Modulators of integrated stress response pathway

Abstract

To provide a new class of compounds as modulators of the integrated stress response pathway, which may be effective in the treatment of integrated stress response pathway related diseases and which may show improved pharmaceutically relevant properties including activity, solubility, selectivity, ADMET properties and / or reduced side effects.SOLUTION: The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, and pharmaceutical compositions comprising the compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound of formula (I) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 2a , R 3 , R a2 , R a4、 R a5 , R a6 , R a7 , X 1 , X 1a , A 1 and A 2 has the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicaments and their use in methods for treating and preventing one or more diseases or disorders associated with the integrated stress response. [Background technology]

[0002] The integrated stress response (ISR) is a cellular stress response common to all eukaryotes. (1) Dysregulation of ISR signaling has important pathological consequences, leading to inflammation, viral infections, diabetes, cancer, and neurodegenerative diseases, among others.

[0003] The ISR is a common factor in different types of cellular stress that results in the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) on serine 51, leading to the repression of normal protein synthesis and the expression of stress-response genes (2). In mammalian cells, this phosphorylation is carried out by a family of four eIF2alpha kinases, each of which responds to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2alpha kinase (HRI), and general control non-derepressible 2 (GCN2) (3).

[0004] eIF2 alpha, together with eIF2 beta and eIF2 gamma, forms the eIF2 complex, a key player in the initiation of normal mRNA translation (4). The eIF2 complex mediates the initiation of mRNA translation by catalyzing GTP and Met-tRNA. i to form the ternary complex (eIF2-GTP-Met-tRNA) that is recruited by the ribosome for translation initiation. i ) to form (5, 6).

[0005] eIF2B is a heterodecameric complex consisting of five subunits (alpha, beta, gamma, delta, and epsilon) that, in duplicate, form a GEF-active decamer ( 7 ).

[0006] In response to ISR activation, phosphorylated eIF2alpha inhibits eIF2B-mediated exchange of GDP for GTP, resulting in reduced ternary complex formation and, therefore, inhibition of translation of normal mRNAs characterized by ribosome binding to the 5' AUG start codon (8). Under these conditions of reduced ternary complex abundance, translation of several specific mRNAs, including the mRNA encoding the transcription factor ATF4, is inhibited by the translation of the upstream ORF (uORF). These mRNAs are activated through a mechanism involving alteration (7, 9, 10). These mRNAs typically contain one or more uORFs that normally function in non-stressed cells to restrict ribosome flow to the main coding ORF. For example, under normal conditions, uORFs in the 5'UTR of ATF occupy ribosomes and prevent translation of the ATF4 coding sequence. However, under stress conditions, i.e., under conditions of reduced ternary complex formation, the probability that ribosomes will scan past these upstream ORFs and initiate translation at the ATF4 coding ORF is increased. ATF4 and other stress response factors expressed in this manner subsequently direct the expression of an array of additional stress response genes. The acute phase consists in the expression of proteins aimed at restoring homeostasis, whereas the chronic phase leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

[0007] Upregulation of markers of ISR signaling has been demonstrated in a variety of conditions, including cancer and neurodegenerative diseases. In cancer, ER stress-regulated translation increases resistance to hypoxic conditions and promotes tumor growth (14, 15, 16), and genetic deletion of PERK results in the transformation of PERK. - / - It has been shown to slow the growth of tumors derived from mouse embryonic fibroblasts (14, 17). Furthermore, a recent report provided proof of concept that activators of eIF2B are effective in treating aggressive metastatic forms of prostate cancer using patient-derived xenograft modeling in mice (28). Taken together, prevention of cytoprotective ISR signaling may represent an effective antiproliferative strategy for the treatment of at least some forms of cancer.

[0008] Furthermore, modulation of ISR signaling has proven effective in preserving synaptic function and reducing neuronal loss, as well as in neurodegenerative diseases characterized by activation of the misfolded and unfolded protein response (UPR), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jakob-Creutzfeldt disease (prion disease) (18, 19, 20). There are examples of neurodegenerative diseases, such as prion disease, where pharmacological as well as genetic inhibition of ISR signaling has been shown to normalize protein translation levels, rescue synaptic function, and prevent neuronal loss (21). Specifically, reducing the level of phosphorylated eIF2α by overexpressing a phosphatase that controls phosphorylated eIF2α increased the survival time of prion-infected mice, whereas sustained eIF2α phosphorylation decreased survival (22).

[0009] Furthermore, direct evidence for the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic diseases affecting the function of eIF2 and eIF2B. Mutations in eIF2gamma, which disrupt the integrity of the eIF2 complex and therefore result in a reduction of normal protein expression levels, lead to intellectual disability syndrome (ID) (23). Partial loss of function mutations in the eIF2B subunit have been shown to be responsible for the rare leukodystrophy vanishing white matter disease (VWMD) (24, 25). Specifically, stabilization of partial loss of function eIF2B in a VWMD mouse model with a small molecule related to ISRIB has been shown to reduce ISR markers and improve functional as well as pathological endpoints (26, 27).

[0010] Modulators of the eIF2 alpha pathway are described in U.S. Patent No. 6,266,239. U.S. Patent No. 6,266,239, U.S. Patent No. 6,266,239, U.S. Patent No. 6,266,239, and U.S. Patent No. 6,266,239 describe modulators of the integrated stress pathway. U.S. Patent No. 6,266,239, ... and U.S. Patent No. 6,266,239 describe inhibitors of the ATF4 pathway. U.S. Patent No. 6,266,239 and U.S. Patent No. 6,266,239 relate to eukaryotic in

[0011] Further documents describing modulators of the integrated stress pathway include US Pat. No. 5,629,999, ... Patent documents include Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 18, Patent Document 19, Patent Document 20, and Patent Document 21. Modulators of eukaryotic initiation factors are described in Patent Document 22. Patent Document 23 describes inhibitors of the integrated stress response pathway. Heteroaryl derivatives as ATF4 inhibitors are described in Patent Document 24. Bicyclic aromatic ring derivatives as ATF4 inhibitors are described in Patent Document 25.

[0012] However, there is a continuing need for new compounds useful as modulators of the integrated stress response pathway that have good pharmacokinetic properties. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] WO2014 / 144952A2 [Patent Document 2] WO2017 / 193030A1 [Patent Document 3] WO2017 / 193034A1 [Patent Document 4] WO2017 / 193041A1 [Patent Document 5] WO2017 / 193063A1 [Patent Document 6] WO2017 / 212423A1 [Patent Document 7] WO2017 / 212425A1 [Patent Document 8] WO2018 / 225093A1 [Patent Document 9] WO2019 / 008506A1 [Patent Document 10] WO2019 / 008507A1 [Patent Document 11] WO2019 / 032743A1 [Patent Document 12] WO2019 / 046779A1 [Patent Document 13] WO2019 / 090069A1 [Patent Document 14] WO2019 / 090074A1 [Patent Document 15] WO2019 / 090076A1 [Patent Document 16] WO2019 / 090078A1 [Patent Document 17] WO2019 / 090081A1 [Patent Document 18] WO2019 / 090082A1 [Patent Document 19] WO2019 / 090085A1 [Patent Document 20] WO2019 / 090088A1 [Patent Document 21] WO2019 / 090090A1 [Patent Document 22] WO2019 / 183589A1 [Patent Document 23] WO2019 / 118785A2 [Patent Document 24] WO2019 / 193540A1 [Patent Document 25] WO2019 / 193541A1 Summary of the Invention [Problem to be solved by the invention]

[0014] It is therefore an object of the present invention to provide a new class of compounds as modulators of the integrated stress response pathway that may be effective in treating integrated stress response pathway-associated diseases and that may have improved pharmaceutically relevant properties, including activity, solubility, selectivity, ADMET properties and / or reduced side effects. [Means for solving the problem]

[0015] Thus, the present invention provides a compound of formula (I) for use as a medicine. [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein X 1 is N(R a1 ) and; X 1a is a covalent single bond, CH(R a3 ) or CH(R a3 )CH2; R a1 is H,C(O)OC 1-4 Alkyl or C 1~4 alkyl, where C(O)OC 1-4 Alkyl and C 1~4 Alkyl is a halogen, OH and OC 1~3 optionally substituted with one or more substituents selected from the group consisting of alkyl, wherein the substituents are the same or different; R a2 , R a3 is H;OH;OC 1-4 Alkyl;Halogen;C 1~4 alkyl; and A 2a independently selected from the group consisting of: R a4 , R a5 , R a6 , R a7 H; halogen; C 1~4 alkyl; and A 2a are independently selected from the group consisting of However, Ra2 , R a3 , R a4 , R a5 , R a6 , R a7 Only one of them is A 2a Is it; or R a1 and R a2 and R a3 one of which forms a methylene or ethylene group; or R a1 and R a6 does it form an ethylene group; or R a2 and R a5 forms a covalent single bond; or R a5 , R a7 are connected to form an oxo group; A 1 is a C5 cycloalkylene, a C5 cycloalkenylene, or a 5-membered heterocyclene containing a nitrogen ring atom, where A 1 is one or more R 4 optionally substituted with; Each R 4 are independently selected from the group consisting of oxo (=O) in which the ring is at least partially saturated, thioxo (=S) in which the ring is at least partially saturated, halogen, CN, OR 5 , or C 1~6 alkyl, where C 1~6 alkyl is optionally substituted with one or more halogens which may be the same or different; R 5 is H or C 1~6 alkyl, where C 1~6 alkyl is optionally substituted with one or more halogens which may be the same or different; A 2 is R 6a or A 2a and; R 6a is OR 6a1 , S.R. 6a1 , N(R 6a1 R 6a2 );C1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is halogen; CN; OR 6a3 ; and A 2a optionally substituted with one or more substituents selected from the group consisting of: R 6a1 , R 6a2 is H;C 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 alkynyl; and A 2a wherein C is independently selected from the group consisting of 1~6 Alkyl; C 2~6 alkenyl; and C 2~6 Alkynyl is halogen; CN; OR 6a3 ;OA 2a and A 2a optionally substituted with one or more substituents selected from the group consisting of: R 6a3 is H; or C 1~4 alkyl, where C 1~4 Alkyl is the same or different, optionally substituted with one or more halogens; A 2a is phenyl; C 3~7 Cycloalkyl; C 4~12 bicycloalkyl; or 3- to 7-membered heterocyclyl, where A 2a is one or more R 6 optionally substituted with; Each R 6 are independent, R 6b ;OH;OR 6b halogen; or CN, where R 6b is cyclopropyl, C 1~6 Alkyl; C 2~6 Alkenyl; or C2~6 alkynyl, where R 6b is optionally substituted with one or more halogens which may be the same or different; or The Two R's 6 are connected, along with the atoms to which they are attached, to the ring A 2b Forming; A 2b is phenyl; C 3~7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A 2b is one or more R 7 optionally substituted with; Each R 7 independently, C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; R 1 is H or C 1~4 alkyl, preferably H, where C 1~4 alkyl is optionally substituted with one or more halogens which may be the same or different; R 2 is H;F; or C 1~4 alkyl, where C 1~4 alkyl is optionally substituted with one or more halogens which may be the same or different; R 3 is A 3 , C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 8 optionally substituted with; or R 2and R 3 are connected to form ring A together with the oxygen atom and the carbon atom to which they are attached. 3a where A 3a is a 7- to 12-membered heterobicyclyl, wherein the 7- to 12-membered heterobicyclyl is selected from the group consisting of one or more R 10 optionally substituted with; R 2a is H or F, preferably H; Each R 8 are independently halogen; CN, C(O)OR 9 , OR 9 , C(O)R 9 , C(O)N(R 9 R 9a ), S(O)2N(R 9 R 9a ), S(O)N(R 9 R 9a ), S(O)2R 9 , S(O)R 9 , N(R 9 )S(O)2N(R 9a R 9b ), SR 9 , N(R 9 R 9a ), NO2, OC(O)R 9 , N(R 9 )C(O)R 9a , N(R 9 )SO2R 9a , N(R 9 )S(O)R 9a , N(R 9 )C(O)N(R 9a R 9b ), N(R 9 )C(O)OR 9a , OC(O)N(R 9 R 9a ), or A 3 and; R 9 , R 9a , R 9b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl may be substituted with one or more halogens, which may be the same or different, or one OH, or one OC. 1-4 Alkyl, or one A 3 optionally substituted with; Each A 3 are independently phenyl, naphthyl, C 3~7 cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, wherein A 3 is one or more R 10 optionally substituted with; Each R 10 are independently halogen, CN, C(O)OR 11 , OR 11 , C(O)R 11 , C(O)N(R 11 R 11a ), S(O)2N(R 11 R 11a ), S(O)N(R 11 R 11a ), S(O)2R 11 , S(O)R 11 , N(R 11 )S(O)2N(R 11a R 11b ), SR 11 , N(R 11 R 11a ), NO2, OC(O)R 11 , N(R 11 )C(O)R 11a , N(R 11 )S(O)2R 11a , N(R 11 )S(O)R 11a , N(R 11 )C(O)OR 11a , N(R 11 )C(O)N(R 11a R 11b ), OC(O)N(R 11 R 11a ), oxo (=O) where the ring is at least partially saturated, C 1~6 Alkyl, C 2~6 Alkenyl or C2~6 Alkynyl, wherein C1 ~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 12 optionally substituted with; R 11 , R 11a , R 11b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; Each R 12 are independently halogen, CN, C(O)OR 13 , OR 13 , C(O)R 13 , C(O)N(R 13 R 13a ), S(O)2N(R 13 R 13a ), S(O)N(R 13 R 13a ), S(O)2R 13 , S(O)R 13 , N(R 13 )S(O)2N(R 13a R 13b ), SR 13 , N(R 13 R 13a ), NO2, OC(O)R 13 , N(R 13 )C(O)R 13a , N(R 13 )SO2R 13a , N(R 13 )S(O)R 13a , N(R 13 )C(O)N(R 13a R 13b ), N(R 13 )C(O)OR 13a , or OC(O)N(R 13 R 13a ) and; R 13 , R 13a , R 13b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is optionally substituted with one or more halogens which may be the same or different.

[0016] Compounds not limited to pharmaceutical use as defined above with the priority as defined below, and pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, are also within the scope of the present invention, excluding the following compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof: [ka] [ka]

[0017] The removed compounds represent commercially available compounds with no indication of use.

[0018] The present invention also provides preferred compounds of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein: X 1 is N(R a1 ) and; X 1a is a covalent single bond, CH(R a3 ), or CH(R a3 )CH2; R a1 is H,C(O)OC 1-4 Alkyl or C 1~4 alkyl, where C(O)OC 1-4 Alkyl and C 1~4Alkyl is a halogen, OH, and OC 1~3 optionally substituted with one or more substituents selected from the group consisting of alkyl, wherein the substituents are the same or different; R a2 , R a3 is H;OH;OC 1-4 Alkyl;Halogen;C 1~4 alkyl; and A 2a independently selected from the group consisting of: R a4 , R a5 , R a6 , R a7 H; halogen; C 1~4 alkyl; and A 2a are independently selected from the group consisting of However, R a2 , R a3 , R a4 , R a5 , R a6 , R a7 Only one of them is A 2a Is it; or R a1 and R a2 and R a3 one of which forms a methylene or ethylene group; or R a1 and R a6 does it form an ethylene group; or R a2 and R a5 forms a covalent single bond; or R a5 , R a7 are connected to form an oxo group; A 1 is a C5 cycloalkylene, a C5 cycloalkenylene, or a 5-membered heterocyclene containing a nitrogen ring atom, where A 1 is one or more R 4 optionally substituted with; Each R 4are independently selected from the group consisting of oxo (=O) in which the ring is at least partially saturated, thioxo (=S) in which the ring is at least partially saturated, halogen, CN, OR 5 , or C 1~6 alkyl, where C 1~6 alkyl is optionally substituted with one or more halogens which may be the same or different; R 5 is H or C 1~6 alkyl, where C 1~6 alkyl is optionally substituted with one or more halogens which may be the same or different; A 2 is R 6a or A 2a and; R 6a is OR 6a1 , S.R. 6a1 , N(R 6a1 R 6a2 );C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is halogen; CN; OR 6a3 ; and A 2a optionally substituted with one or more substituents selected from the group consisting of: R 6a1 , R 6a2 is H;C 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 alkynyl; and A 2a wherein C is independently selected from the group consisting of 1~6 Alkyl; C 2~6 alkenyl; and C 2~6 Alkynyl is halogen; CN; OR 6a3 ; and A 2a optionally substituted with one or more substituents selected from the group consisting of: R 6a3is H; or C 1~4 alkyl, where C 1~4 alkyl is optionally substituted with one or more halogens which may be the same or different; A 2a is phenyl; C 3~7 Cycloalkyl; C 4~12 bicycloalkyl; or 3- to 7-membered heterocyclyl, where A 2a is one or more R 6 optionally substituted with; Each R 6 are independent, R 6b ;OH;OR 6b halogen; or CN, where R 6b is cyclopropyl, C 1~6 Alkyl; C 2~6 Alkenyl; or C 2~6 alkynyl, where R 6b is optionally substituted with one or more halogens which may be the same or different; or The Two R's 6 are connected, along with the atoms to which they are attached, to the ring A 2b Forming; A 2b is phenyl; C 3~7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A 2b is one or more R 7 optionally substituted with; Each R 7 independently, C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; R 1 is H or C 1~4 alkyl, preferably H, where C 1~4alkyl is optionally substituted with one or more halogens which may be the same or different; R 2 is H;F; or C 1~4 alkyl, where C 1~4 alkyl is optionally substituted with one or more halogens which may be the same or different; R 3 is A 3 , C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is the same or one or more different R 8 optionally substituted with; or R 2 and R 3 are connected to form ring A together with the oxygen atom and the carbon atom to which they are attached. 3a where A 3a is a 7- to 12-membered heterobicyclyl, wherein the 7- to 12-membered heterobicyclyl is selected from the group consisting of one or more R 10 optionally substituted with; R 2a is H or F, preferably H; Each R 8 are independently halogen; CN, C(O)OR 9 , OR 9 , C(O)R 9 , C(O)N(R 9 R 9a ), S(O)2N(R 9 R 9a ), S(O)N(R 9 R 9a ), S(O)2R 9 , S(O)R 9 , N(R 9 )S(O)2N(R 9a R 9b ), SR 9 , N(R 9 R9a ), NO2, OC(O)R 9 , N(R 9 )C(O)R 9a , N(R 9 )SO2R 9a , N(R 9 )S(O)R 9a , N(R 9 )C(O)N(R 9a R 9b ), N(R 9 )C(O)OR 9a , OC(O)N(R 9 R 9a ), or A 3 and; R 9 , R 9a , R 9b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl may contain one or more halogen atoms, which may be the same or different, or one OH, or one OC. 1~4 Alkyl, or one A 3 optionally substituted with; Each A 3 are independently phenyl, naphthyl, C 3~7 cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, wherein A 3 is one or more R 10 optionally substituted with; Each R 10 are independently halogen, CN, C(O)OR 11 , OR 11 , C(O)R 11 , C(O)N(R 11 R 11a ), S(O)2N(R 11 R 11a ), S(O)N(R 11 R 11a ), S(O)2R 11 , S(O)R 11, N(R 11 )S(O)2N(R 11a R 11b ), SR 11 , N(R 11 R 11a ), NO2, OC(O)R 11 , N(R 11 )C(O)R 11a , N(R 11 )S(O)2R 11a , N(R 11 )S(O)R 11a , N(R 11 )C(O)OR 11a , N(R 11 )C(O)N(R 11a R 11b ), OC(O)N(R 11 R 11a ), oxo (=O) where the ring is at least partially saturated, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 12 optionally substituted with; R 11 , R 11a , R 11b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; Each R 12 are independently halogen, CN, C(O)OR 13 , OR 13 , C(O)R 13 , C(O)N(R 13 R 13a ), S(O)2N(R 13 R 13a ), S(O)N(R 13 R13a ), S(O)2R 13 , S(O)R 13 , N(R 13 )S(O)2N(R 13a R 13b ), SR 13 , N(R 13 R 13a ), NO2, OC(O)R 13 , N(R 13 )C(O)R 13a , N(R 13 )SO2R 13a , N(R 13 )S(O)R 13a , N(R 13 )C(O)N(R 13a R 13b ), N(R 13 )C(O)OR 13a , or OC(O)N(R 13 R 13a ) and; R 13 , R 13a , R 13b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is also provided as being optionally substituted with one or more halogens which may be the same or different.

[0019] The present invention also provides preferred compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein X 1a is CH(R a3 ) and R a7 and R 2a is H, and therefore, the formula (I-1) [ka] wherein X 1 is N(R a1 ) and; R a1is H or C 1~4 alkyl, where C 1~4 Alkyl is a halogen, OH and OC 1~3 alkyl, wherein the substituents are the same or different, and preferably R a1 is H; R a2 , R a3 , R a4 , R a5 , R a6 Is H; or R a1 and R a2 and R a3 one of which forms a methylene or ethylene group; or R a1 and R a6 forms an ethylene group; A 1 is a C5 cycloalkylene, a C5 cycloalkenylene, or a 5-membered heterocyclene containing a nitrogen ring atom, where A 1 is one or more R 4 optionally substituted with; Each R 4 are independently halogen, CN, OR 5 , oxo (=O) in which the ring is at least partially saturated, or C 1~6 alkyl, where C 1~6 alkyl is optionally substituted with one or more halogens which may be the same or different; R 5 is H or C 1~6 alkyl, where C 1~6 alkyl is optionally substituted with one or more halogens which may be the same or different; A 2 is phenyl or a 5- to 6-membered aromatic heterocyclyl, where A 2 is one or more R 6 optionally substituted with; Each R 6 are independently OH, O(C1~6 Alkyl), halogen, CN, cyclopropyl, C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where cyclopropyl, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; or The Two R's 6 are connected, along with the atoms to which they are attached, to the ring A 2b Forming; A 2b is phenyl; C 3~7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A 2b is one or more R 7 optionally substituted with; Each R 7 independently, C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; R 1 is H or C 1~4 alkyl, preferably H, where C 1~4 alkyl is optionally substituted with one or more halogens which may be the same or different; R 2 is H or C 1~4 alkyl, where C 1~4 alkyl is optionally substituted with one or more halogens which may be the same or different; R 3 is A 3 , C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 8 optionally substituted with; or R 2 and R 3 are connected to form a 7- to 12-membered heterobicyclyl, wherein the 7- to 12-membered heterobicyclyl is one or more R 10 optionally substituted with; Each R 8 are independently halogen; CN, C(O)OR 9 , OR 9 , C(O)R 9 , C(O)N(R 9 R 9a ), S(O)2N(R 9 R 9a ), S(O)N(R 9 R 9a ), S(O)2R 9 , S(O)R 9 , N(R 9 )S(O)2N(R 9a R 9b ), SR 9 , N(R 9 R 9a ), NO2, OC(O)R 9 , N(R 9 )C(O)R 9a , N(R 9 )SO2R 9a , N(R 9 )S(O)R 9a , N(R 9 )C(O)N(R 9a R 9b ), N(R 9 )C(O)OR 9a , OC(O)N(R 9 R 9a ), or A 3 and; R 9 , R 9a , R 9b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; Each A 3 are independently phenyl, naphthyl, C 3~7 cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, wherein A 3 is one or more R 10 optionally substituted with; Each R 10 are independently halogen, CN, C(O)OR 11 , OR 11 , C(O)R 11 , C(O)N(R 11 R 11a ), S(O)2N(R 11 R 11a ), S(O)N(R 11 R 11a ), S(O)2R 11 , S(O)R 11 , N(R 11 )S(O)2N(R 11a R 11b ), SR 11 , N(R 11 R 11a ), NO2, OC(O)R 11 , N(R 11 )C(O)R 11a , N(R 11 )S(O)2R 11a , N(R 11 )S(O)R 11a , N(R 11 )C(O)OR 11a , N(R 11 )C(O)N(R 11a R 11b ), OC(O)N(R 11 R 11a ), oxo (=O) where the ring is at least partially saturated, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl, where C1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 12 optionally substituted with; R 11 , R 11a , R 11b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl is optionally substituted with one or more halogens which may be the same or different; Each R 12 are independently halogen, CN, C(O)OR 13 , OR 13 , C(O)R 13 , C(O)N(R 13 R 13a ), S(O)2N(R 13 R 13a ), S(O)N(R 13 R 13a ), S(O)2R 13 , S(O)R 13 , N(R 13 )S(O)2N(R 13a R 13b ), SR 13 , N(R 13 R 13a ), NO2, OC(O)R 13 , N(R 13 )C(O)R 13a , N(R 13 )SO2R 13a , N(R 13 )S(O)R 13a , N(R 13 )C(O)N(R 13a R 13b ), N(R 13 )C(O)OR 13a , or OC(O)N(R 13 R 13a ) and; R 13 , R 13a , R13b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is also provided as being optionally substituted with one or more halogens which may be the same or different. DETAILED DESCRIPTION OF THE INVENTION

[0020] Surprisingly, the disclosed example compounds according to the present invention possess favorable physicochemical properties and / or selectivity that, in combination, help achieve beneficial therapeutic efficacy while limiting unintended reactivity.

[0021] A variable or substituent can be selected from a group of different variants, and when such a variable or substituent occurs more than once, each variant can be the same or different.

[0022] Within the meaning of the present invention, the terms are used as follows:

[0023] The term "optionally substituted" means unsubstituted or substituted. Generally, but not limited to, "one or more substituents" means 1, 2 or 3, preferably 1 or 2 substituents, more preferably 1 substituent. Generally, these substituents may be the same or different. The term "one or more substituents" also means, for example, 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4, for example.

[0024] "Alkyl" means a straight or branched hydrocarbon chain. Each hydrogen of an alkyl carbon can be replaced by a substituent as further specified.

[0025] "Alkenyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon can be replaced by a substituent as further specified.

[0026] "Alkynyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon can be replaced by a substituent as further specified.

[0027] "C 1~4 "Alkyl" means, for example, an alkyl chain having 1 to 4 carbon atoms at the end of the molecule, if present: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, when two parts of the molecule are connected by an alkyl group, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C 1~4 Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified. 1~3 The term "alkyl" is defined accordingly.

[0028] "C 1~6 "Alkyl" refers to, for example, an alkyl chain having 1 to 6 carbon atoms at the end of the molecule, if present: C 1~4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or when two parts of the molecule are connected by an alkyl group, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C 1~6 Each hydrogen of an alkyl carbon can be replaced by a substituent as further specified.

[0029] "C 2~6"Alkenyl" means, for example, an alkenyl chain having 2 to 6 carbon atoms, if present, at the end of the molecule: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or, if two parts of the molecule are linked by an alkenyl group, for example, -CH=CH-. 2~6 Each hydrogen of an alkenyl carbon can be replaced by a substituent as further specified.

[0030] "C 2~6 "Alkynyl" means, for example, an alkynyl chain having 2 to 6 carbon atoms at the end of the molecule, if present: -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, CH2-C≡C-CH3, or, if two parts of the molecule are linked by an alkynyl group, for example, -C≡C-. 2~6 Each hydrogen of an alkynyl carbon can be replaced by a substituent as further specified.

[0031] "C 3~7 cycloalkyl" or "C 3~7 A cycloalkyl ring is a ring consisting of 3 to 7 carbon atoms. "C" refers to a cyclic alkyl chain having atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen of a cycloalkyl carbon can be replaced by a substituent as further specified herein. 3~5 cycloalkyl" or "C 3~5 The term "cycloalkyl ring" is defined accordingly.

[0032] "C5 cycloalkylene" refers to a divalent cycloalkyl having 5 carbon atoms, i.e., a divalent cyclopentyl ring.

[0033] "C5 cycloalkenylene" refers to a divalent cycloalkenylene, i.e., a divalent cyclopentene or cyclopentadiene.

[0034] "C 4~12 bicycloalkyl" or "C 4~12 "Bicycloalkyl ring" means a bicyclic fused, bridged, or spiro alkyl chain having from 4 to 12 carbon atoms, e.g., hexahydroindane, octahydropentalene, bicyclic [2.2.1]heptane, or spiro(3.2)hexane. Each hydrogen of a bicycloalkyl carbon can be replaced by a substituent as further specified herein.

[0035] "Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

[0036] A "3- to 7-membered heterocyclyl" or "3- to 7-membered heterocycle" means a ring having 3, 4, 5, 6, or 7 ring atoms, which may contain up to a maximum number of double bonds (aromatic or non-aromatic ring that is fully, partially, or unsaturated), wherein at least one ring atom and up to four ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is connected to the remainder of the molecule through a carbon or nitrogen atom. Examples for 3- to 7-membered heterocycles are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolidine, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term "5- to 6-membered heterocyclyl" or "5- to 6-membered heterocycle" is defined accordingly and includes a 5- to 6-membered aromatic heterocyclyl or heterocycle. The term "5-membered heterocyclyl" or "5-membered heterocycle" is defined accordingly and includes a 5-membered aromatic heterocyclyl or heterocycle.

[0037] The term "nitrogen ring atom-containing five-membered heterocyclene" refers to a divalent five-membered heterocycle in which at least one of the five ring atoms is a nitrogen atom and the ring is connected to the remainder of the molecule through a carbon or nitrogen atom.

[0038] A "saturated 4- to 7-membered heterocyclyl" or "saturated 4- to 7-membered heterocycle" means a fully saturated "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocycle".

[0039] A "4- to 7-membered at least partially saturated heterocyclyl" or "4- to 7-membered at least partially saturated heterocycle" means a "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocycle" that is at least partially saturated.

[0040] "5- to 6-membered aromatic heterocyclyl" or "5- to 6-membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene, in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0041] "5-membered aromatic heterocyclyl" or "5-membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl, in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, and tetrazole.

[0042] A "7- to 12-membered heterobicyclyl" or "7- to 12-membered heterobicycle" means a two-ring heterocyclic system having 7 to 12 ring atoms, wherein at least one ring atom is shared by both rings and the system can contain up to a maximum number of double bonds (aromatic or non-aromatic rings that are fully, partially, or unsaturated), and wherein at least one ring atom and up to six ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the remainder of the molecule via a carbon or nitrogen atom. Examples for 7- to 12-membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 7- to 12-membered heterobicycle also includes two-ring spiro structures such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl, or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8-diazabicyclo[3.2.1]octane.

[0043] A "saturated 7- to 12-membered heterobicyclyl" or "saturated 7- to 12-membered heterobicycle" means a fully saturated "7- to 12-membered heterobicyclyl" or "7- to 12-membered heterobicycle".

[0044] A "7- to 12-membered at least partially saturated heterobicyclyl" or "7- to 12-membered at least partially saturated heterobicycle" means a "7- to 12-membered heterobicyclyl" or "7- to 12-membered heterobicycle" that is at least partially saturated.

[0045] A "9- to 11-membered aromatic heterobicyclyl" or "9- to 11-membered aromatic heterobicycle" means a two-ring heterocyclic system, wherein at least one ring is aromatic, the heterocyclic ring system having 9 to 11 ring atoms, wherein two ring atoms are shared by both rings and the system can contain up to a maximum number of double bonds (fully or partially aromatic), wherein at least one ring atom and up to six ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and wherein the ring is linked to the remainder of the molecule via a carbon or nitrogen atom. Examples of 9- to 11-membered aromatic heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The terms "9- to 10-membered aromatic heterobicyclyl" or "9- to 10-membered aromatic heterobicycle" are defined accordingly.

[0046] Preferred compounds of formula (I) are those in which one or more of the residues contained therein have the meanings given above or below, and all combinations of preferred substituent definitions are subject of the present invention. With respect to all preferred compounds of formula (I), the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, as well as their pharmaceutically acceptable salts.

[0047] In preferred embodiments of the invention, the substituents described below independently have the following meanings: Therefore, one or more of these substituents can have the preferred or more preferred meanings given below.

[0048] Preferably, X 1 NH or NC 1~4 alkyl, where C 1~4 Alkyl is a halogen, OH, and OC 1~3 alkyl, wherein the substituents are the same or different; more preferably, X 1 is NH, N(CH3), N(CH2CH3) or N(CH2CH2OCH3); more preferably NH or N(CH3); even more preferably NH.

[0049] Preferably, X 1a is CH(R a3 ) or CH(R a3 )CH2, more preferably CH(R a3 )

[0050] Preferably, R a2 , R a3 is H;OH;OC 1~4 Alkyl;Halogen;C 1~4 alkyl; and A 2a independently selected from the group consisting of: R a4 , R a5 , R a6 , R a7 H; halogen; C 1~4 alkyl; and A 2a independently selected from the group consisting of: a2 , R a3 , R a4 , R a5 , R a6 , R a7 Only one of them is A 2a Is it; or R a5 , R a7are connected to form an oxo group.

[0051] Preferably, R a2 , R a3 , R a4 , R a5 , R a6 , R a7 H; halogen; C 1~4 alkyl; and A 2a independently selected from the group consisting of: a2 , R a3 , R a4 , R a5 , R a6 , R a7 Only one of them is A 2a More preferably, R a2 , R a3 , R a4 , R a5 , R a6 , R a7 is H or R a2 , R a3 , R a4 , R a6 is H and R a5 , R a7 are connected to form an oxo group. More preferably, R a2 , R a3 , R a4 , R a5 , R a6 , R a7 is H.

[0052] Preferably, A 1 is a nitrogen ring atom-containing five-membered heterocyclene, and A 1 is one or more R 4 is optionally replaced by

[0053] More preferably, A 1 is a nitrogen ring atom-containing 5-membered heterocyclene selected from the group of divalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole and triazole, preferably oxadiazole; A 1 is one or more R4 is optionally replaced by

[0054] Preferably, A 1 is unsubstituted or contains one or two R 4 and preferably A 1 is non-substituted.

[0055] Preferably, R 4 are independently selected from oxo (=O), halogen, CN, OR, and aryl, each of which is at least partially saturated. 5 , or C 1~6 alkyl, where C 1~6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0056] Preferably, R 4 is an oxo in which the ring is at least partially saturated.

[0057] Preferably, A 1 teeth, [ka] and more preferably, A 1 teeth, [ka] is.

[0058] In one embodiment, A 2 is R 6a is.

[0059] Preferably, R 6a is OR 6a1 is.

[0060] In one embodiment, R 6a1 , R 6a2 is H;C 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 alkynyl; and A 2aand independently selected from the group consisting of: C 1~6 Alkyl; C 2~6 alkenyl; and C 2~6 Alkynyl is halogen; CN; OR 6a3 ; and A 2a and optionally substituted with one or more substituents selected from the group consisting of:

[0061] R 6a1 is preferably A 2a , or one or more halogens and / or one A 2a and / or one OR 6a3 optionally substituted with C 1~6 More preferably, R 6a1 is one or more F and / or one OR 6a3 optionally substituted with C 1~6 It is alkyl.

[0062] Preferably, R 6a contains one or more halogens and / or one A 2a and / or one OR 6a3 optionally substituted with C 1~6 More preferably, R 6a is one or more halogens and / or one OR 6a3 optionally substituted with C 1~6 It is alkyl.

[0063] In one preferred embodiment, R 6a1 is the unsubstituted C 4~6 alkyl; more preferably 3-methylbut-1-yl or n-butyl. In another preferred embodiment, R 6a1 is C substituted with one or more halogens, preferably one or more fluoros, which may be the same or different; 2~6 alkyl; more preferably, R 6a1is 3,3,3-trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, 4,4,4-trifluorobut-2-yl, 2,2,3,3,3-pentafluoropropyl, 3,3-difluorobutyl or 3,3,3-trifluorobutyl. 6a1 is A 2a , CH2A 2a , CH2CH2A 2a where A 2a is unsubstituted or substituted with one or more halogens, which may be the same or different, preferably one or more fluoro; more preferably, R 6a1 is cyclobutyl, cyclopentyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2CH2-cyclopropyl, where R 6a1 is substituted with one or more F's.

[0064] In a particularly preferred embodiment, A 2 is R 6a and R 6a is OR 6a1 and R 6a1 is CH2CH2CF3 or CH2CH2OCF3, preferably CH2CH2OCF3.

[0065] Preferably, R 6a2 is H.

[0066] Preferably, R 6a is O.C. 1~4 Alkyl;OC 1~4 Alkyl-OC 1~4 alkyl, where each C 1~4 Alkyl is one to three F; or OCH2A 2a is optionally replaced by

[0067] In another embodiment, A 2 is A 2a is.

[0068] Preferably, A 2a is phenyl; C3~7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A 2a is one or more R 6 is optionally replaced by

[0069] Preferably, A 2a is phenyl; cyclobutyl; azetidinyl; pyrrolidinyl; or a 5- to 6-membered aromatic heterocyclyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, or 1,2,4-oxadiazolyl, where A 2a is one or more R 6 More preferably, A 2a is phenyl or a 5- to 6-membered aromatic heterocyclyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl or 1,2,4-oxadiazolyl, So, A 2a is one or more R 6 is optionally replaced by

[0070] More preferably, A 2a is phenyl; cyclobutyl; pyridyl; azetidinyl; pyrazolyl; or pyrrolidinyl, where A 2a is one or more R 6 is optionally replaced by

[0071] Preferably, A 2a is C 3~7 cycloalkyl, more preferably cyclobutyl, where A 2a is one or more R 6 is optionally replaced by

[0072] Preferably, A 2a is one or two R's that may be the same or different 6 is replaced by .

[0073] Preferably, R6 are independently F, Cl, CF, OCH, OCF, OCHF, CH, CHCH, CHCF, O-cyclopropyl or cyclopropyl. More preferably, R 6 are independently F, Cl, CF3, OCH3, OCF3, CH3, CH2CH3 or cyclopropyl, preferably F, Cl, CF3, OCH3, CH3, CH2CH3 or cyclopropyl.

[0074] Preferably, R 2 is CH3; F; or H, more preferably H.

[0075] Preferably, R 9 , R 9a , R 9b is H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl may be substituted with one or more halogens, which may be the same or different, or one OH, or one OC. 1~4 Alkyl, or one A 3 is optionally replaced by

[0076] Preferably, R 3 is A 3 is.

[0077] Preferably, A 3 is phenyl, pyridyl, pyrazinyl, pyrimidazyl, cyclopropyl, cyclobutyl or cyclohexyl, where A 3 is one or more R 10 More preferably, A 3 is phenyl, where A 3 is one or more R 10 is optionally replaced by

[0078] Preferably, A 3 are the same or different, one, two or three, preferably one or two (more preferably two) R 10 is replaced by .

[0079] Preferably, R 2 and R 3 are joined together with the oxygen and the carbon atom to which they are attached to form a dihydrobenzopyran ring, wherein the ring is joined together with one or more R 10 and preferably the ring is optionally substituted with one or two R 10 is replaced by .

[0080] Preferably, R 10 are independently F, Cl, Br, CN, CHF2, CF3, OCH3, OCF3, CH=O, CH2OH or CH3; preferably F, Cl, Br, CF3, OCF3, CH=O, CH2OH or CH3; more preferably F, Cl, CF3, CH=O, CH2OH or CH3. More preferably, R 10 are independently F or Cl.

[0081] Preferably, R a1 is H or C 1~4 alkyl, where C 1~4 Alkyl are halogens, OH and OC 1~3 alkyl, wherein the substituents are the same or different; preferably, R a1 is H; CH or CHCH; more preferably, R a1 is H.

[0082] Compounds of formula (I) in which some or all of the radicals mentioned above have the preferred or more preferred meanings are also a subject of the present invention.

[0083] Preferred specific compounds of the present invention are tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-[(1s,3s)-3-(trifluoromethoxy)cyclobutoxy]acetamide tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(3,4-Dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-[4-chloro-3-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-methylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(3,4-Dimethylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-{[6-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-{[ (Oromethyl)pyridin-3-yl]oxy}acetamide 2-[3-Methoxy-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-2-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3-chloro-4-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4-Dichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-2,3-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3,5-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-Fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-2,2-difluoro-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4,5-trichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-Bromophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-cyanophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,5R)-5-[5-(4 -chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-2-oxo-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide tert-Butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-(2-methoxyethyl)piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-[5-(5-chloro-1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4-Dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(difluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[( 4,4,4-trifluorobutan-2-yl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclopropyl)methoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-(5-butoxy-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3,3-difluorocyclopentyl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropylethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methylbutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclobutyl)methoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorocyclobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2,2,3,3,3-pentafluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(difluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(pentyloxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methoxypropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2 -Ethoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclobutoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(4,4-difluoropentyl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(3,4-Dichlorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-[5-(2-cyclopropoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-(3,4-dichlorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{[2-(trifluoromethyl)cyclopropyl]methoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-methyl-3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{methyl[2-(trifluoromethoxy)ethyl]amino}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxyazetidin-1-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-1-methyl-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1R)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1S)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1r,3r)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (2R)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide (2S)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide and 2-[3-Fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazo {2-yl}piperidin-3-yl}acetamide is selected from the group consisting of:

[0084] Where tautomerism, such as keto-enol tautomerism, of the compounds of formula (I) may occur, the individual forms, such as keto and enol forms, are included both separately and together as mixtures in any ratio. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, conformers, etc.

[0085] In particular, when enantiomeric or diastereomeric forms are shown in a compound according to formula (I), each pure form separately and any mixture of at least two of the pure forms in any ratio are encompassed by formula (I) and are subject of the present invention.

[0086] Preferred compounds are of formula (Ia) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0087] Isotopically labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotopic labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S. Solvates and hydrates of compounds of formula (I) are also within the scope of the present invention.

[0088] If desired, isomers can be separated by methods well known in the art, for example, by liquid chromatography. The same applies to enantiomers, for example, by using a chiral stationary phase. Additionally, enantiomers can be isolated by converting them into diastereomers, i.e., coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers, and cleavage of the auxiliary residue. Alternatively, any enantiomer of the compound of formula (I) can be obtained from stereoselective synthesis using optically pure starting materials, reagents, and / or catalysts.

[0089] In cases where compounds according to formula (I) contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically usable salts. Thus, compounds of formula (I) containing acidic groups can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. Compounds of formula (I) containing one or more basic groups, i.e., groups that can be protonated, can exist and be used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, gypsum acid, hydroxybenzoic ... Examples of suitable salts include propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compound of formula (I) contains both acidic and basic groups in the molecule, the present invention includes, in addition to the salt forms described, inner salts or betaines (zwitterions). The respective salts according to formula (I) can be obtained by conventional methods known to those skilled in the art, such as by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of the compound of formula (I) that are not directly suitable for use in pharmaceuticals due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0090] As demonstrated below, the compounds of the present invention are believed to be suitable for modulating the integrated stress response pathway.

[0091] The integrated stress response (ISR) is a cellular stress response common to all eukaryotes. (1) Dysregulation of ISR signaling has important pathological consequences, leading to inflammation, viral infections, diabetes, cancer, and neurodegenerative diseases, among others.

[0092] ISR is a common factor in different types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) on serine 51, leading to the repression of normal protein synthesis and the expression of stress-response genes (2). In mammalian cells, this phosphorylation is carried out by a family of four eIF2alpha kinases, each of which responds to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2alpha kinase (HRI), and general control non-derepressible 2 (GCN2) (3).

[0093] eIF2 alpha, together with eIF2 beta and eIF2 gamma, forms the eIF2 complex, a key player in the initiation of normal mRNA translation (4). The eIF2 complex mediates the initiation of mRNA translation by catalyzing GTP and Met-tRNA. i to form the ternary complex (eIF2-GTP-Met-tRNA) that is recruited by the ribosome for translation initiation. i ) to form (5, 6).

[0094] eIF2B is a heterodecameric complex consisting of five subunits (alpha, beta, gamma, delta, and epsilon) that, in duplicate, form a GEF-active decamer ( 7 ).

[0095] In response to ISR activation, phosphorylated eIF2alpha inhibits eIF2B-mediated exchange of GDP for GTP, resulting in reduced ternary complex formation and, therefore, inhibition of translation of normal mRNAs characterized by ribosome binding to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, translation of several specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated through a mechanism involving altered translation of upstream ORFs (uORFs) (7, 9, 10). Under these conditions of reduced ternary complex abundance, translation of several specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated through a mechanism involving altered translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in unstressed cells to restrict ribosome flow to the primary coding ORF. For example, under normal conditions, the uORFs in the 5'UTR of ATF occupy ribosomes and prevent translation of the coding sequence of ATF4. However, under stress conditions, i.e., under conditions of reduced ternary complex formation, ribosomes may occupy these upstream ORFs. The probability that the ATF4-encoding ORF will scan through the ATF4 gene and initiate translation at the ORF is increased. ATF4 and other stress response factors expressed in this manner subsequently direct the expression of an array of additional stress response genes. The acute phase consists in the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

[0096] Upregulation of markers of ISR signaling has been demonstrated in a variety of conditions, including cancer and neurodegenerative diseases. In cancer, ER stress-regulated translation increases resistance to hypoxic conditions and promotes tumor growth (14, 15, 16), and genetic deletion of PERK results in the transformation of PERK. - / - It has been shown to slow the growth of tumors derived from mouse embryonic fibroblasts (14, 17). Furthermore, a recent report provided proof of concept that activators of eIF2B are effective in treating aggressive metastatic forms of prostate cancer using patient-derived xenograft modeling in mice (28). Taken together, prevention of cytoprotective ISR signaling may represent an effective antiproliferative strategy for the treatment of at least some forms of cancer.

[0097] Furthermore, modulation of ISR signaling has proven effective in preserving synaptic function and reducing neuronal loss, as well as in neurodegenerative diseases characterized by activation of the misfolded and unfolded protein response (UPR), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jakob-Creutzfeldt disease (prion disease) (18, 19, 20). There are examples of neurodegenerative diseases, such as prion disease, where pharmacological as well as genetic inhibition of ISR signaling has been shown to normalize protein translation levels, rescue synaptic function, and prevent neuronal loss (21). Specifically, reducing the level of phosphorylated eIF2α by overexpressing a phosphatase that controls phosphorylated eIF2α increased the survival time of prion-infected mice, whereas sustained eIF2α phosphorylation decreased survival (22).

[0098] Furthermore, direct evidence for the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic diseases affecting the function of eIF2 and eIF2B. Mutations in eIF2gamma, which disrupt the integrity of the eIF2 complex and therefore result in a reduction of normal protein expression levels, lead to intellectual disability syndrome (ID) (23). Partial loss of function mutations in the eIF2B subunit have been shown to be responsible for the rare leukodystrophy vanishing white matter disease (VWMD) (24, 25). Specifically, stabilization of partial loss of function eIF2B in a VWMD mouse model with a small molecule related to ISRIB has been shown to reduce ISR markers and improve functional as well as pathological endpoints (26, 27).

[0099] The present invention provides compounds of the present invention, in free form or in pharmaceutically acceptable salt form, or in the form of a solvate, hydrate, tautomer, or stereoisomer, for use in the treatment of the diseases or disorders described herein. The same applies to pharmaceutical compositions of the present invention.

[0100] Thus, one aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, for use as a pharmaceutical as described above. The same applies to a pharmaceutical composition of the present invention.

[0101] The described methods of treatment can be applied to mammals such as dogs, cats, cows, horses, rabbits, monkeys and humans. Preferably, the mammalian patient is a human patient.

[0102] Accordingly, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer, or pharmaceutical composition thereof, for use in the treatment or prevention of one or more diseases or disorders associated with the integrated stress response.

[0103] A further aspect of the invention is a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer, or pharmaceutical composition thereof, for use in a method for treating or preventing one or more disorders or diseases associated with the integrated stress response.

[0104] A further aspect of the invention is the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment or prevention of one or more disorders or diseases associated with the integrated stress response.

[0105] Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing one or more diseases or disorders associated with the integrated stress response in a mammalian patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof.

[0106] The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer, or pharmaceutical composition thereof, for use in the treatment or prevention of one or more of the diseases or disorders described below.

[0107] A further aspect of the invention is a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer, or pharmaceutical composition thereof, for use in a method for treating or preventing one or more of the disorders or diseases described below.

[0108] A further aspect of the invention is the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment or prevention of one or more of the disorders or diseases described below.

[0109] Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing one or more of the diseases or disorders described below in a mammalian patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof.

[0110] The disease or disorder includes, but is not limited to, a disease selected from the group consisting of leukodystrophies, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases, as well as organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0111] Leukodystrophy Examples of leukodystrophies include, but are not limited to, vanishing white matter disease with CNS hypomyelination (VWMD) and childhood ataxia (e.g., associated with defects in the function of eIF2 or components in signal transduction or signaling pathways including eIF2).

[0112] Intellectual disability syndrome Intellectual disability specifically refers to a condition in which a person has certain limitations in intellectual functions, such as communicating and caring for themselves, and / or has a deficit in social skills. Intellectual disability syndromes include, but are not limited to, intellectual disability conditions associated with a deficiency in the function of eIF2 or components in signal transduction or signal transduction pathways, including eIF2.

[0113] Neurodegenerative diseases / disorders Examples of neurodegenerative diseases and disorders include, but are not limited to, Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Voigt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheiker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Coutts-Barr syndrome, and HIV-associated dementia. These include Lewy body dementia, Lewy body dementia, Machado-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration (multiple types with variable features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal cord deafness, and tauopathies.

[0114] In particular, the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

[0115] Neoplastic disease Neoplastic disease, in the broadest sense, can be understood as any tissue resulting from misregulation of cell growth. In many cases, neoplasms lead to at least a bulky tissue mass, possibly innervated by blood vessels. It may or may not involve the formation of one or more metastases / metastases. The neoplastic disease of the present invention can be any neoplasm as classified by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) classification C00-D48.

[0116] By way of example, a neoplastic disease according to the present invention may be the presence of one or more malignant neoplasm(s) (tumors) (ICD-10 classifications C00-C97), may be the presence of one or more in situ neoplasm(s) (ICD-10 classifications D00-D09), may be the presence of one or more benign neoplasm(s) (ICD-10 classifications D10-D36), or may be the presence of one or more neoplasm(s) of indeterminate or unknown behavior (ICD-10 classifications D37-D48). Preferably, a neoplastic disease according to the present invention refers to the presence of one or more malignant neoplasm(s), i.e., malignant neoplasms (ICD-10 classifications C00-C97).

[0117] In a more preferred embodiment, the neoplastic disease is cancer.

[0118] Cancer, in its broadest sense, refers to any malignant neoplastic disease in a patient, i.e., one or more Cancer can be understood as the presence of a further malignant neoplasm or neoplasms. Cancer can be a solid or hematological malignancy. Contemplated herein are, but are not limited to, leukemia, lymphoma, carcinoma, and sarcoma.

[0119] In particular, neoplastic diseases such as cancers characterized by upregulated ISR markers are included herein.

[0120] Illustrative cancers include, but are not limited to, thyroid cancer, cancers of the endocrine system, pancreatic cancer, brain cancer (e.g., glioblastoma multiforme, glioma), breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), cervical cancer, ovarian cancer, uterine cancer, colon cancer, head and neck cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer, lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), colon cancer, esophageal cancer, stomach cancer, bladder cancer, bone cancer, stomach cancer, prostate cancer, and skin cancer (e.g., melanoma).

[0121] Further examples include, but are not limited to, myeloma, leukemia, mesothelioma, and sarcoma.

[0122] Additional examples include, but are not limited to, medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, carcinoma of the pancreatic stellate cells, and carcinoma of the hepatic stellate cells.

[0123] Illustrative leukemias include, but are not limited to, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, non-leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, acute myeloid ... Leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphotropic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0124] Illustrative sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, and fibrosarcoma. These include cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0125] Illustrative melanomas include, but are not limited to, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0126] Exemplary carcinomas include, but are not limited to, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, ductal carcinoma, compact carcinoma durum, embryonal carcinoma, encephalomyocarcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, preulcerative carcinoma (carcinoma ex ulcere), fibrous carcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, renal cell carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, carcinoma in situ carcinoma), Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanotic carcinoma, soft carcinoma, mucinous carcinoma, mucinous adenocarcinoma (carcinoma muciparum), mucocellular carcinoma (carcinoma mucocellulare), mucoepidermoid carcinoma, mucinous carcinoma, mucinous carcinoma, myxomatous carcinoma (carcinoma myxomatodes), nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solenoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, linear carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, tubular carcinoma, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0127] infectious disease Examples include, but are not limited to, infections caused by viruses (such as infections caused by HIV-1: human immunodeficiency virus type 1; IAV: influenza A virus; HCV: hepatitis C virus; DENV: dengue virus; ASFV: African swine fever virus; EBV: Epstein-Barr virus; HSV1: herpes simplex virus 1; CHIKV: chikungunya virus; HCMV: human cytomegalovirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2), and infections caused by bacteria (such as infections caused by Legionella, Brucella, Simkania, Chlamydia, Helicobacter, and Campylobacter).

[0128] inflammatory diseases Examples of inflammatory diseases include, but are not limited to, postoperative cognitive dysfunction (decline in cognitive function after surgery), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, and Sjogren's syndrome. , vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and Atopic dermatitis is one example.

[0129] musculoskeletal disorders Examples of musculoskeletal disorders include, but are not limited to, muscular dystrophy, multiple sclerosis, Friedrich's ataxia, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscular atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendonitis, back pain, muscle pain, muscle soreness, repetitive strain disorders, and paralysis.

[0130] metabolic disease Examples of metabolic diseases include, but are not limited to, diabetes (especially type II diabetes), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), Niemann-Pick disease, liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, and Kearns-Sayre disease.

[0131] eye disease Examples of ocular diseases include, but are not limited to, edema or neovascularization associated with any occlusive or inflammatory retinal vascular disorder, e.g., iris neovascularization, neovascular glaucoma, pterygium, neovascularization of the glaucoma filtering bleb, conjunctival papilloma; choroidal neovascularization, e.g., neovascular age-related macular degeneration (AMD), myopia, pre-uveitis, trauma, or idiopathic; macular edema, e.g., post-surgical macular edema, secondary to uveitis, including retinal and / or choroidal inflammation. macular edema due to diabetes, macular edema secondary to diabetes, and macular edema secondary to retinal vascular occlusive disease (i.e., branch retinal and central retinal vein occlusion); retinal neovascularization due to diabetes, e.g., retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ocular or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eales' disease; and genetic disorders, e.g., von Hippel-Lindau syndrome.

[0132] Further diseases Additional diseases include, but are not limited to, organ fibrosis (such as liver fibrosis, pulmonary fibrosis, or kidney fibrosis), chronic and acute diseases of the liver (such as fatty liver disease, or hepatic steatosis), chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular disease, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

[0133] Yet another aspect of the present invention is a pharmaceutical composition comprising at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other biologically active compounds or pharmaceutical compositions.

[0134] Preferably, the one or more biologically active compounds are modulators of the integrated stress response pathway other than the compounds of formula (I).

[0135] "Pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that comprise the carrier, as well as any product that results directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from other types of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present invention encompasses any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0136] The pharmaceutical compositions of the present invention may contain one or more additional compounds as active ingredients, such as a mixture of compounds of formula (I) in the composition or other modulators of the integrated stress response pathway.

[0137] The active ingredients may be contained in one or more different pharmaceutical compositions (combination pharmaceutical compositions).

[0138] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

[0139] Compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or intranasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the active ingredient. They are conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0140] In practical use, the compound of formula (I) can be combined as an active ingredient in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques.Carriers can take a variety of forms, depending on the desired form of preparation for administration, for example, oral or parenteral (including intravenous).When preparing compositions for oral dosage forms, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used in the case of oral liquid preparations, such as suspensions, elixirs and solutions; or carriers, such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., can be used in the case of oral solid preparations, such as powders, hard and soft capsules and tablets, and solid oral preparations are preferred over liquid preparations.

[0141] Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, and in this case, solid pharmaceutical carriers are obviously used.If desired, tablets can be coated by standard aqueous or non-aqueous techniques.Such compositions and preparations should contain at least 0.1% of active compound.The percentage of active compound in these compositions can of course vary, and can conveniently be between about 2% and about 60% by weight of the unit.The amount of active compound in such therapeutically useful compositions is such that an effective dosage is obtained.The active compound can also be administered intranasally, for example, as liquid drops or spray.

[0142] Tablets, pills, capsules, etc. may also contain binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dibasic calcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0143] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, and a dye and flavoring, such as cherry or orange flavor.

[0144] Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant, such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microbial organisms.

[0145] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form should be sterile and fluid to the extent that easy syringeability exists.It should be stable under the conditions of manufacture and storage, and should be protected against the contaminating action of microorganisms such as bacteria and fungi.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0146] Any suitable route of administration can be used to provide a mammal, especially a human, with an effective dose of the compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Preferably, the compound of formula (I) is administered orally.

[0147] The effective dosage of the active ingredient employed can vary depending on the particular compound employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages can be readily ascertained by one skilled in the art.

[0148] Starting materials for the synthesis of preferred embodiments of the present invention can be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR, etc., or can be synthesized using known methods by those skilled in the art.

[0149] In general, several methods are applicable to preparing the compounds of the present invention. In some cases, various strategies are combined. Sequential or convergent routes are used. Illustrative synthetic routes are described below. [Example]

[0150] I Chemical synthesis Testing Procedure: The following abbreviations and acronyms are used: aq water-based ACN Acetonitrile AgOTf Silver trifluoromethanesulfonate BrCN Cyanogen bromide Brine A saturated solution of NaCl in water BnONH2·HCl O-Benzylhydroxylamine hydrochloride Boc tert-butoxycarbonyl Boc2O di-tert-butyl dicarbonate t BuOK Potassium tert-butoxide CSA (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid CV column volume DAST N,N-diethylaminosulfur trifluoride DCM dichloromethane DCE Dichloroethane DMSO dimethyl sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide DIPEA Diisopropylethylamine DMF Dimethylformamide DMAP N,N-dimethylpyridin-4-amine ESI + Positive ionization mode ESI - Negative ionization mode EtOAc ethyl acetate EtOH ethanol Et2O diethyl ether H2SO4 Sulfuric Acid HATU 1-[bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate HCl Hydrochloric acid HPLC High Performance Liquid Chromatography h hour(s) IPA Isopropyl Alcohol KHCO3 Potassium Bicarbonate LiOH Lithium hydroxide LiOH.H2O Lithium hydroxide hydrate m multiplet m-CPBA 3-chlorobenzenecarboperoxoic acid MeOH Methanol MgSO4 Potassium Sulfate min MsOH methanesulfonic acid mL milliliter(s) N2 nitrogen atmosphere Na2SO3 Sodium sulfite Na2SO4 Sodium Sulfate NaBH4 Sodium borohydride NaHCO3 Sodium Bicarbonate NH2-NH2·H2O Hydrazine hydrate NH4Cl Ammonium chloride NiCl2·6H2O Nickel(II) chloride hexahydrate NMM 4-methylmorpholine NMR nuclear magnetic resonance prep. for preparative preparation rt room temperature Rochelle Salt Potassium Sodium L(+)-Tartrate Tetrahydrate RT retention time satd saturated SOCl2 Thionyl chloride STAB Sodium triacetoxyborohydride T3P Propanephosphonic Anhydride TsCl 4-Methylbenzenesulfonyl chloride TCDI 1,1'-thiocarbonyldiimidazole THF tetrahydrofuran TFA 2,2,2-trifluoroacetic acid TFAA Trifluoroacetic anhydride TMS-CF3 Trimethyl(trifluoromethyl)silane TMSOI Trimethylsulfoxonium iodide ZnBr2 Zinc Dibromide

[0151] The analytical LCMS conditions are as follows:

[0152] System 1 (S1): Acidic IPC Methods (MS18 and MS19) Analytical (MET / CR / 1410) HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core Shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40 °C) and a gradient of 5 to 100% B over 1.2 min (A = 0.1% formic acid in HO; B = 0.1% formic acid in ACN) followed by 100% B for 0.1 min. A second gradient of 100 to 5% B was then applied at a flow rate of 1.2 mL / min with an injection volume of 3 μL over 0.01 min. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector spectral range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0153] System 2 (S2): Acidic IPC Methods (MSQ2 and MSQ4): Analytical (MET / uPLC / 1704) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm × 50 mm, 1.7 μm; temperature 40 °C) and a gradient of 5 to 100% B over 1.1 min (A = 0.1% formic acid in HO; B = 0.1% formic acid in ACN) followed by 100% B for 0.25 min. A second gradient of 100 to 5% B was then applied over 0.05 min and held for 0.1 min at a flow rate of 0.9 mL / min with an injection volume of 1 μL. UV spectra were recorded at 215 nm on a Waters Acquity PDA using a spectral range of 200–400 nm. Mass spectra were acquired using a Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0154] System 3 (S3): Basic IPC Method (MS16): Analytical (MET / CR / 1602) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 40°C) and a gradient of 5 to 100% B over 0.75 min (A: 2 mM ammonium bicarbonate, buffered to pH 10; B: ACN) followed by 100% B for 0.1 min. A second gradient of 100 to 5% B was then applied over 0.05 min and held for 0.1 min at a flow rate of 1 mL / min with an injection volume of 1 μL. UV spectra were recorded at 215 nm on a Waters Acquity PDA using a spectral range of 200–400 nm. Mass spectra were acquired using a Waters Quattro Premier XE. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0155] System 4 (S4): Acidic Final Method (MSQ1 and MSQ2): Analytical (MET / uPLC / AB101) uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μM; temperature: 40 °C) and a gradient of 5 to 100% B over 5.3 min (A = 0.1% formic acid in HO; B = 0.1% formic acid in ACN) followed by 100% B for 0.5 min. A second gradient of 100 to 5% B was then performed. The chromatogram was applied over 0.02 min and held for 1.18 min at a flow rate of 0.6 mL / min with a 1 μL injection volume. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector spectral range: 200–400 nm. Mass spectra were acquired using a Waters SQD (MSQ1) or Waters Acquity QDA (MSQ2). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0156] System 5 (S5): Acidic final method (MS18, MS19) Analytical (MET / CR / 1416) HPLC-MS was performed on a Shimadzu LCMS system using a Waters Atlantis dC18 column (2.1 mm x 100 mm, 3 μm; temperature: 40 °C) and a gradient of 5 to 100% B over 5 min (A = 0.1% formic acid in HO; B = 0.1% formic acid in ACN), followed by 100% B for 0.4 min. A second gradient of 100 to 5% B was then applied over 0.02 min and held for 1.58 min at a flow rate of 0.6 mL / min with an injection volume of 3 μL. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector spectral range: 200-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0157] System 6 (S6): Basic final method (MS16) Analytical (MET / uHPLC / AB105) uPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40 °C) and a gradient of 5 to 100% (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) over 5.3 min, followed by 100% B for 0.5 min. A second gradient of 100 to 5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity photodiode array detector spectral range: 200-400 nm. Mass spectra were acquired using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0158] The purification method is as follows: Method 1: Acidic initial method Purification (P1) LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient of 10 to 95% B over 14.44 min (A = 0.1% formic acid in HO; B = 0.1% formic acid in ACN) followed by 95% B in 2.11 min. A second gradient of 95 to 10% B was then applied over 0.2 min with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0159] Method 2: Acidic standard method Purification (P2) LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) and a gradient of 30 to 95% B over 11.00 min (A = 0.1% formic acid in water; B = 0.1% formic acid in ACN) followed by 95% B over 2.10 min. A second gradient of 95 to 30% B was then applied over 0.2 min with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0160] Method 3: Basic initial method Purification (P3) LC was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient of 10 to 95% B over 14.44 min (A = 0.2% NH4OH in HO; B = 0.2% NH4OH in ACN) followed by 95% B in 2.11 min. A second gradient of 95 to 10% B was then applied over 0.2 min with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0161] Method 4: Basic Standard Method Purification (P4) LC was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) and a gradient of 30 to 95% B over 11.00 min (A = 0.2% NH4OH in water; B = 0.2% NH4OH in ACN) followed by 95% B over 2.10 min. A second gradient of 95 to 30% B was then applied over 0.21 min with an injection volume of 1500 μL at a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0162] Method 5: Reversed-phase chromatography using acidic pH, standard elution method Purification by FCC on reversed-phase silica (acidic pH, standard elution method) was performed on a Biotage Isolera system using an appropriate SNAP C18 cartridge and a gradient of 10% B over 1.7 CV (A = 0.1% formic acid in HO; B = 0.1% formic acid in ACN) followed by 10 to 100% B over 19.5 CV and 100% B for 2 CV.

[0163] Method 6: Reversed-phase chromatography using basic pH, standard elution method Purification by FCC on reversed-phase silica (basic pH, standard elution method) was performed on a Biotage Isolera system using an appropriate SNAP C18 cartridge and a gradient of 10% B over 1.7 CV (A = 0.1% NH3 in HO; B = 0.1% NH3 in ACN) followed by 10 to 100% B over 19.5 CV and 100% B for 2 CV.

[0164] Method 7: Reversed-phase chromatography using acidic pH, standard elution method Purification by FCC on reversed-phase silica (acidic pH, standard elution method) was performed on a Biotage Isolera system using an appropriate SNAP C18 cartridge and a gradient of 10% B over 1.7 CV (A = 0.1% TFA in HO; B = 0.1% TFA in ACN) followed by 10 to 100% B over 19.5 CV and 100% B for 2 CV.

[0165] Chiral Separation Methods: Method C1 Purification method: 15% IPA:85% heptane; Chiralcel OD-H, 20 x 250 mm, 5 μm at 18 mL / min. Sample diluents: MeOH, ACN. Method C2 Purification method: EtOH with cellulose-4; 21.2 x 250 mm, 5 μm column at 9 mL / min. Sample diluents: EtOH, MeOH. Method C3 Purification method: 15% IPA + 0.2% diethylamine: 85% CO2; ChiralPak AD-H, 10 x 250 mm, 5 μm at 15 mL / min. Sample diluent: IPA, MeOH, ACN. Method C4 Purification method: MeOH + 0.2% diethylamine; Chiralpak AD-H, 20 x 250 mm, 5 μm at 7 mL / min. Sample diluent: MeOH. Method C5 Purification method: 75:25 CO2:MeOH; ChiralPak AD-H, 10 x 250 mm, 5 μm at 15 mL / min. Sample diluent: MeOH. Method C6 Purification method: 15% MeOH, 85% CO2; Chiralcel OJ-H, 10 x 250 mm, 5 μm at 15 mL / min. Sample diluents: MeOH, IPA, ACN. Method C7 Purification method = 80:20 heptane:EtOH; ChiralPak AD-H, 20 x 250 mm, 5 μm at 18 mL / min. Sample diluents: methanol, IPA.

[0166] NMR conditions Unless otherwise specified, 1H NMR spectra were recorded at 500 MHz, 400 MHz, or 250 MHz on either a Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz, or Bruker Avance III HD 250 MHz spectrometer, respectively. Chemical shifts δ are given in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to indicate multiplicity and general assignment: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). Coupling constants J are given to the nearest 0.1 Hz.

[0167] General synthesis: All compounds were synthesized to a purity of >95% unless otherwise specified. Chemical names were generated by Marvin Sketch, version 19.19.0 from ChemAxon Ltd.

[0168] Scheme for Route 1 [ka]

[0169] Step 1.a: Ethyl (2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate [ka] DMSO (75 mL) was dissolved in anhydrous THF (60 mL) and TMSOI (12.89 g, 58.3 mmol) tA solution of BuOK (6.27 g, 55.9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -12 °C, and a solution of ethyl Boc-D-pyroglutamate (12.5 g, 48.6 mmol) in anhydrous THF (38 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NH4Cl (80 mL), HO (15 mL), and EtOAc (200 mL), and the organic layer was isolated, washed with brine, and concentrated in vacuo to approximately 100 mL. A solution of BnONH2·HCl (8.14 g, 51.0 mmol) in EtOAc (62 mL) was added, and the mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature, washed with HO and brine, and the organic layer was concentrated in vacuo to give the title compound (85% purity, 19.5 g, 40.1 mmol, 83% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ 7.16 - 7.33 (m, 5H), 5.01 - 5.06 (m, 2H), 3.95 - 4.30 (m, 5H), 2.32 - 2.50 (m, 2H), 1.98 - 2.13 (m, 1H), 1.75 - 1.92 (m, 1H),1.30 - 1.40 (m, 9H), 1.12 - 1.24 (m, 3H),

[0170] Step 1.b: Ethyl (2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate [ka] To a solution of ethyl (2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate (85% purity, 19.5 g, 40.1 mmol) in EtOAc (157 mL) was added MsOH (7.8 mL, 0.12 mol), and the mixture was stirred at 42 °C for 2 h. The resulting mixture was added to a solution of KHCO (20.1 g, 0.201 mol) in HO (100 mL) and stirred at 52 °C for 2 h. The reaction mixture was cooled to room temperature, and the organic layer was isolated, washed with brine, dried over NaSO, and concentrated in vacuo to give the title compound (85% purity, 13.0 g, 40.0 mmol) as a dark orange oil in quantitative yield. 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.34 (m, 5H), 4.99 (d, J = 4.8 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.45 - 3.56 (m, 1H), 3.25 (dd, J = 14.9, 9.8 Hz, 1H), 3.08 (dt, J = 14.5, 4.3 Hz, 1H), 2.01 - 2.32 (m, 3H), 1.55 - 1.80 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

[0171] Intermediate 1 (Step 1.c): Ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalate [ka] Propanoic acid (23 mL, 0.240 mol) was added to a suspension of NaBH (3.03 g, 80.0 mmol) in EtOAc (95 mL), and the mixture was stirred at room temperature for 1 h. The resulting mixture was added to a solution of ethyl (2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate (85% purity, 13.0 g, 40.0 mmol) in EtOAc (95 mL) and HSO (11 mL, 0.20 mol) at −20° C. and stirred at room temperature for 60 h. The reaction mixture was diluted with HO (75 mL) and neutralized with aqueous NHOH. The organic layer was isolated, washed with brine, dried over NaSO, and concentrated in vacuo to a volume of approximately 75 mL. The solution was warmed to 45° C. and MeOH (30 mL) was added, followed by a solution of oxalic acid (3.60 g, 40.0 mmol) in MeOH (15 mL). The mixture was cooled to 0° C. and the resulting precipitate was isolated via vacuum filtration and washed with MeOH:EtOH (1:4) and EtOAc to afford the title compound (7.17 g, 19.1 mmol, 48% yield); 1 H NMR (500 MHz, DMSO-d6) δ 7.25 - 7.42 (m, 5H), 4.59 (s, 2H), 4.17 - 4.24 (m, 2H), 3.92 (dd, J = 12.3, 3.2 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.10 (ddd, J = 15.1, 7.6, 3.9 Hz, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.13 (dt, J = 10.2, 3.4 Hz, 1H), 1.87 (dd, J = 9.0, 3.8 Hz, 1H), 1.65 (qd, J = 13.2, 3.6 Hz, 1H), 1.40 (qd, J = 12.8, 3.9 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H); M / Z: 279, [M+H] + , ESI + , RT = 0.81 (S1).

[0172] Intermediate 2 (Step 1.d): 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate [ka] To a solution of ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalate (2.22 g, 6.03 mmol, Intermediate 1) in anhydrous DCM (30 mL) at 0 °C, EtN (3.6 mL, 25.8 mmol), DMAP (76 mg, 0.622 mmol), and BocO (4.2 mL, 18.3 mmol) were added, and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with saturated aqueous NHCl and DCM, and the organic layer was isolated, washed with HO and brine, dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0–20% EtOAc in heptane) to afford the title compound (86% purity, 1.40 g, 3.18 mmol, 53% yield) as a colorless oil. 1 H NMR (500 MHz, chloroform-d) δ 7.40 - 7.26 (m, 5H), 5.51 - 5.41 (m, 1H), 4.92 - 4.80 (m, 1H), 4.79 - 4.62 (m, 2H), 4.19 (q, J = 7.0 Hz, 3H), 3.11 (d, J = 45.4 Hz, 2H), 1.96 (s, 2H), 1.73 - 1.60 (m, 1H), 1.55 - 1.49 (m, 1H), 1.46 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H); M / Z: 379, [M+H] + , ESI + , RT = 1.09 (S2).

[0173] Scheme for Route 2 [ka]

[0174] Intermediate 3 (Step 2.a): 1-tert-butyl 2-ethyl (2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate [ka] To a solution of 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate (82% purity, 24.9 g, 54.0 mmol, Intermediate 2) in anhydrous EtOH (1 L) was added 10% Pd / C (2.87 g, 2.70 mmol), and the mixture was stirred at room temperature under H for 24 hours. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was dissolved in EtO and washed with 2 M aqueous HCl. The organic layer was discarded, and the aqueous layer was basified using solid NaHCO and then extracted with IPA:DCM (2:8). The organic extract was washed with brine, dried over MgSO, and concentrated in vacuo to give the title compound (11.5 g, 42.2 mmol, 78% yield) as a pale yellow oil; 1 H NMR (400 MHz, chloroform-d) 1.29 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.51 - 1.70 (m, 4H), 1.93 - 2.22 (m, 2H), 3.06 - 3.38 (m, 2H), 3.66 - 3.97 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.56 - 5.01 (m, 1H).

[0175] Step 2.b: 1-tert-butyl 2-ethyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,2-dicarboxylate [ka] To a solution of 1-tert-butyl 2-ethyl(2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (2.50 g, 9.18 mmol), DMAP (90 mg, 0.739 mmol), and pyridine (1.49 mL, 18.4 mmol) in DCM (45 mL) at 0° C., benzyl carbonochloridate (1.99 mL, 13.9 mmol) was added, and the reaction mixture was stirred at room temperature for 20 h. An additional portion of pyridine (700 μL, 8.6 mmol), DMAP (42 mg, 0.34 mmol), and benzyl carbonochloridate (930 μL, 6.5 mmol) was added at 0° C., and the mixture was stirred at room temperature. The mixture was stirred at rt for 1 h. The reaction mixture was diluted with HO (20 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo, and purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (84% purity, 3.18 g, 6.57 mmol, 72% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ 7.36 - 7.21 (m, 5H), 5.16 - 4.92 (m, 3H), 4.87 - 4.50 (m, 1H), 4.13 (q, J = 6.7 Hz, 2H), 3.98 - 3.72 (m, 2H), 3.21 - 2.94 (m, 1H), 2.13 - 1.99 (m, 1H), 1.93 - 1.67 (m, 2H), 1.37 (s, 9H), 1.19 (d, J = 7.1 Hz, 3H), NH proton not observed; M / Z: 307 [M-Boc+H] + , ESI + , RT = 1.08 (S1).

[0176] Intermediate 4 (Step 2.c): (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid [ka] A mixture of 1-tert-butyl 2-ethyl(2R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,2-dicarboxylate (84% purity, 3.18 g, 6.57 mmol) and LiOH·HO (311 mg, 7.23 mmol) in EtOH (25 mL):THF (25 mL):water (25 mL) was stirred at room temperature for 24 h. The reaction mixture was partitioned between HO (30 mL) and EtOAc (30 mL), and the organic layer was discarded. The aqueous layer was then acidified using 1 M aqueous HCl and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO, and concentrated in vacuo to afford the title compound (86% purity, 2.04 g, 4.64 mmol, 71% yield) as a colorless solid; M / Z: 377 [MH] + , ESI - ,RT=0.90(S2).

[0177] Scheme for Route 3 [ka]

[0178] Step 3.a: Ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate [ka] To a solution of ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate; oxalic acid (10 g, 27.1 mmol) in MeOH (100 mL) SCX powder (50 g) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered under vacuum, washed with 4M NH3 in MeOH, and concentrated in vacuo to give the title compound (6.22 g, 22.3 mmol, 82% yield) as a viscous yellow oil; 1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.21 (m, 5H), 6.46 (s, 1H), 4.57 (s, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.19 - 3.08 (m, 3H), 2.84 - 2.70 M / Z: 279 [M+H] + , ESI + , RT = 0.50 (S2).

[0179] Intermediate 5 (Step 3.b): 1-tert-butyl 2-ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate [ka] BocO (7.32 g, 33.5 mmol) was added to a solution of ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (6.22 g, 22.3 mmol) and EtN (12 mL, 89.4 mmol) in anhydrous DCM (110 mL), and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was washed with saturated aqueous NHCl (100 mL) and brine (100 mL), dried over NaSO, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (5-50% EtOAc in heptane) to afford the title compound (94% purity, 6.82 g, 16.9 mmol, 76% yield) as a colorless oil. 1H NMR (500 MHz, chloroform-d) δ 7.44 - 7.27 (m, 5H), 5.48 (s, 1H), 4.87 (d, J = 9.9 Hz, 1H), 4.79 - 4.58 (m, 2H), 4.20 (q, J = 7.0 Hz, 3H), 3.12 (d, J = 44.6 Hz, 2H), 1.97 (s, 2H), 1.77 - 1.62 (m, 2H), 1.58 - 1.50 (m, 1H), 1.46 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H); M / Z: 324 [M- t Butyl+H] + , ESI + , RT = 1.34 (S1).

[0180] Scheme for Route 4 [ka]

[0181] Step 4.a: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-({[4-(trifluoromethyl)phenyl]formohydrazide} (carbonyl)piperidine-1-carboxylate [ka] To a solution of (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (90% purity, 2.04 g, 4.85 mmol, Intermediate 4), 4-(trifluoromethyl)benzohydrazide (1.29 g, 6.31 mmol), and HATU (2.21 g, 5.82 mmol) in anhydrous DMF (24 mL) was added DIPEA (1.7 mL, 9.70 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and 1 M aqueous HCl (50 mL). The organic layer was isolated, washed with brine (5 × 50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (70% purity, 3.80 g, 4.71 mmol, 97% yield) as an off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.01 (s, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.46 - 7.27 (m, 6H), 5.05 (s, 2H), 4.84 - 4.52 (m, 2H), 4.12 - 3.92 (m, 1H), 3.74 - 3.46 (m, 2H), 2.23 - 2.03 (m, 1H), 1.78 - 1.62 (m, 1H), 1.63 - 1.49 (m, 1H), 1.38 (s, 9H); M / Z: 465 [M-Boc+H] + , ESI + , RT = 1.01 (S2).

[0182] Step 4.b: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] A suspension of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-({[4-(trifluoromethyl)phenyl]formohydrazide}carbonyl)piperidine-1-carboxylate (70% purity, 3.80 g, 4.71 mmol), TsCl (2.70 g, 14.1 mmol), and KCO (1.95 g, 14.1 mmol) in ACN (100 mL) was stirred at 80 °C for 3 h. The reaction mixture was partitioned between EtOAc (100 mL) and HO (100 mL). The organic layer was isolated, washed with brine (50 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0 to 100% EtOAc in heptane). The resulting residue was triturated with Et2O, the solid was discarded, and the filtrate was concentrated in vacuo and purified by preparative HPLC (Method 5) to afford the title compound (75% purity, 2.90 g, 3.98 mmol, 84% yield) as a pale yellow oil; 1 H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.34 - 7.21 (m, 5H), 5.78 - 5.41 (m, 1H), 5.17 - 4.95 (m, 3H), 4.73 (s, 1H), 3.86 (s, 1H), 3.11 (s, 1H), 2.24 - 2.02 (m, 2H), 1.84 (d, J = 22.6 Hz, 2H), 1.41 (s, 9H); M / Z: 447 [M-Boc+H] + , ESI + , RT = 1.22 (S2).

[0183] Intermediate 6 (Step 4.c): tert-Butyl(2R,5S)-5-amino-2-{5 -[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (75% purity, 2.90 g, 3.98 mmol) in absolute EtOH (80 mL), Pd / C (10%, 0.21 g, 0.199 mmol) was added, and the mixture was stirred under H at room temperature for 24 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and 2 M aqueous HCl. The organic layer was isolated, and after 20 min, a precipitate was observed. The suspension was filtered under vacuum and washed with H O to give the title compound as the HCl salt (0.76 g, 1.68 mmol, 42% yield) as a white solid; 1 H NMR (400 MHz, chloroform-d) δ 8.74 (s, 3H), 8.08 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 5.67 (s, 1H), 4.51 - 4.36 (m, 1H), 3.63 (s, 1H), 3.19 (s, 2H), 2.61 - 2.47 (m, 1H), 2.31 - 2.14 (m, 2H), 1.47 (s, 9H); M / Z: 413 [M+H] + , ESI + , RT = 1.08 (S2).

[0184] Scheme for Route 5 [ka]

[0185] Step 5.a: tert-Butyl 2-[3-chloro-4-(trifluoromethyl)phenoxy]acetate [ka] A mixture of 3-chloro-4-(trifluoromethyl)phenol (1.00 g, 5.09 mmol), tert-butyl 2-bromoacetate (0.83 mL, 5.60 mmol), and K2CO3 (1.41 g, 10.2 mmol) in anhydrous DMF (5 mL) was stirred at 65 °C for 2.5 h. The reaction mixture was cooled to room temperature, diluted with HO (30 mL), and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-50% EtOAc in heptane) to give the title compound (1.35 g, 4.35 mmol, 85% yield) as a colorless oil. 1 H NMR (500 MHz, chloroform-d) δ 7.61 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.88 - 6.79 (m, 1H), 4.56 (s, 2H), 1.50 (s, 9H); M / Z: not observed, ESI + , RT = 1.16 (S2).

[0186] Intermediate 7 (Step 5.b): 2-[3-chloro-4-(trifluoromethyl)phenoxy]acetic acid [ka] A solution of tert-butyl 2-[3-chloro-4-(trifluoromethyl)phenoxy]acetate (1.35 g, 4.35 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred for 6 hours at 50° C. The reaction mixture was concentrated in vacuo to give the title compound (1.09 g, 4.28 mmol, 99% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 8.7, 2.4 Hz, 1H), 4.86 (s, 2H); 19 F NMR (376 MHz, DMSO-d6) δ -59.84 (2F, s).

[0187] Following general route 5, as exemplified by intermediate 7, the intermediates in Table 1 were synthesized using the corresponding starting materials.

[0188] [Table 1-1] [Table 1-2]

[0189] Scheme for Route 6 [ka]

[0190] Step 6.a: tert-Butyl 2-(4-chloro-3-cyanophenoxy)acetate [ka] A mixture of tert-butyl 2-bromoacetate (1.1 mL, 7.16 mmol), 2-chloro-5-hydroxybenzonitrile (1.00 g, 6.51 mmol), and K2CO3 (1.80 g, 13.0 mmol) in DMF (6 mL) was stirred at 65 °C for 2 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound (84% purity, 2.10 g, 6.59 mmol) as an orange oil in quantitative yield; 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.32 (dd, J = 9.0, 3.1 Hz, 1H), 4.79 (s, 2H), 1.43 (s, 9H); M / Z: 269, 271 [M+H] + , ESI + , RT = 1.11 (S2).

[0191] Intermediate 16 (Step 6.b): 2-(4-chloro-3-cyanophenoxy)acetic acid [ka] To a solution of tert-butyl 2-(4-chloro-3-cyano-phenoxy)acetate (84% purity, 2.50 g, 7.84 mmol) in DCM (5 mL) was added TFA (3.0 mL, 39.2 mmol), and the mixture was stirred at 50° C. for 2.5 h. The reaction mixture was concentrated in vacuo, and the residue was suspended in HO and stirred at room temperature for 15 min. The resulting precipitate was filtered under vacuum and washed with HO to give the title compound (94% purity, 1.03 g, 4.58 mmol, 58% yield) as an off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 7.69 - 7.56 (m, 2H), 7.32 (dd, J = 9.0, 3.1 Hz, 1H), 4.81 (s, 2H); M / Z: 210, 212 [MH] - , ESI - , RT = 0.76 (S2).

[0192] Scheme for Route 7 [ka]

[0193] Step 7.a: tert-Butyl 2-(4-chloro-3-formylphenoxy)acetate [ka] To a solution of 2-chloro-5-hydroxybenzaldehyde (1.0 g, 6.39 mmol) in anhydrous DMF (10 mL) was added K2CO3 (1.77 g, 12.8 mmol), followed by tert-butyl bromoacetate (1.0 mL, 7.03 mmol), and the mixture was stirred at 65 °C for 1 h. The reaction mixture was cooled to room temperature, poured onto HO (100 mL), and extracted with EtOAc (2 × 70 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (10–80% EtOAc in heptane) to afford the title compound (1.70 mg, 6.23 mmol, 98% yield) as a white solid; 1 H NMR (500 MHz, CDCl3) δ 10.42 (s, 1H), 7.40 - 7.30 (m, 2H), 7.15 (dd, J = 8.8, 3.2 Hz, 1H), 4.55 (s, 2H), 1.49 (s, 9H); M / Z: no mass ion observed [M+ H] + , ESI + , RT = 1.01 (S2).

[0194] Step 7.b: tert-Butyl 2-[4-chloro-3-(difluoromethyl)phenoxy]acetate [ka] To a solution of tert-butyl 2-(4-chloro-3-formylphenoxy)acetate (1.0 g, 3.66 mmol) in anhydrous DCM (10 mL) at 0 °C, DAST (0.72 mL, 5.49 mmol) was added dropwise, and the mixture was stirred at room temperature for 20 h. The reaction mixture was poured onto saturated aqueous NaHCO (30 mL) and extracted with DCM (2 × 30 mL). The combined organic extracts were dried over NaSO, concentrated in vacuo, and purified by chromatography on silica gel (10-40% EtOAc in heptane) to give the title compound (809 mg, 2.74 mmol, 75% yield) as a colorless oil. 1 H NMR (500 MHz, chloroform-d) δ 7.32 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 3.0 Hz, 1H), 7.02 - 6.76 (m, 2H), 4.53 (s, 2H), 1.49 (s, 9H); 19 F NMR (376 MHz, chloroform-d) δ -115.44; M / Z: 316, 318 [M+Na] + , ESI + , RT = 1.08 (S2).

[0195] Intermediate 17 (Step 7.c): 2-[4-chloro-3-(difluoromethyl)phenoxy]acetic acid [ka] To a solution of tert-butyl 2-[4-chloro-3-(difluoromethyl)phenoxy]acetate (809 mg, 2.74 mmol) in 1,4-dioxane (10 mL) at 0° C., 4 M HCl in 1,4-dioxane (3.4 mL, 13.7 mmol) was added, and the mixture was stirred at room temperature for 20 hours under N 2 . Another portion of 4 M HCl in 1,4-dioxane (3.4 mL, 13.7 mmol) was added, and the mixture was stirred at 50° C. for 7 hours. Another portion of 4 M HCl in 1,4-dioxane (3.4 mL, 13.7 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, triturated with HO, and dried under vacuum filtration for 1 hour to give the title compound (574 mg, 2.35 mmol, 86% yield) as a white powder; 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.8 Hz, 1H), 7.30 - 6.97 (m, 3H), 4.78 (s, 2H); M / Z: 235, 237 [MH] - , ESI - , RT = 1.07 (S2).

[0196] Following general route 7, as exemplified by intermediate 17, the intermediates in Table 2 were synthesized using the corresponding starting materials.

[0197] [Table 2]

[0198] Scheme for Route 8 [ka]

[0199] Intermediate 18: 2-[4-(trifluoromethyl)phenoxy]acetic acid [ka] To a suspension of 4-(trifluoromethyl)phenol (2.00 g, 12.3 mmol) and ethyl 2-bromoacetate (1.4 mL, 12.6 mmol) in anhydrous ACN (50 mL) was added CsCO (6.00 g, 18.4 mmol), and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with EtOAc (20 mL), washed with HO (2 × 20 mL) and brine (20 mL), dried using a phase separator, and concentrated in vacuo. The residue was dissolved in THF (50 mL), and a solution of 0.5 M aqueous LiOH (49 mL, 24.7 mmol) was added, and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with HO (20 mL), extracted with EtOAc (2 × 20 mL), and the organic extract was discarded. The aqueous solution was then acidified to pH 1–2 using 1 M aqueous HCl and extracted with DCM (3 × 20 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo to give the title compound (2.90 g, 12.9 mmol) as a white solid in quantitative yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.16 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 4.79 (s, 2H); M / Z: 219 [MH] - , ESI-, RT = 1.03 (S1).

[0200] Scheme for Route 9 [ka]

[0201] Intermediate 19: 2-(4-chloro-3-fluorophenoxy)acetyl chloride [ka] To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (5.16 g, 22.7 mmol) in DCM (45 mL) was added oxalic acid dichloride (10 mL, 0.115 mol) followed by DMF (81 μL, 1.11 mmol) at 0° C., and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo to give the title compound (90% purity, 5.30 g, 21.4 mmol, 94% yield) as an orange oil; 1 H NMR (400 MHz, chloroform-d) δ 7.31 (t, J = 8.6 Hz, 1H), 6.75 (dt, J = 10.2, 2.9 Hz, 1H), 6.66 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.96 (s, 2H).

[0202] Following general route 9, as exemplified by intermediate 19, the intermediates in Table 3 were synthesized using the corresponding starting materials.

[0203] [Table 3]

[0204] Scheme for Route 10 [ka]

[0205] Intermediate 3 (Step 10.a): 1-tert-butyl 2-ethyl (2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate [ka] To a solution of 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate (93% purity, 8.7 g, 21.3 mmol, Intermediate 2) in anhydrous EtOH (200 mL) under N was added Pd / C (10%, 2.28 g, 2.14 mmol), and the mixture was stirred under H at room temperature for 17 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified using an SCX-2 cartridge, first flushed with MeOH and second eluted with 3M NH in MeOH, to give the title compound (4.88 g, 17.0 mmol, 80% yield) as a pale yellow oil; 1 H NMR (400 MHz, chloroform-d) δ 4.98 - 4.57 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.87 - 3.64 (m, 1H), 3.35 - 2.99 (m, 2H), 2.14 - 1.92 (m, 2H), 1.64 - 1.52 (m, 2H), 1.45 (s, 11H), 1.26 (t, J = 7.1 Hz, 3H).

[0206] Step 10.b: 1-tert-butyl 2-ethyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1,2-dicarboxylate [ka] To a mixture of 1-tert-butyl 2-ethyl (2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (4.89 g, 17.1 mmol) and EtN (14 mL, 0.103 mol) in DCM (170 mL) at 0° C. was added dropwise a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (4.19 g, 18.8 mmol, Intermediate 19) in DCM (10 mL) and stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (250 mL), washed with saturated aqueous NaHCO (2 × 100 mL) and brine (100 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (7.14 g, 15.6 mmol, 91% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ 7.32 (t, J = 8.6 Hz, 1H), 6.86 - 6.72 (m, 2H), 6.69 - 6.63 (m, 1H), 4.98 - 4.66 (m, 1H), 4.45 (s, 2H), 4.29 - 4.13 (m, 3H), 4.09 - 3.87 (m, 1H), 3.33 - 3.10 (m, 1H), 2.23 - 2.02 (m, 1H), 2.00 - 1.71 (m, 2H), 1.56 (s, 1H), 1.44 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H); M / Z: 459, 461 [M+H] + , ESI + , RT = 3.83 (S4).

[0207] Intermediate 22 (Step 10.c): (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid [ka] LiOH (0.78 g, 31.1 mmol) was added to a solution of 1-tert-butyl 2-ethyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1,2-dicarboxylate (7.1 g, 15.6 mmol) in EtOH (80 mL) and HO (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, redissolved in HO (50 mL), and extracted with DCM (2 × 100 mL). The aqueous layer was then acidified to pH 2 using 2 M aqueous HCl and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the title compound (87% purity, 5.60 g, 11.3 mmol, 73% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.03 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 - 6.75 (m, 1H), 4.59 - 4.54 (m, 2H), 3.93 (s, 1H), 3.73 (d, J = 54.2 Hz, 1H), 3.13 - 2.94 (m, 1H), 2.06 - 1.87 (m, 2H), 1.61 (d, J = 12.2 Hz, 1H), 1.56 - 1.43 (m, 1H), 1.37 (s, 10H); M / Z: 429, 431 [M+H], ESI + , RT = 0.91 min (S1).

[0208] Following general route 10, as exemplified by intermediate 22, the intermediates in Table 4 were synthesized using the corresponding starting materials.

[0209] [Table 4]

[0210] Scheme for Route 11 [ka] Intermediate 26: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate [ka] To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (8.43 g, 19.2 mmol, Intermediate 22) and HATU (8.75 g, 23.0 mmol) in DMF (80 mL) was added DIPEA (4.0 mL, 23.0 mmol) and stirred at room temperature under N for 30 min. The resulting solution was added dropwise via cannula to a solution of NH-NH·HO (1.9 mL, 38.3 mmol) in DMF (40 mL) and stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (150 mL) and washed with HO (4 × 100 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo, and purified by chromatography on silica gel (0-10% MeOH in DCM) to afford the title compound (4.57 g, 10.3 mmol, 54% yield) as a white solid; 1 H NMR (400 MHz, chloroform-d) δ 7.35 - 7.27 (m, 2H), 6.88 - 6.58 (m, 3H), 4.75 (s, 1H), 4.45 (d, J = 3.8 Hz, 2H), 4.12 (s, 2H), 3.88 (s, 2H), 3.09 (d, J = 13.2 Hz, 1H), 2.21 - 2.12 (m, 1H), 1.86 (s, 2H), 1.69 (ddt, J = 17.8, 14.0, 6.1 Hz, 1H), 1.44 (s, 9H); M / Z: 345, 347 [M-Boc+H] + , ESI + , RT = 0.82 (S2).

[0211] Following general route 11, as exemplified by intermediate 26, the intermediates in Table 5 were synthesized using the corresponding starting materials.

[0212] [Table 5-1] [Table 5-2]

[0213] Scheme for Route 12 [ka]

[0214] Step 12.a: tert-butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (3.50 g, 7.87 mmol, Intermediate 26) and NaHCO (991 mg, 11.8 mmol) in HO (10 mL) and 1,4-dioxane (40 mL), BrCN (833 mg, 7.87 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with HO (60 mL) and extracted with EtOAc (3 × 60 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo to give the title compound (2.30 g, 4.65 mmol, 59% yield) as a white solid; 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.88 - 6.64 (m, 3H), 5.48 (s, 1H), 4.95 (s, 2H), 4.53 - 4.40 (m, 2H), 4.22 - 4.01 (m, 2H), 3.15 (s, 1H), 2.23 - 1.83 (m, 4H), 1.46 (s, 9H); M / Z: 470, 472 [M+H] + , ESI + , RT = 0.87 (S2).

[0215] Intermediate 31 (Step 12.b): tert-Butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate (2.30 g, 4.65 mmol) in anhydrous ACN (35 mL) was added CuBr (3.16 g, 14.0 mmol), and the mixture was stirred at room temperature for 5 minutes. tert-Butyl nitrite (1.9 mL, 14.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours, then at 40 °C for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with Rochelle's salt (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo, and purified by chromatography on silica gel (12-100% EtOAc in heptane) to afford the title compound (1.10 g, 2.03 mmol, 43% yield) as a pale yellow solid; 1 H NMR (500 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.87 - 6.71 (m, 2H), 6.67 (ddd, J = 8.9, 2.8, 1.1 Hz, 1H), 5.77 - 5.37 (m, 1H), 4.57 - 4.41 (m, 2H), 4.27 - 3.98 (m, 2H), 3.35 - 2.95 (m, 1H), 2.29 - 2.12 (m, 1H), 2.07 - 1.79 (m, 3H), 1.46 (s, 9H); M / Z: 433, 435 [M-Boc+H] + , ESI + , RT = 1.05 (S2).

[0216] Following general route 12, as exemplified by intermediate 31, the intermediates in Table 6 were synthesized using the corresponding starting materials.

[0217] [Table 6]

[0218] Scheme for Route 13 [ka]

[0219] Step 13.a: 1-tert-butyl 2-ethyl(2R,4S)-4-[2-(4- Chloro-3-fluorophenoxy)acetamido]pyrrolidine-1,2-dicarboxylate [ka] To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (250 mg, 1.22 mmol) in anhydrous DMF (4 mL), HATU (558 mg, 1.47 mmol) and DIPEA (0.32 mL, 1.83 mmol) were added and stirred at room temperature for 10 minutes. 1-tert-Butyl 2-ethyl (2R,4S)-4-aminopyrrolidine-1,2-dicarboxylate (299 mg, 1.22 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was partitioned between EtOAc (50 mL) and HO (30 mL), and the organic layer was isolated, washed with brine, dried over MgSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0–70% EtOAc in heptane) to afford the title compound (87% purity, 505 mg, 1.02 mmol, 83% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 6.7 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.80 (m, 1H), 4.54 (s, 2H), 4.40 - 4.26 (m, 2H), 3.67 (d, J = 11.1 Hz, 3H), 3.64 - 3.52 (m, 1H), 3.28 - 3.16 (m, 1H), 2.30 - 2.15 (m, 1H), 2.09 (dt, J = 12.7, 6.1Hz, 1H), 1.37 (d, J = 22.2 Hz, 9H); M / Z: 331, 333 [M-Boc+H] + , ESI + , RT = 0.97 (S2).

[0220] Intermediate 34 (Step 13.b): (2R,4S)-1-[(tert-butoxy)carbonyl]-4-[2-(4-chloro-3-fluorophenoxy)acetamido]pyrrolidine-2-carboxylic acid [ka] To a solution of 1-tert-butyl 2-ethyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]pyrrolidine-1,2-dicarboxylate (87% purity, 505 mg, 1.02 mmol) in MeOH (2 mL):THF (2 mL):HO (2 mL) was added LiOH·HO (53 mg, 1.22 mmol), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was partitioned between EtOAc (30 mL) and 1 M aqueous HCl (10 mL). The organic layer was isolated, washed with brine, dried over MgSO, and concentrated in vacuo to give the title compound (80% purity, 401 mg, 0.770 mmol, 76% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 6.9 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (dt, J = 9.0, 1.4 Hz, 1H), 4.54 (s, 2H), 4.35 (dq, J = 12.1, 6.5 Hz, 1H), 4.26 - 4.15 (m, 1H), 3.64 - 3.52 (m, 1H), 3.20 (dq, J = 15.0, 5.9, 5.5 M / Z: 317, 319 [M-Boc+H] + , ESI + , RT = 0.86 (S2).

[0221] Scheme for Route 14 [ka]

[0222] Step 14.a: tert-Butyl 4-(trifluoromethoxy)butanoate [ka] 2-Fluoropyridine (1.6 mL, 18.2 mmol) and TMS-CF3 (2.7 mL, 18.2 mmol) were added dropwise sequentially to a solution of tert-butyl 4-hydroxybutanoate (1.0 g, 6.05 mmol), AgOTf (4.69 g, 18.2 mmol), Selectfluor (3.22 g, 9.08 mmol), and KF (1.41 g, 24.2 mmol) in EtOAc (50 mL) in a foil-covered flask under N2, and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite, washed with EtOAc (30 mL), and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-30% EtOAc in heptane) to afford the title compound (90% purity, 330 mg, 1.30 mmol, 21% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 4.02 (t, J = 6.2 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 1.98 (p, J = 6.7 Hz, 2H), 1.46 (s, 9H); 19 F NMR (376 MHz, chloroform-d) δ -60.81 (3F, s).

[0223] Intermediate 35 (Step 14.b): 4-(trifluoromethoxy)butanoic acid [ka] A solution of tert-butyl 4-(trifluoromethoxy)butanoate (330 mg, 1.45 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (83% purity, 73 mg, 0.352 mmol, 24% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 4.32 (td, J = 6.4, 4.2 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 2.32 (td, J = 7.2, 2.8 Hz, 3H), 1.95 - 1.80 (m, 3H), 1.40 (s, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -58.82 (3F, s).

[0224] Scheme for Route 15 [ka]

[0225] Step 15.a: tert-Butyl 3-methyl-3-(trifluoromethoxy)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (1.00 g, 5.34 mmol) in EtOAc (30 mL) in a foil-covered flask at room temperature under N2, AgOTf (4.13 g, 16.0 mmol), KF (1.24 g, 21.4 mmol), and Selectfluor (2.84 g, 8.01 mmol) were added and stirred at room temperature for 5 minutes. 2-Fluoropyridine (1.4 mL, 16.0 mmol) and TMS-CF3 (2.4 mL, 16.0 mmol) were then added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL), and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (163 mg, 0.639 mmol, 12% yield) as a colorless oil; 1H NMR (400 MHz, DMSO-d6) δ 4.02 (d, J = 9.5 Hz, 2H), 3.91 (d, J = 9.6 Hz, 2H), 1.67 (s, 3H), 1.39 (s, 9H).

[0226] Intermediate 36 (Step 15.b): 3-Methyl-3-(trifluoromethoxy)azetidine hydrochloride [ka] To a solution of tert-butyl 3-methyl-3-(trifluoromethoxy)azetidine-1-carboxylate (160 mg, 0.627 mmol) in anhydrous 1,4-dioxane (3 mL), 4 M HCl in 1,4-dioxane (1.0 mL, 4.00 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to give the title compound (116 mg, 0.605 mmol, 97% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 2H), 4.22 (d, J = 12.2 Hz, 2H), 4.07 (d, J = 12.5 Hz, 2H), 1.74 (s, 3H); M / Z: 156 [M+H] + , ESI + , RT = 0.37 (S2).

[0227] Scheme for Route 16 [ka]

[0228] Step 16.a: ({[(benzyloxy)carbonyl]amino}amino)[3-(trifluoromethoxy)azetidin-1-yl]methanone [ka] To a solution of benzylhydrazine carboxylate (406 μL, 2.52 mmol) and pyridine (407 μL, 5.03 mmol) in anhydrous THF (5 mL) was added a solution of 4-nitrophenyl carbonochloridate (558 mg, 2.77 mmol) in anhydrous THF (3 mL), and the mixture was stirred at room temperature under N for 1 hour. The mixture was then slowly added to a solution of 3-(trifluoromethoxy)azetidine hydrochloride (469 mg, 2.64 mmol) and DIPEA (1.3 mL, 7.55 mmol) in anhydrous THF (5 mL) and stirred at room temperature under N for 30 minutes. The reaction mixture was quenched with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with HO (30 mL) and brine (30 mL), dried over MgSO, and concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous KCO (3 x 10 mL). The organic layer was dried over MgSO and concentrated in vacuo to give the title compound (92% purity, 770 mg, 2.13 mmol, 85% yield) as an off-white powder; 1 H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.51 (s, 1H), 7.41 - 7.26 (m, 5H), 5.21 - 5.11 (m, 1H), 5.07 (s, 2H), 4.27 - 4.17 (m, 2H), 3.92 - 3.83 (m, 2H); M / Z: 334 [M+H] + , ESI + , RT = 0.74 (S2).

[0229] Intermediate 37 (Step 16.b): 3-(trifluoromethoxy)azetidine-1-carbohydrazide [ka] ({[(benzyloxy)carbonyl]amino}amino)[3-(trifluoromethoxy)azetidin-1-yl]methanone (92% purity, 7 mL) in absolute EtOH (21 mL) To a solution of 10% Pd / C (226 mg, 0.212 mmol) under N was added 10% Pd / C (226 mg, 0.212 mmol), and the mixture was stirred under H at room temperature for 4 h. The reaction mixture was filtered through a pad of Celite, washed with warm EtOH (3 x 15 mL), and concentrated in vacuo to give the title compound (88% purity, 269 mg, 1.19 mmol, 56% yield) as a brown solid; 1 H NMR (500 MHz, DMSO-d6) δ 7.65 (s, 1H), 5.18 - 5.07 (m, 1H), 4.23 - 4.11 (m, 2H), 3.88 (s, 2H), 3.86 - 3.76 (m, 2H).

[0230] Scheme for Route 17 [ka]

[0231] Step 17.a: 3,3,3-trifluoropropylimidazole-1-carboxylate [ka] 3,3,3-Trifluoropropan-1-ol (1.00 g, 8.77 mmol) in DCM (20 mL) was added to a solution of CDI (2.13 g, 13.1 mmol) in THF (50 mL) at 0 °C under N2, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel (12 to 100% EtOAc in heptane) to give the title compound (92% purity, 827 mg, 3.89 mmol, 44% yield) as a colorless oil; 1 H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.58 (s, 1H), 7.12 - 7.08 (m, 1H), 4.64 - 4.58 (m, 2H), 2.87 (tp, J = 11.3, 5.8 Hz, 2H).

[0232] Intermediate 38 (Step 17.b): (3,3,3-trifluoropropoxy)carbohydrazide [ka] A solution of 3,3,3-trifluoropropylimidazole-1-carboxylate (92% purity, 8.95 g, 39.6 mmol) in DCM (140 mL) was treated with NH2NH2·HO (7.8 mL, 0.158 mol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with IPA (30 mL) and HO (50 mL), and the organic layer was isolated and washed sequentially with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (90% purity, 4.09 g, 21.4 mmol, 54% yield) as a pale yellow oil. 1 H NMR (500 MHz, chloroform-d) δ 2.28 - 2.57 (m, 2H), 3.69 (s, 2H), 4.19 - 4.36 (m, 2H), 5.99 (s, 1H).

[0233] Scheme for Route 18 [ka]

[0234] Step 18.a: {[2-(difluoromethoxy)ethoxy]methyl}benzene [ka] To a solution of 2-(benzyloxy)ethanol (1.50 g, 9.86 mmol) in anhydrous ACN (20 mL) was added CuI (469 mg, 2.46 mmol), and the mixture was stirred at 50° C. for 5 minutes. A solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.63 g, 14.8 mmol) in anhydrous ACN (10 mL) was added dropwise over 25 minutes, and the resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc. The resulting precipitate was filtered under vacuum, and the filtrate was isolated and concentrated in vacuo. The residue was purified by chromatography on silica gel (10 to 100% EtOAc in heptane) to afford the title compound (90% purity, 620 mg, 2.76 mmol, 28% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ 7.40 - 7.27 (m, 5H), 6.28 (t, J = 74.8 Hz, 1H), 4.58 (s, 2H), 4.04 - 3.97 (m, 2H), 3.71 - 3.62 (m, 2H); 19 F NMR (376 MHz, chloroform-d) δ -84.27.

[0235] Intermediate 39 (Step 18.b): 2-(Difluoromethoxy)ethan-1-ol [ka] A suspension of {[2-(difluoromethoxy)ethoxy]methyl}benzene (90% purity, 620 mg, 2.76 mmol) and 10% Pd / C (587 mg, 0.552 mmol) in THF (7.5 mL) was stirred under H for 18 h. The reaction mixture was filtered through Celite and washed with THF. The filtrate was recharged with 10% Pd / C (1.47 g, 1.38 mmol), and the mixture was stirred under H for 18 h. The reaction mixture was filtered through Celite and washed with THF to give a crude solution estimated to be 2.23% of the title compound in THF / toluene (2.23:95.9:1.83, approximately 10 mL); 1H NMR (400 MHz, chloroform-d) δ 6.20 (t, J = 74.9 Hz, 1H), 3.89 - 3.81 (m, 2H), 3.76 - 3.56 (m, 2H).

[0236] Scheme for Route 19 [ka]

[0237] Step 19.a: 2-(ethenyloxy)ethyl benzoate [ka] To a solution of 2-(ethenyloxy)ethan-1-ol (1.00 g, 11.3 mmol) in DCM (40 mL) at 0 °C, EtN (4.0 mL, 28.4 mmol) was added dropwise, followed by benzoyl chloride (2.0 mL, 17.0 mmol), and the mixture was stirred at room temperature for 6 h. The reaction mixture was cooled to 0 °C and quenched with 1 M aqueous HCl (10 mL). The aqueous solution was extracted with DCM (3 × 20 mL), and the combined organic extracts were washed successively with saturated aqueous NaHCO (15 mL) and brine (15 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0–80% EtOAc in heptane) to afford the title compound (760 mg, 3.95 mmol, 35% yield) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.93 (m, 2H), 7.70 - 7.61 (m, 1H), 7.58 - 7.49 (m, 2H), 6.55 (dd, J = 14.3, 6.8 Hz, 1H), 4.51 - 4.45 (m, 2H), 4.26 (dd, J = 14.3, 1.9 Hz, 1H), 4.05 - 3.99 (m, 3H).

[0238] Step 19.b: 2-(2,2-difluorocyclopropoxy)ethyl benzoate [ka] To a solution of 2-(ethenyloxy)ethyl benzoate (50 mg, 0.260 mmol) in THF (2 mL) was added TMSCF (77 μL, 0.520 mmol) and NaI (86 mg, 0.572 mmol), and the mixture was stirred at 65 °C under N for 4 h. The reaction mixture was cooled to room temperature, diluted with HO (5 mL), and extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-80% EtOAc in heptane) to afford the title compound (62 mg, 0.246 mmol, 94% yield) as a clear oil. 1 H NMR (500 MHz, DMSO-d6) δ 8.02 - 7.91 (m, 2H), 7.71 - 7.62 (m, 1H), 7.59 - 7.48 (m, 2H), 4.49 - 4.37 (m, 2H), 4.02 - 3.93 (m, 1H), 3.95 - 3.84 (m, 2H), 1.76 - 1.65 (m, 1H), 1.60 - 1.50 (m, 1H); M / Z: 243 [M+H] + , ESI + , RT = 1.22 (S1).

[0239] Intermediate 40 (Step 19.c): 2-(2,2-Difluorocyclopropoxy)ethan-1-ol [ka] To a solution of 2-(2,2-difluorocyclopropoxy)ethyl benzoate (60 mg, 0.248 mmol) in 2-methyloxolane (1 mL) was added 1 M aqueous NaOH (0.99 mL, 0.991 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with HO (3 mL) and extracted with EtO (3 × 3 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo at room temperature to give the title compound (17 mg, 0.123 mmol, 50% yield) as a clear oil. 1 H NMR (500 MHz, DMSO-d6) δ 4.72 (t, J = 5.3 Hz, 1H), 3.91 - 3.84 (m, 1H), 3.59 - 3.49 (m, 4H), 1.71 - 1.59 (m, 1H), 1.54 - 1.43 (m, 1H).

[0240] Scheme for Route 20 [ka]

[0241] Step 20.a: 1,6-Diethyl 2,5-bis(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanedioate [ka] A mixture of (1,3-dioxoisoindolin-2-yl)potassium (4.55 g, 24.4 mmol) and diethyl 2,5-dibromohexanedioate (4.0 g, 11.1 mmol) in DMF (40 mL) was stirred at 90° C. for 4 h and then allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was diluted with HO (150 mL) and Extraction with EtOAc (2 x 100 mL) was performed. The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC (Method 5) to give the title compound (91% purity, 2.51 g, 4.64 mmol, 42% yield) as a yellow oil; 1H NMR (500 MHz, chloroform-d) δ 7.92 - 7.80 (m, 4H), 7.79 - 7.70 (m, 4H), 4.95 - 4.89 (m, 1H), 4.82 - 4.74 (m, 1H), 4.23 - 4.07 (m, 4H), 2.38 - 2.21 (m, 4H), 1.20 - 1.13 (m, 6H); M / Z: 493 [M+H] + , ESI + , RT = 1.02 (S1).

[0242] Step 20.b: Ethyl 5-amino-6-oxopiperidine-2-carboxylate [ka] Methylhydrazine (0.73 mL, 13.72 mmol) was added to a suspension of 1,6-diethyl 2,5-bis(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanedioate (2.40 g, 4.64 mmol) in EtOH (25 mL), and the mixture was stirred at reflux for 6 h. The reaction mixture was semi-concentrated and cooled to 0 °C. The solid was filtered under vacuum, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOH (5 mL) and purified using an SCX-2 cartridge, first flushed with EtOH (2 × 20 mL) and secondly eluted with 7 M NH in MeOH, to give the title compound (835 mg, 4.48 mmol, 97% yield) as a brown oil; M / Z: 187 [M+H] + , ESI + ,RT=0.16(S1).

[0243] Step 20.c: Ethyl 5-[2-(4-chloro-3-fluorophenoxy)acetamido]-6-oxopiperidine-2-carboxylate [ka] To a stirred solution of ethyl 5-amino-6-oxo-piperidine-2-carboxylate (700 mg, 3.76 mmol) and DIPEA (1.3 mL, 7.52 mmol) in DCM (8 mL) at 0 °C, a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (838 mg, 3.76 mmol) in DCM (2 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with DCM (20 mL) and washed with 1 M aqueous HCl (20 mL). The organic extract was dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC (Method 5) to give the title compound (72% purity, 433 mg, 0.836 mmol, 22% yield) as a white solid; 1 H NMR (400 MHz, chloroform-d) δ 7.41 - 7.28 (m, 2H), 6.80 - 6.74 (m, 1H), 6.73 - 6.66 (m, 1H), 6.33 - 6.25 (m, 1H), 4.51 - 4.46 (m, 2H), 4.35 - 4.22 (m, 2H), 4.20 - 4.11 (m, 1H), 2.71 - 2.49 (m, 1H), 2.47 - 2.13 (m, 2H), 2.01 - 1.88 (m, 1H), 1.80 - 1.67 (m, 1H), 1.64 - 1.50 (m, 1H), 1.35 - 1.26 (m, 2H), (contains 25% methyl ester impurity); M / Z: 373, 375 [M+Na] + , ESI + , RT = 0.80 (S2).

[0244] Intermediate 41 (Step 20.d): 5-[2-(4-chloro-3-fluorophenoxy)acetamido]-6-oxopiperidine-2-carboxylic acid [ka] To a solution of ethyl 5-[2-(4-chloro-3-fluorophenoxy)acetamido]-6-oxopiperidine-2-carboxylate (72% purity, 330 mg, 0.637 mmol) in HO (3 mL) and MeOH (5 mL) was added dropwise 2 M aqueous LiOH (0.38 mL, 0.765 mmol), and the mixture was stirred at room temperature for 5 h. The reaction mixture was acidified to pH 5 using 1 M aqueous HCl (0.6 mL), then concentrated in vacuo to give the title compound (55% purity, 397 mg, 0.633 mmol, 99% yield) as an off-white solid; M / Z: 345, 347, [M+H] + , ESI + ,RT=0.66, 0.68(S2).

[0245] Scheme for Route 21 [ka]

[0246] Step 21.a: 1-tert-butyl 2-ethyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-1,2-dicarboxylate [ka] To a mixture of 1-tert-butyl 2-ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate (2.30 g, 6.08 mmol, Intermediate 5), DMAP (74 mg, 0.608 mmol), and pyridine (0.98 mL, 12.2 mmol) in DCM (23 mL) at 0 °C, benzyl carbonochloridate (1.3 mL, 9.12 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured onto brine and extracted with DCM. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (91% purity, 2.97 g, 5.27 mmol, 87% yield) as a colorless oil;1 H NMR (400 MHz, chloroform-d) δ 7.45 - 7.27 (m, 10H), 5.28 - 5.17 (m, 2H), 4.92 - 4.84 (m, 2H), 4.56 (s, 1H), 4.28 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.51 (dd, J = 14.2, 5.0 Hz, 1H), 2.27 - 2.18 (m, 1H), 1.94 - 1.85 (m, 2H), 1.77 - 1.68 (m, 1H), 1.40 (s, 9H), 1.26 (td, J = 7.1, 3.0Hz, 3H); M / Z: 535 [M+Na] + , ESI + , RT = 1.44 (S1).

[0247] Intermediate 42 (Step 21.b): (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid [ka] To a solution of 1-tert-butyl 2-ethyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-1,2-dicarboxylate (91% purity, 2.97 g, 5.27 mmol) in THF (10 mL) and EtOH (10 mL) was added a solution of LiOH.HO (249 mg, 5.80 mmol) in HO (10 mL) and stirred at room temperature for 16 h. The reaction mixture was acidified to approximately pH 4 using 1 M aqueous HCl and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over NaSO, concentrated in vacuo, and purified by chromatography on silica gel (25–100% EtOAc in heptane) to afford the title compound (77% purity, 2.01 g, 3.19 mmol, 61% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.17 (m, 10H), 5.22 - 5.17 (m, 2H), 4.88 - 4.77 (m, 2H), 4.66 - 4.54 (m, 1H), 4.52 - 4.47 (m, 1H), 4.43 - 4.32 (m, 1H), 4.26 - 4.12 (m, 1H), 3.97 - 3.88 (m, 1H), 2.16 - 2.02 (m, 1H), 1.83 - 1.66 (m, 3H), 1.30 (s, 9H); M / Z: 507 [M+H] + , ESI + , RT = 1.28 (S1).

[0248] Step 21.c: (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-2-carboxylic acid hydrochloride [ka] To a stirred solution of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (77% purity, 200 mg, 0.318 mmol, Intermediate 42) in DCM (2 mL) at 0° C., 4 M HCl in 1,4-dioxane (0.50 mL, 2.0 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound (58% purity, 180 mg, 0.248 mmol, 78% yield) as a white solid; M / Z: 385 [M+H] + , ESI + ,RT=0.97(S1).

[0249] Step 21.d: (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-ethylpiperidine-2-carboxylic acid [ka] To a suspension of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-2-carboxylic acid hydrochloride (58% purity, 169 mg, 0.233 mmol) in DCE (5 mL), acetaldehyde (36 mg, 0.806 mmol) was added and stirred at room temperature for 10 min. STAB (198 mg, 0.93 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method 5) to give the title compound (78 mg, 0.183 mmol, 59% yield) as a beige solid; M / Z: 413 [M+H] + , ESI + ,RT=1.00(S1).

[0250] Intermediate 43 (Step 21.e): (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-ethylpiperidine-2-carboxylic acid [ka] To a solution of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-ethylpiperidine-2-carboxylic acid (78 mg, 0.183 mmol) and BocO (52 mg, 0.238 mmol) in EtOH (10 mL) was added 10% Pd / C (10 mg, 0.0940 mmol), and the mixture was stirred under H at room temperature for 6 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound (35% purity, 130 mg, 0.167 mmol, 91% yield) as a colorless gum; M / Z: 273 [M+H] + , ESI + ,RT=0.76(S1).

[0251] Following general route 21, as exemplified by intermediate 42, the intermediates in Table 7 were synthesized using the corresponding starting materials.

[0252] [Table 7]

[0253] Scheme for Route 22 [ka]

[0254] Step 22.a: Ethyl (2S,5R)-5-[(benzyloxy)amino]-1-(2-methoxyethyl)piperidine-2-carboxylate [ka] Ethyl (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate oxalate (500 mg, 1.36 mmol) was free-based using an SCX-2 cartridge, first flushed with DCM / MeOH (3:1) and then eluted with 2 M NH in MeOH / DCM (1:3), to give the amine. The solvent was concentrated in vacuo, and the residue was dissolved in anhydrous DMF (5 mL) and transferred to a microwave vial. KCO (375 mg, 2.71 mmol) and 1-bromo-2-methoxy-ethane (3 83 μL, 4.07 mmol) was added, and the mixture was stirred at 120° C. for 1 h. The reaction mixture was poured onto brine and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-10% 7 M NH3 in MeOH in DCM) to give the title compound (90% purity, 423 mg, 1.13 mmol, 83% yield) as a brown oil; 1 H NMR (400 MHz, chloroform-d) δ 7.40 - 7.26 (m, 5H), 5.57 (s, 1H), 4.68 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.49 (td, J = 5.9, 1.8 Hz, 2H), 3.35 - 3.26 (m, 4H), 3.24 - 3.12 (m, 1H), 3.08 (dd, J = 8.8, 3.7 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.65 - 2.55 (m, 1H), 2.18 (dd, J = 11.2, 8.2 Hz, 1H), 1.98 - 1.72 (m, 3H), 1.39 - 1.20 (m, 4H); + , ESI + , RT = 0.86 (S1).

[0255] Step 22.b: Ethyl (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-(2-methoxyethyl)piperidine-2-carboxylate [ka] A solution of ethyl (2S,5R)-5-[(benzyloxy)amino]-1-(2-methoxyethyl)piperidine-2-carboxylate (90% purity, 423 mg, 1.13 mmol), BocO (321 mg, 1.47 mmol), and 10% Pd / C (120 mg, 0.113 mmol) in EtOH (10 mL) was stirred at room temperature under H for 16 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give the title compound (50% purity, 627 mg, 0.949 mmol, 84% yield) as a colorless oil; M / Z: 331 [M+H] + , ESI + ,RT=0.78(S1).

[0256] Intermediate 45 (Step 22.c): (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-(2-methoxyethyl)piperidine-2-carboxylic acid [ka] A solution of ethyl (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-(2-methoxyethyl)piperidine-2-carboxylate (50% purity, 627 mg, 0.949 mmol) in THF (10 mL) was treated with a solution of LiOH·HO (408 mg, 9.48 mmol) in HO (10 mL) at room temperature for 16 h. 1 M aqueous HCl HO (7.6 mL, 7.59 mmol) was added dropwise, and the organic solvent was extracted and evaporated to give the title compound (286 mg, 0.95 mmol, 99% yield) as a white solid; M / Z: 303 [M+H]. + , ESI + ,RT=0.79(S1).

[0257] Scheme for Route 23 [ka]

[0258] Step 23.a: tert-butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}piperidine-1-carboxylate [ka] To a solution of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (77% purity, 1.0 g, 1.59 mmol, Intermediate 42) in anhydrous DMF (10 mL) at 0 °C, HATU (725 mg, 1.91 mmol) was added, followed by DIPEA (0.56 mL, 3.18 mmol) and stirred at room temperature for 10 minutes. 4-Chlorobenzohydrazide (271 mg, 1.59 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with HO (80 mL), stirred at room temperature for 20 minutes, and the resulting suspension was filtered under vacuum and washed with HO (50 mL). The residue was purified by chromatography on silica gel (5-80% EtOAc in heptane) to give the title compound (91% purity, 640 mg, 0.91 mmol, 57% yield) as a white solid; M / Z: 537, 539 [M-Boc+H] + , ESI + ,RT=1.33(S1).

[0259] Step 23.b: tert-butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] tert-Butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}piperidine-1-carboxylate (91% purity, 640 mg, To a solution of 0.91 mmol) of HCl (2.0 mL), DIPEA (0.12 mL, 0.669 mmol) and TsCl (191 mg, 1.0 mmol) were added, and the mixture was stirred at room temperature for 48 h. 15% aqueous NHOH (20 mL) was added, and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated in vacuo, diluted with HO (20 mL), and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (10–80% EtOAc in heptane) to afford the title compound (560 mg, 0.877 mmol, 96% yield) as a white gum; 1 H NMR (400 MHz, chloroform-d) δ 8.02 - 7.90 (m, 2H), 7.54 - 7.47 (m, 2H), 7.47 - 7.31 (m, 9H), 7.27 - 7.19 (m, 1H), 5.52 (s, 1H), 5.35 - 5.20 (m, 2H), 4.99 - 4.88 (m, 2H), 4.32 - 4.22 (m, 2H), 3.54 - 3.45 (m, 1H), 2.58 - 2.43 (m, 1H), 2.23 - 2.11 (m, 1H), 2.09 - 2.01 (m, 2H), 1.41 (s, 9H); M / Z: 641, 643 [M+Na] + , ESI + , RT = 1.53 (S1).

[0260] Step 23.c: tert-Butyl (2S,5R)-5-[(benzyloxy)amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (480 mg, 0.752 mmol) in MeOH (5 mL) was added 2 M aqueous LiOH (10 mL, 20.0 mmol), and the mixture was stirred at room temperature for 15 hours. The mixture was then heated to 50 °C for 3 hours, followed by stirring at room temperature for 110 hours. The reaction mixture was concentrated in vacuo, dissolved in HO (20 mL), and acidified to pH 9 using 1 M aqueous HCl. The solution was extracted with EtOAc (2 × 30 mL), and the combined organic extracts were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-100% EtOAc in heptane) to give the title compound (92% purity, 195 mg, 0.370 mmol, 49% yield); 1 H NMR (500 MHz, chloroform-d) δ 8.00 - 7.88 (m, 2H), 7.53 - 7.41 (m, 2H), 7.39 - 7.23 (m, 5H), 4.81 - 4.61 (m, 2H), 4.41 (d, J = 72.2 Hz, 2H), 3.14 (d, J = 65.3 Hz, 2H), 2.73 (s, 1H), 2.51 - 2.40 (m, 1H), 2.23 - 2.08 (m, 1H), 1.93 - 1.66 (m, 2H), 1.55 - 1.44 (m, 9H); M / Z: 485, 487 [M+H] + , ESI + , RT = 1.39 (S1).

[0261] Intermediate 46 (Step 23.d): tert-Butyl (2S,5R)-5-amino-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] tert-Butyl (2S,5R)-5-[(benzyloxy)amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2- To a solution of [methyl]piperidine-1-carboxylate (92% purity, 160 mg, 0.304 mmol) at −10 °C, NiCl 6H O (291 mg, 1.21 mmol) was added, followed by NaBH (344 mg, 9.11 mmol), and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method 5) to give the title compound (50 mg, 0.132 mmol, 43% yield) as a colorless gum; M / Z: 379, 381 [M+H] + , ESI + ,RT=0.97(S1).

[0262] Following general route 23, as exemplified by intermediate 46, the intermediates in Table 8 were synthesized using the corresponding starting materials.

[0263] [Table 8]

[0264] Scheme for Route 24 [ka]

[0265] Step 24.a: tert-butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-(hydrazinecarbonyl)piperidine-1-carboxylate (79% purity, 10.2 g, 20.5 mmol, Intermediate 30) in 1,4-dioxane (70 mL) was added a solution of NaHCO (2.58 g, 30.8 mmol) in HO (20 mL), followed by BrCN (2.17 g, 20.5 mmol), and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with HO, and the resulting precipitate was filtered under vacuum and washed with HO to give the title compound in quantitative yield (84% purity, 11.02 g, 22.2 mmol) as an off-white powder. 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.42 (m, 1H), 7.41 - 7.27 (m, 5H), 7.05 - 6.95 (m, 2H), 5.30 (s, 1H), 5.09 - 4.97 (m, 2H), 4.11 - 3.98 (m, 1H), 2.86 - 2.76 (m, 1H), 2.29 - 2.14 (m, 1H), 1.95 - 1.79 (m, 2H), 1.65 - 1.53 (m, 1H), 1.44 - 1.30 (m, 10H); M / Z: 318 [M-Boc+H] + , ESI + , RT = 0.86 (S2).

[0266] Step 24.b: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-(5-bromo-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate (84% purity, 11.02 g, 22.2 mmol) and CuBr (3 equivalents, 9.54 g, 66.5 mmol) in anhydrous ACN (400 mL), tert-butyl nitrite (90%, 17.6 mL, 133.0 mmol) was added, and the mixture was stirred at room temperature for 5 hours. An additional portion of CuBr (1.5 equivalents, 4.77 g, 33.3 mmol) and tert-butyl nitrite (90%, 8.79 mL, 66.5 mmol) was added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with EtOAc (250 mL) and washed with Rochelle's salt (2 × 200 mL) and H O (3 × 200 mL). The organic extract was dried over Na SO , concentrated in vacuo, and purified by chromatography on silica gel (0–100% EtOAc in heptane) to afford the title compound (2.02 g, 4.03 mmol, 18% yield) as a beige solid; 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 6.2 Hz, 1H), 7.41 - 7.28 (m, 5H), 5.57 - 5.41 (m, 1H), 5.05 (s, 2H), 4.08 - 3.91 (m, 1H), 3.65 - 3.53 (m, 1H), 2.96 - 2.84 (m, 1H), 2.33 - 2.23 (m, 1H), 1.99 - 1.90 (m, 1H), 1.88 - 1.72 (m, 1H), 1.65 - 1.57 (m, 1H), 1.38 (s, 9H); M / Z: 383 [M-Boc+H] + , ESI + , RT = 1.09 (S2).

[0267] Step 24.c: tert-Butyl(2R,5S)-5-{[(benzyloxy)carbamate] [bornyl]amino}-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of 2-(trifluoromethoxy)ethan-1-ol (13% in THF / toluene, 4.50 g, 4.43 mmol) in anhydrous THF (15 mL) at 0 °C, NaH (60%, 322 mg, 8.06 mmol) was added, and the mixture was stirred at 0 °C for 10 minutes. tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-(5-bromo-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (2.02 g, 4.03 mmol) in anhydrous THF (10 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo, and purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (85% purity, 1.60 g, 2.56 mmol, 64% yield) as a yellow oil; 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 6.1 Hz, 1H), 7.43 - 7.26 (m, 5H), 5.46 - 5.29 (m, 1H), 5.04 (s, 2H), 4.80 - 4.58 (m, 2H), 4.57 - 4.41 (m, 2H), 4.43 - 4.26 (m, 1H), 3.73 - 3.51 (m, 1H), 2.96 - 2.80 (m, 1H), 2.32 - 2.16 (m, 1H), 1.96 - 1.73 (m, 2H), 1.69 - 1.49 (m, 1H), 1.37 (s, 9H); M / Z: 531 [M-Boc+H] + , ESI + , RT = 3.83 (S4).

[0268] Intermediate 48 (Step 24.d): tert-Butyl (2R,5S)-5-amino-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (85% purity, 1.60 g, 2.56 mmol) in EtOH (45 mL) under N was added 10% Pd / C (3.27 g, 3.08 mmol), and the mixture was stirred under H at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to afford the title compound (49% purity, 843 mg, 1.04 mmol, 41% yield) as a light brown oil; 1 H NMR (400 MHz, DMSO-d6) δ 5.39 - 5.26 (m, 1H), 4.76 - 4.64 (m, 2H), 4.54 - 4.42 (m, 2H), 4.43 - 4.25 (m, 1H), 3.74 - 3.60 (m, 1H), 3.20 - 2.91 (m, 3H), 2.30 - 2.09 (m, 1H), 1.93 - 1.78 (m, 1H), 1.75 - 1.59 (m, 1H), 1.53 - 1.25 (m, 11H); M / Z: 397 [M+H] + , ESI + , RT = 1.76 (S4).

[0269] Scheme for Route 25 [ka]

[0270] Step 25.a: tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{N'-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyl]hydrazinecarbonyl}piperidine-1-carboxylate [ka] To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (500 mg, 2.63 mmol, Intermediate 54) in THF (20 mL) was added DIPEA (1.4 mL, 7.90 mmol), T3P (50% in EtOAc, 4.7 mL, 7.90 mmol), and tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (60% purity, 2.30 g, 2.77 mmol, Intermediate 29), and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (1.60 g, 2.29 mmol, 87% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.01 - 9.69 (m, 2H), 7.49 - 7.21 (m, 10H), 5.21 (s, 2H), 4.92 - 4.74 (m, 3H), 4.52 - 4.17 (m, 2H), 4.01 - 3.70 (m, 2H), 2.76 - 2.68 (m, 1H), 2.29 - 1.99 (m, 2H), 1.93 - 1.47 (m, 4H), 1.42 - 1.34 (m, 2H), 1.30 (s, 9H); M / Z: 687 [M+Na] + , ESI + , RT = 1.21 (S2).

[0271] Step 25.b: tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] A suspension of tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{N'-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (1.6 g, 2.29 mmol), KCO (2.0 g, 14.4 mmol), and TsCl (1.40 g, 7.22 mmol) in ACN (18 mL) was stirred at 80° C. for 1.5 h. The reaction mixture was partitioned between EtOAc (100 mL) and HO (50 mL), and the organic layer was isolated and washed with brine (30 mL). The organic extract was dried over MgSO4, concentrated in vacuo, and purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (92% purity, 1.05 g, 1.49 mmol, 62% yield) as a yellow oil; 1 H NMR (400 MHz, DMSO-d6) δ 7.48 - 7.27 (m, 10H), 5.36 - 5.27 (m, 1H), 5.21 (s, 2H), 4.96 - 4.83 (m, 3H), 4.19 - 4.09 (m, 1H), 4.01 - 3.93 (m, 1H), 3.51 - 3.40 (m, 1H), 2.91 - 2.79 (m, 2H), 2.31 - 2.21 (m, 1H), 2.07 - 1.96 (m, 2H), 1.96 - 1.87 (m, 2H), 1.41 (s, 2H), 1.28 (d, J = 5.8 Hz, 9H); M / Z: 547 [M-Boc+H] + , ESI + , RT = 1.27 (S2).

[0272] Intermediate 49 (Step 25.c): tert-Butyl (2R,5S)-5-amino-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (0.93 g, 1.43 mmol) in absolute EtOH (30 mL) was added 10% Pd / C (0.15 g, 0.144 mmol), and the resulting mixture was stirred at room temperature under H for 24 hours. Another portion of 10% Pd / C (0.15 g, 0.144 mmol) was added, and the reaction mixture was stirred at room temperature under H for 24 hours. Another portion of 10% Pd / C (0.15 g, 0.144 mmol) was added, and the reaction mixture was stirred at room temperature under H for 24 hours. The reaction mixture was warmed to 40°C and filtered through a pad of Celite, washing thoroughly with EtOH. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (0-20% MeOH in DCM) to afford the title compound (321 mg, 0.774 mmol, 54% yield) as a pale yellow oil; 1 H NMR (400 MHz, DMSO-d6) δ 5.39 (s, 1H), 4.90 (p, J = 7.5 Hz, 1H), 3.69 (d, J = 13.1 Hz, 1H), 3.52 - 3.36 (m, 2H), 3.06 - 2.92 (m, 2H), 2.92 - 2.76 (m, 2H), 2.32 - 2.13 (m, 2H), 1.96 - 1.85 (m, 1H), 1.80 - 1.59 (m, 1H), 1.49 (d, J = 13.6 Hz, 1H), 1.41 (s, 9H); M / Z: 407 [M+H] +, ESI + , RT = 0.71 - 0.76 (S2).

[0273] Scheme for Route 26 [ka]

[0274] Step 26.a: tert-Butyl 3-(ethenyloxy)azetidine-1-carboxylate [ka] A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.0 g, 28.9 mmol), 1-(ethenyloxy)butane (56 mL, 0.433 mol), bathophenanthroline (480 mg, 1.44 mmol), Pd(OAc) (981 mg, 1.44 mmol), and EtN (1.7 mL, 12.1 mmol) was degassed with N for 5 min, then sealed and heated at 80 °C for 24 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and washed with EtOAc. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (0–25% EtOAc in heptane) to give the title compound (93% purity, 3.60 g, 16.8 mmol, 58% yield) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ 6.37 (dd, J = 14.5, 6.9 Hz, 1H), 4.58 (tt, J = 6.5, 4.2 Hz, 1H), 4.17 (ddd, J = 9.7, 6.5, 1.0 Hz, 2H), 4.08 (dd, J = M / Z: no mas ion observed [M+H] + , ESI +, RT = 0.94 (S2).

[0275] Step 26.b: tert-Butyl 3-cyclopropoxyazetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(ethenyloxy)azetidine-1-carboxylate (93% purity, 3.60 g, 16.8 mmol) and chloro(iodo)methane (9.48 g, 53.8 mmol) in DCE (14 mL) at −5° C., a solution of 0.9 M diethylzinc in hexanes (30 mL, 26.9 mmol) was added dropwise over 60 min, maintaining the internal temperature between 0° C. and −5° C. The mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched using saturated aqueous NH4Cl (5 mL) followed by NH4OH solution (5 mL). The solution was extracted with methyl tert-butyl ether (3 × 20 mL), and the combined organic extracts were washed with brine (25 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-25% EtOAc in heptane) to afford the title compound (1.05 g, 4.92 mmol, 29% yield) as a colorless oil; 1 H NMR (500 MHz, chloroform-d) δ 4.25 (tt, J = 6.6, 4.5 Hz, 1H), 4.02 (ddd, J = 9.4, 6.6, 0.9 Hz, 2H), 3.82 - 3.72 (m, 2H), 3.17 (tt, J = 6.1, 3.0 Hz, 1H), 1.36 (s, 9H), 0.53 (dq, J = 5.0, 3.4, 2.6 Hz, 2H), 0.45 - 0.37 (m, 2H).

[0276] Intermediate 50 (Step 26.c): 3-Cyclopropoxyazetidine Hydrochloride [ka] To a solution of tert-butyl 3-cyclopropoxyazetidine-1-carboxylate (1.05 g, 4.92 mmol) in THF (3 mL) was added dropwise 4 M HCl in 1,4-dioxane (4.9 mL, 19.7 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and azeotroped with 2-propanol to give the title compound (75% purity, 0.75 g, 3.73 mmol, 76% yield) as a beige powder. 1 H NMR (500 MHz, methanol-d4) δ 4.62 - 4.52 (m, 1H), 4.35 - 4.27 (m, 2H), 4.04 - 3.97 (m, 2H), 3.40 (tt, J = 6.0, 3.0 Hz, 1H), 0.64 - 0.59 (m, 2H), 0.56 - 0.50 (m, 2H).

[0277] Scheme for Route 27 [ka]

[0278] Step 27.a: Benzyl 3-(ethenyloxy)cyclobutane-1-carboxylate [ka] A mixture of benzyl 3-hydroxycyclobutane-1-carboxylate (5.0 g, 24.2 mmol), 1-(ethenyloxy)butane (47 mL, 0.364 mol), bathophenanthroline (403 mg, 1.21 mmol), Pd(OAc) (824 mg, 1.21 mmol), and EtN (1.4 mL, 10.2 mmol) was stirred at 80 °C under N for 24 h. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc (100 mL). The filtrate was concentrated in vacuo, and the resulting residue was purified by chromatography on silica gel (0 to 50% EtOAc in heptane) to afford the title compound (80% purity, 4.64 g, 16.0 mmol, 66% yield) as a yellow oil.1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.27 (m, 5H), 6.37 (dd, J = 14.4, 6.9 Hz, 1H), 5.12 (s, 2H), 4.40 - 4.27 (m, 1H), 4.12 (dd, J = 14.4, M / Z: 233 [M+H] + , ESI + , RT = 1.01 (S2).

[0279] Step 27.b: Benzyl 3-cyclopropoxycyclobutane-1-carboxylate [ka] To a solution of benzyl 3-(ethenyloxy)cyclobutane-1-carboxylate (80% purity, 4.64 g, 16.0 mmol) in DCE (40 mL) was added dropwise at 0 °C chloro(iodo)methane (3.7 mL, 51.1 mmol), followed by 0.9 M ZnEt in hexane (28 mL, 25.6 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH Cl (30 mL), followed by NH OH (30 mL). The aqueous solution was extracted with EtOAc (3 × 100 mL), and the combined organic extracts were dried over Na SO and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (90% purity, 1.55 g, 5.66 mmol, 35% yield) as a colorless oil. 1 H NMR (500 MHz, DMSO-d6) δ 7.40 - 7.31 (m, 5H), 5.09 (s, 2H), 4.00 - 3.91 (m, 1H), 3.23 - 3.16 (m, 1H), 2.82 - 2.71 (m, 1H), 2.48 - 2.44 (m, 2H), 2.08 - 1.94 (m, 2H), 0.48 - 0.40 (m, 2H), 0.43 - 0.35 (m, 2H); M / Z: 247 [M+H] + , ESI + , RT = 1.00 (S2).

[0280] Intermediate 51 (Step 27.c): 3-Cyclopropoxycyclobutane-1-carboxylic acid [ka] To a solution of benzyl 3-cyclopropoxycyclobutane-1-carboxylate (90% purity, 1.55 g, 5.66 mmol) in absolute EtOH (20 mL) was added 10% Pd / C (606 mg, 0.570 mmol), and the mixture was stirred at room temperature under H for 24 h. The reaction mixture was filtered over Celite, washed with EtOAc (50 mL), and the filtrate was concentrated in vacuo to give the title compound (90% purity, 981 mg, 5.65 mmol) as a colorless oil in quantitative yield; 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 4.14 - 3.97 (m, 1H), 3.97 - 3.88 (m, 1H), 3.21 - 3.17 (m, 1H), 2.43 - 2.38 (m, 2H), 1.99 - 1.88 (m, 2H), 0.48 - 0.35 (m, 4H); M / Z: 157 [M+H] + , ESI + , RT = 0.64 (S2).

[0281] Scheme for Route 28 [ka]

[0282] Step 28.a: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-sulfanyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (300 mg, 0.674 mmol, Intermediate 26) in anhydrous THF (15 mL), TCDI (144 mg, 0.809 mmol) was added, and the mixture was stirred at 70 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with HO (20 mL), and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo to give the title compound (85% purity, 360 mg, 0.628 mmol, 93% yield) as a beige powder; 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 6.9 Hz, 1H), 7.98 (s, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.18 (s, 2H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (dd, J = 9.0, 2.0 Hz, 1H), 5.31 (s, 1H), 3.89 (s, 2H), 2.97 (d, J = 12.0 Hz, 1H), 2.15 (dd, J = 11.6, 6.6 Hz, 1H), 1.94 (d, J = 13.9 Hz, 1H), 1.78 (t, J = 13.5 Hz, 1H), 1.62 (d, J = 12.4 Hz, 1H), 1.39 (s, 9H); M / Z: 485, 487 [MH] - , ESI - , RT = 0.98 (S2).

[0283] Step 28.b: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] Mel (0.43 mL, 6.98 mmol) was added dropwise to a suspension of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-sulfanyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (85% purity, 2.0 g, 3.49 mmol), K2CO3 (965 mg, 6.98 mmol) and DMF (15 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 1 M aqueous NaOH (10 mL) and extracted with DCM (2 × 30 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the title compound (1.80 g, 3.41 mmol, 98% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.9 Hz, 1H), 6.90 - 6.72 (m, 1H), 5.48 (s, 1H), 4.69 - 4.52 (m, 2H), 3.91 (d, J = 12.7 Hz, 2H), 2.97 (d, J = 12.4 Hz, 1H), 2.70 M / Z: 401, 403 [M-Boc+H] + , ESI + , RT = 1.02 (S2).

[0284] Intermediate 52 (Step 28.c): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-methanesulfonyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (1.80 g, 3.41 mmol) and m-CPBA (60% purity, 2.95 g, 10.2 mmol) in DCM (40 mL) was stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (20 mL) and saturated NaSO solution and stirred at room temperature for 15 min. The organic layer was isolated using a phase separator and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-40% EtOAc in heptane) to give the title compound (89% purity, 1.07 g, 1.79 mmol, 52% yield) as a light brown solid; M / Z: 433, 435 [M-Boc+H] + , ESI + ,RT=0.99(S2).

[0285] Scheme for Route 29 [ka]

[0286] Step 29.a: tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[N'-(4-chlorobenzoyl)hydrazinecarbonyl]piperidine-1-carboxylate [ka] To a solution of (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (94% purity, 2.21 g, 5.93 mmol, Intermediate 4), DIPEA (2.1 mL, 11.9 mmol), and 4-chlorobenzohydrazide (1.11 g, 6.52 mmol) in anhydrous DMF (20 mL) was added HATU (2.71 g, 7.11 mmol), and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with saturated aqueous NaHCO (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (76% purity, 1.61 g, 2.43 mmol, 41% yield) as a yellow oil; M / Z: 403, 405 [M-Boc+H] + , ESI + ,RT=0.98(S2).

[0287] Step 29.b: tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[N'-(4-chlorobenzoyl)hydrazinecarbonyl] in ACN (12 mL) A mixture of piperidine-1-carboxylate (76%, 1.61 g, 2.43 mmol), KCO (2.02 g, 14.6 mmol), and TsCl (1.39 g, 7.30 mmol) was stirred at 80 °C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with HO (10 mL) and brine (10 mL), and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over NaSO, concentrated in vacuo, and purified by chromatography on silica gel (0–50% EtOAc in heptane) to afford the title compound (85% purity, 410 mg, 0.719 mmol, 30% yield) as a beige gum; M / Z: 485, 487 [M+H] + , ESI + ,RT=1.71(S1).

[0288] Intermediate 53 (Step 29.c): tert-butyl (2R,5S)-5-amino-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (410 mg, 0.845 mmol) in MeOH (40 mL) was added NiCl H O (811 mg, 3.38 mmol) followed by NaBH (959 mg, 25.36 mmol) at 0 °C, and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, dissolved in H O and EtOAc, and the resulting suspension was filtered through Celite. The phases were separated, and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na SO and concentrated in vacuo. The residue was purified by preparative HPLC (Method 7) to give the title compound (142 mg, 0.375 mmol, 44% yield); 1H NMR (500 MHz, chloroform-d) δ 8.40 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.65 (s, 1H), 4.31 (d, J = 13.4 Hz, 1H), 3.61 M / Z: 379, 381 [M+H] + , ESI + , RT = 0.73 (S2).

[0289] Scheme for Route 30 [ka]

[0290] Step 30.a: Benzyl (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylate [ka] 2-Fluoropyridine (15 mL, 0.180 mol) and TMS-CF3 (27 mL, 0.180 mol) were added dropwise sequentially to a solution of benzyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate (12.4 g, 59.9 mmol), AgOTf (46.3 g, 0.180 mol), Selectfluor (31.8 g, 89.8 mmol), and KF (13.9 g, 0.240 mol) in EtOAc (500 mL), and the mixture was stirred in a foil-covered flask at room temperature under N2 for 20 h. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL), and concentrated in vacuo. The residue was purified by chromatography on silica gel (5–30% EtOAc in heptane) to afford the title compound (7.47 g, 27.2 mmol, 45% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.43 - 7.29 (m, 5H), 5.14 (s, 2H), 4.57 (p, J = 7.5 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.64 (dtd, J = 10.0, 7.3, 2.6 Hz, 2H), 2.53 (qd, J = 9.8, 9.4, 2.0 Hz, 2H); 19 F NMR (376 MHz, chloroform-d) δ -59.56.

[0291] Intermediate 54 (Step 30.b): (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid [ka] A suspension of benzyl (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylate (7.85 g, 28.6 mmol) and 5% Pd / C (3.05 g, 1.43 mmol) in EtOH (250 mL) was stirred under H at room temperature for 18 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound ( 5.09 g, 27.6 mmol, 97% yield) obtained as a yellow oil; 1 H NMR (400 MHz, chloroform-d) δ 4.60 (p, J = 7.5 Hz, 1H), 2.89 - 2.61 (m, 4H), 2.61 - 2.37 (m, 2H); 19 F NMR (376 MHz, chloroform-d) δ -59.62 (3F, s).

[0292] Step 30.c: ({[(benzyloxy)carbonyl]amino}amino)[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]methanone [ka] To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (1.00 g, 5.43 mmol, Intermediate 54) in anhydrous DMF (10 mL) at 0 °C, HATU (2.27 g, 5.97 mmol) was added, followed by DIPEA (1.9 mL, 10.9 mmol) and stirred for 10 min. Benzylhydrazine carboxylate (0.90 g, 5.43 mmol) was added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. Purification by chromatography on silica gel (15–100% EtOAc in heptane) afforded the title compound (1.03 g, 3.07 mmol, 56% yield) as a white powder; 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.35 - 8.75 (m, 1H), 7.52 - 7.16 (m, 5H), 5.16 - 4.96 (m, 2H), 4.89 - 4.66 (m, 1H), 2.75 - 2.57 (m, 1H), 2.50 (s, 2H), 2.35 - 2.14 (m, 2H); M / Z: 333 [M+H] + , ESI + , RT = 0.88 (S2).

[0293] Intermediate 55 (Step 30.d): (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carbohydrazide [ka] A mixture of ({[(benzyloxy)carbonyl]amino}amino)[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]methanone (1.03 g, 3.07 mmol) and 10% Pd / C (100 mg, 3.07 mmol) in EtOH (10 mL) was stirred under H at room temperature for 18 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound (0.56 g, 2.68 mmol, 87% yield) as a gray solid; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 4.82 - 4.66 (m, 1H), 4.30 (s, 2H), 2.60 - 2.51 (m, 1H), 2.48 - 2.38 (m, 2H), 2.33 - 2.21 (m, 2H); M / Z: 199 [M+H] + , ESI + , RT = 0.54 (S2).

[0294] Scheme for Route 31 [ka]

[0295] [Example 1] (Step 31.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (90% purity, 70 mg, 0.282 mmol, Intermediate 19) in DCM (2 mL) was added tert-butyl (2R,5S)-5-amino-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (123 mg, 0.282 mmol, Intermediate 6) and DIPEA (0.099 mL, 0.565 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo, and purified by chromatography on silica gel (17-100% EtOAc in heptane) to give the title compound (78 mg, 0.130 mmol, 46% yield) as a brown powder; M / Z: 499, 501 [M-Boc+H] + , ESI +,RT=1.20(S2).

[0296] [Example 2] (Step 31.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenoxy]acetamido}-2-{ To a solution of [[(2-methyl-1,3,4-oxadiazol-2-yl)-piperidine-1-carboxylate] (78 mg, 0.130 mmol, Example 1), ZnBr (88 mg, 0.391 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous NaHCO (3 mL) and extracted with DCM:IPA (80:20) (3 × 3 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo, and purified by preparative HPLC (Method 4) to give the title compound (8.0 mg, 0.0152 mmol, 12% yield) as a white powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.26 - 8.17 (m, 2H), 8.04 - 7.94 (m, 3H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.83 (m, 1H), 4.54 (s, 2H), 4.05 - 3.98 (m, 1H), 3.81 - 3.69 (m, 1H), 3.07 - 2.96 (m, 2H), 2.15 - 2.06 (m, 1H), 1.99 - 1.91 (m, 1H), 1.85 - 1.73 (m, 1H), 1.63 - 1.51 (m, 1H); 501 [M+H] + , ESI +, RT = 2.47 (S4).

[0297] Scheme for Route 32 [ka]

[0298] [Example 3] (Step 32.a): tert-Butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of 2-(4-chlorophenoxy)propanoic acid (69 mg, 0.343 mmol) in DMF (1 mL), DIPEA (0.18 mL, 1.03 mmol) and HATU (143 mg, 0.377 mmol) were added and stirred at room temperature for 10 minutes. tert-Butyl (2R,5S)-5-amino-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (141 mg, 0.343 mmol, Intermediate 6) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (2 × 15 mL), dried over MgSO and concentrated in vacuo. The residue was purified by chromatography on silica gel (12-100% EtOAc in heptane) to give the title compound (90% purity, 123 mg, 0 (186 mmol, 54% yield) Obtained as a clear oil; M / Z: 495, 497 [M-Boc+H] + , ESI + ,RT=1.22(S2).

[0299] [Example 4] (Step 32.b): 2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (107 mg, 0.181 mmol, Example 3) in DCM (2 mL), TFA (70 μL, 0.947 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, dissolved in saturated aqueous NaHCO (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over MgSO, concentrated in vacuo, triturated with DMSO:MeCN:HO (60:30:10), and washed with MeCN (1 mL) to give the title compound (19 mg, 0.0383 mmol, 21% yield) as a white powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.25 - 8.19 (m, 2H), 8.03 - 7.94 (m, 3H), 7.36 - 7.30 (m, 2H), 6.96 - 6.89 (m, 2H), 4.72 - 4.64 (m, 1H), 4.02 - 3.95 (m, 1H), 3.74 - 3.63 (m, 1H), 3.03 - 2.91 (m, 2H), 2.13 - 2.00 (m, 1H), 1.96 - 1.82 (m, 1H), 1.82 - 1.69 (m, 1H), 1.60 - 1.46 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H); M / Z: 495, 497 [M+H] + , ESI + , RT = 2.47 (S4).

[0300] Following the synthetic steps of General Route 32, the example compounds in Table 9 were synthesized using the corresponding intermediates as exemplified by Example 4.

[0301] [Table 9]

[0302] Scheme for Route 33 [ka]

[0303] [Example 6] (Step 33.a): tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] To a suspension of 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetic acid (50 mg, 0.243 mmol, Intermediate 12) in DCM (5 mL) was added thionyl chloride (0.10 mL, 1.37 mmol), and the mixture was stirred at 45° C. for 4 hours and then at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped using heptane. The resulting residue was dissolved in DCM (5 mL) and added to a solution of tert-butyl (2R,5S)-5-amino-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (71 mg, 0.187 mmol, Intermediate 53) and DIPEA (0.16 mL, 0.937 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours and then poured onto saturated aqueous NaHCO (10 mL). The aqueous solution was extracted with DCM (2 x 20 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by chromatography on silica gel (20-100% EtOAc in heptane) afforded the title compound (27 mg, 0.0467 mmol, 25% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 4.60 - 4.48 (m, 2H), 4.24 - 4.08 (m, M / Z: 588, 590, 592 [M+Na] + , ESI + , RT = 1.09 (S2).

[0304] [Example 7] (Step 33.b): 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (48 mg, 0.0830 mmol, Example 6) in DCM (2 mL), ZnBr (56 mg, 0.249 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered under vacuum, washed with DCM, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Method 1) to obtain the title compound (11 mg, 0.0211 mmol, 25% yield) as a white solid; 1 H NMR (500 MHz, DMSO-d6) δ 8.20 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.75 - 7.68 (m, 2H), 4.68 (s, 2H), 4.38 (s, 1H), 3.90 (s, 1H), 3.22 (d, J = 11.4 Hz, 1H), 2.71 (t, J = 11.1 Hz, 1H), 2.24 (d, J = 11.1 Hz, 1H), 1.99 (d, J = 10.3 Hz, 1H), 1.94 - 1.84 (m, 1H), 1.69 - 1.59 (m, 1H); M / Z: 466, 468, 470 [M+H] + , ESI + , RT = 2.01 (S4).

[0305] Scheme for Route 34 [ka]

[0306] [Example 8] (Step 34.a): tert-Butyl (2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of 2-(3,4-dichlorophenoxy)acetic acid (104 mg, 0.472 mmol) in DMF (4 mL), HATU (180 mg, 0.472 mmol) and DIPEA (0.21 mL, 1.18 mmol) were added and stirred at room temperature for 10 minutes. tert-Butyl (2R,5S)-5-amino-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (160 mg, 0.394 mmol, Intermediate 49) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound (52% purity, 105 mg, 0.0896 mmol, 23% yield) as a yellow oil; M / Z: 509, 511 [M- t Butyl + H] + , ESI + ,RT=1.17(S2).

[0307] [Example 9] (Step 34.b): 2-(3,4-Dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (52% purity, 105 mg, 0.0896 mmol, Example 8) in DCM (1 mL), ZnBr (61 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with HO (10 mL) and extracted with DCM / IPA (9:1, 2 × 20 mL). The combined organic extracts were dried over MgSO, concentrated in vacuo, and purified by preparative HPLC (Method 3) to give the title compound (6.7 mg, 0.0130 mmol, 15% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 6.99 (dd, J = 8.9, 2.9 Hz, 1H), 4.98 - 4.87 (m, 1H), 4.53 (s, 2H), 3.86 (dd, J = 10.5, 2.7 Hz, 1H), 3.71 (s, 1H), 3.45 (d, J = 2.1 Hz, 1H), 2.99 (dd, J = 11.8, 2.9 Hz, 1H), 2.89 - 2.80 (m, 3H), 2.43 (s, 3H), 2.00 - 1.97 (m, 1H), 1.92 - 1.88 (m, 1H), 1.69 - 1.64 (m, 1H), 1.54 - 1.49 (m, 1H); M / Z: 509, 511 [M+H] + , ESI + , RT = 2.42 (S4).

[0308] Following the synthetic steps of General Route 34, the example compounds in Table 10 were synthesized using the corresponding intermediates as exemplified by Example 9.

[0309] [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0310] Scheme for Route 35 [ka]

[0311] [Example 16] (Step 35.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] To a solution of 2-(4-chloro-2-fluorophenoxy)acetic acid (20 mg, 0.0999 mmol) in DCM (1 mL), T3P (50% in EtOAc, 713 μL, 0.120 mmol) and DIPEA (41 μL, 0.233 mmol) were added and stirred at room temperature for 10 minutes. tert-Butyl (2R,5S)-5-amino-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (38 mg, 0.10 mmol, Intermediate 47) was added, and the resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with H2O (1 mL) and extracted with DCM (2 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give an orange solid. The crude material was carried forward without purification.

[0312] [Example 17] (Step 35.b): 2-(4-chloro-2-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (57 mg, 0.10 mmol, Example 16) in anhydrous DCM (1 mL), ZnBr (90 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous NaHCO and extracted with DCM / IPA (4:1, 2 × 2 mL). The combined organic extracts were concentrated in vacuo and purified by preparative HPLC (Method 4) to give the title compound (88% purity, 1.7 mg, 0.0032 mmol, 3% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 1.59 - 1.64 (m, 2H), 1.89 - 2.01 (m, 1H), 2.14 (dq, J = 12.8, 4.6, 4.0, 2H), 2.66 (dd, J = 12.0, 7.9, 1H), 2.68 - 2.79 (m, 2H), 3.34 (dd, J = 12.0, 3.5, 1H), 4.02 (dd, J = 8.1, 3.4, 1H), 4.08 (ddt, J = 12.3, 8.2, 4.1, 1H), 4.53 (s, 2H), 4.72 (t, J = 6.2, 2H), 6.86 - 6.97 (m, 2H), 7.11 (ddd, J = 8.7, 2.4, 1.7, 1H), 7.19 (dd, J = 10.6, 2.5, 1H); M / Z: 467, 469 [M+H] + , ESI +, RT = 1.98 (S4).

[0313] Following the synthetic steps of General Route 35, the example compounds in Table 11 were synthesized using the corresponding intermediates as exemplified by Example 17.

[0314] [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5]

[0315] Scheme for Route 36 [ka]

[0316] Step 36.a: tert-butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}pyrrolidine-1-carboxylate [ka] To a solution of (2R,4S)-1-[(tert-butoxy)carbonyl]-4-[2-(4-chloro-3-fluorophenoxy)acetamido]pyrrolidine-2-carboxylic acid (80% purity, 200 mg, 0.384 mmol, Intermediate 34), 4-chlorobenzohydrazide (65 mg, 0.384 mmol), and DIPEA (0.080 mL, 0.461 mmol) in DMF (1 mL), T3P (50% in EtOAc, 0.25 mL, 0.422 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (89% purity, 158 mg, 0.247 mmol, 64% yield) as a pale yellow gum; 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (d, J = 48.5 Hz, 1H), 10.05 (d, J = 9.9 Hz, 1H), 8.34 (t, J = 6.4 Hz, 1H), 7.98 - 7.85 (m, 2H), 7.58 (dd, J = 8.5, 4.7 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (d, J = 11.5 Hz, 1H), 6.91 - 6.80 (m, 1H), 4.55 (s, 2H), 4.52 - 4.39 (m, 1H), 4.34 (dq, J = 12.6, 4.4 Hz, 1H), 3.73 - 3.59 (m, 1H), 3.25 - 3.11 (m, 1H), 2.31 - 2.11 (m, 2H), 1.40 (s, 9H); M / Z: 469, 471, 473 [M-Boc+H] + , ESI + , RT = 0.95 (S2).

[0317] [Example 30] (Step 36.b): tert-Butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate [ka] A suspension of tert-butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}pyrrolidine-1-carboxylate (89% purity, 158 mg, 0.247 mmol), K2CO3 (205 mg, 1.48 mmol), and TsCl (0.012 mL, 0.741 mmol) in ACN (2 mL) was stirred at 80 °C for 2.5 h. The reaction mixture was partitioned between EtOAc (30 mL) and HO (20 mL). The organic layer was isolated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0 to 100% EtOAc in heptane) to afford the title compound (119 mg, 0.208 mmol, 84% yield) as a pale yellow gum. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (dd, J = 9.0, 1.7 Hz, 1H), 5.30 - 5.18 (m, 1H), 4.66 - 4.47 (m, 3H), 3.82 - 3.69 (m, 1H), 3.44 - 3.40 (m, 1H), 2.44 - 2.35 (m, 2H), 1.42 - 1.18 (m, 9H); M / Z: 595, 597 [M+MeCN+H] + , ESI + , RT = 1.11 (S2).

[0318] [Example 31] (Step 36.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,5R)-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-3-yl]acetamide [ka] A solution of tert-butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate (119 mg, 0.207 mmol, Example 30) and TFA (0.15 mL, 2.07 mmol) in DCM (2.5 mL) was stirred at room temperature for 4 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3, and the organic layer was isolated using a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method 3) and then triturated with Et2O to give the title compound (44 mg, 0.0965 mmol, 47% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (d, J = 7.2 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.72 - 7.65 (m, 2H), 7.51 (t, J = 8.9 Hz, 1H), 7.10 (dd, J = 11.4, 2.8 Hz, 1H), 6.90 - 6.85 (m, 1H), 4.65 (s, 1H), 4.55 (s, 2H), 4.46 - 4.37 (m, 1H), 3.16 - 3.07 (m, 2H), 2.87 - 2.79 (m, 1H), 2.44 - 2.38 (m, 1H), 2.19 - 2.10 (m, 1H); M / Z: 451, 453, 455 [M+H] + , ESI + , RT = 2.26 (S4).

[0319] Scheme for Route 37 [ka]

[0320] Step 37.a: tert-butyl (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[(3,3,3-trifluoropropoxycarbonylamino)carbamoyl]piperidine-1-carboxylate [ka] To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (500 mg, 1.10 mmol, Intermediate 22) in anhydrous DMF (6 mL), DIPEA (0.40 mL, 2.29 mmol) and HATU (503 mg, 1.32 mmol) were added and stirred at room temperature for 10 minutes. (3,3,3-Trifluoropropoxy)carbohydrazide (273 mg, 1.43 mmol, Intermediate 38) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo, and purified by chromatography on silica gel (0-80% EtOAc in heptane) to afford the title compound (91% purity, 646 mg, 1.00 mmol, 91% yield) as a colorless oil; M / Z: 485, 487 [M-Boc+H] + , ESI + ,RT=0.96(S2).

[0321] [Example 32] (Step 37.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] A suspension of tert-butyl (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[(3,3,3-trifluoropropoxycarbonylamino)carbamoyl]piperidine-1-carboxylate (91% purity, 646 mg, 1.0 mmol), K2CO3 (833 mg, 6.03 mmol), and TsCl (576 mg, 3.02 mmol) in ACN (5 mL) was stirred at 80 °C for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by chromatography on silica gel (0 to 100% EtOAc in heptane) to afford the title compound (252 mg, 0.440 mmol, 44% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 5.38 (s, 1H), 4.65 (t, J = 5.7 Hz, 2H), 4.62 - 4.52 (m, 2H), 3.96 - 3.85 (m, 2H), 2.99 - 2.85 (m, 3H), 2.25 - 2.11 (m, 1H), 2.03 - 1.94 (m, 1H), 1.86 - 1.73 (m, 1H), 1.63 (d, J = 13.5 Hz, 1H), 1.37 (s, 9H); M / Z: 467, 469 [M-Boc+H] + , ESI + , RT = 1.07 (S2).

[0322] [Example 33] (Step 37.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide [ka] A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (107 mg, 0.185 mmol, Example 32) and TFA (0.14 mL, 1.85 mmol) in DCM (2 mL) was stirred at room temperature for 6 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was isolated, concentrated in vacuo, and purified by preparative HPLC (Method 3) to give the title compound (15 mg, 0.0298 mmol, 16% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.74 - 4.58 (m, 2H), 4.53 (s, 2H), 3.79 (dd, J = 10.5, 2.5 Hz, 1H), 3.76 - 3.62 (m, 1H), 3.06 - 2.80 (m, 3H), 2.47 - 2.41 (m, 1H), 2.05 - 1.81 (m, 2H), 1.76 - 1.59 (m, 1H), 1.50 (qd, J = 12.3, 3.7 Hz, 1H); M / Z: 467, 469 [M+H] + , ESI + , RT = 3.12 (S6).

[0323] Following the synthetic steps of General Route 37, the example compounds in Table 12 were synthesized using the corresponding intermediates as exemplified by Example 33.

[0324] [Table 12-1] [Table 12-2] [Table 12-3]

[0325] Scheme for Route 38 [ka]

[0326] Step 38.a: tert-butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[(3,3,3-trifluoropropoxy)carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate [ka] To a solution of (2S,5R)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (450 mg, 1.04 mmol, Intermediate 25) in anhydrous DMF (5 mL) was added HATU (47 (7 mg, 1.25 mmol) and DIPEA (0.36 mL, 2.09 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. (3,3,3-Trifluoropropoxy)carbohydrazide (90% purity, 260 mg, 1.36 mmol, Intermediate 38) was then added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc (25 mL) and 1 M aqueous HCl (25 mL). The organic layer was isolated, washed with saturated aqueous NaHCO3 (25 mL) and brine (2 x 25 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (20-100% EtOAc in heptane) to give the title compound (85% purity, 268 mg, 0.389 mmol, 37% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.22 (s, 1H), 7.98 (d, J = 7.1 Hz, 1H), 7.48 (m 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (dd, J = 8.9, 1.8 Hz, 1H), 4.74 - 4.44 (m, 3H), 4.22 (m, 2H), 3.87 (m, 2H), 2.63 (m, 2H), 2.02 (m, 2H), 1.85 (m, 1H), 1.58 (s, 2H), 1.37 (s, 9H); M / Z: 485, 487 [M-Boc+H] + , ESI + , RT = 0.96 (S2).

[0327] [Example 41] (Step 38.b): tert-Butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] A suspension of tert-butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[(3,3,3-trifluoropropoxy)carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (85% purity, 265 mg, 0.385 mmol), K2CO3 (319 mg, 2.31 mmol), and TsCl (220 mg, 1.16 mmol) in ACN (2.5 mL) was stirred at 80 °C for 24 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL), dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (88% purity, 68 mg, 0.106 mmol, 27% yield) as a brown oil;1 H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 - 6.78 (m, 1H), 5.38 (s, 1H), 4.65 (t, J = 5.7 Hz, 2H), 4.62 - 4.51 (m, 2H), 3.96 - 3.84 (m, 2H), 3.02 - 2.85 (m, 2H), 2.24 - 2.13 (m, 1H), 2.04 - 1.94 (m, 2H), 1.84 - 1.74 (m, 1H), 1.68 - 1.57 (m, 1H), 1.38 (s, 9H); M / Z: 467, 469 [M-Boc+H] + , ESI + , RT = 1.31 (S1).

[0328] [Example 42] (Step 38.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (88% purity, 55 mg, 0.0854 mmol) in DCM (1 mL), ZnBr (77 mg, 0.341 mmol) was added, and the mixture was stirred at room temperature under N for 18 hours. The reaction mixture was diluted with saturated aqueous NaHCO (3 mL) and extracted with DCM:IPA (80:20) (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (Method 3) to give the title compound (12 mg, 0.0249 mmol, 29% yield) as a white powder; 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 7.07 (dd, J = 11.4, 2.5 Hz, 1H), 6.87 - 6.81 (m, 1H), 4.64 (t, J = 5.5 Hz, 2H), 4.52 (s, 2H), 3.80 - 3.63 (m, 2H), 3.02 - 2.83 (m, 3H), 2.83 - 2.75 (m, 1H), 2.46 - 2.39 (m, 1H), 2.00 - 1.83 (m, 2H), 1.70 - 1.57 (m, 1H), 1.54 - 1.43 (m, 1H); M / Z: 467, 469, [M+H] + , ESI + , RT = 3.12 (S6).

[0329] Following the synthetic steps of general route 38, the example compounds in Table 13 were synthesized using the corresponding intermediates as exemplified by example 42.

[0330] [Table 13]

[0331] Scheme for Route 39 [ka]

[0332] [Example 44] 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperazin-3-yl]acetamide A solution of CSA (200 μL, 0.0172 mmol), 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide (40 mg, 0.0860 mmol, Example 35) and 1,3,5-trioxane (25 μL, 0.215 mmol) in DCE (0.5 mL) was stirred at room temperature under N for 45 minutes. STAB (55 mg, 0.258 mmol) was added, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with DCM (5 mL) and saturated aqueous NaHCO (5 mL). The organic layer was isolated, concentrated in vacuo, and purified by preparative HPLC (Method 2) to give the title compound (9.8 mg, 0.0194 mmol, 23% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 8.0 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.73 - 7.64 (m, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (dd, J = 8.9, 2.0 Hz, 1H), 4.55 (s, 2H), 4.00 - 3.86 (m, 1H), 3.52 (dd, J = M / Z: 479, 481, 482 [M+H] + , ESI + , RT = 3.00 (S4).

[0333] Following general route 39, the example compounds in Table 14 were synthesized using the corresponding intermediates as exemplified by Example 44.

[0334] [Table 14]

[0335] Scheme for Route 40 [ka]

[0336] Step 40.a: tert-butyl N-[(3R,6S)-6-{[(4-chlorophenyl)formohydrazide]carbonyl}-1-ethylpiperidin-3-yl]carbamate [ka] To a solution of (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-ethylpiperidine-2-carboxylic acid (50 mg, 0.183 mmol, Intermediate 43) in DMF (5 mL) at 0 °C, 4-chlorobenzohydrazide (41 mg, 0.238 mmol) was added, followed by HATU (83 mg, 0.220 mmol) and DIPEA (0.064 mL, 0.366 mmol), and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-100% EtOAc in heptane) to give the title compound (75% purity, 100 mg, 0.177 mmol, 96% yield); M / Z: 425, 427 [M+H] + , ESI + ,RT=0.87(S1).

[0337] Step 40.b: tert-butyl N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]carbamate [ka] tert-Butyl N-[(3R,6S)-6-{[(4- To a solution of [chlorophenyl]formohydrazide]carbonyl}-1-ethylpiperidin-3-yl]carbamate (75% purity, 100 mg, 0.177 mmol), TsCl (101 mg, 0.530 mmol) was added, followed by DIPEA (0.092 mL, 0.530 mmol), and the mixture was stirred at room temperature for 16 hours. 15% aqueous NH4OH (10 mL) was added, and the reaction mixture was concentrated in vacuo. The residue was dissolved in HO (20 mL) and extracted with DCM (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-100% EtOAc in heptane) to give the title compound (81% purity, 82 mg, 0.163 mmol, 92% yield) as a white solid; M / Z: 407, 409 [M+H] + , ESI + ,RT=1.02(S1).

[0338] Step 40.c: (3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-amine; trifluoroacetic acid [ka] To a solution of tert-butyl N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]carbamate (81% purity, 82 mg, 0.163 mmol) in DCM (1 mL) at 0° C., TFA (1.0 mL, 13.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound (28% purity, 160 mg, 0.106 mmol, 65% yield) as a beige gum; M / Z: 307, 309 [M+H] + , ESI + ,RT=0.84(S1).

[0339] [Example 47] (Step 40.d): 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide [ka] To a solution of (3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-piperidin-3-amine trifluoroacetic acid (28% purity, 160 mg, 0.106 mmol) in DCM (5 mL) was added DIPEA (0.056 mL, 0.319 mmol) followed by a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (29 mg, 0.128 mmol, Intermediate 19) in DCM (1 mL) at 0 ° C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with HO (10 mL) and extracted with DCM (2 × 10 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. The residue was purified by preparative HPLC (Method 5) to give the title compound (20 mg, 0.0397 mmol, 37% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 - 7.89 (m, 3H), 7.76 - 7.60 (m, 2H), 7.51 (t, J = 8.9 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.91 - 6.83 (m, 1H), 4.56 (s, 2H), 3.99 - 3.83 (m, 2H), 3.03 - 2.94 (m, 1H), 2.49 - 2.39 (m, 1H), 2.34 - 2.15 (m, 2H), 2.04 - 1.82 (m, 3H), 1.57 - 1.43 (m, 1H), 0.92 (t, J = 7.1 Hz, 3H); M / Z: 493, 495, 497 [M+H] + , ESI + , RT = 3.12 (S4).

[0340] Following general route 40, the example compounds in Table 15 were synthesized using the corresponding intermediates as exemplified by Example 47.

[0341] [Table 15]

[0342] Scheme for Route 41 [ka]

[0343] Step 41.a: tert-Butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[(1s,3s)-3-(trifluoromethyl) (trimethoxy)cyclobutanecarbonyl]hydrazinecarbonyl}piperidine-1-carboxylate [ka] To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (397 mg, 2.16 mmol, Intermediate 54) and DIPEA (0.94 mL, 5.39 mmol) in anhydrous DMF (12 mL), HATU (820 mg, 2.16 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (800 mg, 1.80 mmol, Intermediate 26) in DMF (7 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (2 × 50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (86% purity, 970 mg, 1.37 mmol, 76% yield) as an off-white solid;1 H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 2H), 7.98 (d, J = 7.1 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (dd, J = 8.9, 1.8 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.68 - 4.45 (m, 3H), 3.98 - 3.75 (m, 2H), 2.73 - 2.62 (m, 4H), 2.36 - 2.21 (m, 2H), 2.12 - 1.77 (m, 2H), 1.70 - 1.50 (m, 2H), 1.37 (s, 9H); M / Z: 609, 611 [M-Boc+H] + , ESI + , RT = 0.99 (S2).

[0344] [Example 49] (Step 41.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] A suspension of tert-butyl (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[[[(1S,3S)-3-(trifluoromethoxy)cyclobutanecarbonyl]amino]carbamoyl]piperidine-1-carboxylate (86% purity, 970 mg, 1.37 mmol), KCO (1132 mg, 8.19 mmol), and TsCl (781 mg, 4.10 mmol) in ACN (10 mL) was stirred at 80° C. for 3 h. The reaction mixture was partitioned between EtOAc (100 mL) and HO (100 mL), and the organic layer was isolated, washed with brine (100 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (317 mg, 0.524 mmol, 38% yield) as an off-white powder; 1 H NMR (500 MHz, DMSO-d6) δ 8.12 (d, J = 7.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (dd, J = 8.9, 1.9 Hz, 1H), 5.46 (s, 1H), 4. 90 (p, J = 7.5 Hz, 1H), 4.64 - 4.54 (m, 2H), 3.90 (d, J = 12.2 Hz, 2H), 3.44 (tt, J = 9.8, 7.9 Hz, 1H), 3.35 - 3.29 (m, 1H), 2.96 (d, J = 7.8 Hz, 1H), 2.90 - 2.78 (m, 2H), 2.23 (ddq, J = 13.7, 9.7, 4.4 Hz, 1H), 2.05 (d, J = 11.4 Hz, 1H), 1.75 (m, J = 13.7, 10.1, 4.1 Hz, 1H), 1.64 (d, J = 13.3 Hz, 1H), 1.39 (s, 10H); M / Z: 493, 495 [M-Boc+H] + , ESI + , RT = 1.12 (S2).

[0345] [Example 50] (Step 41.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (317 mg, 0.524 mmol, Example 49) in DCM (10 mL) was added ZnBr (714 mg, 3.14 mmol), and the mixture was stirred at room temperature under N for 20 hours. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and 20% IPA in DCM (10 mL). The organic layer was isolated, concentrated in vacuo, and purified by chromatography on silica gel (0-20% MeOH in DCM) to afford the title compound (240 mg, 0.467 mmol, 89% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (m, J = 9.0, 2.9, 1.2 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.52 (s, 2H), 3.92 - 3.82 (m, 1H), 3.79 - 3.63 (m, 1H), 3.48 - 3.37 (m, 1H), 3.00 (d, J = 12.3 Hz, 1H), 2.91 - 2.77 (m, 3H), 2.49 - 2.40 (m, 3H), 2.06 - 1.97 (m, 1H), 1.96 - 1.86 (m, 1H), 1.77 - 1.61 (m, 1H), 1.58 - 1.43 (m, 1H); M / Z: 493, 495 [M+H] + , ESI + , RT = 1.12 (S4).

[0346] Following general route 41, the example compounds in Table 16 were synthesized using the corresponding intermediates as exemplified by Example 50.

[0347] [Table 16-1] [Table 16-2]

[0348] Scheme for Route 42 [ka]

[0349] Step 42.a: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[1-(2,2,2-trifluoroethyl)azetidine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate [ka] To a solution of 1-(2,2,2-trifluoroethyl)azetidine-3-carboxylic acid (74 mg, 0.405 mmol) in anhydrous DMF (2 mL) was added HATU (185 mg, 0.486 mmol) followed by DIPEA (0.14 mL, 0.809 mmol), and the mixture was stirred at room temperature for 10 minutes. tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (90% purity, 200 mg, 0.405 mmol, Intermediate 26) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane, followed by 0-20% MeOH in EtOAc) to afford the title compound (90% purity, 206 mg, 0.303 mmol, 75% yield) as a pale yellow gum; 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 2H), 8.05 - 7.93 (m, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (dd, J = 9.0, 1.8 Hz, 1H), 4.75 - 4.48 (m, 3H), 3.99 - 3.76 (m, 2H), 3.55 (t, J = 7.4 Hz, 2H), 3.17 (q, J = 10.2 Hz, 2H), 2.11 - 2.01 (m, 1H), 1.96 - 1.81 (m, 1H), 1.70 - 1.50 (m, 2H), 1.37 (s, 9H); M / Z: 610, 612 [M+H] + , ESI + , RT = 0.85 (S2).

[0350] [Example 56] (Step 42.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin Benzene-1-carboxylate [ka] A suspension of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[1-(2,2,2-trifluoroethyl)azetidine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (90% purity, 206 mg, 0.303 mmol), K2CO3 (252 mg, 1.82 mmol), and TsCl (0.012 mL, 0.910 mmol) in ACN (1.5384 mL) was stirred at 80 °C for 45 min. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (110 mg, 0.179 mmol, 59% yield) as a colorless gum; 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 - 6.79 (m, 1H), 5.48 (s, 1H), 4.65 - 4.49 (m, 2H), 4.00 - 3.94 (m, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.78 (t, J = 7.7 Hz, 2H), 3.56 (q, J = 6.8 Hz, 2H), 3.27 (dd, J = 20.3, 10.2 Hz, 2H), 3.09 - 2.93 (m, 1H), 2.31 - 2.17 (m, 1H), 2.11 - 2.00 (m, 1H), 1.76 (t, J = 13.7 Hz, 1H), 1.70 - 1.59 (m, 1H), 1.39 (s, 9H); M / Z: 592, 594 [M+H] + , ESI + , RT = 0.66 (S2)

[0351] [Example 57] (Step 42.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (110 mg, 0.179 mmol, Example 56) and TFA (133 μL, 1.79 mmol) in DCM (2 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated aqueous NaHCO (3 mL) and extracted with DCM (2 × 5 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo, and purified by preparative HPLC (Method 3) to give the title compound (24 mg, 0.0478 mmol, 27% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.53 (s, 2H), 4.01 - 3.92 (m, 1H), 3.88 (ddd, J = 10.4, 6.1, 2.9 Hz, 1H), 3.78 (t, J = 7.7 Hz, 2H), 3.76 - 3.66 (m, 1H), 3.56 (t, J = 6.9 Hz, 2H), 3.28 (q, J = 10.2 Hz, 2H), 3.00 (d, J = 11.5 Hz, 1H), 2.83 (q, J = 6.0 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.06 - 1.97 (m, 1H), 1.95 - 1.87 (m, 1H), 1.75 - 1.64 (m, 1H), 1.52 (qd, J = 12.5, 3.9 Hz, 1H); M / Z: 492, 494 [M+H] + , ESI + , RT = 1.88 (S4).

[0352] Scheme for Route 43 [ka]

[0353] Step 43.a: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[N'-(3-cyclopropoxycyclobutanecarbonyl)hydrazinecarbonyl]piperidine-1-carboxylate [ka] To a solution of 3-cyclopropoxycyclobutane-1-carboxylic acid (90% purity, 100 mg, 0.576 mmol, Intermediate 51) in THF (5 mL) was added DIPEA (302 μL, 1.73 mmol), T3P (50%, 1.0 mL, 1.73 mmol), and tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (256 mg, 0.576 mmol, Intermediate 26), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give a colorless solid. Purification by chromatography on silica gel (0-100% EtOAc in heptane) afforded the title compound (85% purity, 143 mg, 0.208 mmol, 36% yield) as a white solid; M / Z: 583, 585 [M+H] + , ESI + ,RT=3.18(S4).

[0354] [Example 58] (Step 43.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[N'-(3-cyclopropoxycyclobutanecarbonyl)hydrazinecarbonyl]piperidine-1-carboxylate (85% purity, 143 mg, 0.208 mmol) in anhydrous ACN (10 mL) was added TsCl (79 mg, 0.417 mmol) and KCO (144 mg, 1.04 mmol), and the mixture was stirred at 80 °C for 5 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo to give a pale orange oil. Purification by chromatography on silica gel (0-100% EtOAc in heptane) afforded the title compound (70% purity, 111 mg, 0.138 mmol, 66% yield) as a colorless solid; M / Z: 565, 567 [M+H] + , ESI + ,RT=3.85(S4).

[0355] [Example 59] (Step 43.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (70% purity, 110 mg, 0.136 mmol, Example 58) in DCM (5 mL), ZnBr (92 mg, 0.409 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with NaHCO (30 mL), extracted with DCM / IPA (2:1, 2 × 50 mL), and the combined organic extracts were dried over NaSO and concentrated in vacuo. The residue was purified by preparative HPLC (Method 3) to give the title compound (26 mg, 0.0559 mmol, 41% yield) as a white powder; 1 H NMR (400 MHz, methanol-d4) δ 7.44 - 7.35 (m, 1H), 6.97 (dd, J = 11.0, 2.8 Hz, 1H), 6.86 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.55 (s, 2H), 4.27 - 4.15 (m, 1H), 4.05 - 3.92 (m, 2H), 3.41 - 3.34 (m, 2H), 3.25 - 3.19 (m, 1H), 2.81 - 2.60 (m, 3H), 2.40 - 2.26 (m, 2H), 2.23 - 2.06 (m, 2H), 1.94 - 1.81 (m, 1H), 1.73 - 1.59 (m, 1H), 0.60 - 0.42 (m, 4H); M / Z: 465, 467 [M+H] + , ESI + , RT = 1.97 (S4).

[0356] Following general route 43, the example compounds in Table 17 were synthesized using the corresponding intermediates as exemplified by Example 59.

[0357] [Table 17]

[0358] Scheme for Route 44 [ka]

[0359] [Example 62] (Step 44.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] A suspension of 3,3,3-trifluoro-2-methylpropan-1-ol (34 mg, 0.266 mmol) in anhydrous THF (1 mL) was treated with NaH (60%, 11 mg, 0.271 mmol) at 0 °C and stirred at 0 °C under N for 5 min. tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-methanesulfonyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (71 mg, 0.133 mmol, Intermediate 52) in anhydrous THF (1 mL) was added, and the mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with saturated aqueous NaHCO (1 mL) and extracted with EtOAc (2 × 3 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound (77 mg, 0.133 mmol) in quantitative yield. The crude material was carried forward without purification.

[0360] [Example 63] (Step 44.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (77 mg, 0.133 mmol, Example 62) in DCM (2 mL), ZnBr (180 mg, 0.799 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM / IPA (8:2, 2 × 3 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo, and purified by preparative HPLC (Method 3) to give the title compound (94% purity, 7.0 mg, 0.0143 mmol, 11% yield) as a white powder. 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.55 (d, J = 5.0 Hz, 2H), 4.52 (s, 2H), 3.78 - 3.73 (m, 1H), 3.73 - 3.65 (m, 1H), 3.13 - 3.01 (m, 1H), 3.00 - 2.92 (m, 1H), 2.83 - 2.76 (m, 1H), 2.46 - 2.39 (m, 1H), 1.99 - 1.86 (m, 2H), 1.70 - 1.59 (m, 1H), 1.53 - 1.45 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H); M / Z: 481, 483 [M+H] + , ESI + , RT = 2.15 (S4).

[0361] Following general route 44, the example compounds in Table 18 were synthesized using the corresponding intermediates as exemplified by Example 63.

[0362] [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4]

[0363] Scheme for Route 45 [ka]

[0364] [Example 76] (Step 45.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of 2-(trifluoromethoxy)ethanol (139 mg, 1.07 mmol) in anhydrous THF (6 mL) at 0 °C, NaH (60%, 43 mg, 1.07 mmol) was added, and the mixture was stirred for 10 minutes. A solution of tert-butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate (500 mg, 0.890 mmol, Intermediate 31) in anhydrous THF (6 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the title compound (80% purity, 627 mg, 0.860 mmol, 97% yield) as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.91 - 6.61 (m, 3H), 5.48 (d, J = 25.4 Hz, 1H), 4.77 - 4.65 (m, 2H), 4.44 (dd, J = 14.2, 4.1 Hz, 2H), 4.38 - 4.29 (m, 2H), 4.22 - 4.01 (m, 2H), 3.17 (s, 1H), 2.27 - 2.06 (m, 1H), 1.91 (d, J = 26.1 Hz, 3H), 1.45 (s, 9H); M / Z: 483, 485 [M-Boc+H] + , ESI + , RT = 1.11 (S2).

[0365] [Example 77] (Step 45.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (80% purity, 627 mg, 0.860 mmol, Example 76) in DCM (9 mL), ZnBr (581 mg, 2.58 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into H O (20 mL) and extracted with 10% IPA in DCM (3 × 20 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo. The residue was purified by preparative HPLC (Method 4) to give the title compound (194 mg, 0.394 mmol, 46% yield) as a white solid; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (m, J = 9.0, 2.8, 1.1 Hz, 1H), 4.70 - 4.65 (m, 2H), 4.51 (s, 2H), 4.49 - 4.44 (m, 2H), 3.79 - 3.73 (m, 1H), 3.73 - 3.65 (m, 1H), 2.96 (dd, J = 11.5, 3.2 Hz, 1H), 2.79 (s, 1H), 2.47 - 2.38 (m, 1H), 1.99 - 1.84 (m, 2H), 1.69 - 1.58 (m, 1H), 1.54 - 1.44 (m, 1H); M / Z: 483, 485 [M+H] + , ESI + , RT = 2.19 (S4).

[0366] Following general route 45, the example compounds in Table 19 were synthesized using the corresponding intermediates as exemplified by Example 77.

[0367] [Table 19-1] [Table 19-2] [Table 19-3]

[0368] Scheme for Route 46 [ka]

[0369] Step 46.a: N-[(3S,6R)-6-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(3,4-dichlorophenoxy)acetamide [ka] To a solution of tert-butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[2-(3,4-dichlorophenoxy)acetamido]piperidine-1-carboxylate (400 mg, 0.712 mmol, Intermediate 32) in DCM (10 mL) was added ZnBr (642 mg, 2.85 mmol), and the mixture was stirred at room temperature for 6 h. An additional portion of ZnBr (642 mg, 2.85 mmol) was added, and the mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with HO (50 mL) and extracted with DCM / IPA (2:1, 3 × 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound (80% purity, 269 mg, 0.478 mmol, 67% yield) as a pale yellow powder; M / Z: 451, 453, 455 [M+H] + , ESI + ,RT=0.77(S2).

[0370] [Example 85] (Step 46.b): 2-(3,4-Dichlorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] To a solution of 2-(trifluoromethoxy)ethanol (43 μL, 0.427 mmol) in anhydrous THF (3 mL) at 0° C. was added NaH (60%, 17 mg, 0.427 mmol), and the solution was stirred at room temperature for 5 minutes. N-[(3S,6R)-6-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(3,4-dichlorophenoxy)acetamide (80% purity, 200 mg, 0.355 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo to give an orange oil. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) followed by preparative HPLC (Method 3) to give the title compound (17 mg, 0.0337 mmol, 10% yield) as a white powder; 1 H NMR (400 MHz, methanol-d4) δ 7.46 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 6.98 (dd, J = 8.9, 2.9 Hz, 1H), 4.74 - 4.70 (m, 2H), 4.55 (s, 2H), 4.46 - 4.42 (m, 2H), 4.01 - 3.93 (m, 1H), 3.92 - 3.87 (m, 1H), 3.24 - 3.18 (m, 1H), 2.66 - 2.57 (m, 1H), 2.19 - 2.06 (m, 2H), 1.91 - 1.80 (m, 1H), 1.70 - 1.58 (m, 1H); M / Z: 499, 501, 503 [M+H] + , ESI + , RT = 2.30 (S4).

[0371] Following general route 46, the example compounds in Table 20 were synthesized using the corresponding intermediates as exemplified by Example 85.

[0372] [Table 20-1] [Table 20-2]

[0373] Scheme for Route 47 [ka]

[0374] [Example 89] (Step 47.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate [ka] To a solution of 3-(trifluoromethyl)azetidine hydrochloride (60 mg, 0.371 mmol) in anhydrous DMF (1 mL) was added DIPEA (0.16 mL, 0.927 mmol), followed by a solution of tert-butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate (100 mg, 0.185 mmol, Intermediate 31) in anhydrous DMF (1 mL), and the mixture was stirred at 100° C. for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (87% purity, 117 mg, 0.176 mmol, 95% yield) as a brown oil; M / Z: 478, 480 [M+H] + , ESI + ,RT=1.13(S2).

[0375] [Example 90] (Step 47.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (87% purity, 115 mg, 0.173 mmol) in DCM (2 mL), ZnBr (117 mg, 0.519 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with saturated aqueous NaHCO (3 mL) and extracted with DCM:IPA (80:20, 3 × 3 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method 4) to give the title compound (37 mg, 0.0774 mmol, 45% yield) as a white powder; 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (m, 1H), 6.87 - 6.82 (m, 1H), 4.51 (s, 2H), 4.37 - 4.30 (m, 2H), 4.10 - 4.04 (m, 2H), 3.85 - 3.75 (m, 1H), 3.75 - 3.64 (m, 2H), 3.01 - 2.94 (m, 1H), 2.75 - 2.67 M / Z: 480, 482 [M+H] + , ESI + , RT = 1.97 (S4).

[0376] Following general route 47, the example compounds in Table 21 were synthesized using the corresponding intermediates as exemplified by Example 90.

[0377] [Table 21-1] [Table 21-2] [Table 21-3]

[0378] Scheme for Route 48 [ka]

[0379] Step 48.a: tert-butyl (2R,5S)-2-carbamoyl-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate [ka] To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (1.86 g, 4.32 mmol, Intermediate 22), NHCl (253 mg, 4.73 mmol), and DIPEA (3.1 mL, 17.7 mmol) in anhydrous DMF (22 mL) was added HATU (1.80 g, 4.73 mmol) at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (3 × 50 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo to give the title compound (80% purity, 2.36 g, 4.39 mmol) as colorless crystals in quantitative yield; 1H NMR (500 MHz, DMSO-d6) δ 7.99 - 7.93 (m, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.32 (s, 1H), 7.08 - 6.99 (m, 2H), 6.81 (dd, J = 8.9, 1.9 Hz, M / Z: 330, 332 [M+H] + , ESI + , RT = 0.88 (S2).

[0380] Step 48.b: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-cyanopiperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-2-carbamoyl-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate (80% purity, 2.17 g, 4.04 mmol) and EtN (2.6 mL, 18.7 mmol) in anhydrous DCM (40 mL) at 0 °C, TFAA (1.2 mL, 8.27 mmol) was added, and the solution was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and quenched with HO (20 mL). The solution was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO (20 mL). The organic layer was dried using a phase separator, concentrated in vacuo, and purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (0.94 g, 2.22 mmol, 55% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 6.9 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.02 (dd, J = 11.4, 2.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.0 Hz, 1H), 5.37 - 5.27 (m, 1H), 4.61 - 4.50 (m, 2H), 4.03 - 3.90 (m, 2H), 3.07 - 2.92 (m, 1H), 2.17 - 2.04 (m, 1H), 1.84 - 1.68 (m, 3H), 1.39 (s, 9H); M / Z: 429, 431 [M+NH4] + , ESI + , RT = 3.69 (S6).

[0381] Step 48.c: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-cyanopiperidine-1-carboxylate (500 mg, 1.21 mmol) in MeOH (6 mL) was added hydroxylamine hydrochloride (1:1) (125 mg, 1.80 mmol) and NaHCO (225 mg, 2.68 mmol) at 0° C. The reaction mixture was stirred at room temperature for 40 h. The resulting suspension was filtered under vacuum, washed with MeOH, and the filtrate was concentrated in vacuo to give the title compound (69% purity, 620 mg, 0.962 mmol, 79% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.01 - 7.90 (m, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.3, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.8, 0.9 Hz, 1H), 5.22 (s, 1H), 4.67 (s, 1H), 4.62 - 4.51 (m, 2H), 3.95 - 3.78 (m, 2H), 3.19 - 3.11 (m, M / Z: 345, 347 [M-Boc+H] + , ESI + , RT = 0.78 (S2).

[0382] Step 48.d: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyloxy]carbamimidoyl}piperidine-1-carboxylate [ka] To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (90 mg, 0.489 mmol, Intermediate 54) in anhydrous DMF (2.5 mL) was added EtN (202 μL, 1.45 mmol) followed by HATU (200 mg, 0.526 mmol) and stirred at room temperature for 10 minutes. tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate (69% purity, 310 mg, 0.481 mmol) was added, and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (3 × 20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the title compound (59% purity, 367 mg, 0.354 mmol, 74% yield) as an orange oil; M / Z: 511, 513 [M-Boc+H] + , ESI + ,RT=1.12(S2).

[0383] [Example 97] (Step 48.e): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxylate [ka] A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyloxy]carbamimidoyl}piperidine-1-carboxylate (59% purity, 367 mg, 0.354 mmol) in pyridine (3.5 mL) was stirred at 115° C. for 17 h. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (91% purity, 172 mg, 0.264 mmol, 74% yield) as a colorless oil; M / Z: 593, 595 [M+H] + , ESI + ,RT=1.20(S2).

[0384] [Example 98] (Step 48.f): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxylate (91% purity, 152 mg, 0.233 mmol, Example 97) in anhydrous DCM (1.5 mL) was added ZnBr (210 mg, 0.924 mmol), and the resulting mixture was stirred at room temperature under N for 17 hours. The reaction mixture was diluted with saturated aqueous NaHCO (20 mL) and extracted with 80:20 DCM / IPA (3 × 50 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo, and purified by preparative HPLC (Method 4) to give the title compound (68 mg, 0.138 mmol, 59% yield) as a white solid; 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.78 (dd, J = 10.3, 2.8 Hz, 1H), 6.70 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.71 (p, J = 7.6 Hz, 1H), 4.46 (s, 2H), 4.10 - 4.00 (m, 1H), 3.94 (dd, J = 9.1, 3.0 Hz, 1H), 3.40 - 3.28 (m, 2H), 2.94 - 2.85 (m, 2H), 2.78 - 2.66 (m, 2H), 2.64 - 2.57 (m, 1H), 2.18 - 2.01 (m, 3H), 1.94 - 1.82 (m, 1H), 1.63 - 1.57 (m, 1H); M / Z: 493, 495 [M+H] + , ESI + , RT = 2.32 (S4).

[0385] Scheme for Route 49 [ka]

[0386] Step 49.a: 1-tert-butyl 2-ethyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}piperidine-1,2-dicarboxylate [ka] To a solution of 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetic acid (400 mg, 1.95 mmol, Intermediate 12) in anhydrous THF (20 mL) was added isobutyl chloroformate (0.24 mL, 1.85 mmol) followed by NMM (0.21 mL, 1.95 mmol) at 0 °C. After the mixture was stirred for 15 min, 1-tert-butyl 2-ethyl(2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (530 mg, 1.95 mmol, Intermediate 3) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, quenched with HO (0.5 mL), and concentrated in vacuo. The residue was partitioned between EtOAc (10 mL) and HO (10 mL). The organic layer was isolated, washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound (90% purity, 805 mg, 1.58 mmol, 81% yield) as an off-white solid; 1 H NMR (400 MHz, chloroform-d) δ 7.98 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.8, 2.6 Hz, 1H), 6.73 (d, J = 43.3 Hz, 1H), 4.52 (s, 2H), 4.28 - 4.16 (m, 3H), 4.10 - 3.86 (m, 1H), 3.24 (dd, J = 39.3, 13.1 Hz, 1H), 2.15 (d, J = 15.8 Hz, 1H), 2.01 - 1.73 (m, 2H), 1.63 - 1.51 (m, 2H), 1.45 (s, 9H), 1.32 - 1.21 (m, 3H).

[0387] Step 49.b: (2R,5S)-1-[(tert-butoxy)carbonyl]-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}piperidine-2-carboxylic acid [ka] A solution of 1-tert-butyl 2-ethyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}piperidine-1,2-dicarboxylate (90% purity, 805 mg, 1.58 mmol) and LiOH·HO (81 mg, 1.89 mmol) in THF (2.5 mL) / MeOH (2.5 mL) / HO (2.5 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (20 mL) and HO (20 mL). The layers were separated, and the organic layer was discarded. The aqueous layer was cooled to 0 °C and acidified to pH 2 / 3 with 1 M aqueous HCl. The resulting solution was extracted with EtOAc (2×25 mL), and the combined organic extracts were washed with H2O (30 mL), dried over Na2SO4, and concentrated in vacuo to afford the title compound (90% purity, 570 mg, 1.19 mmol, 75% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.66 (dd, J = 10.3, 2.3 Hz, 1H), 4.75 - 4.44 (m, 3H), 3.99 - 3.71 (m, 2H), 3.15 - 2.90 (m, 2H), 2.08 - 1.84 (m, 2H), 1.67 - 1.55 (m, 1H), 1.54 - 1.41 (m, 1H), 1.37 (s, 9H).

[0388] Step 49.c: tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[N'-(3,4-dichlorobenzoyl)hydrazinecarbonyl]piperidine-1-carboxylate [ka] To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}piperidine-2-carboxylic acid (90% purity, 530 mg, 1.10 mmol) in anhydrous THF (11 mL) was added isobutyl chloroformate (0.14 mL, 1.05 mmol) followed by NMM (0.12 mL, 1.10 mmol) at 0 °C. After stirring the mixture for 15 min, 3,4-dichlorobenzohydrazide (226 mg, 1.10 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, quenched with HO (0.5 mL), and concentrated in vacuo. The residue was partitioned between EtOAc (15 mL) and HO (15 mL). The organic layer was isolated, washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound (90% purity, 626 mg, 0.910 mmol, 82% yield) as an off-white solid; 1 H NMR (400 MHz, chloroform-d) δ 8.68 (s, 2H), 8.00 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.56 - 7.50 (m, 1H), 7.13 (dd, J = 8.8, 2.6 Hz, 1H), 5.00 - 4.82 (m, 1H), 4.58 - 4.46 (m, 2H), 4.28 - 4.08 (m, 2H), 3.33 (d, J = 12.5 Hz, 1H), 2.25 - 2.16 (m, 1H), 2.09 - 1.84 (m, 2H), 1.83 - 1.71 (m, 1H), 1.54 - 1.44 (m, 10H).

[0389] [Example 99] (Step 49.d): tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] A suspension of tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[N'-(3,4-dichlorobenzoyl)hydrazinecarbonyl]piperidine-1-carboxylate (601 mg, 0.971 mmol), TsCl (555 mg, 2.91 mmol), and K2CO3 (805 mg, 5.83 mmol) in anhydrous ACN (10 mL) was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and HO (20 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (10 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (5 × 20 mL) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (40-90% EtOAc in heptane) to afford the title compound (310 mg, 0.490 mmol, 50% yield) as an off-white solid; 1 H NMR (500 MHz, chloroform-d) δ 8.10 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 8.4, 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 6.77 (s, 1H), 5.93 - 5.44 (m, 1H), 4.62 - 4.48 (m, 2H), 4.29 - 4.19 (m, 1H), 4.17 - 4.02 (m, 1H), 3.43 - 2.98 (m, 1H), 2.38 - 2.23 (m, 1H), 2.18 - 1.91 (m, 3H), 1.50 (s, 9H).

[0390] [Example 100] (Step 49.e): 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide [ka] To a solution of tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (150 mg, 0.250 mmol, Example 99) in DCM (3 mL), ZnBr (225 mg, 0.999 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between saturated aqueous NaHCO (2 mL) and DCM / IPA (4:1, 2 mL), and the layers were separated using a phase separator. The organic layer was concentrated in vacuo and purified by preparative HPLC (Method 4) to give the title compound (28 mg, 0.0554 mmol, 22% yield) as an off-white powder. 1H NMR (500 MHz, chloroform-d) δ 8.17 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.8, 2.6 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.57 (s, 2H), 4.27 - 4.21 (m, 1H), 4.20 - 4.09 (m, 1H), 3.41 (dd, J = 12.1, 3.3 Hz, 1H), 2.73 (dd, J = 12.1, 7.7 Hz, 1H), 2.29 - 2.20 (m, 1H), 2.20 - 2.04 (m, 3H), 1.78 - 1.67 (m, 1H); + , ESI + , RT = 2.18 (S4).

[0391] Scheme for Route 50 [ka]

[0392] [Example 101] 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-1-methyl-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide [ka] To a solution of 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (100 mg, 0.197 mmol, Example 77) and KCO (57 mg, 0.413 mmol) in DMF (2 mL) was added MeI (134 μL, 2.16 mmol), and the mixture was stirred at room temperature for 5 days. The reaction mixture was quenched with 33% aqueous NHOH (1 mL) and stirred for 30 minutes. The solution was diluted with HO (30 mL), extracted with EtOAc (2 × 30 mL), and the combined organic extracts were dried over NaSO and concentrated in vacuo. Purification by preparative HPLC (Method 5) afforded the title compound (36 mg, 0.0725 mmol, 37% yield) as a white powder; 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.81 (m, 1H), 4.72 - 4.63 (m, 2H), 4.53 (s, 2H), 4.49 - 4.42 (m, 2H), 3.91 - 3.80 (m, 1H), 3.29 - 3.20 (m, 1H), 2.96 - 2.88 (m, 1H), 2.12 - 1.95 (m, 4H), 1.92 - 1.80 (m, 2H), 1.78 - 1.67 (m, 1H), 1.49 - 1.35 (m, 1H); M / Z: 497, 499 [M+H] + , ESI + , RT = 2.75 (S4).

[0393] Scheme for Route 51 [ka]

[0394] [Examples 102 and 103] Chiral separation of 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (Example 87) 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (48 mg, 0.0978 mmol, Example 87) was subjected to chiral purification using Method C4 to give 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (48 mg, 0.0978 mmol, Example 87). 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1R)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide (98% chiral purity, 13.3 mg, 0.0268 mmol, 27% yield) and 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1S)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide (100% chiral purity, 12.4 mg, 0.025 mmol), 26% yield) were obtained as white powders. The stereochemistry of each compound was arbitrarily assigned.

[0395] Following general route 51, the example compounds in Table 22 were chiral purified using the corresponding intermediates and methods as exemplified by Examples 102 and 103.

[0396] [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4]

[0397] II Assay HEK-ATF4 high-content imaging assay Example compounds were tested in a HEK-ATF4 high-content imaging assay to determine their pharmacological efficacy in preventing tunicamycin-induced ISR. Wild-type HEK293 cells were plated in growth medium (DMEM / F12, 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin-100 μg / mL streptomycin) at a density of 12,000 cells per well in a 384-well imaging assay plate and incubated at 37°C and 5% CO2. After 24 hours, the medium was changed to 50 μL of assay medium (DMEM / F12, 0.3% FBS, 2 mM L-glutamine, 100 U / mL penicillin-100 μg / mL streptomycin) per well. Example compounds were serially diluted in DMSO and spotted into the intermediate plate, prediluted with assay medium containing 3.3 μM tunicamycin to achieve an 11-fold excess final assay concentration. In addition to the example compound test area, the plate also contained multiple control wells for assay normalization purposes: wells containing tunicamycin but no example compound (high control), as well as wells containing neither example compound nor tunicamycin (low control). The assay was initiated by transferring 5 μL from the intermediate plate into the assay plate, followed by incubation for 6 hours at 37°C and 5% CO2. Cells were subsequently fixed (4% PFA in PBS, 20 minutes at room temperature) and subjected to indirect ATF4 immunofluorescence staining (primary antibody rabbit anti-ATF4, clone D4B8, Cell Signaling Technologies; secondary antibody Alexa Fluor 488 goat anti-rabbit IgG (H+L), Thermofisher Scientific). Nuclei were stained using Hoechst dye (Thermofisher Scientific), and plates were imaged on an Opera Phenix High Content Imaging Platform equipped with 405 nm and 488 nm excitation. Finally, images were analyzed using a script-based algorithm. The primary readout, HEK-ATF4, monitored the ATF4 signal ratio between the nucleus and cytoplasm. Tunicamycin induced an increase in the overall ATF4 signal ratio, which was prevented by ISR-modulating example compounds.In addition, the HEK-CellCount readout was derived from counting the number of stained nuclei corresponding to healthy cells. This readout served as an internal toxicity control. The example compounds herein did not produce a significant reduction in CellCount.

[0398] The HEK ATF4 activities of the tested example compounds are provided in Table 23 as follows: +++=IC 50 1–500 nM; ++=IC 50 >500~2000nM;+=IC50 >2000~15000nM.

[0399] [Table 23-1] [Table 23-2] [Table 23-3]

[0400] Protocol - Thermodynamic (Equilibrium) Solubility in Selected Buffers Example compounds were tested for thermodynamic (equilibrium) solubility in a selective buffer assay. Test compounds were weighed in powder form into 4 mL glass vials, and the calculated volume of selective medium was added to reach the target concentration for solubility testing (1 mg / mL). The solution was then stirred overnight at room temperature, protected from light. The solution was filtered through a 0.45 μm PTFE membrane at ambient temperature. Aliquots of the resulting filtrate were quantified using the UPLC-UV method described below against a reference solution of 0.8 mg / mL of the test compound in DMSO. Media composition: 50 mM phosphate buffer (pH = 2.0), 690 mg NaH2PO4·H2O in 200 mL of ultrapure water adjusted to pH 2 with 85% phosphoric acid; 50 mM acetate buffer (pH = 5.5), 820 mg anhydrous sodium acetate in 200 mL of ultrapure water adjusted to pH 5.5 with 99.8% acetic acid; 50 mM phosphate buffer (pH = 7.4), 40.5 mL of a 0.1 M solution of Na2HPO4 + 9.5 mL of a 0.1 M solution of NaH2PO4. Analytical conditions: Reverse-phase Acquity BEH C18 column (2.1 mm x 50 mm, 1. UPLC-UV-MS analysis was performed using a Waters Acquity UPLC Class-PDA-QDa system with a 0.4 μL injection volume at a flow rate of 0.65 mL / min, using a gradient of 10 to 95% B (A = 0.1% formic acid in HO; B = 0.05% formic acid in ACN) over 1.8 min, followed by 100% B for 0.8 min (A = 0.1% formic acid in HO; B = 0.05% formic acid in ACN). UV chromatograms were recorded at 220 nm, 254 nm, and 290 nm using a photodiode array detector. Mass spectra were recorded using a QDa detector at a sampling rate of 10 scans per second in the 150 to 900 M / Z range. Data were integrated using Empower® 3 software. Data analysis: The equilibrium solubility of the test compound in the selective medium was calculated via the ratio of the surface area of ​​the UV chromatographic peak of the compound in the filtrate to the surface area of ​​the UV chromatographic peak of the compound in the reference solution.

[0401] Protocol - Measuring effects on hERG channels by tail current recording using in vitro Rapid ICE The efficacy of example compounds in inhibiting human ERG potassium channel (hERG) tail currents was determined using a Rapid ICE (rapid ion channel electrophysiology) assay in a recombinant HEK293 cell line stably transfected with hERG cDNA under an inducible promoter. Rapid ICE is an automated patch-clamp assay using the QPatch HTX system (Sophion Bioscience A / S). Briefly, inducible HEKhERG cells were cultured in minimal essential medium supplemented with 10% FBS, 1% non-essential amino acids, 1% sodium pyruvate, 2 mM l-glutamine, 15 μg / mL blasticidin, and 100 μg / mL hygromycin. hERG channel expression induction was achieved by adding 10 μg / mL tetracycline for 24, 48, or 72 hours before recording.

[0402] On the day of the experiment, cells were detached with TrypLE and prepared for loading onto the instrument. Cells were resuspended in 7 mL of serum-free medium containing 25 mM Hepes and soybean trypsin inhibitor and immediately placed in the instrument's cell storage tank. The extracellular buffer solution consisted of (mM): NaCl 137, KCl 4, CaCl2 1.8, MgCl2 1.0, d-glucose 10, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) 10, and 1 M NaOH at pH 7.4. The intracellular solution consisted of (mM): KCl 130, MgCl2 1.0, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) 5, MgATP 5, HEPES 10, and 1 M KOH at pH 7.2. The voltage protocol included the following steps: -80 mV to -50 mV for 200 ms, a step to +20 mV for 4.8 s, a step to -50 mV for 5 s, and then a step to a holding potential of -80 mV. Compounds were dissolved in DMSO and diluted into extracellular buffer to achieve final test concentrations (0.3, 3, and 30 μM) in 0.3% DMSO. The voltage protocol was run and recorded continuously throughout the experiment. Vehicle, corresponding to 0.3% DMSO in extracellular buffer, was then applied for 3 min, followed by test substances in triplicate. The standard combined exposure time was 5 min. The effect of test substances was calculated for each cell by calculating the residual current (% control) compared to vehicle pretreatment using the average tail current amplitude values ​​recorded from four sequential voltage pulses. Data were reported as % inhibition for each concentration tested and were calculated using QPatch software as IC. 50 Values ​​were estimated. At least two cells were tested, and if results were discrepant, more cells were tested.

[0403] Protocol - LogD7.4 Assay Phosphate buffer (1 M) was diluted to 20 mM with deionized water and adjusted to pH 7.4 (±0.05) with phosphoric acid or sodium hydroxide. A 1:1 mixture of phosphate buffer (20 mM) and 1-octanol was saturated by rotating overnight, after which time the two phases were separated. The following procedure was performed using an automated liquid handler: 20 mM DMSO stocks of assay and control compounds were reformatted to provide cassettes of four compounds per well, giving a final concentration of 5 mM per compound. In duplicate, 5 μL of cassette compound was added to 495 μL of 1-octanol (saturated with buffer) followed by 495 μL of buffer (saturated with 1-octanol) in a 96-well plate, giving a final incubation concentration of 25 μM (a maximum concentration of 50 μM in either layer if all compounds were distributed in a single matrix). The buffer and octanol layers were mixed by aspirating and dispensing three times from each other. The plate was sealed and shaken for 120 minutes, then centrifuged at 4600 rpm for 15 minutes at 25°C. The 1-octanol and buffer layers were sampled separately (to ensure no cross-contamination) and each sample was diluted with 60:40 ACN:0.1 M ammonium acetate pH 7.4 (containing an external standard; sulfisoxazole, assay concentration 120 nM) to give final theoretical maximum concentrations of 0.025 μM, 0.5 μM in the 1-octanol layer, and 0.5 μM in the buffer layer. A second buffer sample was prepared by diluting the assay buffer layer with acetonitrile (containing an external standard; sulfisoxazole, assay concentration 120 nM) to give a theoretical maximum concentration of 20 μM. Analytical samples were analyzed by LC-MS / MS, and LogD was calculated as shown below:

number

[0404] where PA = peak area and ES = external standard.

[0405] Biological Examples: Lipophilicity and Solubility In recent years, there have been numerous reports in the medicinal chemistry literature relating the clinical success of drug candidates to their physicochemical properties. The degree of lipophilicity, in particular, has been highlighted as an important factor in defining the overall properties and likely fate of a drug candidate, (29) and typically it is beneficial if the logD is in the range of 1 to 3. Referring to Table 24, selected compounds of the present invention have logD values ​​that fall within this range and in this respect represent improvements over previously reported and similar analogs.

[0406] Similarly, poor solubility of drug candidates is associated with an increased risk of drug development failure. (30) Moreover, with reference to Table 24, select compounds of the present invention exhibit higher aqueous solubility compared to structurally similar compounds in the state of the art. Additional solubility data relating to further example compounds are presented in Table 25 below.

[0407] [Table 24]

[0408] [Table 25]

[0409] Biological Example: hERG Selectivity Drug-induced QT interval prolongation and the occurrence of torsade de pointes (TdP) are well-recognized clinical risks. While these effects are often multifactorial, cardiac hERGK + There is a clear consensus in recognizing the role that drug interactions with the channel play in the manifestation of these clinical side effects. + It is widely accepted that minimizing the interaction of drug molecules with the channel is desirable. (31) To this end, we focused on improving the physicochemical properties described above (i.e., log D and solubility—Tables 24 & 25) and the hERGK channel. + We sought to balance this with selective modulation of ATF4 relative to the channel.

[0410] [Table 26-1] [Table 26-2] [Table 26-3]

[0411] With reference to Tables 23, 25 and 26, selected compounds of the present invention exhibit an advantageous balance of properties, particularly with respect to HEK ATF4 activity and / or solubility and / or selective hERG inhibition.

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The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. (27) Wong YL, LeBon L, Basso AM, Kohlhaas KL, Nikkel AL, Robb HM, Donnelly-Roberts DL, Prakash J, Swensen AM, Rubinstein ND, Krishnan S, McAllister FE, Haste NV, O'Brien JJ, Roy M, Ireland A, Frost JM, Shi L, Riedmaier S, Martin K, Dart MJ, Sidrauski C. Elife. 2019 Jan 9;8. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. (28) Nguyen HG, Conn CS, Kye Y, Xue L, Forester CM, Cowan JE, Hsieh AC, Cunningham JT, Truillet C, Tameire F, Evans MJ, Evans CP, Yang JC, Hann B, Koumenis C, Walter P, Carroll PR, Ruggero D. Sci Transl Med. 2018 May 2;10(439). Development of a stress response therapy targeting aggressive prostate cancer. (29) Waring M, Expert Opinion on Drug Discovery Volume 5, 2010 - Issue 3, 235-248. Lipophilicity in Drug Discovery. (30) Alelyunas YW, et.al. Bioorg.Med.Chem.Lett., 20(24) 2010, 7312-7316. Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate. (31) Redfern WS, et.al., Cardiovascular Research 58(2003), 32-45. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs.

Claims

1. A compound of formula (I) for use as a medicine 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. (In the formula, X １ is N(R ａ１ ) and X １ａ is a covalent single bond, CH(R ａ３ ) or CH(R ａ３ ) CH ２ and R ａ１ is H, C(O)OC １－４ Alkyl or C １～４ alkyl, where C(O)OC １～４ Alkyl and C １～４ Alkyl is halogen, OH and O—C １～３ optionally substituted with one or more substituents selected from the group consisting of alkyl, wherein the substituents are the same or different; R ａ２ , R ａ３ is H;OH;OC １～４ Alkyl; halogen; C １～４ Alkyl; and A ２ａ are independently selected from the group consisting of: R ａ４ , R ａ５ , R ａ６ , R ａ７ is H; halogen; C １～４ Alkyl; and A ２ａ are independently selected from the group consisting of: However, R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ Only one of them is A ２ａ Is it; Or R ａ１ And R ａ２ and R ａ３ one of which forms a methylene or ethylene group; Or R ａ１ and R ａ６ forms an ethylene group; Or R ａ２ and R ａ５ forms a single covalent bond; Or R ａ５ , R ａ７ are connected to form an oxo group; A １ is C ５ Cycloalkylene, C ５ cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, where A １ represents one or more R ４ optionally substituted with; Each R ４ are independently selected from oxo (=O) in which the ring is at least partially saturated, thioxo (=S) in which the ring is at least partially saturated, halogen, CN, OR ５ , or C １～６ alkyl, where C １～６ The alkyl is optionally substituted with one or more halogens which may be the same or different; R ５ is H or C １～６ alkyl, where C １～６ The alkyl is optionally substituted with one or more halogens which may be the same or different; A ２ is R ６ａ Or A ２ａ and R ６ａ is OR ６ａ１ , S.R. ６ａ１ , N(R ６ａ１ R ６ａ２ ); C １～６ Alkyl, C ２～６ Alkenyl or C ２～６ alkynyl, where C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is halogen; OR ６ａ３ CN; and A ２ａ and optionally substituted with one or more substituents selected from the group consisting of: R ６ａ１ , R ６ａ２ is H;C １～６ Alkyl; C ２～６ Alkenyl; C ２～６ alkynyl; and A ２ａ Independently selected from the group consisting of: １～６ Alkyl; C ２～６ alkenyl; and C ２～６ Alkynyl is halogen; CN; OR ６ａ３ ; O.A. ２ａ oh Call A ２ａ and optionally substituted with one or more substituents selected from the group consisting of: R ６ａ３ is H; or C １～４ alkyl, where C １～４ The alkyl is optionally substituted with one or more halogens which may be the same or different; A ２ａ is phenyl; ３～７ Cycloalkyl; C ４～１２ bicycloalkyl; or 3- to 7-membered heterocyclyl, where A ２ａ represents one or more R ６ optionally substituted with; Each R ６ are independently ６ｂ ;OH;OR ６ｂ halogen; or CN, where R ６ｂ is cyclopropyl, C １～６ Alkyl; C ２～６ alkenyl; or C ２～６ alkynyl, where R ６ｂ is optionally substituted with one or more halogens which may be the same or different; or Two R's ６ are connected to form ring A together with the atom to which they are attached. ２ｂ Forming A ２ｂ is phenyl; ３～７ cycloalkyl; or 3- to 7-membered heterocyclyl, where A ２ｂ represents one or more R ７ optionally substituted with; Each R ７ is independent, C １～６ Alkyl, C ２～６ Alkenyl or C ２～６ alkynyl, where C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ alkynyl is optionally substituted with one or more halogens which may be the same or different; R １ is H or C １～４ Alkyl, preferably H, where C １～４ The alkyl is optionally substituted with one or more halogens which may be the same or different; R ２ is H; F; or C １～４ alkyl, where C １～４ The alkyl is optionally substituted with one or more halogens which may be the same or different; R ３ A ３ , C １～６ Alkyl, C ２～６ Alkenyl or C ２～６ alkynyl, where C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R ８ optionally substituted with; or R ２ and R ３ are connected to form ring A together with the oxygen atom and the carbon atom to which they are attached. ３ａ where A ３ａ is a 7- to 12-membered heterobicyclyl, wherein the 7- to 12-membered heterobicyclyl is selected from the group consisting of one or more R １０ optionally substituted with; R ２ａ is H or F, preferably H; Each R ８ are independently halogen; CN, C(O)OR ９ , OR ９ , C(O)R ９ , C(O)N(R ９ R ９ａ ), S(O) ２ N (R ９ R ９ａ ), S(O)N(R ９ R ９ａ ), S(O) ２ R ９ , S(O)R ９ , N(R ９ ) S (O) ２ N (R ９ａ R ９ｂ ), S.R. ９ , N(R ９ R ９ａ ), NO ２ , O.C.(O)R ９ , N(R ９ ) C(O)R ９ａ , N(R ９ ) S.O. ２ R ９ａ , N(R ９ ) S(O)R ９ａ , N(R ９ ) C(O)N(R ９ａ R ９ｂ ), N(R ９ ) C(O)OR ９ａ , O C (O) N (R ９ R ９ａ ), or A ３ and R ９ , R ９ａ , R ９ｂ is H, C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ alkynyl, wherein C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkynyl can be substituted with one or more halogens, which may be the same or different, or with one OH or with one OC. １～４ Alkyl, or one A ３ optionally substituted with; Each A ３ are independently phenyl, naphthyl, C ３～７ cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, where A ３ represents one or more R １０ optionally substituted with; Each R １０ are independently halogen, CN, C(O)OR １１ , OR １１ , C(O)R １１ , C(O)N(R １１ R １１ａ ), S(O) ２ N (R １１ R １１ａ ), S(O)N(R １１ R １１ａ ), S(O) ２ R １１ , S(O)R １１ , N(R １１ ) S (O) ２ N (R １１ａ R １１ｂ ), S.R. １１ , N(R １１ R １１ａ ), NO ２ , O.C.(O)R １１ , N(R １１ ) C(O)R １１ａ , N(R １１ ) S (O) ２ R １１ａ , N(R １１ )S(O)R １１ａ , N(R １１ ) C(O)OR １１ａ , N(R １１ ) C(O)N(R １１ａ R １１ｂ ), OC(O)N(R １１ R １１ａ ), oxo (=O) in which the ring is at least partially saturated, C １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ alkynyl, where C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is a group consisting of one or more R １２ optionally substituted with; R １１ , R １１ａ , R １１ｂ is H, C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ alkynyl, wherein C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ alkynyl is optionally substituted with one or more halogens which may be the same or different; Each R １２ are independently halogen, CN, C(O)OR １３ , OR １３ , C(O)R １３ , C(O)N(R １３ R １３ａ ), S(O) ２ N (R １３ R １３ａ ), S(O)N(R １３ R １３ａ ), S(O) ２ R １３ , S(O)R １３ , N(R １３ ) S (O) ２ N (R １３ａ R １３ｂ ), S.R. １３ , N(R １３ R １３ａ ), NO ２ , O.C.(O)R １３ , N(R １３ ) C(O)R １３ａ , N(R １３ ) S.O. ２ R １３ａ , N(R １３ )S(O)R １３ａ , N(R １３ ) C(O)N(R １３ａ R １３ｂ ), N(R １３ ) C(O)OR １３ａ , or OC(O)N(R １３ R １３ａ ) and R １３ , R １３ａ , R １３ｂ is H, C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ alkynyl, wherein C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ The alkynyl is optionally substituted with one or more halogens which may be the same or different.

2. X １ is NH or N-C １～４ alkyl, where C １～４ Alkyl is a group consisting of halogen, OH, and O—C １～３ Optionally substituted with one or more substituents selected from the group consisting of alkyl, where the substituents are the same or different; preferably NH, N(CH ３ ), N(CH ２ CH ３ ), or N(CH ２ CH ２ OCH ３ ); more preferably NH or N(CH ３ ) ; more preferably NH or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, for use as a medicament according to claim 1 .

3. X １ａ is CH(R ａ３ ) or CH(R ａ３ ) CH ２ , preferably CH(R ａ３ 3. The compound for use as a medicine according to claim 1 or 2, wherein:

4. R ａ２ , R ａ３ is H;OH;OC １～４ Alkyl; halogen; C １～４ Alkyl; and A ２ａ are independently selected from the group consisting of: R ａ４ , R ａ５ , R ａ６ , R ａ７ is H; halogen; C １～４ Alkyl; and A ２ａ Independently selected from the group consisting of: ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ Only one of them is A ２ａ Is it; Or R ａ５ , R ａ７ are connected to form an oxo group; Preferably, R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ is H, or R ａ２ , R ａ３ , R ａ４ , R ａ６ is H, and R ａ５ , R ａ７ are connected to form an oxo group, 4. A compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use as a medicament.

5. R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ 5. The compound for use as a medicine according to any one of claims 1 to 4, wherein is H, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

6. A １ is a nitrogen ring atom-containing 5-membered heterocyclene; A １ can be the same or different one or is more R ４ 6. A compound for use as a medicine according to any one of claims 1 to 5, optionally substituted with:

7. A １ is a nitrogen ring atom-containing 5-membered heterocyclene selected from the group of divalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole and triazole, preferably oxadiazole; A １ represents one or more R ４ 7. A compound for use as a medicine according to any one of claims 1 to 6, optionally substituted with:

8. A １ is unsubstituted or is substituted with one or two identical or different R ４ and preferably, A １ 8. The compound for use as a medicine according to any one of claims 1 to 7, wherein is unsubstituted, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

9. R ４ is oxo, the ring being at least partially saturated, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

10. A １ teeth, 【Chemistry 2】 10. The compound for use as a medicine according to any one of claims 1 to 9, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

11. A ２ is R ６ａ 11. The compound for use as a medicament according to any one of claims 1 to 10, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

12. R ６ａ Is OR ６ａ１ and R ６ａ１ is preferably A ２ａ or one or more halogens and / or one A ２ａ and / or one OR ６ａ３ C optionally substituted with １～６ alkyl; or R ６ａ is one or more halogens and / or one A ２ａ and / or one OR ６ａ３ C optionally substituted with １～６ The pharmaceutical use according to claim 11, wherein the aryl group is an alkyl group. or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

13. R ６ａ１ , R ６ａ２ is H;C １～６ Alkyl; C ２～６ Alkenyl; C ２～６ alkynyl; and A ２ａ Independently selected from the group consisting of: １～６ Alkyl; C ２～６ alkenyl; and C ２～６ Alkynyl is halogen; CN; OR ６ａ３ and A ２ａ 13. The compound for use as a medicament according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, optionally substituted with one or more substituents selected from the group consisting of:

14. R ６ａ is one or more halogens and / or one OR ６ａ３ C optionally substituted with １～６ alkyl, or R ６ａ Is OR ６ａ１ and R ６ａ１ is preferably one or more F and / or one OR ６ａ３ C optionally substituted with １～６ More preferably, R ６ａ１ is CH ２ CH ２ CF ３ or CH ２ CH ２ O.C.F. ３ , more preferably CH ２ CH ２ O.C.F. ３ 14. The compound for use as a medicament according to any one of claims 11 to 13, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

15. A ２ A ２ａ 11. The compound for use as a medicament according to any one of claims 1 to 10, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

16. A ２ａ is phenyl; cyclobutyl; azetidinyl; pyrrolidinyl; or a 5- to 6-membered aromatic heterocyclyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl or 1,2,4-oxadiazolyl, and A is ２ａ represents one or more R ６ 16. The compound for use as a medicine according to claim 15, optionally substituted with:

17. A ２ａ is one or two R ６ 17. A compound for use as a medicine according to any one of claims 1 to 10, 15 and 16, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein

18. Each R ６ are independently F, Cl, CF ３ , O.C.H. ３ , O.C.H.F. ２ , O.C.F. ３ , C.H. ３ , C.H. ２ CH ３ , C.H. ２ CF ３ 18. The compound for use as a medicine according to any one of claims 1 to 10, 15 to 17, wherein R is O-cyclopropyl or O-cyclopropyl, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

19. R ２ is CH ３ 19. A compound for use as a medicine according to any one of claims 1 to 18, wherein R is H; F; or H, preferably H, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

20. R ３ A ３ 20. The compound for use as a medicine according to any one of claims 1 to 19, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

21. A ３ is phenyl, pyridyl, pyrazinyl, pyrimidazyl, cyclopropyl, cyclobutyl or cyclohexyl, preferably phenyl; A ３ represents one or more R １０ 21. Any one of claims 1 to 20, optionally substituted with or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use as a medicament.

22. A ３ R is the same or different, 1, 2 or 3, preferably 1 or 2, more preferably 2 R １０ 22. The compound for use as a medicine according to any one of claims 1 to 21, wherein the compound is substituted with:

23. R ２ and R ３ are joined together with the oxygen and the carbon atom to which they are attached to form a dihydrobenzopyran ring, wherein the ring is joined together with one or more R １０ and preferably the ring is optionally substituted with one or two R １０ 23. A compound for use as a medicine according to any one of claims 1 to 22, substituted with:

24. R １０ are independently F, Cl, Br, CN, CHF ２ , C.F. ３ , O.C.H. ３、 O.C.F. ３ , CH=O, CH ２ OH or CH ３ 24. The compound for use as a medicament according to any one of claims 1 to 23, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

25. R ａ１ is H or C １～４ alkyl, where C １～４ Alkyl is halogen, OH and O—C １～３ alkyl, wherein the substituents are the same or different; preferably, R ａ１ is H;CH ３ or CH ２ CH ３ and more preferably, R ａ１ 25. The compound for use as a medicine according to any one of claims 1 to 24, wherein is H, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

26. tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-[(1s,3s)-3-(trifluoromethoxy)cyclobutoxy]acetamide tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide tert-Butyl(2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-[4-chloro-3-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-methylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(3,4-Dimethylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-{[6-(trifluoromethyl)pyridin-3-yl]oxy}acetamide 2-[3-Methoxy-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-2-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3-chloro-4-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-2,3-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3,5-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-2,2-difluoro-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)- 6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4,5-trichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-bromophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-cyanophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,5R)-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-2-oxo-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide tert-Butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-(2-methoxyethyl)piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-[5-(5-chloro-1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy) acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4-Dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(difluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(4,4,4-trifluorobutan-2-yl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclopropyl)methoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-(5-butoxy-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3,3-difluorocyclopentyl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropylethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methylbutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclobutyl)methoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorocyclobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2,2,3,3,3-pentafluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2 -(difluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(pentyloxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methoxypropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-ethoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclobutoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(4,4-difluoropentyl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-[5-(2-cyclopropoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-(3,4-dichlorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{[2-(trifluoromethyl)cyclopropyl]methoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-methyl-3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{methyl[2-(trifluoromethoxy)ethyl]amino}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxyazetidin-1-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidin-3-yl]acetamide tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-1-methyl-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1R)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1S)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1r,3r)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (2R)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide (2S)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidinyl 3-(3-yl)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide or 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 26. The compound for use as a medicine according to any one of claims 1 to 25, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

27. Formula (Ia) 【Chemistry 3】 27. The compound for use as a medicament according to any one of claims 1 to 26, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

28. 28. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, together with a pharma- ceutically acceptable carrier, optionally in combination with one or more other biologically active compounds or pharmaceutical compositions.

29. A compound as defined in any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition as defined in claim 28, for use in a method for the treatment or prevention of one or more diseases or disorders associated with the integrated stress response.

30. One or more diseases or disorders selected from the group consisting of leukodystrophies, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases, as well as organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injuries, ischemic stroke, and neuropathic pain.

29. A compound as defined in any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition as defined in claim 28, for use in a method for treating or preventing one or more diseases selected from the group consisting of:

31. The following compound or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof: 【Chemistry 4-1】 【Chemistry 4-2】 28. A compound as defined in any one of claims 1 to 27, except: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

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