtained in analogy to Example 1 (83.8% yield) using 2-[(15,25)-1 -am i no-2- [( / c 7-buty 1 di pheny 1 si 1 y 1 ) oxy] propyl] -5 -(difluoromethoxy)- H- 1,3-benzodiazole and cyclobutylacetic acid. LCMS (ESI) [M + H]+: 592.0. b) 2-cyclobutyl-N-[(lS,2S)-l-[5-(difluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide

[0424] A mixture of N-[(lS,2S)-2-[(tert-butyldiphenylsilyl) oxy]-l-[5-(difluoromethoxy)-lH-l,3-benzodiazol-2-yl] propyl]-2-cyclobutylacetamide (140.0 mg, 0.24 mmol, 1.00 equiv) and triethylamine trihydrofluoride (190.7 mg, 1.18 mmol, 5.00 equiv) in DMF (2.00 mL) was stirred at 25 °C for 6 h. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, H2O in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-cyclobutyl-N-[(lS,2S)-l-[5-(difluoromethoxy)-lH-l,3-benzodiazol-2-yl]-2-hydroxypropyl] acetamide (60.8 mg, 72.51% yield) as a white solid. LCMS (ESI) [M + H]+: 354.15. 1HNMR (400 MHz, DMSO-d6) δ 12.22 (d, J = 15.7 Hz, 1H), 7.98 (dd, J = 8.6, 4.3 Hz, 1H), 7.52 (dd, J = 35.6, 8.7 Hz, 1H), 7.37 – 6.93 (m, 3H), 5.08 – 4.95 (m, 2H), 4.14 (p, J = 4.4 Hz, 1H), 2.60 (p, J = 7.8 Hz, 1H), 2.42 (ddd, J = 13.9, 7.8, 1.3 Hz, 1H), 2.36 – 2.22 (m, 1H), 2.06 – 1.94 (m, 2H), 1.87 – 1.60 (m, 4H), 1.13 – 0.99 (m, 3H).

[0425] Example 5: 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[7-(trifluoromethyl)-lH-benzimidazol-2-yl] propyl] acetamide

[0426] O OH

[0427]

[0428] The title compound was obtained in analogy to Example 1 (22.8% yield) as a white solid using ( 15*, 25)- 1 -amino- 1 -[4-(trifluoromethyl)-3 H- 1,3 -benzodiazol-2-yl]propan-2-ol and cyclobutylacetic acid. LCMS (ESI) [M + H]+: 356.05.;HNMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 5.06 (s, 2H), 4.17 (s, 1H), 2.68 - 2.54 (m, 1H), 2.42 (dd, J= 13.9, 7.7 Hz, 1H), 2.34 (dd, J= 13.8, 7.4 Hz, 1H), 2.08 - 1.94 (m, 2H), 1.87 - 1.63 (m, 4H), 1.08 (d, J = 6.3 Hz, 3H).

[0429] Example 6: 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethyl)-lH-benzimidazol-2-yl] propyl] acetamide

[0430]

[0431] The title compound was obtained in analogy to Example 1 (58.9% yield) as a white solid using ( 15*, 25)- 1 -amino- 1 -[5 -(trifluoromethyl)- 1 H- 1,3 -benzodiazol-2-yl]propan-2-ol and cyclobutylacetic acid. MS (ESIpos): m / z = 356.15 [M+H]+. ‘HNMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4, 1.7 Hz, 1H), 5.07 (dd, J = 8.3, 4.0 Hz, 1H), 4.24 - 4.14 (m, 1H), 2.67 - 2.53 (m, 1H), 2.45 (dd, J= 13.9, 7.8 Hz, 1H), 2.34 (dd, J= 13.9, 7.3 Hz, 1H), 2.10 - 1.95 (m, 2H), 1.90 - 1.78 (m, 2H), 1.78 - 1.62 (m, 2H), 1.07 (d, J= 6.3 Hz, 3H).

[0432] Example 7: 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethyl)-lH-benzimidazol-2-yl] propyl] acetamide

[0433]

[0434] The title compound was obtained in analogy to Example 1 (31.3% yield) as a white solid using (U?*,25)-l-amino-l-(5-(trifluoromethyl)-U / -benzo[ ]imidazol-2-yl)propan-2-ol and cyclobutylacetic acid. MS (ESIpos): m / z = 356.05 [M+H]+. 'H NMR (400 MHz, DMSO-d6) δ 12.60 (d, J = 8.8 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.91 – 7.63 (m, 2H), 7.51 – 7.42 (m, 1H), 5.10 – 5.03 (m, 1H), 4.98 – 4.88 (m, 1H), 4.11 – 4.00 (m, 1H), 2.65 – 2.53 (m, 1H), 2.34 (d, J = 13.8 Hz, 1H), 2.30 – 2.21 (m, 1H), 2.05 – 1.93 (m, 2H), 1.85 – 1.77 (m, 1H), 1.77 – 1.58 (m, 3H), 1.12 (d, J = 6.3 Hz, 3H).Example 8: 2-cyclobutyl-N-[(lR*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide

[0435]

[0436] a) N-[(lS,2S)-2-[(tert-butyldiphenylsilyl)oxy]-l-[5-fluoro-6-(trifluoromethoxy)-3H-l,3-benzodiazol-2-yl]propyl]-2-cyclobutylacetamide

[0437] The title compound was obtained in analogy to Example 1 (32.1% yield) using 2-[(15,25)- l-amino-2-[( / c / 7-butyldiphenylsilyl)oxy]propyl]-5-fluoro-6-(trifluoromethoxy)-37 / -l,3-benzodiazole and cyclobutylacetic acid. MS (ESIpos): m / z = 628.25 [M+NEU]+.

[0438] b) 2-cyclobutyl-N-[(lR*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide

[0439] To a stirred solution of7V-[(15',25)-2-[(tert-butyldiphenylsilyl)oxy]-l-[5-fluoro-6-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]propyl]-2-cyclobutylacetamide (100 mg, 0.159 mmol, 1 equiv) in DMF (1 mL) were added EtsNJHF (128.40 mg, 0.795 mmol, 5 equiv) in portions at 25 °C under nitrogen atmosphere over 2 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2 diastereomers: 2-cyclobutyl-7V-((15'*,25)-l-(6-fluoro-5-(tri fluoromethoxy)- l7 / -benzo[t / ]imidazol-2-yl)-2-hydroxypropyl)acetamide (Example 9)(25.5 mg, 40.95% yield, first peak) as a white solid and the title compound 2-cyclobutyl-7V-((U?*,25)-l-(6-fluoro-5-(trifluoromethoxy)-lJ / -benzo[ ]imidazol-2-yl)-2-hydroxypropyl)acetamide (5.3 mg, 8.51% yield, second peak) as a white solid. MS (ESIpos): m / z = 390.10 [M+H]+. ‘HNMR (300 MHz, DMSO-6) 6 12.81 - 12.04 (m, 1H),7.95 (d, J= 8.7 Hz, 1H), 7.60 (dd, J= 22.2, 8.8 Hz, 2H), 4.94 (dd, J= 8.5, 6.7 Hz, 2H), 4.07 (t, J= 6.4 Hz, 1H), 2.67 -2.56 (m, 1H), 2.41 -2.25 (m, 2H), 2.02 (d, J= 11.0 Hz, 2H), 1.90 - 1.74 (m, 2H), 1.74 - 1.65 (m, 2H), 1.14 (d, J= 6.3 Hz, 3H).

[0440] Example 9: 2-cyclobutyl-N-[(lS*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide

[0441]

[0442] The title compound is the first peak isolated in the purification of 2-cyclobutyl-N-[(lR*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl] acetamide (Example 8). MS (ESIpos): m / z = 390.05 [M+H]+. 'HNMR (400 MHz, DMSO-d6) δ 12.45 (d, J = 21.9 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.76 – 7.54 (m, 2H), 5.00 (dd, J = 8.6, 4.1 Hz, 2H), 4.15 (d, J = 5.0 Hz, 1H), 2.66 – 2.55 (m, 1H), 2.42 (dd, J = 13.9, 7.8 Hz, 1H), 2.31 (dd, J = 13.9, 7.3 Hz, 1H), 2.07 – 1.94 (m, 2H), 1.89 – 1.61 (m, 4H), 1.05 (d, J = 6.3 Hz, 3H).

[0443] Example 10: trans-(lR*,2R*)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-2-(trifluoromethyl)cyclopropanecarboxamide

[0444] O OH

[0445]

[0446] The title compound was obtained in analogy to Example 8 (4.7% yield, first peak) as a white solid using (U?,27?)-7V-[(15',25)-2-[(tert-butyldiphenylsilyl) oxy]-l-[5- (trifluorom ethoxy)- 1H- 1,3 -benzodiazol-2-yl] propyl]-2-(trifluoromethyl) cyclopropane- 1 -carboxamide and Et3N.3HF. LC-MS (ESI, m / z): [M+ H]+: 412.05. ‘HNMR (400 MHz, DMSO-d6) δ 12.534(s, 1H), 8.88 (d, J = 8.3 Hz, 1H), 7.54 (s, 2H), 7.15 (d, J = 8.7 Hz, 1H), 5.16 (s, 1H), 5.02 (dd, J = 8.3, 4.7 Hz, 1H), 4.19 (d, J = 6.1 Hz, 1H), 2.47 (q, J = 5.0, 4.4 Hz, 1H), 2.14 (s, 1H), 1.21 – 1.03 (m, 5H).

[0447] Example 11: 2-(3,3-difluorocyclopentyl)-N-[(lS*,2S)-2-hydroxy-l-[5- (trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0448] F

[0449] 'F

[0450] O OH

[0451]

[0452] The title compound was obtained in analogy to Example 1 (12.3% yield) as a white solid using (25)- 1 -amino- 1 -(5 -(trifluoromethoxy)- U / -benzo[ ]imidazol-2-yl)propan-2-ol and (3,3-difluorocyclopentyl) acetic acid. LC-MS (ESI, m / z): [M+ H]+: 422.20. ’H NMR (400 MHz, DMSO-d6) δ 12.51 (m, H), 8.38 (dd, J = 8.5, 4.6 Hz, 1H), 7.62 – 7.54 (m, 2H), 7.15 (d, J = 8.7 Hz, 1H), 5.21 – 4.89 (m, 2H), 4.07 (s, 1H), 2.41 – 1.75 (m, 8H), 1.49 – 1.35 (m, 1H), 1.13 (d, J = 6.2 Hz, 3H).Example 12: 2-cyclobutyl-l-[(2S,3R)-3-hydroxy-2-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]pyrrolidin-l-yl]ethanone

[0453]

[0454] The title compound was obtained in analogy to Example 1 (18.2% yield) as a white solid using (25',37?)-2-[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]pyrrolidin-3-ol and cyclobutylacetic acid. LCMS (ESI) [M + H]+: 384.05. 'H NMR (400 MHz, DMSO-d6) δ 12.80-12.46 (m, 1H), 7.62 (d, J = 9.6 Hz, 1H), 7.53 (s, 2H), 5.60 – 5.50 (s, 1H), 4.97 (d, J = 19.0 Hz, 1H), 4.34 (s, 1H), 3.81 – 3.64 (m, 2H), 2.51 – 2.42 (m, 1H), 2.35 (dd, J = 15.6, 7.2 Hz, 1H), 2.21 (d, J = 10.8 Hz, 1H), 2.11 – 1.71 (m, 5H), 1.74 – 1.61 (m, 5H), 1.64 –1.46 (m, 2H), 1.44 – 1.32 (m, 1H).

[0455] Example 13: 4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] butanamide

[0456] H / \

[0457] N HN^

[0458] / ) < O F F

[0459] N >-OH

[0460]

[0461] The title compound was obtained in analogy to Example 1 (13.2% yield) as a white solid using (25)- 1 -amino- 1 -(5 -(trifluoromethoxy)- U / -benzo[ ]imidazol-2-yl)propan-2-ol and 4,4,4-trifluorobutanoic acid. LC-MS (ESI, m / z): [M+ H]+: 400.05. 'H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.55 (s, 2H), 7.15 (d, J = 8.7 Hz, 1H), 5.07 (s, 1H), 5.02 (dd, J = 8.4, 4.2 Hz, 1H), 4.24 – 4.17 (m, 1H), 2.66 – 2.50 (m, 4H), 1.07 (d, J = 6.3 Hz, 3H).

[0462] Example 14: 2-cyclobutyl-N-[(lS*,2S)-l-[4-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide

[0463] H /

[0464] N HN— Z

[0465] O I F Cy V N OH

[0466]

[0467] F

[0468] The title compound was obtained in analogy to Example 1 (23.9% yield) as a white solid using (25)- 1 -amino- 1 -[4-fluoro-5-(trifluoromethoxy)- 1 H- 1,3 -benzodiazol-2-yl] propan-2-ol and cyclobutylacetic acid. LC-MS (ESI, m / z): [M+ H]+: 390.10. ’H NMR (400 MHz,DMSO-d6) δ 12.69 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.32 – 7.24 (m, 1H), 5.07 – 4.93 (m, 2H), 4.17 (dq, J = 11.3, 5.9 Hz, 1H), 2.60 (p, J = 7.7 Hz, 1H), 2.44 (dd, J = 13.9, 7.8 Hz, 1H), 2.33 (dd, J = 13.8, 7.3 Hz, 1H), 2.07 – 1.94 (m, 2H), 1.87 – 1.74 (m, 2H), 1.78 – 1.62 (m, 2H), 1.06 (d, J = 6.3 Hz, 3H).

[0469] Example 15: 2-cyclobutyl-N-[(lS*,2R)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] acetamide

[0470]

[0471] The title compound was obtained in analogy to Example 1 (12.5% yield) as a white solid using (2R)~ 1 -amino- 1 -(5 -(trifluoromethoxy)- 17 / -benzo[ t / ]i mi dazol -2-yl )propan-2-ol and cyclobutylacetic acid. LC-MS (ESI, m / z): [M+ H]+: 372.05. 'HNMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 7.14 (dd, J = 8.7, 2.4 Hz, 1H), 5.07 (s, 1H), 4.90 (dd, J = 8.6, 7.2 Hz, 1H), 4.06 (q, J = 6.5 Hz, 1H), 2.58 (p, J = 7.7 Hz, 1H), 2.32 (dd, J = 13.8, 7.8 Hz, 1H), 2.25 (dd, J = 13.8, 7.3 Hz, 1H), 1.98 (pq, J = 7.1, 3.3 Hz, 2H), 1.88 – 1.76 (m, 1H), 1.80 – 1.71 (m, 1H), 1.67 (dq, J = 11.6, 8.7, 8.1 Hz, 2H), 1.12 (d, J = 6.2 Hz, 3H).

[0472] Example 16: 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-indol-2-yl] propyl] acetamide

[0473]

[0474] a) (25)-2-(benzyloxy)propan-l-ol

[0475] A solution of (25)-2-(benzyloxy)propanoic acid (5 g, 27.746 mmol, 1 equivalent) in THF (100 mL) was followed by the addition of LAH (2.11 g, 55.492 mmol, 2 equivalent) in portions at 0°C. The resulting mixture was stirred for 3 h at 0 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (50mL) at 0 °C. The resulting mixture was extracted with EA (3x55 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (2S)-2-(benzyloxy)propan-1-ol (3 g, 65.05% yield) as yellow oil.

[0476] b) (25)-2-(benzyloxy)propanalA solution of DMSO (2.82 g, 36.096 mmol, 3 equivalent) in DCM (100 mL) was treated with oxalic dichloride (4.58 g, 36.084 mmol, 3.00 equivalent) for 1 hour, then a solution of (25)-2-(benzyloxy)propan-l-ol (2 g, 12.032 mmol, 1 equivalent) in dichloromethane (10 mL) was added slowly. The resulted solution was stirred for 4 hours at -20 °C, followed by the addition of TEA (6.09 g, 60.182 mmol, 5.00 equivalent) at -78 °C. After additional 1 hour at -50 °C, the reaction was quenched by water (55 mL) and extracted with dichloromethane (2x20 mL). The organic layers combined, washed with brine (3x16 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrates were concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 20 % ethyl acetate in dichloromethane to give compound (25)-2-(benzyloxy)propanal (1.2 g, 60.74% yield) as yellow oil.

[0477] c) A-[(lZ,25)-2-(benzyloxy)propylidene]-2-methylpropane-2-sulfinamide

[0478] A solution of (25)-2-(benzyloxy)propanal (1 g, 6.090 mmol, 1 equivalent) in THF (30 mL) was treated with Ti(OEt)4 (1.67 g, 7.308 mmol, 1.2 equivalent) and tert-butanesulfmamide (0.89 g, 7.308 mmol, 1.2 equivalent) for 2 h at room temperature under nitrogen atmosphere. The reaction was diluted with 15 mL of brine. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford N-[(1Z,2S)-2-(benzyloxy)propylidene]-2-methylpropane-2-sulfinamide (780 mg, 47.90% yield) as a white solid.

[0479] d) tert-butyl 6-(trifluoromethoxy)indole-l -carboxylate

[0480] A solution of 6-(trifluoromethoxy)-lH-indole (700 mg, 3.480 mmol, 1 equivalent) in DMF (10 mL) was treated with Boc2O (1.52 g, 6.960 mmol, 2 equivalent) and DMAP (85.03 mg, 0.696 mmol, 0.2 equivalent) at room temperature under nitrogen atmosphere followed by the addition of DIPEA (0.90 g, 6.960 mmol, 2 equivalent) dropwise at room temperature. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 6-(trifluoromethoxy)indole-l -carboxylate (750 mg, 71.54% yield) as yellow oil. LCMS(ECI) [M - H]: 300.0

[0481] e) tert-butyl 2-((l S*,25)-2-(benzyloxy)-l-((tert-butylsulfinyl)amino)propyl)-6-(trifluorom ethoxy)- 1 JT-indole- 1 -carboxylate

[0482] To a stirred solution of tert-butyl 6-(trifluoromethoxy)indole-l -carboxylate (600 mg, 1.992 mmol, 1 equivalent) in THF (40 mL) was added LDA (426.72 mg, 3.984 mmol, 2 equivalent) dropwise at -78°C under nitrogen atmosphere, 1 h later, A-[(lZ,25)-2-(benzyloxy)propylidene]-2-methylpropane-2-sulfinamide (585.79 mg, 2.191 mmol, 1.1 equivalent) in 2 mL of THF was added into the mixture dropwise at -78 °C. The resulting mixture was stirred for 2 h at -78 °C under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep.-TLC, eluted with PE / EA (1: 1) to afford tert-butyl 2-((1A* 25)-2-(benzyloxy)- 1 -((tert-butylsulfinyl)amino)propyl)-6-(tri fluoromethoxy)- H-indole-1 -carboxylate (170 mg, 15% yield) as yellow oil and tert-butyl 2-((lS*,25)-2-(benzyloxy)- 1 -((tert-butylsulfmyl)amino)propyl)-6-(trifluorom ethoxy)- 1 JT-indole- 1 -carboxylate (180 mg, 15.88% yield) as yellow oil. LCMS(ECI) [M + H]+: 569.0

[0483] f) (lS*,25)-2-(benzyloxy)-l-(6-(trifluoromethoxy)-lJH-indol-2-yl)propan-l-amine hydrochloride

[0484] A solution of tert-butyl 2-((lS*,25)-2-(benzyloxy)-l-((tert-butylsulfmyl)amino)propyl)-6-(trifluoromethoxy)-lJT-indole-l -carboxylate (175 mg, 0.307 mmol, 1 equivalent) in 40 mL vial were added HC1 (gas) in 1,4-di oxane (5 mL) at room temperature. The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford (lS*,25)-2-(benzyloxy)-l-(6-(trifluoromethoxy)-U / -indol-2-yl)propan-l -amine hydrochloride (120 mg, 97.5% yield) as yellow oil. LCMS(ECI) [M + H]+: 365

[0485] g)A-((lS*,25)-2-(benzyloxy)-l-(6-(tri fluoromethoxy)- U / -indol-2-yl)propyl)-2-cy clobuty 1 acetami de

[0486] To a stirred solution of (lS*,25)-2-(benzyloxy)-l-(6-(trifluoromethoxy)-lJ / -indol-2-yl)propan-l -amine hydrochloride (120 mg, 0.299 mmol, 1 equivalent) and cyclobutylacetic acid (34.1 mg, 0.299 mmol, 1 equivalent) in DMF (5 mL) was added TCFH (103.49 mg, 0.368 mmol, 1.2 equivalent) andNMI (75.71 mg, 0.921 mmol, 3 equivalent) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (3: 1) to afford A-((lS*,25)-2-(benzyloxy)-l-(6-(trifluoromethoxy)-U / -indol-2-yl)propyl)-2-cyclobutylacetamide (65 mg, 47.2% yield) as a yellow oil. LCMS(ECI) [M + H]+: 461.0

[0487] h) 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-indol-2-yl]propyl]acetamideA solution of A-((lS*,25)-2-(benzyloxy)-l-(6-(trifluoromethoxy)-U / -indol-2-yl)propyl)-2-cyclobutylacetamide (65 mg, 0.1411 mmol, 1 equivalent) in THF (4 mL) was treated with Pd(OH)2 / C (60.99 mg, 0.434 mmol, 2 equivalent) for 5 min at room temperature. The resulting mixture was stirred for 12 h at room temperature under hydrogen atmosphere. The residue was purified by reverse phase flash chromatography to afford 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-indol-2-yl]propyl]acetamide (20.8 mg, 23.05% yield) as a colorless semi-solid. LCMS(ECI) [M - H]’: 369.10. 'HNMR (400 MHz, DMSO-d6) δ 11.01 (d, J = 15.9 Hz, 1H), 7.97 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.31 (s, 1H), 6.95 – 6.88 (m, 1H), 6.33 (d, J = 1.7 Hz, 1H), 5.02 – 4.85 (m, 2H), 4.03 – 3.95 (m, 1H), 2.68 – 2.52 (m, 3H), 2.41 – 2.21 (m, 2H), 2.05 – 1.96 (m, 2H), 1.87 –1.73 (m, 2H), 1.76 – 1.63 (m, 2H), 1.04 (dd, J = 13.3, 6.2 Hz, 3H).

[0488] Example 17: 3-fluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-3-methyl-butanamide

[0489] O OH

[0490]

[0491] The title compound was obtained in analogy to Example 1 (7.8% yield) as a white solid using (25)-l-amino-l-[5-(trifluoromethoxy)-U / -l,3-benzodiazol-2-yl] propan-2-ol and 3-fluoro-3 -methylbutanoic acid. LCMS (ESI) [M + H]+: 378.05. 'H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.54 (s, 2H), 7.14 (d, J = 8.5 Hz, 1H), 5.17 – 4.95 (m, 2H), 4.18 (s, 1H), 2.75 (dd, J = 15.1, 13.5 Hz, 1H), 2.63 –2.55 (m, 1H), 1.41 (dd, J = 21.9, 1.8 Hz, 6H), 1.06 (d, J = 6.3 Hz, 3H).

[0492] Example 18: 4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-3,3-dimethyl-butanamide

[0493] H / \

[0494] N HN— <( \~F

[0495] / >“< O F F

[0496] N >-OH

[0497]

[0498] The title compound was obtained in analogy to Example 1 (6.5% yield) as a white solid using (25)-l-amino-l-[5-(trifluoromethoxy)-U / -l,3-benzodiazol-2-yl] propan-2-ol and 4,4,4-trifluoro-3,3-dimethylbutanoic acid. LCMS (ESI) [M + H]+: 428.10. *HNMR (400 MHz, DMSO-d6) δ 12.40 (d, J = 23.9 Hz, 1H), 8.50 – 8.43 (m, 1H), 7.67 – 7.43 (m, 2H), 7.19 – 7.09 (m, 1H), 5.05 (td, J = 10.4, 9.9, 4.4 Hz, 2H), 4.22 – 4.14 (m, 1H), 2.61 – 2.53 (m, 1H), 2.38 (d, J = 13.3 Hz, 1H), 1.21 (s, 6H), 1.07 (dd, J = 6.4, 2.1 Hz, 3H).Example 19: 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl] butyl] acetamide

[0499] N HN— 6.

[0500] A N >— O °H

[0501]

[0502] a) tert-butyl (45)-4-[(15)-l-hydroxypropyl]-2,2-dimethyl-l,3-oxazolidine-3-carboxylate

[0503] A solution of tert-butyl (45)-4-formyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (1 g, 4.362 mmol, 1 equiv) in THF (10 mL) was treated with ethylmagnesium bromide (1.74 g, 13.086 mmol, 3.0equiv) for 10 min at -78 °C under nitrogen atmosphere. The mixture was stirred for 2 hours at RT. The resulting mixture was quenched with saturated aq. NH4CI (50 mL) solution. The aqueous layer was extracted with EA (20 mL x 3), the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with 0-50% (EA in PE) to afford tert-butyl (4, S')-4-[(LS')- l-hydroxypropyl]-2,2-dimethyl- l,3-oxazolidine-3 -carboxylate (700 mg, 61.88% yield) as a colorless oil. LC-MS (ESI, m / z):

[0504] [M+ H]+: 260.0.

[0505] b) tert-butyl (45)-4-[(l S)- 1 -(acetyloxy) propyl]-2,2-dimethyl-l,3-oxazolidine-3-carb oxy late

[0506] A solution of tert-butyl (45)-4-[(15)-l-hydroxypropyl]-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (2.2 g, 8.483 mmol, 1 equiv) and Ac2O (1.30 g, 12.725 mmol, 1.5 equiv) in Pyridine (20 mL) was stirred for 4 hours at RT. The combined organic layer was concentrated under reduced pressure to give crude product. The residue was purified by reverse phase separation column Mobile Phase B: acetonitrile; Gradient: 0%B to 70% B in 30 min] to give tert-butyl (45)-4-[(15)-l-(acetyloxy) propyl]-2,2-dimethyl-l,3-oxazolidine-3 -carboxylate (1.5 g, 58.67% yield) as a white solid. LC-MS (ESI, m / z): [M+ H]+: 302.2

[0507] c) (25,35)-2-amino-l-hydroxypentan-3-yl acetate

[0508] A solution of tert-butyl (45)-4-[(15)-l-(acetyloxy) propyl]-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (1.5 g, 4.977 mmol, 1 equiv) in cone. HC1 (5 mL) was stirred for 3 hours at 80 °C. The resulting mixture was concentrated under reduced pressure to give crude product (25,35)-2-amino-l-hydroxypentan-3-yl acetate (1 g crude) as yellow solid. LC-MS (ESI, m / z): [M+ H]+: 198.1d) (25,35)-2-(2-cyclobutylacetamido)-l-hydroxypentan-3-yl acetate

[0509] A solution of (25,35)-2-amino-l -hydroxypentan-3 -yl acetate (800 mg, 4.963 mmol, 1 equiv) and cyclobutylacetic acid (453.17 mg, 3.970 mmol, 0.8 equiv) in ACN (10 mL) was treated with NMI (2.04 g, 24.815 mmol, 5equiv), followed by the addition of TCFH (2.09 g, 7.444 mmol, 1.5 equiv) dropwise at 0 °C. The mixture was stirred for 2 hours at RT. The residue was purified by reverse phase separation column Mobile Phase B: acetonitrile; Gradient: 0%B to 70% B in 30 min] to give (25,35)-2-(2-cyclobutylacetamido)-l-hydroxypentan-3-yl acetate (500 mg, 39.15% yield) as a yellow solid. LC-MS (ESI, m / z):

[0510] [M+ H]+: 258.1

[0511] e) (2A,35)-2-(2-cyclobutylacetamido)-l -oxopentan-3 -yl acetate

[0512] A solution of (25,35)-2-(2-cyclobutylacetamido)-l -hydroxypentan-3 -yl acetate (500 mg, 1.943 mmol, 1 equiv) in DCM (8 mL), Dess-Martin reagent (1.24 g, 2.915 mmol, 1.5 equiv) was stirred at 0 °C. The mixture was stirred for 2 hours at RT. The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layer was concentrated under reduced pressure to give crude product (2A,35)-2-(2-cyclobutylacetamido)-l-oxopentan-3-yl acetate (300 mg, 60.47% yield) as a black solid. LC-MS (ESI, m / z): [M+ H]+: 256.2

[0513] f) (15,25)- 1 -(2-cyclobutylacetamido)- 1 -[5-(trifluoromethoxy)-3 H- 1,3 -benzodiazol-2-yl] butan-2-yl acetate

[0514] A solution of (2A,35)-2-(2-cyclobutylacetamido)-l-oxopentan-3-yl acetate (400 mg, 1.567 mmol, 1 equiv) and 4-(trifluoromethoxy) benzene- 1,2-diamine (270.92 mg, 1.410 mmol, 0.9 equiv) in ACN (4 mL) was treated with iodine (1192.93 mg, 4.701 mmol, 3 equiv) at 0 °C. The mixture was stirred for 2 hours at RT. The residue was purified by reverse phase separation column Mobile Phase B: acetonitrile; Gradient: 0%B to 70% B in 30 min] to give (15,25)-l-(2-cyclobutylacetamido)-l-[5-(trifluoromethoxy)-3-1,3-benzodiazol-2-yl] butan-2-yl acetate (100 mg, 14.93% yield) as a black solid. LC-MS (ESI, m / z): [M+ H]+: 428.1

[0515] g) 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl ] acetamide

[0516] A solution of (15,25)-l-(2-cyclobutylacetamido)-l-[5-(trifluoromethoxy)-3-1,3-benzodiazol-2-yl] butan-2-yl acetate (100 mg, 0.234 mmol, 1 equiv) in MeOH (5 mL) was added NaOH (46.8 mg, 1.17 mmol, 5 equiv) at RT. The mixture was stirred for 1.5 hours at RT. The residue was purified by reverse phase separation column [Mobile Phase A: Water (0.3% NH4HCO3), Mobile Phase B: acetonitrile; Gradient: 0% B to 70% B in 30min] to afford the title product 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide (4.6 mg, 4.92% yield) as a white solid and 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide (7.1 mg, 7.79% yield) as a white solid. LC-MS (ESI, m / z): [M+ H]+: 386.05. 'H NMR (400 MHz, DMSO-6) 6 12.39 (s, 1H), 7.94 (t, J= 8.5 Hz, 1H), 7.55 (d, J= 8.8 Hz, 2H), 7.14 (t, J= 10.6 Hz, 1H), 5.09 (dd, J= 8.8, 3.6 Hz, 1H), 4.99 (dd, J= 7.8, 5.8 Hz, 1H), 3.90 (s, 1H), 2.61 (dt, J= 15.4, 7.7 Hz, 1H), 2.44 (dd, J= 14.2, 8.0 Hz, 1H), 2.32 (dd, J= 13.9, 7.2 Hz, 1H), 2.10 - 1.98 (m, 1H), 2.02 - 1.95 (m, 1H), 1.87 - 1.72 (m, 2H), 1.69 (q, J= 8.6 Hz, 2H), 1.48 - 1.33 (m, 2H), 1.24 (s, 1H), 0.88 (t, J = 7.4 Hz, 3H).

[0517] Example 20: 2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl] butyl] acetamide

[0518]

[0519] The title product is the second peak obtained in the purification of 2-cyclobutyl-N-[(2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide (Example 19). LC-MS (ESI, m / z): [M+ H]+: 386.05. 'HNMR (400 MHz, DMSO-6) 8 12.45 (s, 1H), 8.22 (d, J= 8.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.13 (t, J= 10.6 Hz, 1H), 5.02 (d, J= 5.5 Hz, 2H), 3.79 (s, 1H), 2.57 (p, J= 7.8 Hz, 1H), 2.27 (qd, J= 13.8, 7.6 Hz, 2H), 1.98 (ddq,.7= 11.0, 7.7, 3.7 Hz, 2H), 1.85 - 1.72 (m, 2H), 1.71 - 1.60 (m, 2H), 1.54(s, 1H), 1.33 (dt, J= 14.4, 7.4 Hz, 1H), 0.89 (t, J= 7.4 Hz, 3H).

[0520] Example 21: 2-(l-fluorocyclobutyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0521]

[0522] The title compound was obtained in analogy to Example 1 (8.9% yield) as a white solid using (25)-l-amino-l-[5-(trifluoromethoxy)-1-1,3-benzodiazol-2-yl]propan-2-ol and (1-fluorocyclobutyl)acetic acid. LCMS (ESI) [M + H]+: 390.20.1H NMR (400 MHz, DMSO-6) δ 12.42 (d, J= 23.1 Hz, 1H), 8.21 (d, J= 8.5 Hz, 1H), 7.65 - 7.45 (m, 2H), 7.14 (s, 1H), 5.04 (dd, J= 8.5, 4.2 Hz, 2H), 4.17 (s, 1H), 2.90 -2.62 (m, 2H), 2.40 -2.16 (m, 4H), 1.77 - 1.67 (m, 1H), 1.59 - 1.50 (m, 1H), 1.05 (d, J= 6.3 Hz, 3H).Example 22: 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(2,2,2-trifluoroethyl)-lH-benzimidazol-2-yl] propyl] acetamide

[0523] H /

[0524] 4 N HN— K

[0525] O N OH

[0526]

[0527] The title compound was obtained in analogy to Example 1 (39.9% yield) as a white solid using (25)-l-amino-l-[5-(2,2,2-trifluoroethyl)-1-1,3-benzodiazol-2-yl]propan-2-ol and cyclobutylacetic acid. MS (ESIpos): m / z = 370.05 [M+H]+. *HNMR (400 MHz, DMSO-6) δ 12.19 (s, 1H), 7.98 (d, J= 8.7 Hz, 1H), 7.50 (d, J= 20.9 Hz, 2H), 7.12 (d, J= 8.3 Hz, 1H), 5.00 (dt, J= 8.6, 4.7 Hz, 2H), 4.15 (s, 1H), 3.70 (q, J= 11.6 Hz, 2H), 2.60 (p, J= 7.7 Hz, 1H), 2.42 (dd, J= 13.9, 7.7 Hz, 1H), 2.31 (dd, J= 13.9, 7.3 Hz, 1H), 2.00 (dqq, J = 10.8, 5.4, 3.3, 2.6 Hz, 2H), 1.89 - 1.74 (m, 2H), 1.74 - 1.61 (m, 2H), 1.04 (d, J= 6.3 Hz, 3H).

[0528] Example 23: 2-(3-fluorobicyclo[l.l.l]pentan-l-yl)-N-((lS*,2S)-2-hydroxy-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propyl)acetamide

[0529] H /

[0530] N HN—

[0531] 4* — C o

[0532] N )— OH

[0533]

[0534] The title compound was obtained in analogy to Example 1 (12.2% yield) as a white solid using (25)-l-amino-l-[5-(trifluoromethoxy)-1-1,3-benzodiazol-2-yl] propan-2-ol and {3-fluorobicyclo [1.1.1] pentan-l-yl} acetic acid. LC-MS (ESI, m / z): [M+H]+: 402.15. 'H NMR (400 MHz, DMSO-6) 8 12.43 (s, 1H), 8.18 (dd, J= 8.4, 5.4 Hz, 1H), 7.55 (d, J= 8.9 Hz, 2H), 7.19 - 7.09 (m, 1H), 5.03 (dd, J= 21.4, 8.6, 4.6 Hz, 2H), 4.17 (q, J= 5.2 Hz, 1H), 2.71 (d, J= 14.5 Hz, 1H), 2.57 (d, J= 14.2 Hz, 1H), 1.97 (d, J= 2.7 Hz, 6H), 1.06 (dd, J = 6.3, 1.8 Hz, 3H).

[0535] Example 24: 2-(3-fluorocyclobutyl)-N-((lS*,2S)-2-hydroxy-l-(5-(trifluoromethoxy)- IH-benzo [d] imidazol-2-yl)propyl)acetamide

[0536] H /

[0537] N HN— Z

[0538] / ) — \ o

[0539] N >-OH

[0540]

[0541] The title compound was obtained in analogy to Example 1 (8.6% yield) as a white solid using (25)-l-amino-l-[5-(trifluoromethoxy)-1-1,3-benzodiazol-2-yl]propan-2-ol and (3-fluorocyclobutyl)acetic acid. LCMS (ESI) [M + H]+: 390.05. 'H NMR (400 MHz, DMSO-6) δ 12.54 (s, 1H), 8.42 - 8.32 (m, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.14 (d, J= 8.8 Hz, 1H), 5.08 (q,.7= 6.1 Hz, 1H), 5.01-4.92 (m, 2H), 4.05 (t, J= 6.6Hz, 1H), 2.58 (ddq, J = 12.8, 8.3, 4.2 Hz, 1H), 2.45 -2.33 (m, 1H), 2.37 - 2.29 (m, 1H), 2.32 - 2.19 (m, 1H), 2.22 -2.06 (m, 2H), 1.92 - 1.75 (m, 1H), 1.12 (d, J = 6.3 Hz, 3H).

[0542] Example 25: N-[(lS*,2S)-l-[5-(difluoromethylsulfanyl)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]-2-(l-fluorocyclobutyl)acetamide

[0543] H /

[0544] N HN—

[0545] — \

[0546] N >-00

[0547] H

[0548]

[0549] The title compound was obtained in analogy to Example 1 (30.9% yield) as a white solid using (25)-l-amino-l-{5-[(difluoromethyl)sulfanyl]-1-1,3-benzodiazol-2-yl}propan-2-ol and (1-fluorocyclobutyl)acetic acid. LCMS (ESI) [M + H]+: 388.00. 'H NMR (400 MHz, DMSO-6) δ 12.45 (s, 1H), 8.19 (d, J= 8.4 Hz, 1H), 7.76 (d, J= 21.7 Hz, 1H), 7.56 (d, J= 19.1 Hz, 1H), 7.41 - 7.23 (m, 2H), 5.05 (dd, J= 8.5, 4.3 Hz, 2H), 4.19 (d, J= 6.1 Hz, 1H), 2.91 -2.63 (m, 2H), 2.40 - 2.15 (m, 4H), 1.80 - 1.68 (m, 1H), 1.60 - 1.47 (m, 1H), 1.06 (d, J= 6.3 Hz, 3H).

[0550] Example 26: (S)-2-cyclobutyl-N-[(l-hydroxycyclopropyl)-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl] methyl] acetamide

[0551] HN—

[0552] VoH

[0553]

[0554] The title compound was obtained in analogy to Example 1 (22.5% yield, er=3:l) as a white solid using l-[(5)-amino[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]methyl]cyclopropan-l-ol and cyclobutylacetic acid. LCMS (ESI) [M + H]+: 384.05. 'H NMR (400 MHz, DMSO-6) 6 12.41 (s, 1H), 8.21 (d, J= 7.8 Hz, 1H), 7.57 (m, 2H), 7.15 (dd, J= 14.4, 8.8 Hz, 1H), 5.64 (d, J= 6.3 Hz, 1H), 4.90 (d, J= 8.4 Hz, 1H), 2.59 (p, J= 7.8 Hz, 1H), 2.34 (qd, J= 13.9, 7.6 Hz, 2H), 2.01 (td, J= 10.1, 8.3, 5.0 Hz, 2H), 1.87 -1.71 (m, 2H), 1.67 (dt, J= 16.8, 8.9 Hz, 2H), 0.81 (d, J= 9.6 Hz, 1H), 0.66 (d, J= 7.9 Hz, 3H).Example 27: 2-cyclobutyl-N-[(lS,2S)-l-[5-(2,2-difluoroethyl)-lH-benzimidazol-2-yl]-2-hydroxy-propyl] acetamide

[0555]

[0556] The title compound was obtained in analogy to Example 1 (14.5% yield) as a white solid using ( 1 S,25)- 1 -amino- 1 -[5-(2,2-difluoroethyl)- 1 H- 1,3 -benzodiazol -2 -yl]propan-2-ol and cyclobutylacetic acid. LCMS (ESI) [M + H]+: 352.15.1H NMR (400 MHz, DMSO-6) d 12.17 (s, 1H), 8.00 (d, J= 8.7 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.07 (dd, J= 8.2, 1.6 Hz, 1H), 6.22 (t, J= 4.6 Hz, 1H), 4.99 (dd, J= 8.7, 4.2 Hz, 2H), 4.19 - 4.09 (m, 1H), 3.32 - 3.17 (m, 2H), 2.68 - 2.52 (m, 1H), 2.41 (dd, J= 13.9, 7.8 Hz, 1H), 2.31 (dd, J= 13.8, 7.4 Hz, 1H), 2.07 - 1.93 (m, 2H), 1.87 - 1.61 (m, 4H), 1.03 (d, J= 6.3 Hz, 3H).

[0557] Example 28: rac-(lS,2R)-2-cyclopropyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]cyclopropanecarboxamide

[0558]

[0559] The title compound was obtained in analogy to Example 1 (array synthesis, 37.9% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and rac-(lR,2S)-[l,l'-bi(cyclopropane)]-2-carboxylic acid. LCMS (ESI) [M + H]+: 384.15. 1H NMR (300 MHz, DMSO-d6) 5 12.42 (dd, J = 20.6, 8.5 Hz, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.69 - 7.43 (m, 2H), 7.15 (s, 1H), 5.04 (dd, J = 13.0, 4.9 Hz, 2H), 4.20 -4.07 (m, 1H), 1.73 - 1.64 (m, 1H), 1.26 - 1.16 (m, 1H), 1.04 (t, J = 6.6 Hz, 3H), 0.92 -0.74 (m, 2H), 0.58 - 0.48 (m, 1H), 0.42 - 0.30 (m, 2H), 0.14 - 0.04 (m, 2H).

[0560] (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol was obtained after purification of terLbutyl ((25)-2-hydroxy-l -(5 -(trifluoromethoxy)- 1 H-benzo[]imidazol-2-yl) propyl) carbamate (30 g, 79.93 mmol) by high-pressure flash chromatography with the following condition Column: YMC-Triant perpC 18-S, 50*250 nm, 10 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 15%-45% in 30 min; Wave Length: 220 / 254 nm, to yield the undesired isomer as the first peak (RTl=26.0min) followed by the desired isomer tert-butyl N-[(1 S*,25)-2-hydroxy-l-[5-(trifluoromethoxy)-l / / -l,3-benzodiazol-2-yl] propyl] carbamate (12 g, 40% yield, RT2=28.5min) as a white solid, which was then dissolved in DCM(lOOmL) at OC prior to the addition of TFA (20 mL). The mixture was stirred for 2 hours at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase separation column [Mobile Phase A: Water (0.3% TFA), Mobile Phase B: acetonitrile; Gradient: 0% B to 70% B in 30 min] to give (1S*,25)-1-amino-l-(5-(trifluoromethoxy)-1-benzo[]imidazol-2-yl)propan-2-ol 2,2,2-trifluoroacetate (6.0g, 48.2% yield, 99.6% purity) as a white solid. LC-MS (ESI, m / z): [M+ H] +: 276.1. 1HNMR (400 MHz, DMSO-d6) 58.60 (s, 3H), 7.72 (d, J = 8.8 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.25 (ddd, J = 8.8, 2.2, 1.1 Hz, 1H), 5.77(s, 1H), 4.33(s, 1H) 4.16 (p, J = 6.4 Hz, 1H), 1.07 (d, J = 6.3 Hz, 3H).

[0561] Example 29: (2S)-2-(l-bicyclo[l.l.l]pentanyl)-N-[(lS*,2S)-2-hydroxy-l-[5- (trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]propanamide

[0562] H /

[0563] N HN-A

[0564] / > — < o

[0565] N >— OH

[0566]

[0567] 'A

[0568] The title compound was obtained in analogy to Example 1 (29.5% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and (S)-2-(bicyclo[l.l.l]pentan-l-yl)propanoic acid. LCMS (ESI) [M + H]+: 398.16. 1H NMR (300 MHz, DMSO-d6) 57.90 (dd, J = 13.9, 8.5 Hz, 1H), 7.56 (d, J = 22.0 Hz, 2H), 7.15 (d, J = 8.7 Hz, 1H), 5.17 -4.96 (m, 2H), 4.22 - 4.05 (m, 1H), 1.67 (s, 3H), 1.63 -1.51 (m, 3H), 1.10 (d, J = 6.3 Hz, 2H), 1.06 - 0.92 (m, 4H).

[0569] Example 30: 3-ethynyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] benzamide

[0570] N HN— /

[0571] / ) — \ o

[0572] N >-OH

[0573]

[0574] A

[0575] The title compound was obtained in analogy to Example 1 (29.8% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifhioromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and 3-ethynylbenzoic acid. LCMS (ESI) [M + H]+: 404.11. 1H NMR (300 MHz, DMSO-d6) 58.67 (d, J = 8.3 Hz, 1H), 8.13 (t, J = 1.7 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.73 - 7.64 (m, 1H), 7.64 - 7.50 (m, 3H), 7.22 - 7.11 (m, 1H), 5.23 (dd, J = 8.2, 5.1 Hz, 1H), 4.35 -4.25 (m, 2H), 1.13 (d, J = 6.3 Hz, 3H).Example 31: (2R)-2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] propanamide

[0576]

[0577] The title compound was obtained in analogy to Example 1 (41.1% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and (R)-2-cyclobutylpropanoic acid. LCMS (ESI) [M + H]+: 386.16. 1H NMR (300 MHz, DMSO-d6) 57.99 (t, J = 9.1 Hz, 1H), 7.56 (d, J = 24.2 Hz, 2H), 7.15 (d, J = 8.7 Hz, 1H), 5.12 - 4.99 (m, 2H), 4.13 (s, 1H), 2.34 (d, J = 8.2 Hz, 1H), 2.06 - 1.60 (m, 6H), 1.05 (dd, J = 8.5, 6.3 Hz, 3H), 0.94 (dd, J = 17.2, 6.7 Hz, 3H).

[0578] Example 32: 2-cyclopentyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] acetamide

[0579]

[0580] The title compound was obtained in analogy to Example 1 (30.2% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and 2-cyclopentylacetic acid. LCMS (ESI) [M + H]+: 386.16. 1HNMR (300 MHz, DMSO-d6) 58.05 (d, J = 8.4 Hz, 1H), 7.70 - 7.42 (m, 2H), 7.16 (d, J = 8.6 Hz, 1H), 5.04 (dd, J = 8.6, 4.2 Hz, 2H), 4.17 (d, J = 5.9 Hz, 1H), 2.35 - 2.12 (m, 3H), 1.77 - 1.43 (m, 6H), 1.24 - 1.12 (m, 2H), 1.07 (d, J = 6.3 Hz, 3H).

[0581] Example 33: 2-cyclopropyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] cyclopropanecarboxamide

[0582]

[0583] The title compound was obtained in analogy to Example 1 (30.8% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and [l,l'-bi(cyclopropane)]-2-carboxylic acid. LCMS (ESI) [M + H]+: 384.15. 1HNMR (300 MHz, DMSO-6) δ 8.35 (d, J= 8.5 Hz, 1H), 7.51 (d, J= 23.7 Hz, 2H), 7.16 (s, 1H),5.10 -4.99 (m, 2H), 4.13 (s, 1H), 1.72 - 1.65 (m, 1H), 1.05 (t, J= 6.5 Hz, 3H), 0.90 - 0.75 (m, 2H), 0.54 (s, 1H), 0.44 - 0.32 (m, 2H), 0.15 - 0.06 (m, 2H).

[0584] Example 34: 2-(l-methylcyclopropyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0585] H /

[0586] N HN^K

[0587] / ) — < o

[0588] N >-OH

[0589]

[0590] %

[0591] The title compound was obtained in analogy to Example 1 (43.1% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and 2-(l-methylcyclopropyl)acetic acid. LCMS (ESI) [M + H]+: 372.15. 1H NMR (300 MHz, DMSO-6) δ 7.96 (d, J= 8.5 Hz, 1H), 7.66 - 7.45 (m, 2H), 7.23 - 7.09 (m, 1H), 5.05 (dd, J= 8.5, 4.0 Hz, 1H), 4.19 (dd, J= 6.4, 4.1 Hz, 1H), 2.30 -2.11 (m, 2H), 1.13 -1.04 (m, 6H), 0.56 - 0.40 (m, 2H), 0.30 - 0.23 (m, 2H).

[0592] Example 35: N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] spiro [3.3] heptane-2-carboxamide

[0593] H /

[0594] N HN— k

[0595] / ) — \0

[0596] N >-OH

[0597]

[0598] %

[0599] The title compound was obtained in analogy to Example 1 (38.5% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and spiro[3.3]heptane-2-carboxylic. LCMS (ESI) [M + H]+: 398.16. 1H NMR (300 MHz, DMSO-6) δ 12.37 (s, 1H), 7.88 (d, J= 8.5 Hz, 1H), 7.67 - 7.42 (m, 2H), 7.14 (s, 1H), 5.01 (dd, J= 8.5, 4.3 Hz, 2H), 4.21 - 4.09 (m, 1H), 3.14 - 3.02 (m, 1H), 2.18 - 1.98 (m, 6H), 1.88 - 1.72 (m, 4H), 1.03 (d, J= 6.3 Hz, 3H).

[0600] Example 36: 3,3-dimethyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] cyclobutanecarboxamide

[0601] H /

[0602] N HN— \

[0603] / > — \ o

[0604] N >-OH

[0605]

[0606] %The title compound was obtained in analogy to Example 1 (38.5% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and 3,3-dimethylcyclobutane-l-carboxylic acid. LCMS (ESI) [M + H]+: 386.16. 1HNMR (300 MHz, DMSO-6) δ 12.34 (s, 1H), 7.87 (d, J= 8.5 Hz, 1H), 7.54 (d, J= 22.1 Hz, 2H), 7.14 (d, J= 8.7 Hz, 1H), 5.02 (dd, J= 8.5, 4.3 Hz, 2H), 4.15 (s, 1H), 3.19 (t, J= 8.6 Hz, 1H), 1.98 - 1.78 (m, 4H), 1.15 (s, 3H), 1.04 (t, J = 3.2 Hz, 6H).

[0607] Example 37: N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-2-[l-(trifluoromethyl)cyclopropyl]acetamide

[0608]

[0609] The title compound was obtained in analogy to Example 1 (36.3% yield) as a white solid using (lS*,2S)-l-amino-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and 2-(l-(trifluoromethyl)cyclopropyl)acetic acid. LCMS (ESI) [M + H]+: 426.12. 1H NMR (300 MHz, DMSO-6) 88.39 (d, J= 8.4 Hz, 1H), 7.64 - 7.47 (m, 2H), 7.15 (d, J= 9.1 Hz, 1H), 5.02 (dd, J = 8.4, 4.3 Hz, 1H), 4.23 - 4.12 (m, 1H), 2.80 (d, J= 14.7 Hz, 1H), 1.06 (d, J= 6.3 Hz, 3H), 0.92 (dd, J= 13.1, 7.7 Hz, 4H).

[0610] Example 38: 2-cyclobutyl-N-[(lR*,2R)-3,3,3-trifluoro-2-hydroxy-l-[5- (trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0611]

[0612] The title compound was obtained in analogy to Example 1 (15.5% yield) as a white solid using (27?,37?*)-3 -amino- 1,1,1 -trifluoro-3 -(6-(trifluoromethoxy)- U / -benzo[ ]imidazol-2-yl)propan-2-ol and cyclobutylacetic acid. LCMS (ESI): m / z = 426.05 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 12.55 (s, 1H), 8.62 (d, J= 9.0 Hz, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.54 (s, 1H), 7.19 (dd, J= 8.7, 2.4 Hz, 1H), 6.86 (s, 1H), 5.40 (t, J= 8.8 Hz, 1H), 4.46 (t, J = 7.8 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.29 - 2.16 (m, 2H), 1.95 (tdd, J= 14.8, 8.0, 4.2 Hz, 2H), 1.81 - 1.70 (m, 2H), 1.62 (dtd, J= 16.7, 8.0, 1.9 Hz, 2H).

[0613] Example 39: 2-cyclobutyl-N-[(2S)-2-hydroxy-l-[4-methyl-5-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl] acetamide

[0614]

[0615] The title compound was obtained in analogy to Example 1 (26.3% yield, a mixture of two diastereoisomers, dr = 1:2) as a white solid using (25)-l-amino-l-[4-methyl-5-(trifluorom ethoxy)- H- 1, 3 -benzodiazol-2-yl]propan-2-ol and cyclobutylacetic acid. LCMS (ESI) [M + H]+: 386.20. 'H NMR (400 MHz, DMSO-6) 6 12.40 (d, J= 65.5 Hz, 1H), 7.97 (d, J= 8.7 Hz, 1H), 7.42 (dd, J= 38.4, 8.6 Hz, 1H), 7.10 (d, J= 8.8 Hz, 1H), 5.01 (s, 2H), 4.17 (s, 1H), 2.60 (q, J= 7.5 Hz, 1H), 2.47 (d, J= 2.3 Hz, 3H), 2.43 - 2.25 (m, 2H), 2.01 (s, 2H), 1.85 - 1.63 (m, 4H), 1.06 (s, 3H).

[0616] Example 40: 2-cyclobutyl-N-[(lS*,2R)-3,3,3-trifluoro-2-hydroxy-l-[5- (trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0617]

[0618] The title compound was obtained in analogy to Example 1 (29.4% yield) as a white solid using (2R, 3 S*)-3 -amino- 1,1,1 -trifluoro-3-(6-(trifluoromethoxy)-lJ / -benzo[J]imidazol-2-yl)propan-2-ol and cyclobutylacetic acid. LCMS (ESI): m / z = 426.10 [M + H]+.JH NMR (400 MHz, DMSO-6) δ 12.57 (s, 1H), 8.28 (d, J= 9.3 Hz, 1H), 7.58 (s, 2H), 7.18 (d, J = 8.7 Hz, 1H), 6.92 (s, 1H), 5.59 (dd, J= 9.3, 2.5 Hz, 1H), 4.78 (d, J= 6.8 Hz, 1H), 2.60 (h, J= 7.6 Hz, 1H), 2.46 (d, J= 7.9 Hz, 1H), 2.35 (dd, J= 14.0, 7.2 Hz, 1H), 2.07 - 1.96 (m, 2H), 1.85 - 1.76 (m, 2H), 1.70 (dddd, J= 13.6, 10.5, 5.6, 3.2 Hz, 2H).

[0619] Example 41: 2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-methyl-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0620]

[0621] The title compound was obtained in analogy to Example 1 (29.4% yield) as a white solid using (2S)-l-amino-l-(5-methyl-6-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propan-2-ol and cyclobutylacetic acid. LCMS (ESI) [M + H]+: 386.25. 'H NMR (400 MHz, DMSO-6) δ 12.27 (s, 1H), 8.00 (d, J= 8.6 Hz, 1H), 7.47 (d, J= 9.9 Hz, 2H), 4.99 (dd, J=8.5, 4.1 Hz, 2H), 4.18 - 4.11 (m, 1H), 2.65 -2.55 (m, 1H), 2.42 (dd, J= 13.8, 7.8 Hz, 1H), 2.37 - 2.27 (m, 4H), 2.05 - 1.95 (m, 2H), 1.84 - 1.63 (m, 4H), 1.04 (d, J= 6.3 Hz, 3H).

[0622] Example 42: (2S*,3R*)-3-[(2-cyclobutylacetyl)amino]-2-methyl-3-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propanamide

[0623] H° \

[0624] N NH

[0625] Z> — \

[0626]

[0627] A '2

[0628] a) (2A,35)-4-(tert-butoxy)-2-(2-cyclobutylacetamido)-3-methyl-4-oxobutanoic acid

[0629] A solution of (2A,35)-2-amino-4-(tert-butoxy)-3-methyl-4-oxobutanoic acid (2.6 g, 12.793 mmol, 1 equiv) in DCM (20 mL) was treated with EtsN (3.88 g, 38.379 mmol, 3 equiv) at rt for 5 min under nitrogen atmosphere followed by the addition of cyclobutylacetyl chloride (2.21 g, 16.631 mmol, 1.3 equiv) dropwise at rt. The resulting mixture was stirred at rt for additional 1 h. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (2A,35)-4-(tert-butoxy)-2-(2-cyclobutylacetamido)-3-methyl-4-oxobutanoic acid (2 g, 52.22% yield) as a yellow solid. LCMS(ECI) [M + H]+: 300.

[0630] b) tert-butyl (25,3A)-3-{[2-amino-4-(trifluoromethoxy)phenyl]carbamoyl}-3-(2-cyclobutylacetamido)-2-methylpropanoate

[0631] A mixture of (2A,35)-4-(tert-butoxy)-2-(2-cyclobutylacetamido)-3-methyl-4-oxobutanoic acid (2.0 g, 6.681 mmol, 1 equiv) and 4-(trifluorom ethoxy )benzene-l,2-diamine (1.41 g, 7.349 mmol, 1.1 equiv) and HATU (2.79 g, 7.349 mmol, 1.1 equiv) and DIPEA (2.59 g, 20.043 mmol, 3 equiv) in DMF (20 mL) was stirred at rt for 30min under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (1:2) to afford tert-butyl (25,3A)-3-{[2-amino-4-(trifluoromethoxy)phenyl]carbamoyl}-3-(2-cyclobutylacetamido)-2-methylpropanoate (1 g, 31.61% yield) as a yellow solid. LCMS(ESI) [M + H]+: 474.0.c) tert-butyl 3-(2-cyclobutylacetamido)-2-methyl-3-[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]propanoate

[0632] A solution of -butyl (2,3)-3-{[2-amino-4-(trifluoromethoxy)phenyl]carbamoyl}-3-(2-cyclobutylacetamido)-2-methylpropanoate (900 mg, 1.901 mmol, 1 equiv) in HO Ac (10 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford tert-butyl 3-(2-cyclobutylacetamido)- 2-methyl-3-[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]propanoate (650 mg, 75.08% yield) as a white solid. LCMS(ESI) [M + H]+: 456.0

[0633] d) 3-(2-cyclobutylacetamido)-2-methyl-3-[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]propanoic acid

[0634] A solution of tert-butyl 3-(2-cyclobutylacetamido)-2-methyl-3-[5-(trifluoromethoxy)-3JT-l,3-benzodiazol-2-yl]propanoate (600 mg, 1.317 mmol, 1 equiv) in TFA (2 mL) and DCM (8 mL) was stirred at rt for 8 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% acid), 15% to 75% gradient in 20 min; UV 254 nm to afford 3-(2-cyclobutylacetamido)-2-methyl-3-[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]propanoic acid (350 mg, 66.53% yield) as a yellow soild. LCMS(ESI) [M + H]+: 400.0.

[0635] e) (2S*,3R*)-3-[(2-cyclobutylacetyl)amino]-2-methyl-3-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propanamide

[0636] A mixture of 3-(2-cyclobutylacetamido)-2-methyl-3-[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]propanoic acid (340 mg, 0.851 mmol, 1 equiv) and NH4CI (455.3 mg, 8.513 mmol, 10.00 equiv) and HATU (388.4 mg, 1.021 mmol, 1.2 equiv) and DIPEA (330.1 mg, 2.553 mmol, 3 equiv) in DMF (5 mL) was stirred at rt for 2 h under nitrogen atmosphere. To the above mixture was added NH3 in dioxane (8 mol / L) (3 mL) dropwise over 1 min at rt. The resulting mixture was stirred at 50 °C for additional 2 h. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% acid ), 0% to 75% gradient in 20 min, UV 254 nm to afford 3-(2-cyclobutylacetamido)-2-methyl- 3-[5-(trifluoromethoxy)-1-1,3-benzodiazol-2-yl]propanamide (195 mg, 57.49% yield) as a white solid. The crude product (195 mg) was purified by Column: Torus Diol OBD, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH(1% 2M NH3-MEOH);Flow rate: 100 mL / min; Gradient: isocratic 15% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1: 3.98min: assumed isomer A (82 mg, 42.05% yield); RT2: 4.65min: assumed isomer B (74 mg, 37.95% yield); Sample Solvent: MeOH— HPLC; Injection Volume: 1.5 mL; Number Of Runs: 5. Isomer B (74 mg) was further purified by Column: Enantiocel- A4-5, 3.0*25CM, 5um; Mobile Phase A: Hex(10 mM NHs-MeOH), Mobile Phase B: ETOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 20; Wave Length: 212 / 254 nm; Sample Solvent: MEOH; Injection Volume: 1.0 mL; Number Of Runs: 4 to afford title product (28.3 mg, 38.24% yield, RT=7.0min, first peak) and its diastereomer (24.5 mg, 33.11% yield, RT=14.2min, second peak). LCMS (ESI): [M+H]+:399.15. ‘HNMR (400 MHz, DMSO-6) 8 12.48 (d, J= 24.4 Hz, 1H), 8.14 (dd, J = 8.6, 5.6 Hz, 1H), 7.67 - 7.32 (m, 3H), 7.20 - 7.10 (m, 1H), 6.92 (s, 1H), 5.14 (ddd, J= 8.5, 7.0, 1.3 Hz, 1H), 3.11 - 3.02 (m, 1H), 2.63 - 2.55 (m, 1H), 2.34 (ddd, J= 14.1, 7.7, 2.0 Hz, 1H), 2.26 (dd, J= 14.1, 7.5 Hz, 1H), 2.01 (ddq, = 10.8, 7.8, 3.6 Hz, 2H), 1.85 - 1.74 (m, 2H), 1.73 - 1.61 (m, 2H), 1.01 (d, J= 7.1 Hz, 3H).

[0637] Example 43: N-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butanamide

[0638] F H NHO °w y— NrH F

[0639] N

[0640]

[0641] a) A-[(3,3-difluorocyclobutyl)methyl]-2-oxobutanamide

[0642] A solution of l-(3,3-difluorocyclobutyl)methanamine (2.26 g, 18.66 mmol, 1.5 equiv) and EtsN (3.78 g, 37.33 mmol, 3 equiv) in DCM (40 mL) was added 2-oxobutanoyl chloride (1.5 g, 12.44 mmol, 1 equiv) at room temperature for additional overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford A-[(3,3-difluorocyclobutyl)methyl]-2-oxobutanamide (400 mg, 15.66% yield) as a yellow solid. LC-MS (ES, m / z): [M+H]+= 206.0

[0643] b)A-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-benzodiazol-2-yl]butanamide

[0644] A solution of 2-iodo-6-(trifluoromethoxy)-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-benzodiazole (500 mg, 1.09 mmol, 1 equiv) in THF (20 mL) was added n-BuLi (209.7 mg, 3.27 mmol, 3 equiv) at -78 °C for 30 min under nitrogen atmosphere followed by the addition of A-[(3,3-difluorocyclobutyl)methyl]-2-oxobutanamide (335.8 mg, 1.63 mmol, 1.5 equiv) at -78 °C. The resulting mixture was stirred for 1 h at -78 °C under nitrogenatmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA =2: 1) to afford 7V-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-benzodiazol-2-yl]butanamide (230.0 mg, 39.21% yield) as a white solid. LC-MS (ES, m / z): [M+H]+= 538.0

[0645] c) -[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-1-benzimidazol-2-yl]butanamide

[0646] A solution of A-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-benzodiazol-2-yl]butanamide (30 mg, 0.056 mmol, 1 equiv) in TFA (0.5 mL). The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 30 min, UV 254 nm. This resulted in -[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-1-benzimidazol-2-yl]butanamide (10.2 mg, 46.95% yield) as a white solid. LC-MS (ES, m / z): [M+H]+= 408.0. H-NMR-PH-ICA-P136- T1452-0-l:1HNMR (400 MHz, DMSO-6) δ 12.49 (s, 1H), 8.29 (t, J= 6.3 Hz, 1H), 7.8-7.3 (s, 2H), 7.16 (d, J = 8.7 Hz, 1H), 6.26 (s, 1H), 3.28 (t, J= 6.1 Hz, 2H), 3.19 (dt, J= 12.9, 5.8 Hz, 2H), 2.30 (dd, J= 14.3, 8.9, 4.0 Hz, 4H), 2.08 (dq, J= 14.3, 7.3 Hz, 1H), 0.84 (t, J= 7.2 Hz, 3H). Example 44: 2-(3,3-difluorocyclobutyl)-N-[3-hydroxy-2-methyl-l-[5- (trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0647] F

[0648] H /

[0649] N HN— <( F

[0650] / >-< o

[0651]

[0652] a) (2A)-3-[(terLbutyldiphenylsilyl)oxy]-A-methoxy-7V,2-dimethylpropanamide

[0653] A solution of methyl (2A)-3-[(tert-butyldiphenylsilyl)oxy]-2-methylpropanoate (5 g, 14.024 mmol, 1 equiv) in THF (100 mL) was treated with A, O-dimethylhydroxylamine hydrochloride (4.10 g, 42.072 mmol, 3 equiv) at 0 °C for 5 min under nitrogen atmosphere followed by the addition of isopropylmagnesium chloride (2.0 M in diethyl ether) (17.53 mL, 35.060 mmol, 2.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at 0°C for additional 2 h. Desired product could be detected by LCMS. The reaction was quenched by addition of sat. aq. NH4CI (25 mL) at 0 °C. he resulting mixture wasextracted with EA (3 x 100 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, he residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford (2)-3-[(-butyldiphenylsilyl)oxy]--methoxy-,2-dimethylpropanamide (3 g, 55.48% yield) as a white solid. LCMS (ESI) [M + H]+: 386

[0654] b)(2A)-3-[(tert-butyldiphenylsilyl)oxy]-2-methyl- 1 -[5-(tri fluoromethoxy)- 1 -{ [2-(trimethylsilyl)ethoxy]methyl}-l,3-benzodiazol-2-yl]propan-l-one

[0655] A solution of 5-(trifluoromethoxy)-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-benzodiazole (1.55 g, 4.668 mmol, 1.2 equiv) in THF (10 mL) was treated with n-butyllithium (2.5 M in n-hexane) (1.87 mL, 4.668 mmol, 1.2 equiv) at -78 °C for 30 min under nitrogen atmosphere followed by the addition of (2A)-3-[(tert-butyldiphenylsilyl)oxy]-A-methoxy-A,2-dimethylpropanamide (1.5 g, 3.890 mmol, 1 equiv) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for additional 8 h. Desired product could be detected by LCMS. The reaction was quenched by addition of sat. aq. NH4CI (15 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (2)-3-[(-butyldiphenylsilyl)oxy]-2-methyl-1-[5-(trifluoromethoxy)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzodiazol-2-yl]propan-1-one (1.0 g, 39.13% yield) as a yellow liquid. LCMS (ESI) [M + H]+: 657.0

[0656] c) 2-[l-amino-3-[(tert-butyldiphenylsilyl)oxy]-2-methylpropyl]-5-(trifluoromethoxy)-l-{ [2-(trimethylsilyl)ethoxy]methyl } - 1,3 -benzodiazole

[0657] A mixture of (2)-3-[(-butyldiphenylsilyl)oxy]-2-methyl-1-[5-(trifluoromethoxy)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzodiazol-2-yl]propan-1-one (2 g, 3.045 mmol, 1 equiv), NH4CI (1.63 g, 30.450 mmol, 10 equiv) and tetrakis(propan-2-yloxy)titanium (8.65 g, 30.450 mmol, 10 equiv) in EtOH (50 mL) was stirred at room temperature for 2 days under nitrogen atmosphere. To the above mixture was added NaBH4(0.35 g, 9.135 mmol, 3 equiv) in portions over 10 min at room temperature. The resulting mixture was stirred at room temperature for additional 4 h. The reaction was quenched with sat. NH4CI (aq.) (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1%- 1 -

[0658] FA), 10% to 80% gradient in 10 min, UV 254 nm to afford crude 2-[l-amino-3-[(tert-butyldiphenylsilyl)oxy]-2-methylpropyl]-5-(trifluoromethoxy)-l-{[2-(trimethylsilyl)ethoxy]methyl}- 1,3 -benzodiazole (500 mg, crude) as a colorless liquid. LCMS (ESI) [M + H]+: 658.0

[0659] d) 2-(3,3-difluorocyclobutyl)-N-[3-[(tert-butyldiphenylsilyl)oxy]-2-methyl-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0660] A mixture of 2-[1-amino-3-[(-butyldiphenylsilyl)oxy]-2-methylpropyl]-5-(trifluoromethoxy)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzodiazole (500 mg, 0.760 mmol, 1 equiv), (3,3-difluorocyclobutyl)acetic acid (125.5 mg, 0.836 mmol, 1.1 equiv), HATU (346.7 mg, 0.912 mmol, 1.2 equiv) and DIPEA (294.7 mg, 2.280 mmol, 3 equiv) in DMF (5 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min, UV 254 nm to afford 2-(3,3-difluorocyclobutyl)-N-[3-[(tert-butyldiphenylsilyl)oxy]-2-methyl-l-[5-(trifluoromethoxy)- lH-benzimidazol-2-yl]propyl]acetamide (300 mg, 50.0% yield) as a yellow liquid. LCMS (ESI) [M + H]+: 790.0

[0661] e) 2-(3,3-difluorocyclobutyl)-N-[3-hydroxy-2-methyl-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide

[0662] A solution of 2-(3,3-difluorocyclobutyl)-N-[3-[(tert-butyldiphenylsilyl)oxy]-2-methyl-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide (100 mg, 0.127 mmol, 1 equiv) in THF (1 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. To the above mixture was added TFA (1 mL) dropwise over 1 min at room temperature. The resulting mixture was stirred at room temperature for additional 2 h. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): isocratic 20% to 35% B in 10 min; Wave Length: 254 / 220 nm; RT1 (min): 10.33 min to afford 2-(3, 3-difluorocyclobutyl)-N-[3-hydroxy-2-methyl-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide (22.4 mg, 29.32% yield) as a white solid. LCMS (ESI) [M + H]+: 422.2. 'H NMR (400 MHz, DMSO-6) 8 12.51 (dd, J = 17.5, 7.1 Hz, 1H), 8.38 (dd, J= 16.1, 8.6 Hz, 1H), 7.64 (d, J= 8.7 Hz, 0.5H), 7.58 - 7.47 (m, 1H), 7.43 (s, 0.5H), 7.14 (t, J= 10.5 Hz, 1H), 5.20 (dd, J= 8.7, 6.2 Hz, 0.5H), 5.03 (t, J= 7.9 Hz, 0.5H), 4.60 (q, J= 5.2 Hz, 1H), 3.49 - 3.40 (m, 0.5H), 3.40 - 3.33 (m, 0.5H),3.30 - 3.25 (m, 0.5H), 3.19 (dt, J= 10.8, 5.7 Hz, 0.5H), 2.72 - 2.57 (m, 2H), 2.48 - 2.13 (m, 6H), 0.83 (dd, J= 24.9, 6.8 Hz, 3H).

[0663] Example 45: 5-[(2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl] propyl]-5-azaspiro [2.4] heptan-4-one

[0664] N FT

[0665] F^ X)'

[0666]

[0667] a) 1-[2-(benzyloxy)ethyl]--[(2)-2-hydroxy-1-[5-(trifluoromethoxy)-3-1,3-benzodiazol- 2-yl]propyl]cyclopropane- 1 -carboxamide

[0668] The title compound was obtained in analogy to Example 1 (79.0% yield) as a yellow solid using (25)-l-amino-l-[5-(trifluoromethoxy)-3J / -l,3-benzodiazol-2-yl]propan-2-ol and 1-[2-(benzyloxy)ethyl]cyclopropane-l -carboxylic acid. LCMS (ESI) [M+H]+: 478.25.

[0669] b) -[(2)-2-hydroxy-1-[5-(trifluoromethoxy)-3-1,3-benzodiazol-2-yl]propyl]-1-(2-hydroxyethyl)cyclopropane-1-carboxamide

[0670] A mixture of 1 -[2-(benzyloxy)ethyl]-A-[(25)-2-hydroxy-l -[5-(trifluoromethoxy)-37 / - l,3-benzodiazol-2-yl]propyl]cyclopropane-l -carboxamide (330 mg, 0.691 mmol, 1 equiv) and Pd / C (147.1 mg, 0.138 mmol, 0.2 equiv, 10%) in MeOH (5 mL) was stirred at 25 °C for 24 hours under hydrogen atmosphere. Then the resulting mixture was filtered, the filtrate was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% acid), 45% to 50% gradient in 15 min, UV 254 nm to afford -[(2)-2-hydroxy-1-[5-(trifluoromethoxy)-3-1,3-benzodiazol-2-yl]propyl]-1-(2-hydroxyethyl)cyclopropane-1-carboxamide (200 mg, 74.71% yield) as a colorless oil. LCMS (ESI) [M+H]+: 388.15.

[0671] c) 2-(1-{[(2)-2-hydroxy-1-[5-(trifluoromethoxy)-3-1,3-benzodiazol-2-yl]propyl]carbamoyl}cyclopropyl)ethyl 4-methylbenzenesulfonate

[0672] A solution of -[(2)-2-hydroxy-1-[5-(trifluoromethoxy)-3-1,3-benzodiazol-2-yl]propyl]-1-(2-hydroxyethyl)cyclopropane-1-carboxamide (200 mg, 0.517 mmol, 1 equiv) in DCM (10 mL) was treated with TsCl (108.27 mg, 0.568 mmol, 1.1 equiv) and EtsN (62.70 mg, 0.62 mmol, 1.2 equiv) at 0 °C. And the mixture was stirred for 2 hours at 25 °C. The reaction was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4and concentrated under vacuum to give 2-(l-{[(25)-2-hydroxy-l-[5-(trifhioromethoxy)-3J7-l,3-benzodiazol-2-yl]propyl]carbamoyl}cyclopropyl)ethyl 4-methylbenzenesulfonate (250 mg, crude) which was used without further purification. LCMS (ESI) [M+H]+: 542.25.

[0673] d) 5-[(2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-5-azaspiro[2.4]heptan-4-one

[0674] A solution of 2-(1-{[(2)-2-hydroxy-1-[5-(trifluoromethoxy)-3-1,3-benzodiazol-2-yl]propyl]carbamoyl}cyclopropyl)ethyl 4-methylbenzenesulfonate (240 mg, 0.443 mmol, 1 equiv) in THF (10 mL) was treated with NaH (70.9 mg, 1.772 mmol, 4 equiv, 60%) at 0 °C. After that, the reaction was stirred for half an hour at 25 °C. The reaction was quenched with saturated NEUCl and extracted with EA (3 x 30 mL). The organic layer was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): isocratic 25% to 38% B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 12.22 min) to afford 5-[(2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-5-azaspiro[2.4]heptan-4-one (40.7 mg, 24.86% yield) as a white solid. LCMS (ESI) [M+H]+: 370.10. 'H NMR (400 MHz, DMSO-6) δ 12.79 (d, J= 14.1 Hz, 1H), 7.75 - 7.38 (m, 2H), 7.17 (dd, = 9.3, 5.6 Hz, 1H), 5.14 (d, J= 5.5 Hz, 1H), 5.10 (d, J= 8.0 Hz, 1H), 4.56 - 4.29 (m, 1H), 3.82 -3.69 (m, 1H), 3.73 - 3.57 (m, 1H), 2.19 - 1.90 (m, 2H), 1.03 (d, J= 6.2 Hz, 3H), 0.94 -0.74 (m, 3H), 0.75 - 0.63 (m, 1H).

[0675] Example 46: 2-(3,3-difluorocyclobutyl)-N-[(lS*,2S)-l-[6-(3-fluorophenyl)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide

[0676] F F

[0677] H° \

[0678] N NH N OH

[0679]

[0680] a) -[(1*,2)-1-(5-bromo-3-1,3-benzodiazol-2-yl)-2-hydroxypropyl]-2-(3,3-difluorocyclobutyl) acetamide

[0681] The title compound was obtained in analogy to Example 1 (34.5% yield) as a white solid using (1*,2)-1-amino-1-(5-bromo-3-1,3-benzodiazol-2-yl) propan-2-ol and (3,3-difluorocyclobutyl) acetic acid. MS (ESIpos): m / z = 402.00 [M+H]+

[0682] b) 2-(3,3-difluorocyclobutyl)--[(1*,2)-1-[6-(3-fluorophenyl)-1-benzimidazol-2-yl]-2-hydroxy-propyl]acetamideA solution of -[(1*,2)-1-(5-bromo-3-1,3-benzodiazol-2-yl)-2-hydroxypropyl]-2-(3,3-difluorocyclobutyl) acetamide (170 mg, 0.423 mmol, 1 equiv), 3-fluorophenylboronic acid (71.5 mg, 0.511 mmol, 1.21 equiv), Pd(dppf)C12 (61.8 mg, 0.084 mmol, 0.20 equiv) and K2CO3 (146.0 mg, 1.056 mmol, 2.50 equiv) in dioxane (4 mL) and water (1 mL) was stirred at 80 °C for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 18% B to 32% B in 20 min; Wave Length: 254nm / 220 nm; RTl(min): 8.82min) to afford 2-(3,3-difluorocyclobutyl)-A-[(15*,25)-l-[5-(3-fluorophenyl)-3H-l,3-benzodiazol-2-yl]-2-hydroxypropyl] acetamide (80.2 mg, 45.46%yield) as a white solid. MS (ESIpos): m / z = 418.10 [M+H]+.

[0683] 1H NMR (400 MHz, DMSO-6) d 12.27 (s, 1H), 8.23 (d, J= 8.4 Hz, 1H), 7.92 - 7.35 (m, 6H), 7.15 (t, J= 8.2 Hz, 1H), 5.08 - 5.00 (m, 2H), 4.18 (d, J= 6.4 Hz, 1H), 2.74 - 2.58 (m, 2H), 2.59 - 2.52 (m, 1H), 2.49 - 2.26 (m, 4H), 1.06 (d, J= 6.3 Hz, 3H).

[0684] Example 47: methyl 2-[2-[(lS*,2S)-l-[[2-(3,3-difluorocyclobutyl)acetyl]amino]-2-hydroxy-propyl]-6-methoxy-lH-benzimidazol-4-yl]acetate

[0685]

[0686] The title compound was obtained in analogy to Example 1 (22.4% yield) as a white solid using methyl 2-(2-((2S)-l-amino-2-hydroxypropyl)-6-methoxy-lH-benzo[d]imidazol-4-yl)acetate and (3, 3 -difluorocyclobutyl) acetic acid. LCMS(ESI) [M + H]+: 462.00.JH NMR (400 MHz, DMSO-6) d 12.04 (d, J= 38.1 Hz, 1H), 8.15 (t, J= 8.8 Hz, 1H), 6.93 (dd, J= 51.5, 2.3 Hz, 1H), 6.68 (dd, J= 8.0, 2.4 Hz, 1H), 5.11 - 4.85 (m, 2H), 4.17 - 4.06 (m, 1H), 3.92 (s, 2H), 3.75 (d, J= 5.3 Hz, 3H), 3.61 (d, J= 10.4 Hz, 3H), 2.63 (d, J= 11.8 Hz, 2H), 2.49 - 2.21 (m, 5H), 1.03 (t, J= 6.9 Hz, 3H).

[0687] Example 48: Biological experiments

[0688] a) The potency of exemplary compounds of formula (I) was determined using thallium fluorescence.Cell Culture

[0689] Flip-IN Hek293-Trex or Hek293 Trex cells stably expressing TMEM175 under a tetracycline inducible CMV promoter were used for these studies. Cells were maintained in DMEM-HG supplemented with heat inactivated 10% FBS (Gemini), 2mM sodium pyruvate, 10mM Hepes, 50ug / ml Hygromycin and 5ug / ml Blasticidin at 37°C in 5% CO₂. All cells were induced with 0.2ug / ml or 2ug / ml Doxycycline 18-24 hour prior to thallium assay.

[0690] Assay solution and compound preparation

[0691] The assay solution consisted of (in mM): 132 Na-Gluconate, 10 K-Gluconate, 1.8 Ca-Gluconate, 0.8 Mg-Gluconate, 10 HEPES, pH 7.4. Test agents were dissolved in DMSO to give 10 mM stocks. 10-point dose response curves were constructed using the Labcyte Echo 550 acoustic dispenser to generate final test concentrations of 30, 15, 7.5, 3.75, 1.88, 0.94, 0.47, 0.23, 0.12, 0.06 uM.

[0692] Assay Protocol

[0693] All thallium fluorescence studies were performed using the Molecular Devices FLIPR TETRA™ fluorescence platform. Plates seeded with Hek-293FlipIN Trex cells expressing TMEM175 channels were loaded with 10 µl of a thallium sensitive AM-ester fluorescent dye made up in IX Hank’s buffer + 20mM HEPES. The dye loading buffer contained an extracellular fluorescence quenching agent allowing the dye to remain in the plate throughout the assay. Cells were incubated with dye for 45-60 minutes at room temperature, protected from light.

[0694] After the dye loading incubation time, cell plates and assay plates were loaded into the FLIPR TETRA instrument. The FLIPR program measured a 20 second baseline, after which the embedded 384-well pipetting head added lOul of 2X test agent or controls made up in chloride free assay buffer containing ImM thallium sulfate. Changes in fluorescence (measured at 490nm excitation and 520nm emission) were measured for a 3-minute period.

[0695] Data Analysis

[0696] Percent activation was calculated from changes in fluorescent response using the following equation:

[0697] % activation = ((RFU test agent - RFU buffer) / (RFU positive control - RFU buffer))* 100EC50 values were calculated using IDBS ActivityBase software using a 4-parameter logistic fit. Fit criteria were defined as follows: Fit minimum values were allowed to float between -10% to 5%, Fit maximum values were allowed to float between 40% and 120%. The data are reported in Table 1 (first column).

[0698] b) The potency of exemplary compounds of formula (I) was determined using the SyncroPatch 384 (Nani on) high throughput electrophysiology platform.

[0699] Cell Culture

[0700] Flip-IN Hek293-Trex or Hek293 Trex cells stably expressing TMEM175 under a tetracycline inducible CMV promoter were used for these studies. Cells were maintained in DMEM-HG supplemented with heat inactivated 10% FBS (Gemini), 2mM sodium pyruvate, 10mM Hepes, 50ug / ml Hygromycin and 5ug / ml Blasticidin at 37°C in 5% CO₂. Cells were cultured in T-225 flasks (Nunc) for 3-4 days to reach 85-95% confluence prior to electrophysiological recording and cells were seeded in PDL coated plates 24hours prior to testing. All cells were induced with 0.2ug / ml or 2ug / ml Doxycycline 18-24hour prior to electrophysiological recording or fluorescent assays, respectively.

[0701] Solutions

[0702] Solutions were of the following composition:

[0703] Extracellular recording solution (in mM): 105 NaCl, 40 NMDG, 4 KCl, 5 CaCl₂, 1 MgCl₂, 10 HEPES, pH 7.4. Seal enhancer solution (in mM): 90 NaCl, 3 KCl, 35 CaCl₂, 10 MgCl₂, 10 HEPES, pH 7.4. Intracellular recording solution (in mM): 150 CsF, 1 Mg-ATP, 10 EGTA, 10 HEPES, 5 MgCl₂, 0.01 Escin, pH 7.2.

[0704] Cell Preparation

[0705] Cells were harvested for electrophysiological recording upon reaching appropriate confluence. Cells were first washed in DPBS (Hyclone, Cat #SH30028.03) and then 2 ml of Accutase (MP Biomedicals #1000449) was added at 28°C until -90% of cells were suspended. F12 HAM’s media + 1 mM L-glutamine (Hyclone, SH30026.02) was then added to the flask to dilute the accutase. Cells were then triturated until a single cell suspension was achieved, a cell count was performed, and cells were centrifuged for 2 min. at 1,000 rpm. Media was then aspirated, and cells were resuspended in Earle’s balanced salt solution to a concentration of 0.75 X 106 cells / ml and allowed to recover for 25 min at 10°C.

[0706] SyncroPatch RecordingAt the beginning of each assay, 20 µl of cell suspension was dispensed into each well of a multi-hole 384-well SyncroPatch chip by the onboard pipettor. Cell sealing was initiated, and seal enhancer solution was added to facilitate seal formation. Upon completion of sealing, cells were washed 3 times with extracellular recording solution and the assay voltage protocol was started. Human TMEM175 channels were evaluated using a voltage protocol where cells were voltage-clamped at a holding potential of 0 mV. Ionic currents were evoked every 5 sec with a 200 msec voltage ramp from -100 mV to 60 mV, followed by series of 100 msec voltage steps to -80, 0 mv and +40 mV. The current amplitude at the 100 msec 0 mV step was used to for analysis. Baseline current was assessed for 4 minutes prior to the addition of test compound for 2.5 min. This was followed by addition of the positive control, 10 µM DCPIB for an additional 2.5 min. The experiment was completed with addition of 2 mM 4-AP to fully block the channel.

[0707] Data Analysis

[0708] Data were collected on the SyncroPatch platform using PatchControl software (Nanion) and processed and analyzed using DataControl Software (Nanion). The average leak-subtracted current was determined for control, test compound and DCPIB conditions by subtracting the remaining current following block by 4-AP. Percent activation of test compound was determined from the leak-corrected current using the following equation:

[0709] % Activation = ((Test compoundCorr -ControlCorr) / (DCPIBCorr - ControlCorr))*100

[0710] The % activation data were then plotted as a function of compound concentration and fit will a Hill equation to derive EC50. The data are reported in Table 1 (second column).

[0711] TMEM175 TMEM175

[0712] Example FLIPR EC50 EP EC50

[0713] (uM) (uM)

[0714] 1 8.49 4.07

[0715] 2 0.83 0.44

[0716] 3 1.66 0.58

[0717] 4 2.23 1.06

[0718] 5 18.25 3.05

[0719] 6 2.66 1.90

[0720] 7 9.14 4.27

[0721] 8 4.59 2.76

[0722] 9 0.61 1.30

[0723] 10 4.35 2.49

[0724] 11 2.69 5.77

[0725]

[0726] 4.79 1.98 3.83 2.85 0.53 0.21 1.51 0.36 4.98 3.10 2.82 0.94 1.29 0.34 1.70 0.50 3.33 0.59 2.35 1.49 3.39 4.76 1.77 0.31 2.62 0.89 4.04 1.71 1.92 0.91 4.55 1.37 3.06 1.42 3.66 2.17 4.24 2.83 3.43 4.20 1.56 17.60 3.23 1.77 1.80 2.16 0.86 0.62 1.22 6.16 1.10 1.11 4.13 3.37 3.15 0.56 1.22 0.25 0.80 1.98 17.52 4.37 1.19 0.23 19.87 4.06 6.91 3.67 8.94 4.32 14.95 4.56

[0727]

[0728] Table 1Example A

[0729] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0730] Ingredients Per tablet

[0731] Kernel:

[0732] Compound of formula (I) 10.0 mg 200.0 mg

[0733] Microcrystalline cellulose 23.5 mg 43.5 mg

[0734] Lactose hydrous 60.0 mg 70.0 mg

[0735] Povidone K30 12.5 mg 15.0 mg

[0736] Sodium starch glycolate 12.5 mg 17.0 mg

[0737] Magnesium stearate 1.5 mg 4.5 mg

[0738] (Kernel Weight) 120.0 mg 350.0 mg

[0739] Film Coat:

[0740] Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg

[0741] Polyethylene glycol 6000 0.8 mg 1.6 mg

[0742] Talc 1.3 mg 2.6 mg

[0743] Iron oxide (yellow) 0.8 mg 1.6 mg

[0744] Titan dioxide 0.8 mg 1.6 mg

[0745]

[0746] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.

[0747] Example BCapsules containing the following ingredients can be manufactured in a conventional manner:

[0748] Ingredients Per capsule

[0749] Compound of formula (I) 25.0 mg

[0750] Lactose 150.0 mg

[0751] Maize starch 20.0 mg

[0752] Talc 5.0 mg

[0753]

[0754] The components are sieved and mixed and filled into capsules of size 2.

[0755] Example C

[0756] Injection solutions can have the following composition:

[0757] Compound of formula (I) 3.0 mg

[0758] Polyethylene glycol 400 150.0 mg

[0759] Acetic acid q.s. ad pH 5.0

[0760] Water for injection solutions ad 1.0 ml

[0761]

[0762] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims

Claims1. A compound of formula (I)whereinA is nitrogen or -CH-;one of R1and R2is hydrogen, haloalkoxy, haloalkyl, haloalkylsulfanyl, halophenyl or alkoxy and the other one is hydrogen, halogen or alkyl;one of R3and R4is hydrogen and the other one is hydrogen, haloalkyl, halogen, alkyl or alkoxycarbonylalkyl;R5is hydroxyalkyl, hydroxycycloalkyl, halohydroxyalkyl or aminocarbonylalkyl;R6is hydrogen; andR7is cycloalkylalkyl, halocycloalkylalkyl, haloalkylcycloalkyl, haloalkyl, cycloalkylcycloalkyl, cycloalkyl, alkynylphenyl, alkylcycloalkyl or haloalkylcycloalkylalkyl;or R6and R7, together with the carbonyl and nitrogen atom to which they are attached, form azaspiro[2.4]heptan-4-one and R5is as defined above;or R5and R6, together with the carbon and nitrogen atoms to which they are attached, form hydroxypyrrolidinyl and R7is as defined above;or a pharmaceutically acceptable salt thereof;provided that2-chloro-N-[2-hydroxy-l-(6-methyl-lH-benzimidazol-2-yl)ethyl]-acetamide;2-chloro-N-[l-(5,7-difluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;N-[2-hydroxy-l-(6-methyl-lH-benzimidazol-2-yl)propyl]-2-methyl-cyclopropanecarboxamide;2-chloro-N-[l-(5-fluoro-7-methyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;2-chloro-N-[l-(6-chloro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[2-hydroxy-l-(6-methoxy-5-methyl-lH-benzimidazol-2-yl)ethyl]-acetamide;N-[l-(7-fluoro-lH-benzimidazol-2-yl)-2-hydroxypropyl]-2-methyl-cyclopropanecarboxamide;2-chloro-N-[l-(5,7-dimethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; N-[2-hydroxy-l-(7-methyl-lH-benzimidazol-2-yl)propyl]-2-methyl-cyclopropanecarboxamide;2-chloro-N-[l-(7-chloro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[l-(6,7-dimethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[l-(6-fluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[l-(6-fluoro-7-methyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;N-[l-(6-fluoro-lH-benzimidazol-2-yl)-2-hydroxypropyl]-2-methyl-cyclopropanecarboxamide;2-chloro-N-[l-(6-ethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[l-(7-fluoro-5-methyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;2-chloro-N-[2-hydroxy-l-[6-(l-methylethyl)-lH-benzimidazol-2-yl]ethyl]-acetamide;2-chloro-N-[2-hydroxy-l-(7-methoxy-lH-benzimidazol-2-yl)ethyl]-acetamide; 2-chloro-N-[l-(6,7-difluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[2-hydroxy-l-(6-methoxy-lH-benzimidazol-2-yl)ethyl]-acetamide;2-chloro-N-[l-(7-fluoro-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide;2-chloro-N-[l-(4,7-dimethyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]-acetamide; 2-chloro-N-[2-hydroxy-l-(7-methyl-lH-benzimidazol-2-yl)ethyl]-acetamide; and 2-chloro-N-[l-(6-fluoro-5-methyl-lH-benzimidazol-2-yl)-2-hydroxyethyl]- acetamide;are excluded.

2. A compound according to claim 1, wherein A is nitrogen.

3. A compound according to claim 1 or 2, wherein one of R1and R2is haloalkoxy and the other one is hydrogen or halogen, in particular hydrogen.

4. A compound according to any one of claims 1 to 3, wherein one of R1and R2is trifluoromethoxy and the other one is hydrogen or fluoro, in particular hydrogen.

5. A compound according to any one of claims 1 to 4, wherein one of R3and R4is hydrogen and the other one is hydrogen or halogen.

6. A compound according to any one of claims 1 to 5, wherein one of R3and R4is hydrogen and the other one is hydrogen or fluorine.

7. A compound according to any one of claims 1 to 6, wherein R3and R4are both hydrogen at the same time.

8. A compound according to any one of claims 1 to 7, wherein R5is hydroxyalkyl, hydroxy cycloalkyl or halohydroxyalkyl.

9. A compound according to any one of claims 1 to 8, wherein R5is hydroxyethyl, hydroxypropyl, hydroxy cyclopropyl or (trifluoro)(hydroxy)ethyl.

10. A compound according to any one of claims 1 to 9, wherein R5is hydroxyethyl.

11. A compound according to any one of claims 1 to 10, wherein R7is cycloalkylalkyl, halocycloalkylalkyl, haloalkyl, cycloalkyl or haloalkylcycloalkylalkyl.

12. A compound according to any one of claims 1 to 11, wherein R7is cyclobutylmethyl, difluorocyclobutymethyl, trifluoropentyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, spiro[3.3]heptanyl ortri fluoromethylcyclopropylmethyl.

13. A compound according to any one of claims 1 to 12, wherein R7is difluorocyclobutymethyl or 3-fluorobicyclo[l.l.l]pentan-l-yl.

14. A compound according to any one of claims 1 to 13 selected from2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2- yl]propyl]acetamide;2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2- yl]propyl]acetamide;2-(3,3-difluorocyclobutyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-N-[(lS,2S)-l-[5-(difluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy- propy 1 ] acetami de;2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[7-(trifluoromethyl)-lH-benzimidazol-2- yl]propyl]acetamide;2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethyl)-lH-benzimidazol-2- yl]propyl]acetamide;2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethyl)-lH-benzimidazol-2- yl]propyl]acetamide;2-cyclobutyl-N-[(lR*,2S)- l-[6-fluoro-5-(tri fluoromethoxy)- lH-benzimidazol-2-yl]- 2-hydroxy-propyl]acetamide;2-cyclobutyl-N-[(lS*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;trans-(lR*,2R*)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifhroromethoxy)-lH-benzimidazol- 2-yl]propyl]-2-(trifluoromethyl)cyclopropanecarboxamide;2-(3,3-difhrorocyclopentyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifhroromethoxy)-lH- benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-l-[(2S,3R)-3-hydroxy-2-[6-(trifluoromethoxy)-lH-benzimidazol-2- yl]pyrrolidin- 1 -yl]ethenone;4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2- yl] propyl ]butanami de;2-cyclobutyl-N-[(lS*,2S)-l-[4-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;2-cyclobutyl-N-[(lS*,2R)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-indol-2-yl]propyl]acetamide;3-fluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-3-methyl-butanamide;4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-3,3-dimethyl-butanamide;2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide;2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]butyl]acetamide;2-(l-fluorocyclobutyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(2,2,2-trifluoroethyl)-lH-benzimidazol-2-yl]propyl]acetamide;2-(3 -fluorobicyclof 1.1.1 ]pentan- 1 -yl)-N-((l S *,2S)-2-hydroxy- 1 -(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propyl)acetamide;2-(3-fluorocyclobutyl)-N-((lS*,2S)-2-hydroxy-l-(5-(trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propyl)acetamide;N-[(lS*,2S)-l-[5-(difluoromethylsulfanyl)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]-2-(l-fluorocyclobutyl)acetamide;(S)-2-cyclobutyl-N-[(l-hydroxycyclopropyl)-[6-(trifluoromethoxy)-lH-b enzimi dazol -2-y 1 ] methyl ] acetami de;2-cyclobutyl-N-[(lS,2S)-l-[5-(2,2-difluoroethyl)-lH-benzimidazol-2-yl]-2-hydroxy-propy 1 ] acetami de;rac-(lS,2R)-2-cyclopropyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]cyclopropanecarboxamide;(2S)-2-(l-bicyclo[l.l.l]pentanyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)- 1 H-b enzimi dazol -2-y 1 ] propyl ] propenami de;3-ethynyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]benzamide;(2R)-2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]propenamide;2-cyclopentyl-N-[(lS*,2S)-2-hydroxy-l-[5-(tri fluoromethoxy)- lH-benzimidazol-2-yl]propyl]acetamide;2-cyclopropyl-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]cyclopropanecarboxamide;2-(l-methylcyclopropyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]spiro[3.3]heptane-2-carboxamide;3,3-dimethyl-N-[(l S*,2S)-2-hy droxy-l-[5-(tri fluoromethoxy)- lH-benzimidazol-2-yl] propyl ] cy cl obutanecarb oxami de;N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-2-[l-(trifluoromethyl)cyclopropyl]acetamide;2-cyclobutyl-N-[(lR*,2R)-3,3,3-trifluoro-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-N-[(2S)-2-hydroxy-l-[4-methyl-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-N-[(lS*,2R)-3,3,3-trifluoro-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-methyl-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;(2S*,3R*)-3-[(2-cyclobutylacetyl)amino]-2-methyl-3-[5-(trifluoromethoxy)-lH- benzimidazol-2-yl]propenamide;N-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-lH- benzimidazol-2-yl]butanamide;2-(3,3-difluorocy cl obutyl)-N-[3-hydroxy-2-methyl-l-[5-(tri fluoromethoxy)- 1H- benzimidazol-2-yl]propyl]acetamide;5-[(2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-5- azaspiro[2.4]heptan-4-one;2-(3,3-difluorocyclobutyl)-N-[(lS*,2S)-l-[6-(3-fluorophenyl)-lH-benzimidazol-2- yl]-2-hydroxy-propyl]acetamide; andmethyl 2-[2-[(lS*,2S)-l-[[2-(3,3-difluorocyclobutyl)acetyl]amino]-2-hydroxy- propyl]-6-methoxy-lH-benzimidazol-4-yl]acetate;or a pharmaceutically acceptable salt thereof.

14. A compound according to any one of claims 1 to 13 selected from2-cyclobutyl-N-[(lR*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2- yl]propyl]acetamide;2-(3,3-difluorocyclobutyl)-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]acetamide;2-cyclobutyl-N-[(lS*,2S)-l-[6-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;2-cyclobutyl-N-[(lS*,2S)-l-[4-fluoro-5-(trifluoromethoxy)-lH-benzimidazol-2-yl]-2-hydroxy-propyl]acetamide;2-cyclobutyl-N-[(lS*,2R)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2- yl]propyl]acetamide;4,4,4-trifluoro-N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2- yl]propyl]-3,3-dimethyl-butanamide;2-cyclobutyl-N-[(lS*,2S)-2-hydroxy-l-[6-(trifluoromethoxy)-lH-benzimidazol-2- yl]butyl]acetamide;2-(3 -fluorobicyclof 1.1.1 ]pentan- 1 -yl)-N-((l S *,2S)-2-hydroxy- 1 -(5- (trifluoromethoxy)-lH-benzo[d]imidazol-2-yl)propyl)acetamide;(S)-2-cyclobutyl-N-[(l-hydroxycyclopropyl)-[6-(trifluoromethoxy)-lH- b enzimi dazol -2-y 1 ] methyl ] acetami de;N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2- yl]propyl]spiro[3.3]heptane-2-carboxamide;N-[(lS*,2S)-2-hydroxy-l-[5-(trifluoromethoxy)-lH-benzimidazol-2-yl]propyl]-2-[l- (trifluoromethyl)cyclopropyl]acetamide;2-cyclobutyl-N-[(lS*,2R)-3, 3, 3-tri fluoro-2-hydroxy-l-[5-(tri fluoromethoxy)- 1H- b enzimi dazol -2-y 1 ] propyl ] acetami de; andN-[(3,3-difluorocyclobutyl)methyl]-2-hydroxy-2-[6-(trifluoromethoxy)-lH- benzimidazol-2-yl]butanamide;or a pharmaceutically acceptable salt thereof.

15. A process for the preparation of a compound according to any one of claims 1 to 14 comprising comprising one of the following steps:(a) the reaction of a compound of formula (A)in the presence of R7COOH, a carboxylic acid activating agent and a base;(b) the reaction of a compound of formula (B)in the presence of R7COOH, a carboxylic acid activating agent and a base; or(c) the reaction of a compound of formula (C)in the presence of a base;wherein A and R1to R5are as defined in any one of claims 1 to 12 and X is a leaving group.

16. A compound according to any one of claims 1 to 14, when manufactured according to a process of claim 15.

17. A compound according to any one of claims 1 to 14 for use as therapeutically active substance.

18. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 14 and a therapeutically inert carrier.

19. The use of a compound according to any one of claims 1 to 14 for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders.

20. The use of a compound according to any one of claims 1 to 14 for the preparation of a medicament for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders.

21. A compound according to any one of claims 1 to 14 for use in the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders.

22. A method for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders, which method comprisesadministering an effective amount of a compound as defined in any one of claims 1 to 14 to a patient in need thereof.

23. The invention as hereinbefore described.***

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