Modulators of the 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)

Chemical formula

Background Art

[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, inter alia, inflammation, viral infections, diabetes, cancer and neurodegenerative diseases.

[0003] ISR is a common factor of different types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) on serine 51, leading to the suppression 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 eIF2 alpha kinases, each responding to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2 alpha kinase (HRI), and general control non-derepressible (GCN2) (3).

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

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

[0006] In response to ISR activation, phosphorylated eIF2-alpha inhibits the eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and, therefore, inhibition of normal mRNA translation characterized by ribosomes bound to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, translation of certain mRNAs, including mRNA encoding the transcription factor ATF4, is impaired by the translation of upstream ORFs (uORFs). Activation occurs through alteration mechanisms (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in non-stress cells, restricting ribosome flow to the main coding ORF. For example, under normal conditions, the uORF at the 5'UTR of ATF occupies the ribosome, preventing translation of the ATF4 coding sequence. However, under stress conditions, i.e., under reduced ternary complex formation, the probability of ribosomes scanning through these upstream ORFs and initiating translation at the ATF4 coding ORF is increased. ATF4 and other stress response factors expressed in this manner subsequently dominate the expression of an array of further stress response genes. The acute phase involves the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

[0007] Upregulation of ISR signaling markers has been demonstrated in various conditions among these cancers and neurodegenerative diseases. In cancer, ER stress-modulating translation increases tolerance to hypoxic conditions and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting leads to transformed PERK - / - It has been shown to slow tumor growth induced from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports have provided proof of concept that activators of eIF2B are effective in treating morphologies of invasive metastatic prostate cancer using patient-derived xenograft models in mice (28). Taken together, inhibition of cytoprotective ISR signaling may represent an effective antiproliferative strategy for treating at least some morphologies of cancer.

[0008] Furthermore, modulation of ISR signaling has been shown to be effective in preserving synaptic function and reducing neuronal decline, as well as in neurodegenerative diseases characterized by the activation of misfolded and unfolded protein responses (UPRs), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jacobukureutzfeldt (prion) diseases (18, 19, 20). Regarding prion diseases, there are examples of neurodegenerative diseases in which pharmacological inhibition, 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, reduction of phosphorylated eIF2 alpha levels by overexpression of a phosphatase that controls phosphorylated eIF2 alpha levels increased survival time in prion-infected mice, while maintained eIF2 alpha phosphorylation decreased survival time (22).

[0009] Furthermore, direct evidence exists regarding the importance of regulating protein expression levels for proper brain function in the form of rare genetic disorders affecting the function of eIF2 and eIF2B. Mutations in eIF2 gamma that disrupt the complex integrity of eIF2 and thus result in reduced normal protein expression levels lead to intellectual disability syndrome (ID) (23). Partial loss of functional mutations in the eIF2B subunit has been shown to be the cause of rare leukodystrophy-disappearing white matter disease (VWMD) (24, 25). Specifically, stabilization of partial loss of function of eIF2B in a VWMD mouse model with ISRIB-related small molecules has been shown to reduce ISR markers and improve functional endpoints, as well as pathological endpoints (26, 27).

[0010] A modulator of the eIF2 alpha pathway is described in Patent Document 1. Patent Documents 2, 3, 4, and 5 describe modulators of the integrated stress pathway. Patent Documents 6, 7, 8, 9, and 10 describe inhibitors of the ATF4 pathway. Patent Documents 11 and 12 relate to eukaryotic initiation factor 2B modulators.

[0011] Further literature describing modulators of integrated stress pathways can be found in Patent Document 13, These are 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 still a need for novel compounds that are useful as modulators of integrated stress response pathways with favorable 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 [Overview of the Initiative] [Problems that the invention aims to solve]

[0014] Therefore, an object of the present invention is to provide a novel class of compounds as integrated stress response pathway modulators that may be effective in treating integrated stress response pathway-related disorders and may improve pharmaceutically relevant properties, including activity, solubility, selectivity, ADMET properties, and / or reduction of side effects. [Means for solving the problem]

[0015] Therefore, the present invention relates to formula (I) for use as a pharmaceutical. [ka] Compounds thereof, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof (in the formula, X 1 N(R) a1 ) and; X 1a This is a covalent single bond, CH(R a3 ) or CH(R a3 )CH2; R a1 H, C(O)OC 1-4 Alkyl or C 1~4 It is alkyl, and here, C(O)OC 1-4 Alkyl and C 1~4 Alkyls are halogens, OH and OC 1~3 Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, where the substituents are the same or different; R a2 , R a3 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, However, Ra2 , R a3 , R a4 , R a5 , R a6 , R a7 Only one of them is A 2a Is it; or R a1 Furthermore, R a2 and R a3 One of them forms a methylene or ethylene group; or R a1 and R a6 Does it form an ethylene group? or R a2 and R a5 Does it form a covalent single bond? or R a5 , R a7 By being connected, they form an oxo group; A 1 A is a C5 cycloalkylene, a C5 cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocycloene, where A 1 This refers to one or more R, whether the same or different. 4 It is sometimes replaced by; Each R 4 These are independently oxo (=O) with a ring that is at least partially saturated, thiooxo (=S) with a ring that is at least partially saturated, halogens, CN, OR 5 , or C 1~6 It is alkyl, and here, C 1~6 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 5 is H or C 1~6 It is alkyl, and here, C 1~6 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; A 2 R 6a Or A 2a and; R 6a is OR 6a1 , SR 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 are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR 6a3 ; and A 2a and are optionally substituted with the same or different substituents; R 6a1 , R 6a2 are independently selected from the group consisting of H; C 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; and A 2a and are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR 1~6 Alkyl; C 2~6 Alkenyl; and C 2~6 Alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR 6a3 ; OA 2a and A 2a and are optionally substituted with the same or different substituents; R 6a3 is H; or C 1~4 Alkyl, where C 1~4 Alkyl is optionally substituted with one or more of the same or different halogens; A 2a is phenyl; C 3~7 Cycloalkyl; C 4~12 Bicycloalkyl; or a 3- to 7-membered heterocyclyl, where A 2a is optionally substituted with one or more of the same or different R 6 ; Each R 6 is independently R 6b ; OH; OR 6b ; halogen; or CN, where R 6b is cyclopropyl, C 1~6 Alkyl; C 2~6 Alkenyl; or C2~6 It is alkinyl, and here, R 6b may be replaced by one or more halogens, either the same or different; or Two R's 6 By being connected, they form ring A together with the atoms to which they are attached. 2b form; A 2b is phenyl; C 3~7 Cycloalkyl; or a 3- to 7-membered heterocycline, where A 2b This refers to one or more R, whether the same or different. 7 It is sometimes replaced by; Each R 7 C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; R 1 is H or C 1~4 Alkyl, preferably H, where C 1~4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 2 H;F; or C 1~4 It is alkyl, and here, C 1~4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 3 is, A 3 , C 1~6 Alkyl, C 2~6 Alkenil or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is the same or different one or more R 8 It may be replaced depending on the case; or R 2and R 3 By being connected, the oxygen atoms and the carbon atoms to which they are attached form ring A 3a Forms, and here, A 3a These are heterobisicrills with 7 to 12 members, where each heterobisicrill has one or more identical or different R groups. 10 It is sometimes replaced by; R 2a is H or F, preferably H; Each R 8 These are independently halogens; 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, O(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 , OCN(R) 9 R 9a ), or A 3 and; R 9 , R 9a , R 9b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyl is one or more halogens, one OH group, or one OC group, either the same or different. 1-4 Alkyl, or one A 3 It is sometimes replaced by; Each A 3 These are independently phenyl, naphthyl, and C 3~7 A is a cycloalkyl, a 3- to 7-membered heterocyclyl, or a 7- to 12-membered heterobicyclyl, where A 3 This refers to one or more R, whether the same or different. 10 It is sometimes replaced by; Each R 10 These are independently halogen, CN, and 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, O(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 ), OCN(R 11 R 11a ), the ring is at least partially saturated with oxo (=O), C 1~6 Alkyl, C 2~6 Alkenyl or C2~6 It is an alkynyl, and here C1 ~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is the same or different one or more R 12 It is sometimes replaced by; R 11 , R 11a , R 11b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; Each R 12 These are independently halogen, CN, and 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, O(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 OCN(R) 13 R 13a ) and; R 13 , R 13a , R 13b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyl provides (which may be substituted with one or more halogens, either the same or different).

[0016] Compounds not limited to their use as pharmaceuticals as defined above, having the priority as defined below, and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers are also within the scope of the present invention, except for the following compounds or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers: [ka] [ka]

[0017] The excluded compounds represent commercially available compounds that do not have a usage label.

[0018] The present invention also relates to preferred compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers (wherein formula (I), X 1 N(R) a1 ) and; X 1a This is a covalent single bond, CH(R a3 ), or CH(R a3 )CH2; R a1 H, C(O)OC 1-4 Alkyl or C 1~4 It is alkyl, and here, C(O)OC 1-4 Alkyl and C 1~4alkyl groups include halogens, OH groups, and OC groups. 1~3 Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, where the substituents are the same or different; R a2 , R a3 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, 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 Furthermore, R a2 and R a3 One of them forms a methylene or ethylene group; or R a1 and R a6 Does it form an ethylene group? or R a2 and R a5 Does it form a covalent single bond? or R a5 , R a7 By being connected, they form an oxo group; A 1 A is a C5 cycloalkylene, a C5 cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, where A 1 This refers to one or more R, whether the same or different. 4 It is sometimes replaced by; Each R 4These are independently oxo (=O) with a ring that is at least partially saturated, thiooxo (=S) with a ring that is at least partially saturated, halogens, CN, OR 5 , or C 1~6 It is alkyl, and here, C 1~6 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 5 is H or C 1~6 It is alkyl, and here, C 1~6 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; A 2 R 6a Or A 2a and; R 6a is OR 6a1 , SR 6a1 , N(R 6a1 R 6a2 );C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is a halogen; CN; OR 6a3 ; and A 2a It is optionally substituted with one or more substituents selected from the group consisting of the following, where the substituents are the same or different; R 6a1 , R 6a2 H;C 1~6 Alkyl; C 2~6 Alkenil; C 2~6 Alkinyl; and A 2a Independently selected from the group consisting of, where C 1~6 Alkyl; C 2~6 Alkenyl; and C 2~6 Alkinyl is a halogen; CN; OR 6a3 ; and A 2a It is optionally substituted with one or more substituents selected from the group consisting of the following, where the substituents are the same or different; R 6a3is H; or C 1~4 It is alkyl, and here, C 1~4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; A 2a is phenyl; C 3~7 Cycloalkyl; C 4~12 Bicycloalkyl; or a 3- to 7-membered heterocycline, where A 2a This refers to one or more R, whether the same or different. 6 It is sometimes replaced by; Each R 6 R is independent of R 6b ;OH;OR 6b ;halogen; or CN, where R 6b is cyclopropyl, C 1~6 Alkyl; C 2~6 Alkenil; or C 2~6 It is alkinyl, and here, R 6b may be replaced by one or more halogens, either the same or different; or Two R's 6 By being connected, they form ring A together with the atoms to which they are attached. 2b form; A 2b is phenyl; C 3~7 Cycloalkyl; or a 3- to 7-membered heterocycline, where A 2b This refers to one or more R, whether the same or different. 7 It is sometimes replaced by; Each R 7 C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; R 1 is H or C 1~4 Alkyl, preferably H, where C 1~4Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 2 H;F; or C 1~4 It is alkyl, and here, C 1~4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 3 is, A 3 , C 1~6 Alkyl, C 2~6 Alkenil or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl Or one or more different Rs 8 It may be replaced depending on the case; or R 2 and R 3 By being connected, the oxygen atoms and the carbon atoms to which they are attached form ring A 3a Forms, and here, A 3a These are heterobisicrills with 7 to 12 members, where each heterobisicrill has one or more identical or different R groups. 10 It is sometimes replaced by; R 2a is H or F, preferably H; Each R 8 These are independently halogens; 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, O(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 , OCN(R) 9 R 9a ), or A 3 and; R 9 , R 9a , R 9b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are one or more halogens, one OH group, or one OC group, either the same or different. 1~4 Alkyl, or one A 3 It is sometimes replaced by; Each A 3 These are independently phenyl, naphthyl, and C 3~7 A is a cycloalkyl, a 3- to 7-membered heterocyclyl, or a 7- to 12-membered heterobicyclyl, where A 3 This refers to one or more R, whether the same or different. 10 It is sometimes replaced by; Each R 10 These are independently halogen, CN, and 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, O(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 ), OCN(R 11 R 11a ), oxo (=O) whose ring is at least partially saturated, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is the same or different one or more R 12 It is sometimes replaced by; R 11 , R 11a , R 11b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; Each R 12 These are independently halogen, CN, and 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, O(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 OCN(R) 13 R 13a ) and; R 13 , R 13a , R 13b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 The alkynnyl also provides (which may be substituted with one or more halogens, one or more of the same or different).

[0019] The present invention also relates to preferred compounds of formula (I), or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof (wherein X 1a CH(R a3 ) and R a7 and R 2a Since H is, therefore, equation (I-1) [ka] It has, in the formula, X 1 N(R) a1 ) and; R a1is H or C 1~4 It is alkyl, and here, C 1~4 Alkyls are halogens, OH and OC 1~3 Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, where the substituents are the same or different, preferably R a1 is H; R a2 , R a3 , R a4 , R a5 , R a6 Is it H? or R a1 Furthermore, R a2 and R a3 One of them forms a methylene or ethylene group; or R a1 and R a6 It forms an ethylene group; A 1 A is a C5 cycloalkylene, a C5 cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, where A 1 This refers to one or more R, whether the same or different. 4 It is sometimes replaced by; Each R 4 These are independently halogen, CN, OR 5 , an oxo (=O) or C whose ring is at least partially saturated 1~6 It is alkyl, and here, C 1~6 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 5 is H or C 1~6 It is alkyl, and here, C 1~6 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; A 2 A is a phenyl or a 5- to 6-membered aromatic heterocycline, where A 2 This refers to one or more R, whether the same or different. 6 It is sometimes replaced by; Each R 6 These are independently OH, O(C)1~6 Alkyl), halogen, CN, cyclopropyl, C 1~6 Alkyl, C 2~6 Alkenil or C 2~6 It is an alkynyl, where cyclopropyl, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyl may be substituted by one or more halogens, either the same or different; or Two R's 6 By being connected, they form ring A together with the atoms to which they are attached. 2b form; A 2b is phenyl; C 3~7 Cycloalkyl; or a 3- to 7-membered heterocycline, where A 2b This refers to one or more R, whether the same or different. 7 It is sometimes replaced by; Each R 7 C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 It is an alkinyl, and here, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; R 1 is H or C 1~4 Alkyl, preferably H, where C 1~4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 2 is H or C 1~4 It is alkyl, and here, C 1~4 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different; R 3 is, A 3 , C 1~6 Alkyl, C 2~6 Alkenil or C 2~6 It is an alkinyl, and here, C 1~6Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is the same or different one or more R 8 It may be replaced depending on the case; or R 2 and R 3 These, when connected, form a heterobicyclyl with 7 to 12 members, Thus, heterobisicrills with 7 to 12 members have one or more identical or different R groups. 10 It is sometimes replaced by; Each R 8 These are independently halogens; 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, O(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 , OCN(R) 9 R 9a ), or A 3 and; R 9 , R 9a , R 9b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; Each A 3 These are independently phenyl, naphthyl, and C 3~7 A is a cycloalkyl, a 3- to 7-membered heterocyclyl, or a 7- to 12-membered heterobicyclyl, where A 3 This refers to one or more R, whether the same or different. 10 It is sometimes replaced by; Each R 10 These are independently halogen, CN, and 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, O(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 ), OCN(R 11 R 11a ), oxo (=O) whose ring is at least partially saturated, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 It is an alkinyl, and here, C1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is the same or different one or more R 12 It is sometimes replaced by; R 11 , R 11a , R 11b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are sometimes substituted with one or more halogens, one or more of the same or different; Each R 12 These are independently halogen, CN, and 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, O(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 OCN(R) 13 R 13a ) and; R 13 , R 13a , R13b H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 The alkynnyl also provides (which may be substituted with one or more halogens, one or more of the same or different). [Modes for carrying out the invention]

[0020] Surprisingly, the example compounds disclosed according to the present invention, when combined, possess desirable physicochemical properties and / or selectivity that help achieve beneficial therapeutic efficacy while limiting unintended reliability.

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

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

[0023] The term "optionally substituted" means either unsubstituted or substituted. Generally, "one or more substituents" means one, two or three substituents, preferably one or two substituents, more preferably one substituent, although not limited to the above. Generally, these substituents may be the same or different. The term "one or more substituents" also means, for example, one, two, three, four or five substituents, preferably one, two, three or four substituents.

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

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

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

[0027] "C 1~4 "Alkyl" refers to alkyl chains that, if present, have 1 to 4 carbon atoms at the ends of the molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, when two parts of the molecule are linked by an alkyl group, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1~4 Each hydrogen atom of the alkyl carbon can be replaced by substituents as further specified. 1~3 The term "alkyl" is defined as appropriate.

[0028] "C 1~6 "Alkyl" refers to an alkyl chain, for example, one that has 1 to 6 carbon atoms at the ends 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, if two parts of the molecule are linked by an alkyl group, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1~6 Each hydrogen atom of the alkyl carbon can be replaced by substituents as further specified.

[0029] "C 2~6"Alkenyl" refers to an alkenyl chain, for example, one that has 2 to 6 carbon atoms at the ends of the molecule if present: -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 atom of the alkenyl carbon can be replaced by substituents as further specified.

[0030] "C 2~6 "Alkynyl" refers to, for example, an alkynyl chain having 2 to 6 carbon atoms at the ends 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 atom of the alkynyl carbon can be replaced by substituents as further specified.

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

[0032] "C5 cycloalkylene" refers to a divalent cycloalkyl group having five 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 The term "bicycloalkyl ring" means a bicyclic condensation, bridge, or spiroalkyl chain having 4 to 12 carbon atoms, such as hexahydroindan, octahydropentalene, bicyclic[2.2.1]heptane, or spiro(3.2)hexane. Each hydrogen atom of the bicycloalkyl carbon may be replaced by substituents as further specified herein.

[0035] "Halogen" refers to fluoro, chloro, bromo, or iodine. Generally, halogens are preferred to be 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 can contain up to a maximum number of double bonds (aromatic or non-aromatic rings that are fully, partially, or unsaturated), where at least 1 to 4 ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of heterocycles with 3 to 7 members include aziridine, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidin, isothiazolidin, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidin, diazepane, azepine, or homopiperazine. The terms “5-membered to 6-membered heterocyclyl” or “5-membered to 6-membered heterocycle” are defined as appropriate and include 5-membered to 6-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 linked to the rest of the molecule via a carbon or nitrogen atom.

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

[0039] "A 4- to 7-membered heterocycline or a 4- to 7-membered heterocycle" means a 4- to 7-membered heterocycline or a 4- to 7-membered heterocycle.

[0040] A "5- to 6-membered aromatic heterocyclyl" or "5- to 6-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl or benzene, where 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 include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0041] A "five-membered aromatic heterocyclyl" or "five-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)- and -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, and tetrazole.

[0042] A "7- to 12-membered heterobicyryl" or "7- to 12-membered heterobicyclic" means a heterocyclic system of two rings having 7 to 12 ring atoms, where at least one ring atom is shared by both rings and the system may contain up to a maximum number of double bonds (aromatic or non-aromatic rings that are fully, partially, or unsaturated), and at least one ring atom, up to six ring atoms, are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of heterobicyclic compounds with 7 to 12 members include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, or pteridine. The term seven- to twelve-membered heterobicycle includes spirostructures of two rings such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptane-6-yl, or 2,6-diazaspiro[3.3]heptane-6-yl, or bridging heterocycles such as 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane-2-yl, or 3,8-diazabicyclo[3.2.1]octane.

[0043] "Saturated 7- to 12-membered heterobicyryl" or "saturated 7- to 12-membered heterobicyclic" means a fully saturated "7- to 12-membered heterobicyryl" or "7- to 12-membered heterobicyclic."

[0044] "7- to 12-membered heterobisicrills or 7- to 12-membered heterobicyclic rings" means at least partially saturated "7- to 12-membered heterobisicrills" or "7- to 12-membered heterobicyclic rings".

[0045] A "9- to 11-membered aromatic heterobisicryl" or "9- to 11-membered aromatic heterobicyclic" means a heterocyclic system of two rings, where at least one ring is aromatic, the heterocyclic system has 9 to 11 ring atoms, where two ring atoms are shared by both rings, and the system may contain up to a maximum number of double bonds (fully or partially aromatic), where at least one ring atom and up to six ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of 9- to 11-membered aromatic heterobicycles include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydro-isoquinoline, benzazepine, purine, or pteridine. The terms "9- to 10-membered aromatic heterobicyclyl" or "9- to 10-membered aromatic heterobicycle" are defined as appropriate.

[0046] A preferred compound of formula (I) is a compound in which one or more residues contained herein have the meanings given above or below, and all combinations of the preferred substituent definitions are subject to the present invention. With respect to all preferred compounds of formula (I), the present invention also includes all tautomers and stereoisomers, mixtures thereof in all ratios, and pharmaceutically acceptable salts thereof.

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

[0048] Preferably, X 1 is NH or NC 1~4 It is alkyl, and here, C 1~4 alkyl groups include halogens, OH groups, and OC groups. 1~3 Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, where 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 CH(R a3 ) or CH(R a3 )CH2, more preferably CH(R a3 )

[0050] Preferably, R a2 , R a3 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 They 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 a5 , R a7These molecules, when connected, 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 They 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 It is. 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 H is R a5 , R a7 When connected, it forms an oxo group. More preferably, R a2 , R a3 , R a4 , R a5 , R a6 , R a7 H is H.

[0052] Preferably, A 1 It is a 5-membered heterocyclene containing a nitrogen ring atom, and A 1 This refers to one or more R, whether the same or different. 4 It is sometimes replaced.

[0053] more, A 1 This is a nitrogen ring atom-containing 5-membered heterocyclene selected from the group of divalent heterocyclic compounds consisting of oxadiazole, imidazole, imidazolidine, pyrazole, and triazole, preferably oxadiazole, and A 1 This refers to one or more R, whether the same or different.4 It is sometimes replaced.

[0054] Preferably, A 1 is either unsubstituted or one or two identical or different R 4 It is replaced with, preferably, A 1 This is a non-substitution.

[0055] Preferably, R 4 These are independently oxo (=O), halogen, CN, OR, whose rings are at least partially saturated. 5 , or C 1~6 It is alkyl, and here, C 1~6 Alkyl atoms are sometimes substituted with one or more halogens, either the same or different.

[0056] Preferably, R 4 This is an oxo whose ring is at least partially saturated.

[0057] Preferably, A 1 teeth, [ka] And, moreover, A 1 teeth, [ka] That is the case.

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

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

[0060] In one embodiment, R 6a1 , R 6a2 H;C 1~6 Alkyl; C 2~6 Alkenil; C 2~6 Alkinyl; and A 2aIndependently selected from the group consisting of, where, C 1~6 Alkyl; C 2~6 Alkenyl; and C 2~6 Alkinyl is a halogen; CN; OR 6a3 ; and A 2a It is optionally substituted with one or more substituents selected from the group consisting of the following, where the substituents are the same or different.

[0061] R 6a1 Preferably A 2a , or one or more halogens and / or one A 2a and / or one OR 6a3 C is replaced in some cases. 1~6 It is alkyl. More preferably, R 6a1 is one or more F and / or one OR 6a3 C is replaced in some cases. 1~6 It is alkyl.

[0062] Preferably, R 6a is one or more halogens and / or one A 2a and / or one OR 6a3 C is replaced in some cases. 1~6 It is alkyl. More preferably, R 6a is one or more halogens and / or one OR 6a3 C is replaced in some cases. 1~6 It is alkyl.

[0063] In one preferred embodiment, R 6a1 is unsubstituted C 4~6 Alkyl; more preferably 3-methylbuta-1-yl or n-butyl. In another preferred embodiment, R 6a1 C is substituted with one or more halogens, preferably one or more fluorocarbons, which are the same or different. 2~6 Alkyl; more preferably, R 6a1is 3,3,3-trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, 4,4,4-trifluorobutan-2-yl, 2,2,3,3,3-pentafluoropropyl, 3,3-difluorobutyl or 3,3,3-trifluorobutyl. In another preferred embodiment, R 6a1 is A 2a , CH2A 2a , CH2CH2A 2a , where A 2a is unsubstituted or substituted with one or more of the same or different halogen, preferably one or more fluorine; more preferably, R 6a1 is cyclobutyl, cyclopentyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2CH2-cyclopropyl, where R 6a1 is substituted with one or more F.

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

[0065] Preferably, R 6a2 is H.

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

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

[0068] Preferably, A 2a is phenyl; C3~7 Cycloalkyl; or a 3- to 7-membered heterocyclyl, where A 2a is optionally substituted by one or more of the same or different R 6 .

[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 optionally substituted by one or more of the same or different 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, where A 2a is optionally substituted by one or more of the same or different R 6 .

[0070] Even more preferably, A 2a is phenyl; cyclobutyl; pyridyl; azetidinyl; pyrazolyl; or pyrrolidinyl, where A 2a is optionally substituted by one or more of the same or different R 6 .

[0071] Preferably, A 2a is C 3~7 cycloalkyl, more preferably cyclobutyl, where A 2a is optionally substituted by one or more of the same or different R 6 .

[0072] Preferably, A 2a is substituted by one or two of the same or different R 6 .

[0073] Preferably, R6 These are independently F, Cl, CF3, OCH3, OCF3, OCHF2, CH3, CH2CH3, CH2CF3, O-cyclopropyl, or cyclopropyl. More preferably, R 6 These 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 H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkynnyls, where C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyl is one or more halogens, one OH group, or one OC group, either the same or different. 1~4 Alkyl, or one A 3 It is sometimes replaced.

[0076] Preferably, R 3 is A 3 That is the case.

[0077] Preferably, A 3 A is phenyl, pyridyl, pyrazinyl, pyrimidazyl, cyclopropyl, cyclobutyl, or cyclohexyl, where A 3 This refers to one or more R, whether the same or different. 10 It is sometimes replaced by A. 3 is phenyl, and here, A 3 This refers to one or more R, whether the same or different. 10 It is sometimes replaced.

[0078] Preferably, A 3 This is one, two, or three identical or different Rs, preferably one or two (more preferably two) Rs. 10 It has been replaced with.

[0079] Preferably, R 2 and R 3 These atoms, together with oxygen and the carbon atoms to which they are attached, form a dihydrobenzopyran ring, where the ring is the same or different one or more R atoms. 10 In some cases, the ring is substituted, preferably with one or two R 10 It has been replaced with.

[0080] Preferably, R 10 These 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 These are independently either F or Cl.

[0081] Preferably, R a1 is H or C 1~4 It is alkyl, and here, C 1~4 Alkyl These are halogens, OH and OC 1~3 Optionally substituted with one or more substituents selected from the group consisting of alkyl groups, where the substituents are the same or different; preferably, R a1 is H;CH3 or CH2CH3; more preferably R a1 H is H.

[0082] Compounds of formula (I) in which some or all of the above-described groups have a preferred or more preferred meaning are also subject to the present invention.

[0083] Preferred specific compounds of the present invention are: tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chlorophenoxy)propanamide]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate 2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]propanamide N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]-2-[(1s,3s)-3-(trifluoromethoxy)cyclobutoxy]acetamide tert-butyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetamide}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-[(6-chloro-5-fluoropyridine-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-[4-chloro-3-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-methylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(3,4-dimethylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]-2-{[6-(trifluoromethoxy] Oromethyl)pyridine-3-yl]oxyacetamide 2-[3-Methoxy-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-(4-chloro-2-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(3-chloro-4-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-[4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-2,3-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3,5-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-2,2-difluoro-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(3,4,5-trichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-bromophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-[3-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-cyanophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]pyrrolidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,5R)-5-[5-(4 -Chlorophenyl)-1,3,4-oxadiazole-2-yl]pyrroridine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(6-methylpyridine-3-yl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-2-oxopiperidine-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-2-oxo-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide tert-butyl(2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-methylpiperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-methylpiperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-ethylpiperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-ethylpiperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-(2-methoxyethyl)piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide N-[(3S,6R)-6-[5-(5-chloro-1-methyl-1H-pyrazole-3-yl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[6-(trifluoromethyl)pyridine-3-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(5-chloropyridine-2-yl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chloro-3-fluorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[1-(2,2,2-trifluoroethyl)azetidine-3-yl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[1-(2,2,2-trifluoroethyl)azetidine-3-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(difluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[( 4,4,4-Trifluorobutan-2-yl)oxy]-1,3,4-Oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorobutoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclopropyl)methoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide N-[(3S,6R)-6-(5-butoxy-1,3,4-oxadiazole-2-yl)piperidine-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-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropylethoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methylbutoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclobutyl)methoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorocyclobutoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2,2,3,3,3-pentafluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(difluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(pentyloxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methoxypropoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropoxyethoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2 -Ethoxyethoxy)-1,3,4-Oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclobutoxyethoxy)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(4,4-difluoropentyl)oxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide N-[(3S,6R)-6-[5-(2-cyclopropoxyethoxy)-1,3,4-oxadiazole-2-yl]piperidine-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-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{[2-(trifluoromethyl)cyclopropyl]methoxy}-1,3,4-oxadiazole-2-yl)piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[3-(trifluoromethyl)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethyl)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(2,2,2-trifluoroethyl)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-methyl-3-(trifluoromethoxy)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{methyl[2-(trifluoromethoxy)ethyl]amino}-1,3,4-oxadiazole-2-yl)piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxyazetidine-1-yl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)pyrrolidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazole-3-yl}piperidine-3-yl]acetamide tert-butyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetamide}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate 2-[(6-chloro-5-fluoropyridine-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-1-methyl-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1R)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazole-2-yl)piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1S)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazole-2-yl)piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1r,3r)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide (2R)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]propanamide (2S)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]propanamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-2-oxopiperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-2-oxopiperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3R)-3-(trifluoromethoxy)pyrrolidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide and 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazo [Lu-2-yl]piperidine-3-yl]acetamide It is selected from the group consisting of the following.

[0084] If tautomerism can occur in a compound of formula (I), such as keto-enol tautomerism, then the individual forms, such as keto and enol forms, are included separately and together as mixtures in any ratio. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, and conformational isomers.

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

[0086] The preferred compound is formula (Ia) [ka] The compound of formula (I) having the relative stereoconfiguration as shown, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0087] Isotope-labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope 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 to diastereomers, i.e., by coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomer and cleavage of the auxiliary residue. Alternatively, any enantiomer of the compound of formula (I) can be obtained by stereoselective synthesis using optically pure starting materials, reagents and / or catalysts.

[0089] Where a compound according to formula (I) contains one or more acidic or basic groups, the present invention also includes the corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular pharmaceutically usable salts thereof. 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., protonable groups, can exist and can be used according to the present invention in the form of addition salts thereof 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, and glycerides. Examples include acids, propionic acid, vivariic 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 its molecule, the present invention also includes internal salts or betaines (amphoteric ions) in addition to the salt forms described. Each salt according to formula (I) can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of formula (I) that, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but can be used, for example, as intermediates for chemical reactions or for the production of pharmaceutically acceptable salts.

[0090] As shown below, the compounds of the present invention are considered 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 significant pathological consequences, particularly leading to inflammation, viral infections, diabetes, cancer, and neurodegenerative diseases.

[0092] ISR is a common factor of different types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) on serine 51, leading to the suppression 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 eIF2 alpha kinases, each responding to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2 alpha kinase (HRI), and generalized unrepressive 2 (GCN2) (3).

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

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

[0095] In response to ISR activation, phosphorylated eIF2-alpha inhibits the eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and, therefore, inhibition of translation of normal mRNAs characterized by ribosomes bound to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, the translation of several specific mRNAs, including mRNA encoding the transcription factor ATF4, is activated via a mechanism involving alteration of translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in non-stress cells, restricting ribosome flow to the primary encoding ORF. For example, under normal conditions, the uORF at the 5'UTR of ATF occupies the ribosome and prevents translation of the ATF4 coding sequence. However, under stress conditions, i.e., under conditions of reduced ternary complex formation, the ribosome occupies these upstream ORFs. The probability of scanning through and initiating translation at the ATF4-coded ORF is increased. ATF4 and other stress response factors expressed in this manner subsequently govern the expression of further stress response gene arrays. The acute phase involves 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 ISR signaling markers has been demonstrated in various conditions among these cancers and neurodegenerative diseases. In cancer, ER stress-modulating translation increases tolerance to hypoxic conditions and promotes tumor growth (14, 15, 16), and deletion of PERK by gene targeting leads to transformed PERK - / - It has been shown to slow tumor growth induced from mouse embryonic fibroblasts (14, 17). Furthermore, recent reports have provided proof of concept that activators of eIF2B are effective in treating morphologies of invasive metastatic prostate cancer using patient-derived xenograft models in mice (28). Taken together, inhibition of cytoprotective ISR signaling may represent an effective antiproliferative strategy for treating at least some morphologies of cancer.

[0097] Furthermore, modulation of ISR signaling has been shown to be effective in preserving synaptic function and reducing neuronal decline, as well as in neurodegenerative diseases characterized by the activation of misfolded and unfolded protein responses (UPRs), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and Jacobukureutzfeldt (prion) diseases (18, 19, 20). Regarding prion diseases, there are examples of neurodegenerative diseases in which pharmacological inhibition, 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, reduction of phosphorylated eIF2 alpha levels by overexpression of a phosphatase that controls phosphorylated eIF2 alpha levels increased survival time in prion-infected mice, while maintained eIF2 alpha phosphorylation decreased survival time (22).

[0098] Furthermore, direct evidence exists regarding the importance of regulating protein expression levels for proper brain function in the form of rare genetic disorders affecting the function of eIF2 and eIF2B. Mutations in eIF2 gamma that disrupt the complex integrity of eIF2 and thus result in reduced normal protein expression levels lead to intellectual disability syndrome (ID) (23). Partial loss of functional mutations in the eIF2B subunit has been shown to be the cause of rare leukodystrophy-disappearing white matter disease (VWMD) (24, 25). Specifically, stabilization of partial loss of function of eIF2B in a VWMD mouse model with ISRIB-related small molecules has been shown to reduce ISR markers and improve functional endpoints, as well as pathological endpoints (26, 27).

[0099] The present invention provides the compounds of the present invention in free form, pharmaceutically acceptable salt form, or in the form of solvates, hydrates, tautomers, or stereoisomers for use in the treatment of diseases or disorders described herein. The same applies to the pharmaceutical compositions of the present invention.

[0100] Accordingly, 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 pharmaceutical compositions of the present invention.

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

[0102] Accordingly, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in the treatment or prevention of one or more diseases or disorders associated with the integrated stress response.

[0103] Further aspects of the present invention are the compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in methods of treating or preventing one or more disorders or diseases associated with integrated stress response.

[0104] A further aspect of the present invention is the use of the compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals for the treatment or prevention of one or more disorders or diseases associated with integrated stress response.

[0105] Another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient requiring treatment of one or more diseases or disorders related to the integrated stress response, the method comprising administering to the patient a therapeutically effective amount of the 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 compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in the treatment or prevention of one or more diseases or disorders described below.

[0107] Further aspects of the present invention are compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for use in methods of treating or preventing one or more disorders or diseases described below.

[0108] A further aspect of the present invention is the use of the compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals for the treatment or prevention of one or more disorders or diseases described below.

[0109] Further aspects of the present invention are methods for treating, controlling, delaying or preventing in a mammalian patient requiring treatment of one or more of the diseases or disorders described below, the methods comprising administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof.

[0110] Diseases or disorders include, but are not limited to, leukodystrophy, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplasms, 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 injury, ischemic stroke, and neuropathic pain.

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

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

[0113] Neurodegenerative diseases / disorders Examples of neurodegenerative diseases and disorders include, but are not limited to, Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxic telangiectasia, Batten disease (also known as Spielmeier-Voigt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Streussler-Scheinker syndrome, Huntington's disease, HIV-related dementia, Kennedy disease, Krabbe disease, and Coeurl. These include Lou, Lewy body dementia, Machad-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 fluctuating characteristics), spinal muscular atrophy, Steele-Richardson-Olsewski disease, spinal fistula, and tauopathy.

[0114] In particular, neurodegenerative diseases and disorders are selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0115] Neoplastic disease Neoplastic diseases can be understood in their broadest sense as any tissue resulting from misregistration of cell growth. Often, neoplasms progress to at least bulky tissue tumors, sometimes innervated by blood vessels. They may or may not involve the formation of one or more metastases. The neoplastic diseases of this invention may be any neoplasm as classified by the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) Classification C00-D48.

[0116] For example, the neoplastic disease according to the present invention may be the presence of one or more malignant neoplasms (single or multiple) (tumors) (ICD-10 classification C00-C97), one or more in situ neoplasms (single or multiple) (ICD-10 classification D00-D09), one or more benign neoplasms (single or multiple) (ICD-10 classification D10-D36), or one or more neoplasms (single or multiple) exhibiting uncertain or unknown behavior (ICD-10 classification D37-D48). Preferably, the neoplastic disease according to the present invention refers to the presence of one or more malignant neoplasms (single or multiple), i.e., malignant neoplasms (ICD-10 classification C00-C97).

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

[0118] Cancer, in its broadest sense, is any malignant neoplasm disease in a patient, that is, one type or This can be understood as the presence of one or more malignant neoplasms. Cancer can be a solid or hematological malignancy. The cancers discussed herein are, but are not limited to, leukemia, lymphoma, carcinoma, and sarcoma.

[0119] In particular, neoplasms such as cancers characterized by upwardly modulated ISR markers are included in this specification.

[0120] Illustrative cancers include, but are not limited to, thyroid cancer, endocrine cancer, 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, tubular 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, gastric cancer, bladder cancer, bone 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 lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, urinary vesicle cancer, pre-malignant 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 carcinoma, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, tubular carcinoma, pancreatic stellate cell carcinoma, and hepatic stellate cell carcinoma.

[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, nonleukocytic leukemia, basophilic leukemia, blastocyte leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonic leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, and acute monocytic leukemia. These include leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphotropic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, and anaplastic cell leukemia.

[0124] Illustrative sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemesy's sarcoma, liposarcoma, lipid sarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, staphyloid sarcoma, greenish sarcoma, choriocarcinoma, embryonic sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fasciosarcoma, fibroblastic sarcoma, and giant sarcoma. These include cell sarcomas, granulocytic sarcomas, Hodgkin's sarcomas, idiopathic multiple pigmented hemorrhagic sarcomas, B-cell immunoblastic sarcomas, lymphomas, T-cell immunoblastic sarcomas, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, paraosteal sarcoma, reticular sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and peripheral telangiectatic sarcomas.

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

[0126] Symptomatic carcinomas include, but are not limited to, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal basal carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiololar carcinoma, bronchogenic lung carcinoma, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedone carcinoma, corpus carcinoma, cribriform carcinoma, armory carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, tubular carcinoma, tubular carcinoma, compact carcinoma (carcinoma) Durum carcinoma, embryonic carcinoma, cerebral carcinoma, epidermal carcinoma, epithelial adenoid carcinoma, extrinsic carcinoma, preulative ulcer carcinoma (carcinoma ex ulcere), fibrous carcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, piloma carcinoma, hematoid carcinoma, hepatocellular carcinoma, Haasle cell carcinoma, hyaline carcinoma, high renal carcinoma, infantile 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, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous adenocarcinoma (carcinoma muciparum), mucocellular carcinoma (carcinoma mucocellulare), mucoepidermal carcinoma, mucinous carcinoma, mucinous carcinoma, myxomatous carcinoma (carcinoma Myxomatodes include nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, gooey carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solenoid carcinoma, bulbous cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous carcinoma, squamous cell carcinoma, linear carcinoma, telangiectatic 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 (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 infections, etc.), and infections caused by bacteria (Legionella, Brucella, Simkania, Chlamydia, Helicobacter, and Campylobacter infections, etc.).

[0128] inflammatory diseases Examples of inflammatory diseases include, but are not limited to, postoperative cognitive impairment (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 mellitus, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, and Sjögren'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, ataxia Friedrich, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscular atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendinitis, back pain, muscle pain, muscle soreness, repetitive tonic disorders, and paralysis.

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

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

[0132] Further diseases Further conditions include, but are not limited to, organ fibrosis (such as hepatic fibrosis, pulmonary fibrosis, or renal fibrosis), chronic and acute diseases of the liver (such as fatty liver disease or hepatic steatohepatosis), 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] 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, one or more bioactive compounds are modulators of integrated stress response pathways other than the compound of formula (I).

[0135] "Pharmaceutical composition" means one or more active ingredients, one or more inactive ingredients constituting a carrier, as well as any products directly or indirectly resulting from any combination of two or more ingredients, complexation or aggregation, or dissociation of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by adding and mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0136] The pharmaceutical compositions of the present invention may include 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 ingredient may be contained in one or more different pharmaceutical compositions (combinations of pharmaceutical compositions).

[0138] The term "pharmaceutically acceptable salt" refers to a salt produced from a pharmaceutically acceptable, non-toxic base or acid, including inorganic and organic bases or acids.

[0139] Examples of compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (intranasal or buccal inhalation), or intranasal administration include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), etc., but the most appropriate route in any given case depends on the nature and severity of the condition being treated and the nature of the active ingredient. Conveniently, they exist in unit dosage forms and can be manufactured by any method well known in the art of pharmaceuticals.

[0140] In practical use, the compound of formula (I) can be combined as an active ingredient in a closely compounded mixture with a pharmaceutical carrier, according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the desired form of the product for administration, e.g., orally or parenterally (including intravenously). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media, such as water, glycol, oil, alcohol, flavoring agents, preservatives, and colorants, can be used in the case of oral liquid products such as suspensions, elixirs, and solutions; or carriers, such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants, can be used in the case of oral solid products such as powders, hard and soft capsules, and tablets, with solid oral products being preferred over liquid products.

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

[0142] Tablets, pills, capsules, etc. may also contain a binder, such as tragacanth gum, acacia, corn starch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrant, such as corn starch, potato starch, or alginic acid; a lubricant, such as magnesium stearate; and a sweetener, such as sucrose, lactose, or saccharin. If the dosage unit form is a capsule, it may contain a liquid carrier, such as fatty oil, in addition to the materials of the above types.

[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. In addition to the active ingredient, syrups or elixirs may contain sucrose as a sweetener, methyl and propylparabens as preservatives, and dyes and flavorings such as cherry or orange flavoring.

[0144] The compounds of formula (I) can also be administered parenterally. Solutions or suspensions of these active compounds can be appropriately mixed with water and a surfactant such as hydroxypropyl cellulose. It can be manufactured in [location]. The dispersion can also be manufactured in glycerin, liquid polyethylene glycol, and its mixture in oil. Under normal storage and use conditions, these products contain preservatives to prevent microbial growth.

[0145] Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and fluid to the extent that it is readily available for syringe injection. It should be stable under manufacturing and storage conditions and protected against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0146] Any suitable route of administration can be used to provide an effective dose of the compound of the present invention to mammals, particularly humans. For example, oral, rectal, topical, parenteral, ocular, lung, or nasal administration may be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, and aerosols. Preferably, the compound of formula (I) is administered orally.

[0147] The effective dose of the active ingredient used can vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such doses can be easily determined by those 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, and ABCR, or can be synthesized using methods known to those skilled in the art.

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

[0150] I Chemical Synthesis Experimental 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-dimethylpyridine-4-amine ESI + Positive ionization mode ESI - Negative ionization mode HCl ethyl acetate EtOH Ethanol Et2O Diethyl ether H2SO4 sulfuric acid HATU 1-[bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium-3-oxidehexafluorophosphate HCl (hydrochloric acid) HPLC (High-Performance Liquid Chromatography) h time (singular or plural) IPA Isopropyl Alcohol KHCO3 (potassium bicarbonate) LiOH (Lithium Hydroxide) LiOH,H2O (Lithium Hydroxide Hydrate) m multiplex m-CPBA 3-chlorobenzenecarboperoxoacid MeOH methanol MgSO4 potassium sulfate min MsOH Methanesulfonic Acid mL (milliliter) N2 nitrogen atmosphere Sodium sulfite (Na2SO3) Sodium sulfate (Na2SO4) 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(+)-tartaric acid tetrahydrate RT retention time satd saturated SOCl2 thionyl chloride STAB Sodium Triacetoxyborhydride T3P Propanephosphonic Acid 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 Zinc dibromide (ZnBr2)

[0151] The LCMS conditions for analysis are as follows:

[0152] System 1 (S1): Acidic IPC method (MS18 and MS19) Analytical HPLC-MS (MET / CR / 1410) was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm × 50 mm, 5 μm; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) over 1.2 minutes, followed by a gradient of 100% B over 0.1 minutes. A second gradient of 100–5% B was then applied over 0.01 minutes with an injection volume of 3 μL at a flow rate of 1.2 mL / min. The UV spectrum was recorded at 215 nm using an SPD-M20A photodiode array detector with a spectral range of 200–400 nm. The mass spectrum was obtained using a 2010 EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0153] System 2 (S2): Acidic IPC method (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 5–100% B (A = 0.1% formic acid in H2O: B = 0.1% formic acid in ACN) over 1.1 minutes, followed by a gradient of 100% B over 0.25 minutes. A second gradient of 100–5% B was then applied over 0.05 minutes and held at a flow rate of 0.9 mL / min with an injection volume of 1 μL for 0.1 minutes. The UV spectrum was recorded at 215 nm on a Waters Acquity PDA using the spectral range of 200–400 nm. Mass spectra were obtained using 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 5–100% B (A: 2 mM ammonium bicarbonate, buffered to pH 10, B: ACN) over 0.75 minutes, followed by a gradient of 100% B over 0.1 minutes. A second gradient of 100–5% B was then applied over 0.05 minutes and held at a flow rate of 1 mL / min with an injection volume of 1 μL for 0.1 minutes. The UV spectrum was recorded at 215 nm on a Waters Acquity PDA using the spectral range of 200–400 nm. Mass spectra were obtained 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 uHPLC-MS (MET / uPLC / AB101) was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μM; temperature: 40°C) and a gradient of 5–100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) over 5.3 minutes, followed by a gradient of 100% B over 0.5 minutes. A second gradient of 100–5% B was then performed. The solution was applied over 0.02 minutes and held for 1.18 minutes at a flow rate of 0.6 mL / min with an injection volume of 1 μL. The UV spectrum was recorded at 215 nm using a Waters Acquity PDA detector with a spectral range of 200–400 nm. Mass spectra were obtained using Waters SQD (MSQ1) or Waters AcquityQDA (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 × 100 mm, 3 μm; temperature: 40°C) with a gradient of 5–100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) over 5 minutes, followed by 100% B for 0.4 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes and held for 1.58 minutes at a flow rate of 0.6 mL / min with an injection volume of 3 μL. The UV spectrum was recorded at 215 nm using an SPD-M20A photodiode array detector with a spectral range of 200–400 nm. The mass spectrum was obtained using a 2010 EV 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 × 100 mm, 1.7 μm column; temperature: 40°C) and a gradient of 5–100% (A = 2 mM ammonium bicarbonate, buffered at pH 10; B = ACN) over 5.3 minutes, followed by a 100% B gradient over 0.5 minutes. A second gradient of 100–5% B was then applied over 0.02 minutes and held for 1.18 minutes at an injection volume of 1 μL and a flow rate of 0.6 mL / min. The UV spectrum was recorded at 215 nm using a Waters Acquity photodiode array detector with a spectral range of 200–400 nm. The mass spectrum was obtained 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 × 100 mm, 10 μM; temperature: room temperature) and a gradient of 10–95% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) over 14.44 minutes, followed by a gradient of 95% B over 2.11 minutes. A second gradient of 95–10% B was then applied over 0.2 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. The UV spectrum was 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 × 10 mm, 10 μM; temperature: room temperature) and a gradient of 30–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in ACN) over 11.00 minutes, followed by a gradient of 95% B over 2.10 minutes. A second gradient of 95–30% B was then applied over 0.2 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. The UV spectrum was 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 × 100 mm, 10 μM; temperature: room temperature) and a gradient of 10–95% B (A = 0.2% NH4OH in H2O; B = 0.2% NH4OH in ACN) over 14.44 minutes, followed by a gradient of 95% B over 2.11 minutes. A second gradient of 95–10% B was then applied over 0.2 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. The UV spectrum was 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 × 10 mm, 10 μM; temperature: room temperature) and a gradient of 30–95% B (A = 0.2% NH4OH in water; B = 0.2% NH4OH in ACN) over 11.00 minutes, followed by a gradient of 95% B over 2.10 minutes. A second gradient of 95–30% B was then applied over 0.21 minutes with an injection volume of 1500 μL at a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0162] Method 5: Reverse-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 a suitable SNAP C18 cartridge and gradients of 10% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) above 1.7 CV, followed by 10-100% B above 19.5 CV, and 100% B above 2 CV.

[0163] Method 6: Reverse-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 gradients of 10% B (A = 0.1% NH3 in H2O; B = 0.1% NH3 in ACN) above 1.7 CV, followed by 10-100% B above 19.5 CV, and 100% B for 2 CV.

[0164] Method 7: Reverse-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 gradients of 10% B (A = 0.1% TFA in H2O; B = 0.1% TFA in ACN) above 1.7 CV, followed by 10-100% B above 19.5 CV, and 100% B above 2 CV.

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

[0166] NMR conditions Unless otherwise specified, 1¹H NMR spectra were recorded at 500 MHz, 400 MHz, or 250 MHz using either a Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz spectrometer, or Bruker Avance III HD 250 MHz spectrometer, respectively. Chemical shift δ is expressed in parts per million (ppm), with the residual solvent peak as the reference. The following abbreviations are used to indicate multiplicity and general assignment: s (singlet), d (doublet), t (triplet of doublets), ddd (doublet of doublets), dt (triplet of doublets), dq (quartet of doublets), hep (heptet), m (multiplet), pent (pentet), td (doublet of triplets), qd (doublet of quartet), app. (apparent), and br. (broad). The coupling constant J is shown at the closest frequency, 0.1 Hz.

[0167] General synthesis: All compounds were synthesized with a purity >95% unless otherwise specified. Chemical names were generated using 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) is mixed with TMSOI (12.89 g, 58.3 mmol) in anhydrous THF (60 mL) and tThe mixture was added to a solution of BuOK (6.27 g, 55.9 mmol) and 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 stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NH4Cl (80 mL), H2O (15 mL), and HCl (200 mL), the organic layer was isolated, washed with brine, and concentrated to approximately 100 mL under vacuum. A solution of BnONH2·HCl (8.14 g, 51.0 mmol) in HCl (62 mL) was added and the mixture was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, washed with H2O and brine, and the organic layer was concentrated under vacuum to obtain the title compound as a colorless oil (85% purity, 19.5 g, 40.1 mmol, 83% yield); 1 1H 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 SiO2 (157 mL), MsOH (7.8 mL, 0.12 mol) was added, and the mixture was stirred at 42°C for 2 hours. The resulting mixture was added to a solution of KHCO3 (20.1 g, 0.201 mol) in H2O (100 mL), and the mixture was stirred at 52°C for 2 hours. The reaction mixture was cooled to room temperature, the organic layer was isolated, washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the title compound as a dark orange oil in a quantitative yield of 13.0 g, 40.0 mmol (85% purity). 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] Propanic acid (23 mL, 0.240 mol) was added to a suspension of NaBH4 (3.03 g, 80.0 mmol) in toluene (95 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was added at -20°C to a solution of ethyl(2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate (85% purity, 13.0 g, 40.0 mmol) in toluene (95 mL) and H2SO4 (11 mL, 0.20 mol), and the mixture was stirred at room temperature for 60 hours. The reaction mixture was diluted with H2O (75 mL) and neutralized with aqueous NH4OH. The organic layer was isolated, washed with brine, dried over Na2SO4, and concentrated to approximately 75 mL in vacuum. The solution was heated 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 by vacuum filtration and washed with MeOH:EtOH (1:4) and HCl to obtain 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

Chem.

[0173] Scheme for Route 2

Chem.

[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), 10% Pd / C (2.87 g, 2.70 mmol) was added, and the mixture was stirred at room temperature under H2 for 24 hours. The reaction mixture was filtered through a Celite pad and concentrated under vacuum. The residue was dissolved in Et2O and washed with 2 M aqueous HCl. The organic layer was discarded, the aqueous layer was basicized using solid NaHCO3, and then extracted with IPA:DCM (2:8). The organic extract was washed with brine, dried over MgSO4, and concentrated under vacuum to obtain the title compound (11.5 g, 42.2 mmol, 78% yield) as a pale yellow oily substance; 1 1H 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-butyl2-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), benzylcarbonochloride (1.99 mL, 13.9 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 20 hours. A further fraction of pyridine (700 μL, 8.6 mmol), DMAP (42 mg, 0.34 mmol), and benzylcarbonochloride (930 μL, 6.5 mmol) was added at 0°C, and the mixture was stirred at room temperature. The mixture was stirred for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (2 × 50 mL). The combined organic extract was dried using a phase separator, concentrated under vacuum, and purified by chromatography on silica gel (0-100% ethyl phosphate in heptane) to obtain the title compound as a colorless oil (84% purity, 3.18 g, 6.57 mmol, 72% yield); 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·H2O (311 mg, 7.23 mmol) in EtOH (25 mL):THF (25 mL):Water (25 mL) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between H2O (30 mL) and HCl (30 mL), and the organic layer was discarded. The aqueous layer was then acidified with 1 M aqueous HCl solution and extracted with HCl (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under vacuum to obtain the title compound as a colorless solid (86% purity, 2.04 g, 4.64 mmol, 71% yield); 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] Ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate in a solution of oxalic acid (10g, 27.1 mmol) in MeOH (100mL) 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 4 M NH3 in MeOH, and concentrated under vacuum to obtain the title compound (6.22 g, 22.3 mmol, 82% yield) as a viscous yellow oily substance; 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] Boc2O (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 Et3N (12 mL, 89.4 mmol) in anhydrous DCM (110 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was washed with saturated aqueous NH4Cl (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (5-50% ethyl phosphate in heptane) to obtain the title compound as a colorless oil (94% purity, 6.82 g, 16.9 mmol, 76% yield); 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), DIPEA (1.7 mL, 9.70 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ELISA (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 under vacuum. The residue was purified by chromatography on silica gel (0-100% SiO2 in heptane) to obtain the title compound as an off-white solid (70% purity, 3.80 g, 4.71 mmol, 97% yield); 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-oxadiazole-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 K2CO3 (1.95 g, 14.1 mmol) in ACN (100 mL) was stirred at 80°C for 3 hours. The reaction mixture was partitioned between HCl (100 mL) and H2O (100 mL). The organic layer was isolated, washed with brine (50 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% HCl in heptane). The resulting residue was ground with Et2O, the solid was discarded, the filtrate was concentrated under vacuum, and purified by preparative HPLC (Method 5) to obtain the title compound as a pale yellow oil (75% purity, 2.90 g, 3.98 mmol, 84% yield); 1 1H 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-oxadiazole-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-oxadiazole-2-yl}piperidine-1-carboxylate (75% purity, 2.90 g, 3.98 mmol) in anhydrous EtOH (80 mL), Pd / C (10%, 0.21 g, 0.199 mmol) was added, and the mixture was stirred under H2 at room temperature for 24 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum. The residue was partitioned between siRNA and 2 M aqueous HCl. The organic layer was isolated, and precipitation was observed after 20 minutes. The suspension was filtered under vacuum and washed with H2O, and the title compound was obtained as a white solid (0.76 g, 1.68 mmol, 42% yield) as the HCl salt; 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 hours. The reaction mixture was cooled to room temperature, diluted with H2O (30 mL), and extracted with HCl (2 × 30 mL). The combined organic extract was washed with brine (40 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (5-50% HCl in heptane) to obtain 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 at 50°C for 6 hours. The reaction mixture was concentrated under vacuum to obtain 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, the intermediates in Table 1 were synthesized using the corresponding starting materials, as illustrated by intermediate 7.

[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 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with SiO2 (2 × 50 mL). The combined organic extract was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound as an orange oil in a quantitative yield of 2.10 g, 6.59 mmol (84% purity). 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-cyanophenoxy)acetate (84% purity, 2.50 g, 7.84 mmol) in DCM (5 mL), TFA (3.0 mL, 39.2 mmol) was added, and the mixture was stirred at 50°C for 2.5 hours. The reaction mixture was concentrated under vacuum, and the residue was suspended in H2O and stirred at room temperature for 15 minutes. The resulting precipitate was filtered under vacuum and washed with H2O to obtain 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), K2CO3 (1.77 g, 12.8 mmol) was added, followed by tert-butylbromoacetate (1.0 mL, 7.03 mmol), and the mixture was stirred at 65°C for 1 hour. The reaction mixture was cooled to room temperature, poured over H2O (100 mL), and extracted with siRNA (2 × 70 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10-80% siRNA in heptane) to obtain 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), DAST (0.72 mL, 5.49 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured over saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (2 × 30 mL). The combined organic extract was dried over Na2SO4, concentrated under vacuum, and purified by chromatography on silica gel (10-40% ethyl phosphate in heptane) to obtain 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), 4 M HCl in 1,4-dioxane (3.4 mL, 13.7 mmol) was added at 0°C, and the mixture was stirred at room temperature under N2 for 20 hours. A further fraction 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. A further fraction 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 under vacuum, ground using H2O, and dried under vacuum filtration for 1 hour to obtain 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, the intermediates in Table 2 were synthesized using the corresponding starting materials, as illustrated by intermediate 17.

[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), Cs2CO3 (6.00 g, 18.4 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ELISA (20 mL), washed with H2O (2 × 20 mL) and brine (20 mL), dried using a phase separator, and concentrated under vacuum. The residue was dissolved in THF (50 mL), and a solution of 0.5 M LiOH aqueous solution (49 mL, 24.7 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with H2O (20 mL), extracted with ELISA (2 × 20 mL), and the organic extract was discarded. The aqueous solution was then acidified to pH 1-2 using 1 M HCl aqueous solution and extracted with DCM (3 × 20 mL). The combined organic extracts were dried using a phase separator and concentrated under vacuum to obtain the title compound as a white solid in a quantitative yield of (2.90 g, 12.9 mmol); 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), dichloride oxalate (10 mL, 0.115 mol), followed by DMF (81 μL, 1.11 mmol), was added at 0°C, and the mixture was stirred at room temperature for 17 hours. By concentrating the reaction mixture under vacuum, the title compound was obtained as an orange oil (90% purity, 5.30 g, 21.4 mmol, 94% yield); 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, the intermediates in Table 3 were synthesized using the corresponding starting materials, as illustrated by intermediate 19.

[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), Pd / C (10%, 2.28 g, 2.14 mmol) was added under N2, and the mixture was stirred under H2 at room temperature for 17 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum. The residue was purified using an SCX-2 cartridge that flushed first with MeOH and then eluted second with 3 M NH3 in MeOH, yielding the title compound (4.88 g, 17.0 mmol, 80% yield) as a pale yellow oily substance; 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-butyl2-ethyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1,2-dicarboxylate [ka] A mixture of 1-tert-butyl 2-ethyl (2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (4.89 g, 17.1 mmol) and Et3N (14 mL, 0.103 mol) in DCM (170 mL) was added dropwise at 0°C to a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (4.19 g, 18.8 mmol, intermediate 19) in DCM (10 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with DCM (250 mL), washed with saturated NaHCO3 aqueous solution (2 × 100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-50% ethyl acetate in heptane) to obtain 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)acetamide]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)acetamide]piperidine-1,2-dicarboxylate (7.1 g, 15.6 mmol) in EtOH (80 mL) and H2O (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, redissolved in H2O (50 mL), and extracted with DCM (2 × 100 mL). The aqueous layer was then acidified to pH 2 using a 2 M aqueous HCl solution and extracted with ELISA (3 × 100 mL). The combined organic extracts were washed with brine (100 mL), dried on anhydrous Na2SO4, and concentrated under vacuum to obtain the title compound as a white solid (87% purity, 5.60 g, 11.3 mmol, 73% yield); 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, the intermediates in Table 4 were synthesized using the corresponding starting materials, as illustrated by intermediate 22.

[0209] [Table 4]

[0210] Scheme for Route 11 [ka] Intermediate 26: tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-(hydrazinecarbonyl)piperidine-1-carboxylate [ka] To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-2-carboxylic acid (8.43 g, 19.2 mmol, intermediate 22) and HATU (8.75 g, 23.0 mmol) in DMF (80 mL), DIPEA (4.0 mL, 23.0 mmol) was added and the mixture was stirred at room temperature under N2 for 30 minutes. The resulting solution was added dropwise via cannula to a solution of NH2-NH2·H2O (1.9 mL, 38.3 mmol) in DMF (40 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with RINKAN (150 mL) and washed with H2O (4 × 100 mL). The combined organic extracts were dried on MgSO4, concentrated under vacuum, and purified by chromatography on silica gel (0-10% MeOH in DCM) to obtain 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 the general route 11, the intermediates in Table 5 were synthesized using the corresponding starting materials, as illustrated by intermediate 26.

[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-oxadiazole-2-yl)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (3.50 g, 7.87 mmol, intermediate 26) and NaHCO3 (991 mg, 11.8 mmol) in H2O (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 H2O (60 mL) and extracted with ELISA (3 × 60 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum to obtain 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-oxadiazole-2-yl)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-2-(5-amino-1,3,4-oxadiazole-2-yl)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate (2.30 g, 4.65 mmol) in anhydrous ACN (35 mL), CuBr (3.16 g, 14.0 mmol) was added, 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 under vacuum, and the residue was diluted with Rochelle salt (150 mL) and extracted with ELISA (3 × 150 mL). The combined organic extracts were dried over MgSO4, concentrated under vacuum, and purified by chromatography on silica gel (12-100% phenylethylamine in heptane) to obtain 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, the intermediates in Table 6 were synthesized using the corresponding starting materials, as illustrated by intermediate 31.

[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)acetamide]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 the mixture was 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 RINKAN (50 mL) and H2O (30 mL), the organic layer was isolated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography over silica gel (0-70% RINKAN in heptane) to obtain the title compound as an off-white solid (87% purity, 505 mg, 1.02 mmol, 83% yield); 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)acetamide]pyrrolidine-2-carboxylic acid [ka] To a solution of 1-tert-butyl 2-ethyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamide]pyrrolidine-1,2-dicarboxylate (87% purity, 505 mg, 1.02 mmol) in MeOH (2 mL):THF (2 mL):H2O (2 mL), LiOH·H2O (53 mg, 1.22 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was partitioned between RINKAN (30 mL) and 1 M aqueous HCl (10 mL). The organic layer was isolated, washed with brine, dried over MgSO4, and concentrated under vacuum to obtain 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 sequentially added dropwise under N2 in a foil-covered flask 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 SiO2 (50 mL). The mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite, washed with SiO2 (30 mL), and concentrated under vacuum. The residue was purified by chromatography on silica gel (5-30% SiO2 in heptane) to obtain 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 under vacuum to obtain the title compound (83% purity, 73 mg, 0.352 mmol, 24% yield) as a yellow oily substance; 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 toluene (30 mL), AgOTf (4.13 g, 16.0 mmol), KF (1.24 g, 21.4 mmol), and SelectFluor (2.84 g, 8.01 mmol) were added in a foil-covered flask at room temperature under N2 conditions, and the mixture was stirred for 5 minutes at room temperature. 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 toluene (100 mL), and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (0-50% phenylethylamine in heptane) to obtain 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 under vacuum to obtain 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)azetidine-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), a solution of 4-nitrophenylcarbonochloride (558 mg, 2.77 mmol) in anhydrous THF (3 mL) was added, and the mixture was stirred at room temperature under N2 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 the mixture was stirred at room temperature under N2 for 30 minutes. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (10 mL) and extracted with ₹ (3 × 10 mL). The combined organic extracts were washed with H2O (30 mL) and brine (30 mL), dried on MgSO4, and concentrated under vacuum. The residue was dissolved in SiO2 (10 mL) and washed with saturated K2CO3 aqueous solution (3 × 10 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to obtain the title compound as an off-white powder (92% purity, 770 mg, 2.13 mmol, 85% yield); 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)azetidine-1-yl]methanone (92% purity, 7) in anhydrous EtOH (21 mL) To a solution of 67 mg (2.12 mmol), 10% Pd / C (226 mg, 0.212 mmol) was added under N2, and the mixture was stirred under H2 at room temperature for 4 hours. The reaction mixture was filtered through a Celite pad, washed with warm EtOH (3 × 15 mL), and concentrated under vacuum to obtain the title compound as a brown solid (88% purity, 269 mg, 1.19 mmol, 56% yield); 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) under N2 conditions at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography on silica gel (12-100% phenylethylamine in heptane) to obtain the title compound as a colorless oil (92% purity, 827 mg, 3.89 mmol, 44% yield). 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·H2O (7.8 mL, 0.158 mol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with IPA (30 mL) and H2O (50 mL), the organic layer was isolated, and sequentially washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to obtain the title compound (90% purity, 4.09 g, 21.4 mmol, 54% yield) as a pale yellow oily substance; 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), CuI (469 mg, 2.46 mmol) was added, 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 under vacuum, and the residue was dissolved in ethyl acetate. The resulting precipitate was filtered under vacuum, the filtrate was isolated, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10-100% ethyl acetate in heptane) to obtain 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)ethane-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 H2 for 18 hours. The reaction mixture was filtered through Celite and washed with THF. 10% Pd / C (1.47 g, 1.38 mmol) was added back to the filtrate, and the mixture was stirred under H2 for 18 hours. The reaction mixture was filtered through Celite and washed with THF to obtain a crude solution (2.23:95.9:1.83, approximately 10 mL) estimated to be 2.23% of the title compound in THF / toluene; 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)ethylbenzoate [ka] To a solution of 2-(ethenyloxy)ethane-1-ol (1.00 g, 11.3 mmol) in DCM (40 mL), Et3N (4.0 mL, 28.4 mmol) was added dropwise, followed by benzoyl chloride (2.0 mL, 17.0 mmol), at 0°C. The mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0°C and quenched with 10 mL of 1 M aqueous HCl. The aqueous solution was extracted with DCM (3 × 20 mL), and the combined organic extract was successively washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-80% siRNA heptane) to obtain the title compound (760 mg, 3.95 mmol, 35% yield) as a clear oily substance; 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), TMSCF3 (77 μL, 0.520 mmol) and NaI (86 mg, 0.572 mmol) were added, and the mixture was stirred under N2 at 65°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with H2O (5 mL), and extracted with ethyl acetate (3 × 5 mL). The combined organic extract was washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-80% ethyl acetate in heptane) to obtain 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)ethane-1-ol [ka] To a solution of 2-(2,2-difluorocyclopropoxy)ethyl benzoate (60 mg, 0.248 mmol) in 2-methyloxolane (1 mL), 1 M aqueous NaOH solution (0.99 mL, 0.991 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with H2O (3 mL) and extracted with Et2O (3 × 3 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum at room temperature to obtain the title compound (17 mg, 0.123 mmol, 50% yield) as a clear oily substance; 1 1H 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-diethyl2,5-bis(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)hexanedioate [ka] A mixture of potassium (1,3-dioxoisoindorin-2-yl) (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 hours, and then allowed to cool to room temperature. The reaction mixture was concentrated under vacuum, and the residue was diluted with H2O (150 mL). Extraction was performed with SiO2 (2 × 100 mL). The combined organic extracts were dried over Na2SO4, concentrated under vacuum, and purified by preparative HPLC (Method 5) to obtain the title compound as a yellow oil (91% purity, 2.51 g, 4.64 mmol, 42% yield); 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-isoindole-2-yl)hexanedioate (2.40 g, 4.64 mmol) in EtOH (25 mL), and the mixture was stirred under reflux for 6 hours. The reaction mixture was semi-concentrated and cooled to 0°C. The solid was filtered under vacuum, and the filtrate was concentrated under vacuum. The residue was dissolved in EtOH (5 mL) and purified using an SCX-2 cartridge that flushed first with EtOH (2 × 20 mL) and then eluted with 7 M NH3 in MeOH, yielding the title compound (835 mg, 4.48 mmol, 97% yield) as a brown oily substance; M / Z: 187[M+H] + ESI + RT=0.16(S1).

[0243] Step 20.c: Ethyl 5-[2-(4-chloro-3-fluorophenoxy)acetamide]-6-oxopiperidine-2-carboxylate [ka] To a stirred solution of ethyl 5-amino-6-oxopiperidine-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-fluorophenoxy)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 under vacuum, and purified by preparative HPLC (Method 5) to obtain the title compound as a white solid (72% purity, 433 mg, 0.836 mmol, 22% yield); 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)acetamide]-6-oxopiperidine-2-carboxylic acid [ka] To a solution of ethyl 5-[2-(4-chloro-3-fluorophenoxy)acetamide]-6-oxopiperidine-2-carboxylate (72% purity, 330 mg, 0.637 mmol) in H2O (3 mL) and MeOH (5 mL), 2 M aqueous LiOH (0.38 mL, 0.765 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was acidified to pH 5 using 1 M aqueous HCl (0.6 mL), and then concentrated under vacuum to obtain the title compound as an off-white solid (55% purity, 397 mg, 0.633 mmol, 99% yield); 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-butyl2-ethyl(2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-1,2-dicarboxylate [ka] Benzylcarbonochloride (1.3 mL, 9.12 mmol) was added at 0°C 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), 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 extract was dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-50% ethyl phosphate in heptane) to obtain 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, 3.0 Hz, 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), a solution of LiOH.H2O (249 mg, 5.80 mmol) in H2O (10 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to approximately pH 4 using a 1 M aqueous HCl solution and extracted with SiO2 (2 × 100 mL). The combined organic extract was dried over Na2SO4, concentrated under vacuum, and purified by chromatography on silica gel (25-100% SiO2 in heptane) to obtain the title compound as a clear oil (77% purity, 2.01 g, 3.19 mmol, 61% yield). 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-carboxylate 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), 4 M HCl in 1,4-dioxane (0.50 mL, 2.0 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to obtain the title compound as a white solid (58% purity, 180 mg, 0.248 mmol, 78% yield); 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-carboxylate hydrochloride (58% purity, 169 mg, 0.233 mmol) in DCE (5 mL), acetaldehyde (36 mg, 0.806 mmol) was added and the mixture was stirred at room temperature for 10 minutes. STAB (198 mg, 0.93 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and purified by preparative HPLC (Method 5) to obtain 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 Boc2O (52 mg, 0.238 mmol) in EtOH (10 mL), 10% Pd / C (10 mg, 0.0940 mmol) was added, and the mixture was stirred under H2 at room temperature for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain the title compound as a colorless gum (35% purity, 130 mg, 0.167 mmol, 91% yield); M / Z: 273 [M+H] + ESI + RT=0.76(S1).

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

[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] First, ethyl (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate oxalic acid (500 mg, 1.36 mmol) was flushed with DCM / MeOH (3:1) and then eluted with 2 M NH3 in MeOH / DCM (1:3) using an SCX-2 cartridge to obtain the amine. The solvent was concentrated under vacuum, and the residue was dissolved in anhydrous DMF (5 mL) and transferred to a microwave vial. K2CO3 (375 mg, 2.71 mmol) and 1-bromo-2-methoxyethane (3 83 μL (4.07 mmol) was added, and the mixture was stirred at 120°C for 1 hour. The reaction mixture was poured onto brine and extracted with SiO2 (2 × 50 mL). The combined organic extract was washed with brine, dried on Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (7M NH3 in MeOH in DCM, 0-10%) to obtain the title compound (90% purity, 423 mg, 1.13 mmol, 83% yield) as a brown oily substance; 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), Boc2O (321 mg, 1.47 mmol), and 10% Pd / C (120 mg, 0.113 mmol) in EtOH (10 mL) was stirred at room temperature under H2 for 16 hours. The reaction mixture was filtered through a Celite pad, washed with SiO2, and the filtrate was concentrated under vacuum to obtain 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·H2O (408 mg, 9.48 mmol) in H2O (10 mL) at room temperature for 16 hours. A 1 M aqueous solution of HCl H2O (7.6 mL, 7.59 mmol) was added dropwise, and the organic solvent was extracted and evaporated to obtain 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), HATU (725 mg, 1.91 mmol), followed by DIPEA (0.56 mL, 3.18 mmol), was added at 0°C and the mixture was 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 H2O (80 mL) and stirred at room temperature for 20 minutes. The resulting suspension was filtered under vacuum and washed with H2O (50 mL). The residue was purified by chromatography on silica gel (5-80% toluene in heptane) to obtain the title compound as a white solid (91% purity, 640 mg, 0.91 mmol, 57% yield); 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-oxadiazole-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) in ACN (5 mL) To a 0.91 mmol solution, 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 hours. A 15% aqueous NH4OH solution (20 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under vacuum, diluted with H2O (20 mL), and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10–80% siRNA in heptane) to obtain 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-oxadiazole-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-oxadiazole-2-yl]piperidine-1-carboxylate (480 mg, 0.752 mmol) in MeOH (5 mL), 2 M LiOH aqueous solution (10 mL, 20.0 mmol) was added, 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 under vacuum, dissolved in H2O (20 mL), and acidified to pH 9 using 1 M HCl aqueous solution. The solution was extracted with ELISA (2 × 30 mL), the combined organic extract was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10-100% siRNA in heptane) to obtain 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-oxadiazole-2-yl]piperidine-1-carboxylate [ka] tert-butyl(2S,5R)-5-[(benzyloxy)amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2- in MeOH (20 mL) To a solution of yl[piperidine-1-carboxylate (92% purity, 160 mg, 0.304 mmol) at -10°C, NiCl2·6H2O (291 mg, 1.21 mmol), followed by NaBH4 (344 mg, 9.11 mmol), was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum and purified by preparative HPLC (Method 5) to obtain 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, the intermediates in Table 8 were synthesized using the corresponding starting materials, as illustrated by intermediate 46.

[0263] [Table 8]

[0264] Scheme for Route 24 [ka]

[0265] Step 24.a: tert-butyl(2R,5S)-2-(5-amino-1,3,4-oxadiazole-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), a solution of NaHCO3 (2.58 g, 30.8 mmol) in H2O (20 mL), followed by BrCN (2.17 g, 20.5 mmol), was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with H2O, the resulting precipitate was filtered under vacuum, and washed with H2O to obtain the title compound as an off-white powder in quantitative yield (84% purity, 11.02 g, 22.2 mmol); 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-oxadiazole-2-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-2-(5-amino-1,3,4-oxadiazole-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. A further fraction of CuBr (1.5 equivalents, 4.77 g, 33.3 mmol) and tert-butyl nitrite (90%, 8.79 mL, 66.5 mmol) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with siRNA (250 mL) and washed with Rochelle salt (2 × 200 mL) and H₂O (3 × 200 mL). The organic extract was dried over Na₂SO₄, concentrated under vacuum, and purified by chromatography on silica gel (0–100% siRNA in heptane) to obtain 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)cal Bonyl]amino}-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate [ka] To a solution of 2-(trifluoromethoxy)ethane-1-ol (13% in THF / toluene, 4.50 g, 4.43 mmol) in anhydrous THF (15 mL), NaH (60%, 322 mg, 8.06 mmol) was added at 0°C, and the mixture was stirred at 0°C for 10 minutes. To anhydrous THF (10 mL), tert-butyl(2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-(5-bromo-1,3,4-oxadiazole-2-yl)piperidine-1-carboxylate (2.02 g, 4.03 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with  (3 × 100 mL). The combined organic extracts were dried over MgSO4, concentrated under vacuum, and purified by chromatography on silica gel (0-100% SiO2 in heptane) to obtain the title compound as a yellow oil (85% purity, 1.60 g, 2.56 mmol, 64% yield); 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-oxadiazole-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-oxadiazole-2-yl}piperidine-1-carboxylate (85% purity, 1.60 g, 2.56 mmol) in EtOH (45 mL), 10% Pd / C (3.27 g, 3.08 mmol) was added under N2, and the mixture was stirred under H2 at room temperature for 18 hours. The reaction mixture was filtered through a Celite pad and concentrated under vacuum to obtain the title compound (49% purity, 843 mg, 1.04 mmol, 41% yield) as a light brown oily substance; 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), DIPEA (1.4 mL, 7.90 mmol), T3P (50% in ethyl acetate, 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) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were dried over Na2SO4, concentrated under vacuum, and purified by chromatography on silica gel (0-100% siRNA in heptane) to obtain 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-oxadiazole-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), K2CO3 (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 hours. The reaction mixture was partitioned between RINKAN (100 mL) and H2O (50 mL), the organic layer was isolated, and washed with brine (30 mL). The organic extract was dried over MgSO4, concentrated under vacuum, and purified by chromatography on silica gel (0-50% siRNA in heptane) to obtain the title compound (92% purity, 1.05 g, 1.49 mmol, 62% yield) as a yellow oily substance; 1 1H 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-oxadiazole-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-oxadiazole-2-yl}piperidine-1-carboxylate (0.93 g, 1.43 mmol) in anhydrous EtOH (30 mL), 10% Pd / C (0.15 g, 0.144 mmol) was added, and the resulting mixture was stirred at room temperature under H2 for 24 hours. A further fraction of 10% Pd / C (0.15 g, 0.144 mmol) was added, and the reaction mixture was stirred at room temperature under H2 for 24 hours. A further fraction of 10% Pd / C (0.15 g, 0.144 mmol) was added, and the reaction mixture was stirred at room temperature under H2 for 24 hours. The reaction mixture was heated to 40°C, filtered through a Celite pad, and thoroughly washed with EtOH. The filtrate was concentrated under vacuum and purified by chromatography on silica gel (0-20% MeOH in DCM) to obtain 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)2 (981 mg, 1.44 mmol), and Et3N (1.7 mL, 12.1 mmol), separated into four pressure tubes, was degassed using N2 for 5 minutes, then sealed and heated at 80°C for 24 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with phenylethylamine. The filtrate was concentrated under vacuum and purified by chromatography on silica gel (0-25% phenylethylamine in heptane) to obtain the title compound (93% purity, 3.60 g, 16.8 mmol, 58% yield) as a yellow oily substance; 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), a solution of 0.9 M diethylzinc in hexane (30 mL, 26.9 mmol) was added dropwise over 60 minutes at -5°C, while maintaining the internal temperature between 0°C and -5°C. The mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0°C and quenched with saturated NH4Cl aqueous solution (5 mL), followed by NH4OH solution (5 mL). The solution was extracted with methyl tert-butyl ether (3 × 20 mL), the combined organic extract was washed with brine (25 mL), dried on MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-25% SiO in heptane) to obtain 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), 4 M HCl in 1,4-dioxane (4.9 mL, 19.7 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, and the title compound was obtained as a beige powder (75% purity, 0.75 g, 3.73 mmol, 76% yield) by azeotropic distillation using 2-propanol; 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)2 (824 mg, 1.21 mmol), and Et3N (1.4 mL, 10.2 mmol) was stirred at 80°C for 24 hours under N2. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with SiO2 (100 mL). The filtrate was concentrated under vacuum, and the resulting residue was purified by chromatography on silica gel (0-50% SiO2 in heptane) to obtain the title compound (80% purity, 4.64 g, 16.0 mmol, 66% yield) as a yellow oily substance;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), chloro(iodo)methane (3.7 mL, 51.1 mmol), followed by 0.9 M ZnEt2 in hexane (28 mL, 25.6 mmol), was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C and quenched with saturated NH4Cl aqueous solution (30 mL), followed by NH4OH solution (30 mL). The aqueous solution was extracted with HCl (3 × 100 mL), and the combined organic extract was dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-50% HCl in heptane) to obtain 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 anhydrous EtOH (20 mL), 10% Pd / C (606 mg, 0.570 mmol) was added, and the mixture was stirred at room temperature under H2 for 24 hours. The reaction mixture was filtered over Celite, washed with siRNA (50 mL), and the filtrate was concentrated under vacuum to obtain the title compound as a colorless oil in a quantitative yield of 981 mg, 5.65 mmol (90% purity). 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)acetamide]-2-(5-sulfanyl-1,3,4-oxadiazole-2-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-(hydrazine carbonyl)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 H2O (20 mL), and extracted with ELISA (2 × 30 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum to obtain the title compound as a beige powder (85% purity, 360 mg, 0.628 mmol, 93% yield); 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)acetamide]-2-[5-(methylsulfanyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate [ka] MeI (0.43 mL, 6.98 mmol) was added dropwise to a suspension of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-(5-sulfanyl-1,3,4-oxadiazole-2-yl)piperidine-1-carboxylate (85% purity, 2.0 g, 3.49 mmol), K2CO3 (965 mg, 6.98 mmol), and DMF (15 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 10 mL of 1 M aqueous NaOH solution and extracted with DCM (2 × 30 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum to obtain 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)acetamide]-2-(5-methanesulfonyl-1,3,4-oxadiazole-2-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(methylsulfanyl)-1,3,4-oxadiazole-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 hours. The reaction mixture was diluted in DCM (20 mL) and saturated Na2SO3 solution and stirred at room temperature for 15 minutes. The organic layer was isolated using a phase separator and then concentrated under vacuum. The residue was purified by chromatography over silica gel (0-40% ethyl phosphate in heptane) to obtain 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), HATU (2.71 g, 7.11 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with ELISA (2 × 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% SiO in heptane) to obtain the title compound (76% purity, 1.61 g, 2.43 mmol, 41% yield) as a yellow oily substance; 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-oxadiazole-2-yl]piperidine-1-carboxylate [ka] tert-butyl(2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[N'-(4-chlorobenzoyl)hydrazinecarbonyl in ACN (12mL) A mixture of piperidine-1-carboxylate (76%, 1.61 g, 2.43 mmol), K2CO3 (2.02 g, 14.6 mmol), and TsCl (1.39 g, 7.30 mmol) was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with H2O (10 mL) and brine (10 mL), and extracted with SiO2 (2 × 30 mL). The combined organic extract was dried over Na2SO4, concentrated under vacuum, and purified by chromatography on silica gel (0-50% SiO2 in heptane) to obtain the title compound as a beige gum (85% purity, 410 mg, 0.719 mmol, 30% yield); 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-oxadiazole-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-oxadiazole-2-yl]piperidine-1-carboxylate (410 mg, 0.845 mmol) in MeOH (40 mL), NiCl2·H2O (811 mg, 3.38 mmol), followed by NaBH4 (959 mg, 25.36 mmol), was added at 0°C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum and dissolved in H2O and ELISA, and the resulting suspension was filtered through Celite. The phases were separated, and the aqueous layer was further extracted with ELISA. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (Method 7) to obtain 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 sequentially added dropwise 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 HCl (500 mL). The mixture was stirred in a foil-covered flask at room temperature under N2 for 20 hours. The reaction mixture was filtered through Celite, washed with HCl (100 mL), and concentrated under vacuum. The residue was purified by chromatography on silica gel (5-30% HCl in heptane) to obtain 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 at room temperature under H2 for 18 hours. The reaction mixture was filtered through Celite and concentrated under vacuum to obtain the title compound. (5.09 g, 27.6 mmol, 97% yield) Obtained as a yellow oily substance; 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), HATU (2.27 g, 5.97 mmol), followed by DIPEA (1.9 mL, 10.9 mmol), was added at 0°C and the mixture was stirred for 10 minutes. Benzylhydrazine carboxylate (0.90 g, 5.43 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 50 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum. Chromatographic purification on silica gel (15–100% ELISA in heptane) yielded 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 H2 at room temperature for 18 hours. The reaction mixture was filtered through Celite and concentrated under vacuum to obtain 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)acetamide]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-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), tert-butyl(2R,5S)-5-amino-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate (123 mg, 0.282 mmol, intermediate 6) and DIPEA (0.099 mL, 0.565 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic extracts were dried over MgSO4, concentrated under vacuum, and purified by chromatography over silica gel (17-100% toluene in heptane) to obtain 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-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[4-(trifluoromethyl)acetamide] in DCM (2 mL) To a solution of [nyl]-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate (78 mg, 0.130 mmol, Example 1), ZnBr2 (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 NaHCO3 aqueous solution (3 mL) and extracted with DCM:IPA (80:20) (3 × 3 mL). The combined organic extract was dried using a phase separator, concentrated under vacuum, and purified by preparative HPLC (Method 4) to obtain 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)propanamide]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-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 the mixture was stirred at room temperature for 10 minutes. Tert-butyl(2R,5S)-5-amino-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-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 H2O (5 mL) and extracted with ELISA (3 × 5 mL). The combined organic extracts were washed with brine (2 × 15 mL), dried on MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (12-100% SiO in heptane) to obtain the title compound (90% purity, 123 mg, 0 (0.186 mmol, 54% yield) Obtained as a clear oily substance; 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-oxadiazole-2-yl}piperidine-3-yl]propanamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chlorophenoxy)propanamide]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole-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 under vacuum, dissolved in saturated NaHCO3 aqueous solution (10 mL), and extracted with siRNA (3 × 10 mL). The combined organic extract was dried over MgSO4, concentrated under vacuum, pulverized using DMSO:MeCN:H2O (60:30:10), and washed with MeCN (1 mL) to obtain 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 synthesis steps of the general route 32, the example compounds in Table 9 were synthesized using the corresponding intermediates, as illustrated in 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-fluoropyridine-3-yl)oxy]acetamide}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate [ka] To a suspension of 2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetic acid (50 mg, 0.243 mmol, intermediate 12) in DCM (5 mL), thionyl chloride (0.10 mL, 1.37 mmol) was added, and the mixture was stirred at 45°C for 4 hours, then at room temperature for 18 hours. The reaction mixture was concentrated under vacuum and azeotropically dissolved 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-oxadiazole-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, then poured over saturated NaHCO3 aqueous solution (10 mL). The aqueous solution was extracted with DCM (2 × 20 mL), and the combined organic extract was dried over Na₂SO₄ and concentrated under vacuum. Chromatographic purification on silica gel (20–100% siRNA in heptane) yielded the title compound as a colorless oil (27 mg, 0.0467 mmol, 25% yield). 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-fluoropyridine-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetamide}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate (48 mg, 0.0830 mmol, Example 6) in DCM (2 mL), ZnBr2 (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 under vacuum. 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)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-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 the mixture was stirred at room temperature for 10 minutes. Tert-butyl(2R,5S)-5-amino-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-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 H2O (10 mL) and extracted with ELISA (2 × 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuum to obtain the title compound (52% purity, 105 mg, 0.0896 mmol, 23% yield) as a yellow oily substance; 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-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate (52% purity, 105 mg, 0.0896 mmol, Example 8) in DCM (1 mL), ZnBr2 (61 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM / IPA (9:1, 2 × 20 mL). The combined organic extract was dried over MgSO4, concentrated under vacuum, and purified by preparative HPLC (Method 3) to obtain 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 synthesis steps of the general route 34, the example compounds in Table 10 were synthesized using the corresponding intermediates, as illustrated in 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)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-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 ethyl acetate, 713 μL, 0.120 mmol) and DIPEA (41 μL, 0.233 mmol) were added and the mixture was stirred at room temperature for 10 minutes. Tert-butyl(2R,5S)-5-amino-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-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 extract was dried over Na2SO4 and concentrated under vacuum to obtain an orange solid. The crude material was proceeded to 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-oxadiazole-2-yl]piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate (57 mg, 0.10 mmol, Example 16) in anhydrous DCM (1 mL), ZnBr2 (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 NaHCO3 aqueous solution and extracted with DCM / IPA (4:1, 2 × 2 mL). The combined organic extract was concentrated under vacuum and purified by preparative HPLC (Method 4) to obtain the title compound as a white solid (88% purity, 1.7 mg, 0.0032 mmol, 3% yield); 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 synthesis steps of general route 35, the example compounds in Table 11 were synthesized using the corresponding intermediates, as illustrated in 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)acetamide]-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)acetamide]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 ethyl acetate, 0.25 mL, 0.422 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine, dried on MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% SiO in heptane) to obtain 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)acetamide]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]pyrrolidine-1-carboxylate [ka] A suspension of tert-butyl(2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamide]-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 hours. The reaction mixture was partitioned between HCl (30 mL) and H2O (20 mL). The organic layer was isolated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography over silica gel (0-100% HCl in heptane) to obtain 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-oxadiazole-2-yl]pyrrolidine-3-yl]acetamide [ka] A solution of tert-butyl(2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazole-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 NaHCO3 aqueous solution, and the organic layer was isolated using a phase separator and concentrated under vacuum. The residue was purified by preparative HPLC (Method 3), and then ground with Et2O to obtain 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-fluorophenoxy)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)acetamide]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 the mixture was 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 ELISA (20 mL) and washed with brine (20 mL). The combined organic extracts were dried on MgSO4, concentrated under vacuum, and purified by chromatography on silica gel (0-80% toluene in heptane) to obtain the title compound as a colorless oil (91% purity, 646 mg, 1.00 mmol, 91% yield); 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)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate [ka] A suspension of tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)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 hours. The reaction mixture was diluted with ELISA (20 mL) and washed with brine (20 mL). The organic layer was dried over MgSO4, concentrated under vacuum, and purified by chromatography on silica gel (0-100% ELISA in heptane) to obtain 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-oxadiazole-2-yl]piperidine-3-yl]acetamide [ka] A solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-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 NaHCO3 aqueous solution (5 mL). The organic layer was isolated, concentrated under vacuum, and purified by preparative HPLC (Method 3) to obtain 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 synthesis steps of the general route 37, the example compounds in Table 12 were synthesized using the corresponding intermediates, as illustrated in 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)acetamide]-2-{N'-[(3,3,3-trifluoropropoxy)carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate [ka] A solution of (2S,5R)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-2-carboxylic acid (450 mg, 1.04 mmol, intermediate 25) in anhydrous DMF (5 mL) is prepared by adding 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 HCl (25 mL) and 1 M aqueous HCl (25 mL). The organic layer was isolated, washed with saturated aqueous NaHCO3 (25 mL) and brine (2 × 25 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (20-100% HCl in heptane) to obtain the title compound (85% purity, 268 mg, 0.389 mmol, 37% yield) as a clear oily substance; 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)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate [ka] A suspension of tert-butyl(2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-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 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (3 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL), dried on MgSO4, and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (0-100% SiO2 in heptane) to obtain the title compound (88% purity, 68 mg, 0.106 mmol, 27% yield) as a brown oily substance;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-oxadiazole-2-yl]piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate (88% purity, 55 mg, 0.0854 mmol) in DCM (1 mL), ZnBr2 (77 mg, 0.341 mmol) was added, and the mixture was stirred at room temperature under N2 for 18 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (3 mL) and extracted with DCM:IPA (80:20) (3 × 3 mL). The combined organic extract was washed with brine (5 mL), dried over MgSO4, and concentrated under vacuum. The resulting residue was purified by preparative HPLC (Method 3) to obtain 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] The example compounds in Table 13 were synthesized using the corresponding intermediates, as illustrated in Example 42, following the synthesis steps of the general route 38.

[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-oxadiazole-2-yl]-1-methylpiperazine-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-oxadiazole-2-yl]piperidine-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 N2 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 NaHCO3 aqueous solution (5 mL). The organic layer was isolated, concentrated under vacuum, and purified by preparative HPLC (Method 2) to obtain 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 illustrated in 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-ethylpiperidine-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), 4-chlorobenzohydrazide (41 mg, 0.238 mmol), followed by HATU (83 mg, 0.220 mmol) and DIPEA (0.064 mL, 0.366 mmol) were added at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (2 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10-100% siRNA in heptane) to obtain 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-oxadiazole-2-yl]-1-ethylpiperidine-3-yl]carbamate [ka] tert-butyl N-[(3R,6S)-6-{[(4- To a solution of chlorophenyl)formohydrazide]carbonyl}-1-ethylpiperidine-3-yl]carbamate (75% purity, 100 mg, 0.177 mmol), TsCl (101 mg, 0.530 mmol), followed by DIPEA (0.092 mL, 0.530 mmol), was added, and the mixture was stirred at room temperature for 16 hours. A 15% aqueous solution of NH4OH (10 mL) was added, and the reaction mixture was concentrated under vacuum. The residue was dissolved in H2O (20 mL) and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10-100% SiO2 in heptane) to obtain the title compound as a white solid (81% purity, 82 mg, 0.163 mmol, 92% yield); M / Z: 407, 409 [M+H] + ESI + RT=1.02(S1).

[0338] Step 40.c: (3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-ethylpiperidine-3-amine; trifluoroacetic acid [ka] To a solution of tert-butyl N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-ethylpiperidine-3-yl]carbamate (81% purity, 82 mg, 0.163 mmol) in DCM (1 mL), TFA (1.0 mL, 13.5 mmol) was added at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to obtain 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-oxadiazole-2-yl]-1-ethylpiperidine-3-yl]acetamide [ka] To a solution of (3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazole-2-yl]-1-ethyl-piperidine-3-aminetrifluoroacetic acid (28% purity, 160 mg, 0.106 mmol) in DCM (5 mL), DIPEA (0.056 mL, 0.319 mmol) was added at 0°C, followed by a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (29 mg, 0.128 mmol, intermediate 19) in DCM (1 mL). The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with H2O (10 mL), extracted with DCM (2 × 10 mL), and the combined organic extract was dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC (Method 5) to obtain 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 illustrated in 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)acetamide]-2-{N'-[(1s,3s)-3-(trifluoro [Methoxy)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)acetamide]-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 H2O (50 mL) and extracted with ELISA (2 × 50 mL). The combined organic extracts were washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% siRNA in heptane) to obtain the title compound as an off-white solid (86% purity, 970 mg, 1.37 mmol, 76% yield);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)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate [ka] A suspension of tert-butyl(2R,5S)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-[[[(1S,3S)-3-(trifluoromethoxy)cyclobutanecarbonyl]amino]carbamoyl]piperidine-1-carboxylate (86% purity, 970 mg, 1.37 mmol), K2CO3 (1132 mg, 8.19 mmol), and TsCl (781 mg, 4.10 mmol) in ACN (10 mL) was stirred at 80°C for 3 hours. The reaction mixture was partitioned between ELISA (100 mL) and H2O (100 mL), the organic layer was isolated, washed with brine (100 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% siRNA in heptane) to obtain 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-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate (317 mg, 0.524 mmol, Example 49) in DCM (10 mL), ZnBr2 (714 mg, 3.14 mmol) was added, and the mixture was stirred at room temperature under N2 for 20 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (10 mL) and 20% IPA in DCM (10 mL). The organic layer was isolated, concentrated under vacuum, and purified by chromatography on silica gel (0-20% MeOH in DCM) to obtain 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 the general route 41, the example compounds in Table 16 were synthesized using the corresponding intermediates, as illustrated in 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)acetamide]-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), HATU (185 mg, 0.486 mmol), followed by DIPEA (0.14 mL, 0.809 mmol), the mixture was stirred at room temperature for 10 minutes. Tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-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 H2O (5 mL) and extracted with ELISA (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% HCl in heptane, followed by 0-20% MeOH in HCl) to obtain the title compound (90% purity, 206 mg, 0.303 mmol, 75% yield) as a pale yellow gum; 1 1H 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)acetamide]-2-{5-[1-(2,2,2-trifluoroethyl)azetidine-3-yl]-1,3,4-oxadiazole-2-yl}piperidine n-1-carboxylate [ka] A suspension of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-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 minutes. The reaction mixture was diluted with H2O (5 mL) and extracted with ELISA (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried on MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (0-100% SiO in heptane) to obtain 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)azetidine-3-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] A solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[1-(2,2,2-trifluoroethyl)azetidine-3-yl]-1,3,4-oxadiazole-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 NaHCO3 aqueous solution (3 mL) and extracted with DCM (2 × 5 mL). The combined organic extract was dried using a phase separator, concentrated under vacuum, and purified by preparative HPLC (Method 3) to obtain 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)acetamide]-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), 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)acetamide]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (256 mg, 0.576 mmol, intermediate 26) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (2 × 50 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum to obtain a colorless solid. By chromatographic purification on silica gel (0-100% toluene in heptane), the title compound was obtained as a white solid (85% purity, 143 mg, 0.208 mmol, 36% yield); 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)acetamide]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[N'-(3-cyclopropoxycyclobutanecarbonyl)hydrazinecarbonyl]piperidine-1-carboxylate (85% purity, 143 mg, 0.208 mmol) in anhydrous ACN (10 mL), TsCl (79 mg, 0.417 mmol) and K2CO3 (144 mg, 1.04 mmol) were added, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (2 × 50 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum to obtain a pale orange oily substance. By chromatographic purification on silica gel (0-100% toluene in heptane), the title compound was obtained as a colorless solid (70% purity, 111 mg, 0.138 mmol, 66% yield); 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-oxadiazole-2-yl]piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate (70% purity, 110 mg, 0.136 mmol, Example 58) in DCM (5 mL), ZnBr2 (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 NaHCO3 (30 mL), extracted with DCM / IPA (2:1, 2 × 50 mL), and the combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC (Method 3) to obtain 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 illustrated in 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)acetamide]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazole-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 under N2 at 0°C for 5 minutes. Tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-(5-methanesulfonyl-1,3,4-oxadiazole-2-yl)piperidine-1-carboxylate (71 mg, 0.133 mmol, intermediate 52) was added to anhydrous THF (1 mL), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (1 mL) and extracted with ELISA (2 × 3 mL). The combined organic extracts were dried on Na2SO4 and concentrated in vacuum to obtain the title compound in a quantitative yield of (77 mg, 0.133 mmol). The crude material was then processed 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-oxadiazole-2-yl]piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate (77 mg, 0.133 mmol, Example 62) in DCM (2 mL), ZnBr2 (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 NaHCO3 aqueous solution (10 mL) and extracted with DCM / IPA (8:2, 2 × 3 mL). The combined organic extract was dried using a phase separator, concentrated under vacuum, and purified by preparative HPLC (Method 3) to obtain the title compound as a white powder (94% purity, 7.0 mg, 0.0143 mmol, 11% yield); 1 1H 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 illustrated in 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)acetamide]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate [ka] To a solution of 2-(trifluoromethoxy)ethanol (139 mg, 1.07 mmol) in anhydrous THF (6 mL), NaH (60%, 43 mg, 1.07 mmol) was added at 0°C, and the mixture was stirred for 10 minutes. A solution of tert-butyl(2R,5S)-2-(5-bromo-1,3,4-oxadiazole-2-yl)-5-[[2-(4-chloro-3-fluorophenoxy)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 over water (15 mL) and extracted with RINKAN (3 × 15 mL). The combined organic extracts were dried on MgSO4 and concentrated in vacuum to obtain the title compound (80% purity, 627 mg, 0.860 mmol, 97% yield) as a yellow oily substance; 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-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate (80% purity, 627 mg, 0.860 mmol, Example 76) in DCM (9 mL), ZnBr2 (581 mg, 2.58 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction was poured over H2O (20 mL) and extracted with 10% IPA in DCM (3 × 20 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. The residue was purified by preparative HPLC (Method 4) to obtain 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 illustrated in 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-oxadiazole-2-yl)piperidine-3-yl]-2-(3,4-dichlorophenoxy)acetamide [ka] To a solution of tert-butyl(2R,5S)-2-(5-bromo-1,3,4-oxadiazole-2-yl)-5-[2-(3,4-dichlorophenoxy)acetamide]piperidine-1-carboxylate (400 mg, 0.712 mmol, intermediate 32) in DCM (10 mL), ZnBr2 (642 mg, 2.85 mmol) was added, and the mixture was stirred at room temperature for 6 hours. A further fraction of ZnBr2 (642 mg, 2.85 mmol) was added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM / IPA (2:1, 3 × 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuum to obtain the title compound as a pale yellow powder (80% purity, 269 mg, 0.478 mmol, 67% yield); 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-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] To a solution of 2-(trifluoromethoxy)ethanol (43 μL, 0.427 mmol) in anhydrous THF (3 mL), NaH (60%, 17 mg, 0.427 mmol) was added at 0°C, and the solution was stirred at room temperature for 5 minutes. N-[(3S,6R)-6-(5-bromo-1,3,4-oxadiazole-2-yl)piperidine-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 H2O (30 mL) and extracted with siRNA (2 × 50 mL). The combined organic extract was dried over Na2SO4 and concentrated in vacuum to obtain an orange oily substance. The residue was purified by chromatography on silica gel (0-100% phenylethylamine in heptane), followed by preparative HPLC (Method 3), to obtain 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 illustrated in 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)acetamide]-2-{5-[3-(trifluoromethyl)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate [ka] To a solution of 3-(trifluoromethyl)azetidine hydrochloride (60 mg, 0.371 mmol) in anhydrous DMF (1 mL), DIPEA (0.16 mL, 0.927 mmol) was added, followed by a solution of tert-butyl(2R,5S)-2-(5-bromo-1,3,4-oxadiazole-2-yl)-5-[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]piperidine-1-carboxylate (100 mg, 0.185 mmol, intermediate 31) in anhydrous DMF (1 mL). The mixture was stirred at 100°C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (3 × 10 mL). The combined organic extracts were washed with brine (2 × 30 mL), dried on MgSO4, and concentrated under vacuum to obtain the title compound (87% purity, 117 mg, 0.176 mmol, 95% yield) as a brown oily substance; 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)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[3-(trifluoromethyl)azetidine-1-yl]-1,3,4-oxadiazole-2-yl}piperidine-1-carboxylate (87% purity, 115 mg, 0.173 mmol) in DCM (2 mL), ZnBr2 (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 NaHCO3 aqueous solution (3 mL) and extracted with DCM:IPA (80:20, 3 × 3 mL). The combined organic extracts were dried using a phase separator and concentrated under vacuum. The residue was purified by preparative HPLC (Method 4) to obtain the title compound (37 mg, 0.0774 mmol, 45% yield) as a white powder; 1 1H 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 illustrated in 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)acetamide]piperidine-1-carboxylate [ka] To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-2-carboxylic acid (1.86 g, 4.32 mmol, intermediate 22), NH4Cl (253 mg, 4.73 mmol), and DIPEA (3.1 mL, 17.7 mmol) in anhydrous DMF (22 mL), HATU (1.80 g, 4.73 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with SiO2 (100 mL) and washed with brine (3 × 50 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum to obtain the title compound as colorless crystals in a quantitative yield of 2.36 g, 4.39 mmol (80% purity). 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)acetamide]-2-cyanopiperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-2-carbamoyl-5-[2-(4-chloro-3-fluorophenoxy)acetamide]piperidine-1-carboxylate (80% purity, 2.17 g, 4.04 mmol) and Et3N (2.6 mL, 18.7 mmol) in anhydrous DCM (40 mL), TFAA (1.2 mL, 8.27 mmol) was added at 0°C, and the solution was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C and quenched with H2O (20 mL). The solution was diluted with DCM (50 mL) and washed with saturated NaHCO3 aqueous solution (20 mL). The organic layer was dried using a phase separator, concentrated under vacuum, and purified by chromatography on silica gel (0-50% ethyl acetate in heptane) to obtain 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)acetamide]-2-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-cyanopiperidine-1-carboxylate (500 mg, 1.21 mmol) in MeOH (6 mL), hydroxylamine hydrochloride (1:1) (125 mg, 1.80 mmol) and NaHCO3 (225 mg, 2.68 mmol) were added at 0°C, and the reaction mixture was stirred at room temperature for 40 hours. The resulting suspension was filtered under vacuum, washed with MeOH, and the filtrate was concentrated under vacuum to obtain the title compound as a white powder (69% purity, 620 mg, 0.962 mmol, 79% yield); 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)acetamide]-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), Et3N (202 μL, 1.45 mmol), followed by HATU (200 mg, 0.526 mmol), was added and the mixture was stirred at room temperature for 10 minutes. Tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-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 RINKAN (30 mL) and washed with brine (3 × 20 mL). The combined organic extracts were dried on MgSO4 and concentrated in vacuum to obtain 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)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxylate [ka] A solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-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 hours. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel (0-100% ethyl phosphate in heptane) to obtain 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-oxadiazole-3-yl}piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxylate (91% purity, 152 mg, 0.233 mmol, Example 97) in anhydrous DCM (1.5 mL), ZnBr2 (210 mg, 0.924 mmol) was added, and the resulting mixture was stirred at room temperature under N2 for 17 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with 80:20 DCM / IPA (3 × 50 mL). The combined organic extracts were dried using a phase separator, concentrated under vacuum, and purified by preparative HPLC (Method 4) to obtain 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-butyl2-ethyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetamide}piperidine-1,2-dicarboxylate [ka] To a solution of 2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetic acid (400 mg, 1.95 mmol, intermediate 12) in anhydrous THF (20 mL), isobutyl chloroformate (0.24 mL, 1.85 mmol), followed by NMM (0.21 mL, 1.95 mmol), was added at 0°C. After stirring the mixture for 15 minutes, 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 hour. The reaction mixture was cooled to 0°C, quenched with H2O (0.5 mL), and concentrated under vacuum. The residue was partitioned between RINKAN (10 mL) and H2O (10 mL). The organic layer was isolated, washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound as an off-white solid (90% purity, 805 mg, 1.58 mmol, 81% yield); 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-fluoropyridine-3-yl)oxy]acetamide}piperidine-2-carboxylic acid [ka] A solution of 1-tert-butyl 2-ethyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetamide}piperidine-1,2-dicarboxylate (90% purity, 805 mg, 1.58 mmol) and LiOH·H2O (81 mg, 1.89 mmol) in THF (2.5 mL) / MeOH (2.5 mL) / H2O (2.5 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between ELISA (20 mL) and H2O (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 siRNA (2 × 25 mL), the combined organic extract was washed with H₂O (30 mL), dried over Na₂SO₄, and concentrated in vacuum to obtain the title compound as a white solid (90% purity, 570 mg, 1.19 mmol, 75% yield); 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-fluoropyridine-3-yl)oxy]acetamide}-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-fluoropyridine-3-yl)oxy]acetamide}piperidine-2-carboxylic acid (90% purity, 530 mg, 1.10 mmol) in anhydrous THF (11 mL), isobutyl chloroformate (0.14 mL, 1.05 mmol), followed by NMM (0.12 mL, 1.10 mmol), was added at 0°C. After stirring the mixture for 15 minutes, 3,4-dichlorobenzohydrazide (226 mg, 1.10 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, quenched with H2O (0.5 mL), and concentrated under vacuum. The residue was partitioned between  (15 mL) and H2O (15 mL). The organic layer was isolated, washed with saturated aqueous NaHCO3 solution (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound as an off-white solid (90% purity, 626 mg, 0.910 mmol, 82% yield); 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-fluoropyridine-3-yl)oxy]acetamide}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate [ka] A suspension of tert-butyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetamide}-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 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (20 mL) and H2O (20 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (10 mL). The combined organic extracts were washed with saturated NaHCO3 aqueous solution (5 × 20 mL) and brine (20 mL), dried on Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (40-90% siRNA in heptane) to obtain 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-fluoropyridine-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]acetamide [ka] To a solution of tert-butyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridine-3-yl)oxy]acetamide}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2-yl]piperidine-1-carboxylate (150 mg, 0.250 mmol, Example 99) in DCM (3 mL), ZnBr2 (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 NaHCO3 aqueous solution (2 mL) and DCM / IPA (4:1, 2 mL), and the layers were separated using a phase separator. The organic layer was concentrated under vacuum and purified by preparative HPLC (Method 4) to obtain 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-oxadiazole-2-yl}piperidine-3-yl]acetamide [ka] To a solution of 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide (100 mg, 0.197 mmol, Example 77) and K2CO3 (57 mg, 0.413 mmol) in DMF (2 mL), MeI (134 μL, 2.16 mmol) was added, and the mixture was stirred at room temperature for 5 days. The reaction mixture was quenched with 33% aqueous NH4OH (1 mL) and stirred for 30 minutes. The solution was diluted with H2O (30 mL), extracted with ELISA (2 × 30 mL), and the combined organic extract was dried over Na2SO4 and concentrated under vacuum. Purification by preparative HPLC (Method 5) yielded the title compound as a white powder (36 mg, 0.0725 mmol, 37% yield); 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-oxadiazole-2-yl}piperidine-3-yl]acetamide (Example 87) 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazole-2-yl}piperidine-3-yl]acetamide (48 mg, 0.0978 mmol, Example 87) was subjected to chiral purification using Method C4 to obtain 2-(4-chloro-3-fluorophenoxy) Olophenoxy)-N-[(3S,6R)-6-(5-{2-[(1R)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazole-2-yl)piperidine-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-oxadiazole-2-yl)piperidine-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 chiralized using the corresponding intermediates and methods, as illustrated in 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 The 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 cultured in a 384-well imaging assay plate at a density of 12,000 cells per well in growth medium (containing DMEM / F12, 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin-100 μg / mL streptomycin) and incubated at 37°C and 5% CO2. After 24 hours, the medium was changed to 50 μL of assay medium per well (DMEM / F12, 0.3% FBS, 2 mM L-glutamine, 100 U / mL penicillin-100 μg / mL streptomycin). The example compounds were sequentially diluted in DMSO, spotted onto an intermediate plate, and pre-diluted with assay medium containing 3.3 μM tunicamycin to obtain an 11-fold excess final assay concentration. In addition to the example compound test area, the plate also contained several control wells for assay normalization, wells containing tunicamycin but not the example compound (high control), and similarly, wells containing neither the example compound nor tunicamycin (low control). The assay was initiated by transferring 5 μL from the intermediate plate to the assay plate, followed by incubation at 37°C with 5% CO2 for 6 hours. Subsequently, cells were fixed (in PBS with 4% PFA, 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 excitations at 405 nm and 488 nm. Finally, images were analyzed using a script-based algorithm. The ATF4 signal ratio between the nucleus and cytoplasm was monitored using the main readout HEK-ATF4. Tunicamycin induced an increase in the overall ATF4 ratio signal, which was prevented by the ISR-modulated example compound.In addition, HEK-CellCount readout was derived by counting the number of stained nuclei corresponding to healthy cells. This readout served as an internal toxicity control. The example compounds described herein did not produce a significant reduction in CellCount.

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

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

[0400] Protocol - Thermodynamic (equilibrium) solubility in selected buffer The example compounds were tested for thermodynamic (equilibrium) solubility in a selective buffer assay. The test compound, in powder form, was weighed into a 4 mL glass vial, and the calculated volume of selective medium was added to reach the target concentration for the solubility test (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 against a reference solution of 0.8 mg / mL of the test compound in DMSO using the UPLC-UV method described below. Culture medium composition: 690 mg of NaH2PO4·H2O in 200 mL of ultrapure water adjusted to pH 2 with 50 mM phosphate buffer (pH=2.0) and 85% phosphoric acid; 820 mg of anhydrous sodium acetate in 200 mL of ultrapure water adjusted to pH 5.5 with 50 mM acetate buffer (pH=5.5) and 99.8% acetate; 40.5 mL of 0.1 M solution of Na2HPO4 + 9.5 mL of 0.1 M solution of NaH2PO4 in 50 mM phosphate buffer (pH=7.4). Analytical conditions: Reverse-phase Acquity BEH C18 column (2.1 mm × 50 mm, 1. UPLC-UV-MS analysis was performed using a Waters Acquity UPLCH Class-PDA-QDa system with a flow rate of 0.65 mL / min and an injection volume of 0.4 μL, using a gradient of 10–95% B (A = 0.1% formic acid in H2O; B = 0.05% formic acid in ACN) over 1.8 minutes, followed by a gradient of 100% B over 0.8 minutes. 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 150–900 M / Z range. Data were integrated using Empower® 3 software. Data analysis: The equilibrium solubility of the test compound in the selected 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 - Measure of the effect on hERG channels by tail current recording using in vitro Rapid ICE The efficacy of the example compounds in inhibiting human ERG potassium channel (hERG) tail current was determined using a Rapid ICE (rapid ion channel electrophysiology) assay in recombinant HEK293 cell lines stably transfected with hERG cDNA under an inducible promoter. Rapid ICE is an automated patch-clamp assay utilizing 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 blastosidine, and 100 μg / mL hygromycin. hERG channel expression induction was achieved by adding 10 μg / mL tetracycline 24, 48, or 72 hours prior to recording.

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

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

number

[0404] Here, PA = Peak Area and ES = External Standard.

[0405] Biological examples: Lipophilic and soluble In recent years, numerous reports in the medicinal chemistry literature have linked the clinical success of drug candidates to their physicochemical properties. The degree of lipophilicity has been highlighted as a particularly important factor in defining the overall properties and likely fate of drug candidates (29), and typically, it is beneficial if the logD is in the range of 1 to 3. Referring to Table 24, the selected compound of the present invention has a logD value within this range, and in this respect represents an improvement over previously reported analogues and similar analogues.

[0406] Similarly, poor solubility of drug candidates is associated with an increased risk of drug development failure (30). Furthermore, as shown in Table 24, the selected compounds of the present invention exhibit higher water solubility compared to structurally similar compounds of the most advanced technology. Additional solubility data related to further example compounds are shown in Table 25 below.

[0407] [Table 24]

[0408] [Table 25]

[0409] Biological example: hERG selectivity Drug-induced QT interval prolongation and the development of torsades 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 channels play in the manifestation of these clinical side effects. Generally, hERGK + It is widely accepted that minimizing the interaction between the channel and the drug molecule is desirable (31). For this purpose, we improved the physicochemical properties described above (i.e., logD and solubility - Tables 24 & 25) and hERGK + The aim was to strike a balance with the selective modulation of ATF4 relative to the channel.

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

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

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