Tead inhibitors

Abstract

This invention relates to a compound of formula (I) wherein A, Z, L, R1, R2, R3, R4, R5, and R33 are as defined in claim 1, or pharmaceutically acceptable salts thereof. The compound of formula (I) is effective as a TEAD inhibitor. Such compounds are suitable as medicines for treating diseases or symptoms requiring inhibition of TEAD, such as cancer and chronic pain.

Description

Technical Field

[0001] This invention relates to therapeutically active compounds suitable for inhibiting the transcriptional enhancer-associated domain (TEAD), and to pharmaceutical compositions containing such compounds. These compounds are suitable for treating diseases or conditions associated with increased TEAD activity or TEAD manifestation, such as various cancers and chronic pain. Prior Technology

[0002] TEA domain transcription factors (TEAD1-4) are a family of DNA-binding transcription factors that regulate gene expression involved in cell proliferation, cell fate, cell differentiation, organ overgrowth, and organ regeneration. YAP and TAZ are co-activators of TEAD transcription, capable of shuttling between the cytoplasm and nucleus. Changes in actin dynamics and the Hippo signaling pathway promote YAP and TAZ phosphorylation, cytoplasmic retention, and proteasome degradation, thus leading to a decrease in the nuclear levels of YAP and TAZ and TEAD transcriptional activity.

[0003] The evolutionarily conserved Hippo signaling pathway consists of large tumor suppressor 1 / 2 (LATS1 / 2), serine / threonine kinase, sterile 20-like kinase 1 / 2 (MST1 / 2), the transferor protein Salvador homolog 1 (SAV1), and MOB kinase activator 1A / B (MOB1A / B). The tumor suppressor neurofibromin 2 (NF2) (also known as Merlin) participates upstream of these kinases to inhibit YAP and TAZ activity by promoting pathway activation. The Hippo pathway is associated with various aspects of tumorigenesis, including cell proliferation, cell differentiation, cancer metastasis, and cancer therapy resistance. Therefore, dysregulation of Hippo pathway signaling has been shown to promote tumorigenesis in various cancer types. YAP and TAZ have also been reported as core mechanisms in the pathogenesis of chronic pain, such as chronic neuropathic pain and chronic musculoskeletal pain.

[0004] Compounds with TEAD inhibitory activity have been disclosed in, for example, WO 2020 / 081572, WO 2020 / 070181 and WO 2020051099. The in vivo antitumor activity of the TEAD inhibitor K-975 against malignant pleural mesothelioma has been reported in Am J Cancer Res, 2020; 10(12): 4399-4415.

[0005] There is a need for compounds that target diseases associated with dysregulation of Hippo pathway components, such as compounds that target the YAP-TEAD interaction. Such compounds would be suitable for treating diseases or conditions requiring inhibition of TEAD, such as chronic pain (including neuropathic pain) and various cancers (including cancers resistant to other treatments such as chemotherapy, immunotherapy, and targeted therapy). Summary of the Invention

[0006] Compound (I) has been found to be a potent inhibitor of the YAP-TEAD interaction. Therefore, the compound is suitable for treating symptoms and diseases requiring inhibition of TEAD. Such symptoms and diseases include (but are not limited to) chronic pain, particularly chronic neuralgia and chronic musculoskeletal pain, and cancers, especially those associated with dysregulation of Hippo pathway components including YAP-TEAD. Specific cancers include (but are not limited to) mesothelioma, squamous cell carcinoma, gynecological cancers, bladder cancer, gastric cancer, liver cancer, lung cancer, and colorectal cancer.

[0007] This invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. in A is pyridyl, tetrahydropiperanyl, or a 4- to 10-membered carbide ring; L can be -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, -OC 1-7 alkyl-, or -NH-C 1-7 alkyl-; R1 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36R 37, or a 5- to 6-membered heterocycle with 1 to 3 heteroatoms independently selected from O, S, and N as ring atoms, which may be substituted as required; R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen; R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, or cyano, or R1 and R3 together with the attached carbon atom form a 5- to 6-membered ring having 0-3 independently selected heteroatoms chosen from O, S, and N as ring atoms, which may be substituted as required; R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl; R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the attached carbon atom form a 5- to 6-membered ring having 1 to 3 independently selected heteroatoms chosen from O, S, and N as ring atoms, which may be substituted as required; Z is -CH(NHR 25)-(CH 2) 2-COOH or a group of the following formula. Where B is any of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , and ; Its restrictions are: When B is a ring (2), then L is -O- or -OC1-7 alkyl-, and R1 is C1-7 alkoxy; When B is a ring (3), then L is -O-; When B is a ring (4), then L is -O- and R1 is a C1-7 alkoxy group; When B is a ring (20), (21), (23), (25) or (26), then L is -O- and R1 is a C1-7 alkoxy group; When L is -C1-7 alkyl-O-, then R1 is C1-7 alkoxy, or R1 and R3 together with their attached carbon atoms form a 5- to 6-membered ring with 0-3 independently selected heteroatoms chosen from O, S and N as ring atoms, which may be substituted as needed; When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbocyclic ring, then R1 is a C1-7 alkoxy group; R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-7 alkyl, -C(O)-RX, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxycarbonyl-C1-7 alkyl, -SO2-C1-7 alkyl, -C1-7 alkyl-C(O)-NR23R24, or 4- to 6-membered rings that are substituted as needed, having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms; RX is a C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkyl-NR 36R 37, or a 4- to 6-membered ring having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms; R7, R8, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, hydroxyl, C1-7 alkoxy, or C1-7 alkylcarbonyl. R11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl; R23, R24, R27, R28, R29, R31, R32, R33, R34, R35, R36, R37, R40, R41, R42, R43, R44 and R45 are independently hydrogen or C1-7 alkyl; R 25 is a C1-7 alkyl group; R 30 is a C1-7 alkyl, C1-7 alkyl carbonyl, or -SO 2C1-7 alkyl; R 38 represents hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxy C1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR 23R 24; R 39 is hydrogen, C1-7 alkyl, or hydroxyl; The substitutions selected as needed are, in each instance, one or two independent substituents selected from the following: C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy, and side-oxy; The limiting condition is that the compound of formula (I) is not a N-[2-methyl-3-(phenoxymethyl)phenyl]-5-sideoxy-2-pyrrolidinemethylamine; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-1-methyl-5-sideoxy-2-pyrrolidinemethylamine; N-[3-[(4-chlorophenyl)methyl]phenyl]-5-sideoxy-2-pyrrolidinemethylamine; N-[3-[(cyclohexyloxy)methyl]phenyl]-1-methyl-5-sideoxy-2-pyrrolidinemethylamine; N-[4-methyl-3-[(4-methyl-2-pyridyl)oxy]phenyl]-5-sideoxy-2-pyrrolidinemethylamine; N-[3-(cyclopentylamino)phenyl]-1-methyl-5-sideoxy-2-pyrrolidinemethylamine; N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-sideoxy-3-piperidinemethylamine; 1-Ethyl-5-sideoxy-N-(3-phenoxyphenyl)-3-pyrrolidinemethylamine; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-2-pyrrolidinemethylamine; 1-(1-Ethylpropyl)-N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-5-sideoxy-3-pyrrolidinemethylamine; N-[3-[(4-chlorophenyl)methyl]phenyl]-1,6-dihydro-6-sideoxy-3-pyridinecarboxamide; 1,6-Dihydro-N-[4-methoxy-3-(phenylmethyl)phenyl]-6-sideoxy-3-pyridinecarboxamide; 1,6-Dihydro-6-sideoxy-N-[3-[2-(2-pyridyl)vinyl]phenyl]-3-pyridinemethylamine; N-[3-[(3-fluorophenoxy)methyl]phenyl]-2,3-dihydro-2-sideoxy-1H-imidazol-4-methamide; 1-Methyl-N-[2-methyl-3-(phenoxymethyl)phenyl]-5-sideoxy-3-pyrrolidinemethylamine; N-[3-[(1,3-benzodioxacyclopenten-5-yloxy)methyl]phenyl]-1-(2-methylpropyl)-5-sideoxy-3-pyrrolidinemethylamine; 1,6-Dihydro-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-sideoxy-3-pyridinecarboxamide; N-[3-[(cyclohexyloxy)methyl]phenyl]-1-ethyl-5-sideoxy-3-pyrrolidinemethylamine; 1-Methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-5-sideoxy-3-pyrrolidinemethylamine; 2,3-Dihydro-3-methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-sideoxy-1H-imidazol-4-methamide; 2,3-Dihydro-1,3-dimethyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-sideoxy-1H-imidazol-4-methamide; 1-Ethyl-N-[4-methoxy-3-(4-pyridylmethoxy)phenyl]-5-sideoxy-3-pyrrolidinemethylamine; N-[4-methoxy-3-(4-methoxyphenoxy)phenyl]-1-(2-methylpropyl)-5-sideoxy-3-pyrrolidinemethylamine or 6-Side-O-N-(3-phenoxyphenyl)-2-piperidine Methionine.

[0008] According to a specific example, the present invention provides a method for treating diseases or symptoms requiring suppression of TEAD, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. in A is pyridyl, tetrahydropiperanyl, or a 4- to 10-membered carbide ring; L can be -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, -OC 1-7 alkyl-, or -NH-C 1-7 alkyl-; R1 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36R 37, or a 5- to 6-membered heterocycle with 1 to 3 heteroatoms independently selected from O, S, and N as ring atoms, which may be substituted as required; R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen; R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, or cyano, or R1 and R3 together with the attached carbon atom form a 5- to 6-membered ring having 0-3 independently selected heteroatoms chosen from O, S, and N as ring atoms, which may be substituted as required; R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl; R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the attached carbon atom form a 5- to 6-membered ring having 1 to 3 independently selected heteroatoms chosen from O, S, and N as ring atoms, which may be substituted as required; Z is -CH(NHR 25)-(CH 2) 2-COOH or a group of the following formula. Where B is any of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , and ; Its restrictions are: When B is a ring (2), then L is -O- or -OC1-7 alkyl-, and R1 is C1-7 alkoxy; When B is a ring (3), then L is -O-; When B is a ring (4), then L is -O- and R1 is a C1-7 alkoxy group; When B is a ring (20), (21), (23), (25) or (26), then L is -O- and R1 is a C1-7 alkoxy group; When L is -C1-7 alkyl-O-, then R1 is C1-7 alkoxy, or R1 and R3 together with their attached carbon atoms form a 5- to 6-membered ring with 0-3 independently selected heteroatoms chosen from O, S and N as ring atoms, which may be substituted as needed; When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbocyclic ring, then R1 is a C1-7 alkoxy group; R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-7 alkyl, -C(O)-RX, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxycarbonyl-C1-7 alkyl, -SO2-C1-7 alkyl, -C1-7 alkyl-C(O)-NR23R24, or 4- to 6-membered rings that are substituted as needed, having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms; RX is a C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkyl-NR 36R 37, or a 4- to 6-membered ring having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms; R7, R8, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, hydroxyl, C1-7 alkoxy, or C1-7 alkylcarbonyl. R11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl; R23, R24, R27, R28, R29, R31, R32, R33, R34, R35, R36, R37, R40, R41, R42, R43, R44 and R45 are independently hydrogen or C1-7 alkyl; R 25 is a C1-7 alkyl group; R 30 is a C1-7 alkyl, C1-7 alkyl carbonyl, or -SO 2C1-7 alkyl; R 38 represents hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxy C1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR 23R 24; R 39 is hydrogen, C1-7 alkyl, or hydroxyl; The substitutions selected as needed are 1 to 2 independently selected from the following substituents each time they appear: C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy and side oxygen.

[0009] In a specific case, the disease or symptom that requires suppression of TEAD is cancer, such as mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, stomach cancer, liver cancer, lung cancer, and colorectal cancer.

[0010] In a specific case, the disease or symptom that needs to be suppressed in TEAD is chronic pain, such as chronic neuralgia and chronic musculoskeletal pain.

[0011] According to a specific example, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Implementation

[0012] This application provides a novel (I) compound or a pharmaceutically acceptable salt thereof suitable as a TEAD inhibitor.

[0013] One specific embodiment of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. in A is pyridyl, tetrahydropiperanyl, or a 4- to 10-membered carbide ring; L can be -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, -OC 1-7 alkyl-, or -NH-C 1-7 alkyl-; R1 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36R 37, or a 5- to 6-membered heterocycle with 1 to 3 heteroatoms independently selected from O, S, and N as ring atoms, which may be substituted as required; R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen; R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, or cyano, or R1 and R3 together with the attached carbon atom form a 5- to 6-membered ring having 0-3 independently selected heteroatoms chosen from O, S, and N as ring atoms, which may be substituted as required; R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl; R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the attached carbon atom form a 5- to 6-membered ring having 1 to 3 independently selected heteroatoms chosen from O, S, and N as ring atoms, which may be substituted as required; Z is -CH(NHR 25)-(CH 2) 2-COOH or a group of the following formula. Where B is any of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , and ; Its restrictions are: When B is a ring (2), then L is -O- or -OC1-7 alkyl-, and R1 is C1-7 alkoxy; When B is a ring (3), then L is -O-; When B is a ring (4), then L is -O- and R1 is a C1-7 alkoxy group; When B is a ring (20), (21), (23), (25) or (26), then L is -O- and R1 is a C1-7 alkoxy group; When L is -C1-7 alkyl-O-, then R1 is C1-7 alkoxy, or R1 and R3 together with their attached carbon atoms form a 5- to 6-membered ring with 0-3 independently selected heteroatoms chosen from O, S and N as ring atoms, which may be substituted as needed; When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbocyclic ring, then R1 is a C1-7 alkoxy group; R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-7 alkyl, -C(O)-RX, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxycarbonyl-C1-7 alkyl, -SO2-C1-7 alkyl, -C1-7 alkyl-C(O)-NR23R24, or 4- to 6-membered rings that are substituted as needed, having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms; RX is a C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkyl-NR 36R 37, or a 4- to 6-membered ring having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms; R7, R8, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, hydroxyl, C1-7 alkoxy, or C1-7 alkylcarbonyl. R11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl; R23, R24, R27, R28, R29, R31, R32, R33, R34, R35, R36, R37, R40, R41, R42, R43, R44 and R45 are independently hydrogen or C1-7 alkyl; R 25 is a C1-7 alkyl group; R 30 is a C1-7 alkyl, C1-7 alkyl carbonyl, or -SO 2C1-7 alkyl; R 38 represents hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxy C1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR 23R 24; R 39 is hydrogen, C1-7 alkyl, or hydroxyl; The substitutions selected as needed are, in each instance, one or two independent substituents selected from the following: C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy, and side-oxy; The limiting condition is that the compound of formula (I) is not a N-[2-methyl-3-(phenoxymethyl)phenyl]-5-sideoxy-2-pyrrolidinemethylamine; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-1-methyl-5-sideoxy-2-pyrrolidinemethylamine; N-[3-[(4-chlorophenyl)methyl]phenyl]-5-sideoxy-2-pyrrolidinemethylamine; N-[3-[(cyclohexyloxy)methyl]phenyl]-1-methyl-5-sideoxy-2-pyrrolidinemethylamine; N-[4-methyl-3-[(4-methyl-2-pyridyl)oxy]phenyl]-5-sideoxy-2-pyrrolidinemethylamine; N-[3-(cyclopentylamino)phenyl]-1-methyl-5-sideoxy-2-pyrrolidinemethylamine; N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-sideoxy-3-piperidinemethylamine; 1-Ethyl-5-sideoxy-N-(3-phenoxyphenyl)-3-pyrrolidinemethylamine; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-2-pyrrolidinemethylamine; 1-(1-Ethylpropyl)-N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-5-sideoxy-3-pyrrolidinemethylamine; N-[3-[(4-chlorophenyl)methyl]phenyl]-1,6-dihydro-6-sideoxy-3-pyridinecarboxamide; 1,6-Dihydro-N-[4-methoxy-3-(phenylmethyl)phenyl]-6-sideoxy-3-pyridinecarboxamide; 1,6-Dihydro-6-sideoxy-N-[3-[2-(2-pyridyl)vinyl]phenyl]-3-pyridinemethylamine; N-[3-[(3-fluorophenoxy)methyl]phenyl]-2,3-dihydro-2-sideoxy-1H-imidazol-4-methamide; 1-Methyl-N-[2-methyl-3-(phenoxymethyl)phenyl]-5-sideoxy-3-pyrrolidinemethylamine; N-[3-[(1,3-benzodioxacyclopenten-5-yloxy)methyl]phenyl]-1-(2-methylpropyl)-5-sideoxy-3-pyrrolidinemethylamine; 1,6-Dihydro-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-sideoxy-3-pyridinecarboxamide; N-[3-[(cyclohexyloxy)methyl]phenyl]-1-ethyl-5-sideoxy-3-pyrrolidinemethylamine; 1-Methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-5-sideoxy-3-pyrrolidinemethylamine; 2,3-Dihydro-3-methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-sideoxy-1H-imidazol-4-methamide; 2,3-Dihydro-1,3-dimethyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-sideoxy-1H-imidazol-4-methamide; 1-Ethyl-N-[4-methoxy-3-(4-pyridylmethoxy)phenyl]-5-sideoxy-3-pyrrolidinemethylamine; N-[4-methoxy-3-(4-methoxyphenoxy)phenyl]-1-(2-methylpropyl)-5-sideoxy-3-pyrrolidinemethylamine or 6-Side-O-N-(3-phenoxyphenyl)-2-piperidine Methionine.

[0014] It should be understood that in variants of the linking group L, the left-hand bond is attached to ring A of formula (I) and the right-hand bond is attached to the phenyl group. The wavy line in variants of group B indicates the connection point with the methylamino group.

[0015] According to a specific example, a compound according to formula (I) is provided, wherein A is phenyl, pyridyl, or cyclohexyl. In one subgroup of the foregoing specific examples, A is phenyl or cyclohexyl. In yet another subgroup, A is phenyl or pyridyl. In yet another subgroup, A is phenyl. In yet another subgroup, A is cyclohexyl. In yet another subgroup, A is pyridyl.

[0016] According to yet another specific example, a compound according to any of the above specific examples is provided, wherein R 42 is hydrogen.

[0017] In a specific instance, a compound according to formula (Ia) or a pharmaceutically acceptable salt thereof is provided. A, L, B, R1, R2, R3, R4, R5, R33 and R42 are as defined above.

[0018] According to yet another specific example, a compound is provided according to any of the above specific examples, wherein B is a ring (1a), (3), (4), (6), (8), (9), (10), (11), (12), (13), (16), (17), or (18). In one subgroup of the aforementioned specific examples, B is a ring (1a), (4), (10), (11), (12), (13), (16), or (17). In yet another subgroup, B is a ring (1a), (10), (11), or (12). In yet another subgroup, B is a ring (1a) or (12). In yet another subgroup, B is a ring (1a). In yet another subgroup, B is a ring (12).

[0019] In one subgroup of compounds in which B is a ring (1a), compounds in which R7 and R8 are hydrogen are provided. In another subgroup of the aforementioned specific examples, compounds in which R6 is hydrogen, a C1-7 alkyl, or a C3-7 cycloalkyl are provided. According to another subgroup, compounds in which R6 is -C(O)-RX are provided, wherein RX is a C1-7 alkyl or a 4- to 6-membered ring having 1-3 heteroatoms independently selected from O, S, and N as ring atoms, substituted as desired. Specific examples of such rings are pyrrolidine and azirrobutane rings substituted as desired with 1-2 substituents independently selected from C1-7 alkyl and side oxygen groups.

[0020] In one subgroup of compounds in which B is a ring (12), a compound is provided in which R 20 is hydrogen and R 18 is a C1-7 alkyl or C3-7 cycloalkyl. In yet another subgroup of the foregoing specific examples, a compound is provided in which R 21 is hydrogen or a C1-7 alkyl.

[0021] According to yet another specific example, a compound is provided according to any of the above specific examples, wherein L is -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, or -OC 1-7 alkyl-. In one subgroup of the foregoing specific examples, a compound is provided wherein L is -O-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, or -OC 1-7 alkyl-. In one subgroup of the foregoing specific examples, a compound is provided wherein L is -O-, -C 2-7 alkenyl-, or -OC 1-7 alkyl-. In yet another subgroup, L is -O- or -C 2-7 alkenyl-. In yet another subgroup, L is -O-. A specific example of L being C 1-7 alkyl is a -CH 2- group. A specific example of L being -C 2-7 alkenyl- is a -CH=CH- group. A specific example of an L in -C 1-7 alkyl-O- is a -CH 2-O- group. A specific example of an L in -OC 1-7 alkyl- is an -O-CH 2- group.

[0022] According to a specific example, a compound is provided according to any of the above specific examples, wherein R1 is hydrogen, a C1-7 alkoxy group, or a halogen. In a subgroup of the aforementioned specific examples, a compound is provided wherein R1 is a C1-7 alkoxy group or a halogen. In one subgroup of the aforementioned specific examples, a compound is provided wherein R1 is a C1-7 alkoxy group, particularly a methoxy group. According to a specific example, R1 is a 5- to 6-membered heterocycle having 1-3 heteroatoms independently selected from O, S, and N as ring atoms, substituted as desired. Specific examples of such rings include those substituted as desired with 1-2 C1-7 alkyl or side-oxygen substituents. Diazole and pyrazole rings.

[0023] According to a specific example, a compound is provided according to any of the above specific examples, wherein R2 is hydrogen, C1-7 alkoxy, or halogen. In one subgroup of the aforementioned specific examples, a compound is provided wherein R2 is hydrogen or halogen. In one subgroup of the aforementioned specific examples, a compound is provided wherein R2 is hydrogen.

[0024] According to a specific example, a compound is provided according to any of the above specific examples, wherein R3 is hydrogen, halogen, or C1-7 alkoxy. In a subgroup, a compound is provided wherein R3 is hydrogen or C1-7 alkoxy. In a subgroup, a compound is provided wherein R3 is hydrogen.

[0025] According to a specific example, a compound is provided according to any of the above specific examples, wherein R1 and R3, together with their attached carbon atoms, form a substituted 5- to 6-membered ring having 0-3 independently selected heteroatoms as ring atoms, as desired. In a subgroup, a compound is provided in which R1 and R3, together with their attached carbon atoms, form a 5- to 6-membered ring having 1-2 independently selected heteroatoms as ring atoms, of which the heteroatom is O. In a subgroup, a compound is provided in which R1 and R3, together with their attached carbon atoms, form a 5- to 6-membered ring having 1-2 heteroatoms, wherein the heteroatom is O. Specific examples of such rings are furanyl, dihydrofuranyl, tetrahydrofuranyl, dioxanecyclohexyl, dioxanecyclohexyl, pyridyl, 2,3-dihydro-1,4-dioxane-hexenyl, and 2,3-dihydro-1,4-yl rings, which are substituted with one or two independent substituents selected from C1-7 alkyl and side oxygen groups as needed.

[0026] According to a specific example, a compound according to any of the above specific examples is provided, wherein R1 and R3, together with the benzene ring to which they are attached, form a fused ring that is substituted as desired by any of the following groups: , , , , , , or The left wavy line indicates the site attached to the L group, and the right wavy line indicates the site attached to the methylamine group. The substitutions selected as needed may be 1-2 independent substituents selected from the following: C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy, and side-oxy, especially C1-7 alkyl or side-oxy.

[0027] According to a specific example, a compound is provided according to any of the above specific examples, wherein R4 is hydrogen, halogen, C1-7 alkyl, C1-7 alkoxy, halogenated C1-7 alkyl, or halogenated C1-7 alkoxy, and R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, cyano, amino, or halogen. In a subgroup, a compound is provided wherein R4 is halogen, C1-7 alkyl, halogenated C1-7 alkyl, or halogenated C1-7 alkoxy, and R5 is hydrogen, C1-7 alkyl, cyano, or halogen. In a subgroup, a compound is provided wherein R4 is halogenated C1-7 alkyl or halogenated C1-7 alkoxy, and R5 is hydrogen or halogen. In a subgroup, a compound is provided wherein R4 is halogenated C1-7 alkyl or halogenated C1-7 alkoxy, and R5 is hydrogen. In another subgroup, compounds are provided in which R4 and R5 are both C1-7 alkyl groups, such as methyl. In another subgroup, compounds are provided in which R4 and R5 are both halogens, such as fluorine. Specific examples of R4 being a halogenated C1-7 alkyl group are -CF3 and -CHF2 groups. A specific example of R4 being a halogenated C1-7 alkoxy group is the -OCF3 group.

[0028] According to a specific example, a compound is provided according to any of the above specific examples, wherein ring A together with R4 and R5 represents any of the following groups: , , , , , , , , , , , , , or Where X is a halogen and the wavy line indicates the site attached to the L group.

[0029] According to a specific example, a compound according to any of the above specific examples is provided, wherein A together with R4 and R5 is a group (1'), (2'), (3'), (4'), (7'), (8'), (10'), (11'), or (13'). In a subgroup, a compound according to any of the above specific examples is provided, wherein A together with R4 and R5 is a group (1'), (4'), (7'), (8'), (10'), or (11').

[0030] According to a specific example, a compound according to any of the above specific examples is provided, wherein ring A, together with R4 and R5, is represented by the following groups: , , , , , , , , , , , , , , , , , , , , or , The wavy line indicates the site connected to the L group.

[0031] According to a specific example, a compound according to any of the above specific examples is provided, wherein A, together with R4 and R5, is a group (1''), (2''), (3''), (4''), (7''), (11''), (12''), (13''), (15''), (17''), (19''), or (21''). In a subgroup, a compound according to any of the above specific examples is provided, wherein A, together with R4 and R5, is a group (1''), (2''), (4''), (7''), (11''), (12''), (15''), or (21'').

[0032] According to a specific example, a compound according to any of the above specific examples is provided, wherein A is phenyl or pyridyl, L is -O-, R1 is C1-7 alkoxy, R2, R3, R5, R33 and R42 are hydrogen, Z is cyclo(1a) or (12) and R4 is halogenated C1-7 alkyl.

[0033] According to a specific example, a compound according to any of the above specific examples is provided, wherein Z may also be -CH(NHR 25)-(CH 2) 2-COOH.

[0034] In a specific instance, a compound according to formula (Ib) or a pharmaceutically acceptable salt thereof is provided. in D is either CH or N; R2 is H or a halogen; R4 is H, halogen, or cyano; R5 is a halogen or a halogenated C1-7 alkyl group; B is ring (1a), (10), or (12); R1 is -OCH3 or a halogen, or R1 and R3 together with the benzene ring they are attached to form a fused ring represented by any of the following groups: , , or .

[0035] In a specific instance, a compound according to formula (Ic) or a pharmaceutically acceptable salt thereof is provided. in L represents -O- or -CH=CH-; R2 is H or a halogen; R4 is H, C1-7 alkyl, or halogen; R5 is a halogen, a C1-7 alkyl group, or a halogenated C1-7 alkyl group; B is ring (1a), (10), or (12); R1 is -OCH3 or a halogen, or R1 and R3 together with the benzene ring they are attached to form a fused ring represented by any of the following groups: , , or .

[0036] According to yet another specific example, the present invention provides a method for treating diseases or conditions requiring suppression of TEAD (such as cancer and chronic pain), comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) as defined in any of the above specific examples.

[0037] The compounds of the present invention can be prepared using suitable starting materials via various synthetic routes similar to those known in the literature. Compounds of formula (I) can be prepared, for example, in a manner similar to or according to the following reaction procedures. Some compounds included in formula (I) can be obtained by transforming the functional groups of other compounds of formula (I) obtained according to the following procedures using well-known reaction steps (such as oxidation, reduction, hydrolysis, acetylation, alkylation, acetylation, amination, sulfonation, and others). It should be noted that any suitable leaving group, such as an N-protecting group, such as a tert-butoxycarbonyl (t-BOC) or benzenesulfonyl, can be used in a well-known manner during synthesis to improve the selectivity of the reaction steps.

[0038] Compound of formula (I) can be prepared, for example, according to process 1, wherein A, L, Z, R1, R2, R3, R4, R5, R33 and R42 are as defined above. In the method of process 1, the aniline compound of formula [1] and the carboxylic acid derivative of formula [2] are coupled in a suitable solvent, such as anhydrous acetonitrile or DMF, in the presence of a suitable coupling agent, such as a combination of N,N,N',N'-tetramethylchloromethanemidium hexafluorophosphate and 1-methyl-1H-imidazolium, or a combination of hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU) and N,N-diisopropylethylamine (DIPEA), to produce compound of formula (I).

[0039] Alternatively, a compound of formula (I) in which R 42 is H can be prepared according to process 2, wherein A, L, Z, R 1, R 2, R 3, R 4, R 5 and R 33 are as defined above, and X is a halogen, such as bromine. In the method of process 2, the compound of formula [3] is coupled with the methylamine compound of formula [4] in a suitable solvent, such as toluene, in the presence of a base, such as cesium carbonate, and a suitable catalyst system, such as a combination of Pd 2 (dba) and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanan (XantPhos) or a combination of copper iodide and N1,N2-dimethylcyclohexane-1,2-diamine, to produce the compound of formula (I).

[0040] Alternatively, a compound of formula (I) in which L is -O- can be prepared, for example, according to process 3, wherein A, Z, R1, R2, R3, R4 and R5 are as defined above. In the method of process 3, the compound of formula [3] and the compound of formula [4] are condensed in a suitable solvent, such as tetrahydrofuran, in the presence of a mitsunobu reagent, such as triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD), to produce the compound of formula (I).

[0041] The intermediate compound can be prepared according to the methods disclosed in the literature or as disclosed in this invention.

[0042] For example, an intermediate compound of formula [1a] in which L is -O- can be prepared according to process 4, wherein A, R1, R2, R3, R4, R5 and R33 are as defined above. In the method of process 4, the compound of formula [7] and the compound of formula [8] are coupled in a suitable solvent, such as dichloromethane, in the presence of a base, such as pyridine and a catalyst, such as diacetoxycopper, to produce the compound of formula [8], which can then be reduced, for example by hydrogenation in the presence of a suitable catalyst, such as palladium-carbon, to obtain the intermediate of formula [1a].

[0043] An intermediate compound of formula [3a], wherein L is -O-, can be prepared, for example, according to process 5, wherein A, R1, R2, R3, R4, R5 and R33 are as defined above, and X is a halogen, such as bromine. In the method of process 5, the compound of formula [9] and the compound of formula

[10] are coupled in a suitable solvent, such as dichloromethane, in the presence of a base, such as pyridine and a catalyst, such as diacetoxycopper, to produce the compound of formula [3a].

[0044] For example, the intermediate compound of formula [5] can be prepared according to process 6, wherein Z, R1, R2 and R3 are as defined above. In the method of process 6, the compound of formula

[11] and the compound of formula

[12] are coupled in a suitable solvent, such as DMF, in the presence of a base, such as N,N-diisopropylethylamine (DIPEA) and a coupling agent, such as azirbenzotriazole tetramethyluranium hexafluorophosphate (HATU), to produce the intermediate of formula [5].

[0045] Alternatively, compounds of formula (I) may be prepared as disclosed in specific embodiments of the present invention.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter belongs. As used herein, the following definitions are provided to facilitate understanding of the invention.

[0047] As used in this article, the term "subject" refers to both humans and animals.

[0048] As used herein, either suffix or as part of another group, the term "halo" or "halogen" refers to chlorine, bromine, fluorine, or iodine. Chlorine and fluorine are preferred halogens.

[0049] As used herein, either suffix or as part of another group, the term "C1-7 alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. Representative examples of C1-7 alkyl include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, and n-hexyl. A preferred specific example of "C1-7 alkyl" is C1-3 alkyl. The term "C1-3 alkyl" refers to a specific example of a "C1-7 alkyl" having 1, 2, or 3 carbon atoms. Examples of "C1-3 alkyl" include (but are not limited to) methyl, ethyl, n-propyl, and isopropyl. A preferred "C1-7 alkyl" is methyl.

[0050] As used herein, either suffix or as part of another group, the term "C 2-7 alkenyl" refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or more double bonds. Representative examples include (but are not limited to) vinyl, propenyl, and hexenyl. A preferred specific example of "C 2-7 alkenyl" is C 2-4 alkenyl. The term "C 2-4 alkenyl" refers to a specific example of a "C 2-7 alkenyl" having 2, 3, or 4 carbon atoms. Representative examples include (but are not limited to) vinyl, propenyl, and butenyl. A preferred "C 2-7 alkenyl" is a -CH=CH- group.

[0051] As used herein, either suffix or as part of another group, the term "C 3-7 cycloalkyl" refers to a saturated cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms. Representative examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A preferred "C 3-7 cycloalkyl" is cyclopropyl.

[0052] The term "hydroxyl" as used herein, either succinctly or as part of another group, refers to the -OH group.

[0053] The term "cyano" as used herein, either succinctly or as part of another group, refers to the -CN group.

[0054] The term "carboxy" as used herein, either succinctly or as part of another group, refers to the -COOH group.

[0055] As used herein, either succinctly or as part of another group, the term "carbonyl" refers to a carbon atom bonded to an oxygen atom by a double bond (C=O).

[0056] As used herein, or as part of another group, the term "side oxygen (oxo)" refers to an oxygen atom (=O) bonded to another atom by a double bond.

[0057] As used herein, either suffix or as part of another group, the term "C1-7 alkoxy" refers to a C1-7 alkyl group attached to a parent molecule via an oxygen atom, as defined herein. Representative examples of C1-7 alkoxy groups include (but are not limited to) methoxy, ethoxy, propoxy, butoxy, isobutoxy, secondary butoxy, and tertiary butoxy groups. A preferred specific example of "C1-7 alkoxy" is a C1-3 alkoxy group. The term "C1-3 alkoxy" refers to a specific example of a "C1-7 alkoxy" group having 1, 2, or 3 carbon atoms. Representative examples of C1-3 alkoxy groups include (but are not limited to) methoxy, ethoxy, and propoxy groups. A preferred "C1-7 alkoxy" group is a methoxy group.

[0058] As used herein, the term "hydroxy C1-7 alkyl" means at least one hydroxyl group as defined herein attached to the parent molecule via a C1-7 alkyl group as defined herein. Representative examples of hydroxy C1-7 alkyl groups include (but are not limited to) hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 1-methyl-1-hydroxyethyl, and 1-methyl-1-hydroxypropyl.

[0059] As used herein, the term "halogen C1-7 alkyl" means at least one halogen as defined herein attached to a parent molecule via a C1-7 alkyl group as defined herein. Representative examples of halogen C1-7 alkyl groups include (but are not limited to) fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl. Preferred "halogen C1-7 alkyl" groups are trifluoromethyl and difluoromethyl.

[0060] As used herein, the term "halogen C1-7alkoxy" means at least one halogen as defined herein attached to a parent molecule via a C1-7 alkoxy group as defined herein.

[0061] The term "C1-7alkoxy-C1-7alkyl" as used herein, either succinctly or as part of another group, refers to at least one C1-7 alkoxy group as defined herein attached to the parent molecule via a C1-7 alkyl group as defined herein.

[0062] As used herein, the term "4-10 membered carbocyclic ring" refers to a saturated, partially saturated, or aromatic ring having 4 to 10 ring atoms consisting only of carbon atoms. A specific example of "4-10 membered carbocyclic ring" is "5-6 membered carbocyclic ring," which refers to a saturated, partially saturated, or aromatic ring having 5 to 6 ring atoms consisting only of carbon atoms. Representative examples of 4-10 membered carbocyclic rings include (but are not limited to) phenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclopentyl rings, cyclopentenyl rings, and cyclobutyl rings.

[0063] As used herein, the term "substituted" in conjunction with various residues refers (unless otherwise defined) to a halogen substituent (such as fluorine, chlorine, bromine, iodine) or a C1-7 alkyl, C3-7 cycloalkyl, hydroxyl, amino, nitro, cyano, thiol-C1-7 alkyl, methanesulfonyl, C1-7 alkoxy, halo-C1-7 alkyl, hydroxyl-C1-7 alkyl, or amino-C1-7 alkyl substituent. Halogen, C1-7 alkyl, hydroxyl, amino, halo-C1-7 alkyl, C1-7 alkoxy, and methanesulfonyl substituents are preferred. A preferred set of substituents is one to two substituents selected from C1-7 alkyl or halogen substituents, particularly C1-3 alkyl or halogen substituents, especially methyl, ethyl, chlorine, fluorine, or bromine substituents.

[0064] Unless otherwise defined, a "substituted" group may contain 1 to 3, preferably 1 or 2, of the substituents mentioned above.

[0065] Optically active mirror-image or non-mirror-image isomers of compounds of formula (I) can be prepared, for example, by resolving the racemic final product using known methods or by using suitable optically active starting materials. Similarly, racemic compounds of formula (I) can be prepared by using racemic starting materials. The resolution of racemic compounds of formula (I) or their racemic starting materials can be carried out, for example, by reacting the racemic compound with an optically active acid to convert it into a mixture of its non-mirror-image isomer salts and subsequently separating the non-mirror-image isomers by crystallization. Representative examples of such optically active acids include (but are not limited to) D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative anti-mimetic chromatography can be used to resolve racemic mixtures.

[0066] Pharmaceutically acceptable salts are well-known in the pharmaceutical field. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts of organic bases, salts of inorganic acids, salts of organic acids, and salts of basic or acidic amino acids. Non-limiting examples of metal salts include alkali metal salts, such as sodium and potassium salts; and alkaline earth metal salts, such as calcium and magnesium salts. Non-limiting examples of salts of inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleic acid salts, citrates, benzoates, salicylates, ascorbic acid salts, acetates, oxalates, trans-butenediacetes, hemi-trans-butenediacetes, and succinates. Pharmaceutically acceptable esters, where applicable, can be prepared by known methods using pharmaceutically acceptable acids that are known in the pharmaceutical field and retain the pharmacological properties of their free form. Non-limiting examples of such esters include esters of aliphatic or aromatic alcohols, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, secondary butyl ester, and tertiary butyl ester. Phosphate esters and carbonates are also within the scope of this invention.

[0067] The definition of formula (I) above includes all possible isotopes and isomers of the compound (such as stereoisomers), including geometric isomers (e.g., Z and E isomers (cis and trans isomers)) and optical isomers (e.g., non-mirror image isomers and mirror image isomers) and prodrug esters (e.g., phosphate esters and carbonates).

[0068] Those skilled in the art will understand that the compounds of the present invention may contain at least one antichimeric center. Accordingly, the compounds may exist in optically active or racemic forms. It should be understood that formula (I) includes any racemic or optically active form or a mixture thereof. In one specific example, the compound is a pure (R)-isomer. In another specific example, the compound is a pure (S)-isomer. In yet another specific example, the compound is a mixture of (R) and (S) isomers. In yet another specific example, the compound is a racemic mixture containing equal amounts of (R) and (S) isomers. The compound may contain two antichimeric centers. In such cases, according to one specific example, the compound is a mixture of non-mirror image isomers. According to another specific example, the compounds of the present invention are a mixture of mirror image isomers. According to yet another specific example, the compound is a pure mirror image isomer. Individual isomers may be obtained using starting materials of the corresponding isomeric forms, or may be separated after the preparation of the final compound using conventional separation methods. To separate optical isomers (e.g., mirror-image or non-mirror-image isomers) from their mixtures, conventional resolution methods, such as fractional crystallization, can be used.

[0069] The compounds of the present invention may also exist as tautomers, or as equilibrium mixtures thereof, in which a proton is transferred from one atom to another. Examples of tautomers include (but are not limited to) amide-amide-imino, keto-enol, phenol-ketone, oxime-nitroso, nitro-acid-nitro, imine-enamine, cyclic tautomers of heterocycles such as pyrazole rings, and the like. Even if only one tautomer form can be described, it is intended that the compounds of formula (I) encompass a variety of tautomer forms.

[0070] Examples of preferred compounds of formula (I) include N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 1); 1-Ethyl-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 2); 1-Ethyl-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 3); N-(5-((3-fluorophenoxy)methyl)-2,4-dimethoxyphenyl)-5-sideoxypyrrolidone-2-methylamine (compound 4); 1-(2-Fluoroethyl)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)azacyclobutane-3-methylamine (compound 5); Racemic-(trans)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-5-sideoxypyrrolidone-2-methamide (compound 6); 4-Side-oxy-N-(3-(3-(trifluoromethyl)phenoxy)phenyl)azacyclobutane-2-methylamine (compound 7); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-4-sideoxyaziridine-2-methamide (compound 8); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-(5-sideoxypyrrolidin-2-yl)acetamide (compound 9); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 10); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 11); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)tetrahydrothiophene-3-methamide 1,1-dioxide (compound 12); N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-2-methylisothiazolidin-3-methoxyamine 1,1-dioxide (compound 13); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-methyl-5-sideoxypyrrolidone-2-methamide (compound 14); N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-2-methyl-5-sideoxypyrrolidone-2-methamide (compound 15); 5-Side-oxy-N-(3-(3-(trifluoromethyl)phenoxy)phenyl)pyrrolidone-2-methylamine (compound 16); N-(5-((3-fluorophenoxy)methyl)benzofuran-7-yl)-5-sideoxypyrrolidone-2-methylamine (compound 17); N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-sideoxytetrahydropyrrolo[2,1-b]thiazol-7a(5H)-methoxyphenylamine (compound 18); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxytetrahydropyrrolo[2,1-b]thiazol-7a(5H)-methamide (compound 19); Racemic-(cis)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-5-sideoxypyrrolidone-2-methamide (compound 20); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 21); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 22); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 1 (compound 23); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methoxyamine, mirror isomer 1 (compound 24); (R)-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 25); N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-sideoxypyrrolidone-3-methamide (compound 26); N-(6-((3-fluorophenoxy)methyl)benzo[d][1,3]m-dioxacyclopenten-4-yl)-5-sideoxypyrrolidone-2-methylamine (compound 27); 1-Methyl-5-sideoxy-N-(5-(3-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidone-2-methylamine (compound 28); 1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 29); 1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 2 (compound 30); N-(5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-5-sideoxypyrrolidone-2-methylamine (compound 31); N-(5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 32); 5-Side-oxy-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)pyrrolidone-2-methylamine (compound 33); 1-Methyl-5-sideoxy-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)pyrrolidone-2-methylamine (compound 34); N-(3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 35); N-(3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 36); 1-Ethyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 37); 1-(cyclopropanecarbonyl)-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 38); 1-Acetyl-N-(4-fluoro-2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 39); 1-Acetyl-N-(2-fluoro-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 40); N-(2-fluoro-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 41); N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 42); N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 43); 1-Acetyl-N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 44); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 45); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 46); 1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 47); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 48); N-(2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 49); 1-Acetyl-N-(2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 50); 1-Acetyl-N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 51); N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 52); N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 53); N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)isothiazolidin-3-methamide 1,1-dioxide (compound 54); 5-Side-oxy-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine (compound 55); 1-Acetyl-5-sideoxy-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine (compound 56); N-(7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-5-sideoxypyrrolidone-2-methylamine (compound 57); N-(7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 58); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 59); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 60); N-(8-methyl-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-5-sideoxypyrrolidone-2-methylamine (compound 61); N-(2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 62); N-(2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 63); (E)-N-(2-methoxy-5-(2-(tetrahydro-2H-piperan-4-yl)vinyl)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 64); (E)-N-(2-methoxy-5-(2-(tetrahydro-2H-piperan-4-yl)vinyl)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 65); 5-Side-oxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine (compound 66); 1-Methyl-5-sideoxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine (compound 67); 1-Ethyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 68); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 69); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 70); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-methyl-1,2-thiazazepine-3-methamide 1,1-dioxide (compound 71); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-methyl-1,2-thiazazepine-3-methamide 1,1-dioxide (compound 72); N-(4-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 73); N-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 74); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 75); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methylamine (compound 76); 1-Acetyl-N-(5-(3,5-difluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (Compound 77); N-(5-(3,5-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 78); N-(5-(2,5-difluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 79); 3-Side-oxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)tetrahydro-1H-pyroxy-7a(5H)-methamide (compound 80); 1-Isopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 81); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-isopropyl-5-sideoxypyrrolidone-2-methamide (compound 82); N-(2-(1,3,4- (diazol-2-yl)-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 83); N-(2-(1,3,4- (Diazol-2-yl)-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 84); N-(5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazol-3-yl)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 85); N-(5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 86); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methamide (compound 87); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxy Azolidine-4-methamide (compound 88); N-(5-((3,4-difluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-sideoxy Azolidine-4-methamide (compound 89); N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 90); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-thionylpyrrolidone-2-methamide (compound 91); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-thionylpyrrolidone-2-methamide (compound 92); (R)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 93); (S)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 94); N-(5-((3,4-difluorophenoxy)methyl)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methoxyamine (compound 95); N-(5-(bicyclo[2.2.1]hept-2-yloxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 96); (R)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (Compound 97); (S)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (Compound 98); (R)-1-Methyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methylamine (Compound 99); (S)-N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (Compound 100); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methamide (compound 101); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 102); (R)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 103); N-(5-((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 104); (S)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 105); 1-Methyl-5-sideoxy-N-(3-sideoxy-7-(3-(trifluoromethyl)phenoxy)-3,4-dihydro-2H-benzo[b][1,4] -5-yl)pyrrolidone-2-methylamine (compound 106); (S)-1-Methyl-5-sideoxy-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 107); (R)-1-methyl-5-sideoxy-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 108); 1-Cyclopropyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 109); 1-Cyclopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 110); 1-Cyclopropyl-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 111); N-(2-methoxy-5-((5-(trifluoromethoxy)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 112); N-(7-(((4,4-difluorocyclohexyl)oxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 113); 1-Cyclopropyl-5-sideoxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine (compound 114); N-(2-methoxy-5-((5-(trifluoromethoxy)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 115); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)tetrahydrothiophene-3-methamide 1,1-dioxide (compound 116); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 117); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 118); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-sideoxypiperidine-3-methamide (compound 119); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-sideoxypiperidine-3-methamide (compound 120); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-6-sideoxypiperidine-3-methamide (compound 121); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-sideoxy-1,6-dihydropyridine-3-methamide (compound 122); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3,4-dimethyl-2-sideoxyimidazolidine-4-methamide (compound 123); (R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 124); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxymethylamine (compound 125); (R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxymethylamine (compound 126); 3-Ethyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-sideoxyimidazolidine-4-methamide (compound 127); (R)-1-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 128); (S)-1-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 129); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 130); 3-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-sideoxyimidazolidine-4-methamide (compound 131); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 1 (compound 132); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 2 (compound 133); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-sideoxypyrrolidone-2-methamide (compound 134); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-sideoxypyrrolidone-2-methamide (compound 135); 1-(2-amino-2-sideoxyethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 136); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-1H-pyrazol-4-yl)-5-sideoxypyrrolidone-2-methamide (compound 137); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(tetrahydrofuran-3-yl)pyrrolidone-2-methamide (compound 138); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-methamide (compound 139); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 140); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 141); 3-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-sideoxyimidazolidine-4-methamide (compound 142); (2S)-4-methoxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 143); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-sideoxyimidazolidine-4-methamide (compound 144); N-(2-methoxy-4-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-(methylamino)-2-sideoxyethyl)-5-sideoxypyrrolidone-2-methamide (compound 145); 1-(2-(dimethylamino)-2-sideoxyethyl)-N-(2-methoxy-4-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 146); 1-(cyclopropylmethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 1 (compound 147); 1-(cyclopropylmethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 2 (compound 148); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 149); (S)-1-Methyl-5-sideoxy-N-(5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methylamine (Compound 150); (R)-1-methyl-5-sideoxy-N-(5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methylamine (compound 151); N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 152); N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 153); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)-oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxymethylamine (compound 154); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 155); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 156); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 157); N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 158); 3-Methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (compound 159); 2-Side-oxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidin-4-methamide (compound 160); 6-Side-oxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidin-3-methamide (compound 161); (R)-1-methyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 162); (S)-1-Methyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 163); 3-Cyclopropyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (compound 164); (S)-1-Cyclopropyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 165); (R)-1-Cyclopropyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methylamine (Compound 166); 3-Ethyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (compound 167); (S)-3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (compound 168); (R)-3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (compound 169); (R)-1-Ethyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 170); (S)-1-Ethyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 171); (2R)-1-Methyl-N-(2-methyl-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 1 (compound 172); (2R)-1-methyl-N-(2-methyl-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 2 (compound 173); (S)-1-methyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)octan-8-yl)pyrrolidone-2-methylamine (compound 174); (R)-1-Methyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)octan-8-yl)pyrrolidone-2-methylamine (Compound 175); 3-Methyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)octan-8-yl)imidazolidine-4-methamide (compound 176); 1-Methyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)octan-8-yl)pyrrolidone-2-methylamine (compound 177); 3-Methyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-methylamine (compound 178); 1-Cyclopropyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)pyrrolidone-2-methylamine (compound 179); (S)-3-methyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-methylamine (compound 180); (R)-3-methyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-methylamine (compound 181); 3-Methyl-2-sideoxy-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)imidazolidine-4-methamide (compound 182); 3-Methyl-2-sideoxy-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)imidazolidine-4-methamide, mirror isomer 1 (compound 183); 3-Methyl-2-sideoxy-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)imidazolidine-4-methamide, mirror isomer 2 (compound 184); 1-Methyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidone-2-methylamine (compound 185); 3-Methyl-2-sideoxy-N-(6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-methylamine (compound 186); 2-Side-oxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperidine-4-methamide (compound 187); 1-(2-(methylamino)-2-sideoxyethyl)-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 188); 1-(2-amino-2-sideoxyethyl)-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methylamine (compound 189); N-(5-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)-6-sideoxypiperidine-3-methamide (compound 190); N-(7-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-6-sideoxypiperidine-3-methamide (compound 191); 3-Methyl-2-sideoxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)imidazolidine-4-methamide (compound 192); 3-Methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazol-7-yl)imidazolidine-4-methamide (compound 193); 1-Methyl-N-(1-Methyl-5-((5-(trifluoromethyl)pyridin-4-yl)oxy)-1H-indazol-7-yl)-5-sideoxypyrrolidone-2-methamide (compound 194); (S)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 195); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 196); N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 197); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 198); (S)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 199); N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 200); N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 201); N-(5-((5-fluoropyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 202); N-(5-((5-chloropyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 203); N-(5-(2-fluoro-4-nitrophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 204); N-(5-(((4,4-difluorocyclohexyl)oxy)methyl)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 205); N-(5-((4,4-difluorocyclohexyl)methoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 206); (2S)-N-(5-((4,4-difluorocycloheptyl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 207); (R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-3-methyl-2-sideoxy Azolidine-4-methoxyamine (compound 208); (R)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 209); (S)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 210); N-(5-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 211); N-(5-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 212); N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 213); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 214); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 215); (S)-3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-methamide (compound 216); (R)-3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-methamide (compound 217); (S)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-sideoxyimidazolidine-4-methamide (compound 218); (R)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-sideoxyimidazolidine-4-methamide (compound 219); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 220); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 221); N-(5-(3,4-dichlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 222); N-(5-(3-chloro-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 223); N-(5-(3,4-difluorophenoxy)-2-(1,3,4-) (Diazol-2-yl)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 224); 1-Methyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-1H-indazol-7-yl)pyrrolidone-2-methamide (compound 225); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-methamide (compound 226); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-methamide (compound 227); 4-Hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-3-methamide (compound 228); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(5-sideoxypyrrolidone-2-carbonyl)pyrrolidone-2-methylamine (compound 229); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-5-sideoxypyrrolidone-2-carbonyl)-5-sideoxypyrrolidone-2-methamide (compound 230); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(4-sideoxyazacyclobutane-2-carbonyl)pyrrolidine-2-methylamine (compound 231); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-sideoxy-1-(4-sideoxyazinobutane-2-carbonyl)pyrrolidine-2-methamide (compound 232); 1-Methyl-5-sideoxy-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine (compound 233); 1-Methyl-5-sideoxy-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine, mirror isomer 1 (compound 234); 1-Methyl-5-sideoxy-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-methylamine, mirror isomer 2 (compound 235); 1-Methyl-N-(8-methyl-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-5-sideoxypyrrolidone-2-methylamine (compound 236); 1-Methyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 237); 1-Methyl-5-sideoxy-N-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (compound 238); N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 239); N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 240); N-(7-(4-fluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 241); N-(5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 242); N-(6-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 243); 1-Methyl-N-(1-Methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 1 (compound 244); 1-Methyl-N-(1-Methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-5-sideoxypyrrolidone-2-methamide, mirror isomer 2 (compound 245); N-(5-(((3-fluorophenyl)amino)methyl)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methoxyamine (compound 246); N-(5-((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 247); N-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 248); N-(5-((3-fluorophenoxy)methyl)benzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 249); N-(2-fluoro-3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 250); N-(5-(3,4-difluorophenoxy)-2-fluoro-3-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 251); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxytetrahydropyrrolo[2,1-b]thiazolyl-7a(5H)-methamide 1,1-dioxide (compound 252); N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 253); (E)-N-(5-(3-fluorostyryl)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 254); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 255); N-(2-methoxy-5-(3-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 256); N-(2-methoxy-5-(4-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 257); N-(2-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 258); N-(4-methoxy-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 259); N-(5-(4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 260); N-(3-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 261); N-(5-((6-fluoro-5-methylpyridin-3-yl)oxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 262); (R)-N-(5-((6-fluoro-5-methylpyridin-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 263); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 264); (R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 265); N-(2-methoxy-5-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 266); N-(2-methoxy-5-(((1S,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 267); (R)-N-(2-methoxy-5-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 268); (R)-N-(2-methoxy-5-(((1S,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 269); N-(2-fluoro-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 270); (R)-N-(4-methoxy-3-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 271); (R)-N-(4-methoxy-3-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 272); N-(3-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 273); N-(3-(4-chloro-3-(trifluoromethyl)phenoxy)-5-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 274); (R)-N-(3-((4,4-difluorocyclohexyl)oxy)-5-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 275); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 276); N-(3-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 277); (R)-N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 278); N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 279); 1-Methyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoline-8-yl)pyrrolidone-2-methamide (compound 280); (R)-1-methyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-8-yl)pyrrolidone-2-methylamine (compound 281); (R)-N-(3-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 282); (R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 283); N-(3-(3,4-difluorophenoxy)-5-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 284); (R)-N-(3-(3,4-difluorophenoxy)-5-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 285); N-(5-(cyclohexyloxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 286); N-(5-(cyclohexyl-2-en-1-yloxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 287); (S)-N-(5-((5-chloropyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 288); 1-Ethyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)azacyclobutane-3-methamide (compound 289); (R)-N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 290); N-(2-methoxy-5-(3-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 291); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 292); (R)-N-(5-(4-fluoro-3-methoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 293); N-(5-(cyclohexylmethoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 294); N-(5-(3-fluoro-4-methoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 295); N-(5-((4,4-dimethylcyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 296); N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methoxyamine (compound 297); N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methoxyamine (compound 298); N-(5-(3-bromophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 299); N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 300); N-(5-(4-isopropoxyphenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 301); N-(5-((3,3-difluorocyclobutyl)methoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 302); N-(3-(4-fluorophenoxy)-5-(trifluoromethyl)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 303); N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 304); N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 305); N-(3-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 306); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 307); (R)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 308); N-(5-(3-chloro-4-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 309); (S)-N-(5-(3-chloro-4-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 310); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(methanesulfonyl)pyrrolidone-2-methamide (compound 311); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 312); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 313); N-(2-methoxy-5-((1-methyl-1H-indol-5-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 314); N-(5-((2,3-dihydrobenzofuran-5-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 315); N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 316); N-(5-(4-cyano-3-methylphenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 317); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyethyl)-5-sideoxypyrrolidone-2-methamide (compound 318); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 319); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-sideoxypiperidine-2-methamide (compound 320); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-6-sideoxypiperidine-2-methamide (compound 321); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-sideoxypiperidine-4-methamide (compound 322); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-sideoxypiperidine-4-methamide (compound 323); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-sideoxypiperidine-4-methamide, mirror isomer 1 (compound 324); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-sideoxypiperidine-4-methamide, mirror isomer 2 (compound 325); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(methanesulfonyl)pyrrolidine-3-methamide (compound 326); N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-sideoxypiperidine-4-methamide, mirror isomer 1 (compound 327); N-(2-fluoro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 328); N-(2-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 329); N-(2-aminomethoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 330); N-(2-methoxy-5-((4-(trifluoromethyl)-pyridin-2-yl)oxy)phenyl)-1-(2-methoxyacetyl)-5-sideoxypyrrolidone-2-methamide (compound 331); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-sideoxyimidazolidine-4-methamide (compound 332); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)-5-sideoxypyrrolidone-2-methamide (compound 333); N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-(2-methoxyacetyl)-5-sideoxypyrrolidone-2-methamide (compound 334); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-3-methamide (compound 335); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-methamide (compound 336); (S)-1-(2-amino-2-sideoxyethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidone-2-methamide (compound 337); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 338); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 339); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 340); 2-(1,3-Dimethyl-2,5-di-sideoxyimidazolidine-4-yl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)acetamide (compound 341); (S)-3-acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-sideoxyimidazolidine-4-methamide (compound 342); (S)-3-acetyl-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-2-sideoxyimidazolidine-4-methamide (compound 343); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidone-3-methamide (compound 344); (S)-N-(5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 345); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-methamide (compound 346); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-methamide (compound 347); (S)-N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 348); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-3-methamide (compound 349); N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-methamide (compound 350); (S)-N-(3-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 351); N-(3-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 352); (S)-N-(5-(4-(fluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 353); 2-(2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)aminomethoxy)-5-sideoxypyrrolidin-1-yl)methyl acetate (compound 354); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-3-methamide (compound 355); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 356); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-3-methamide (compound 357); (S)-1-acetyl-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)pyrrolidone-2-methamide (compound 358); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-methamide (compound 359); (S)-1,3-Dimethyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-methylamine (Compound 360); (S)-N-(2,4-difluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 361); (S)-N-(3-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 362); (S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 363); (S)-1,3-Dimethyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (compound 364); (S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 365); N-(2-bromo-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 366); N-(2-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 367); N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 368); N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 369); (2S, 4R)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidone-2-methamide (compound 370); (S)-1-acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 371); N-(2-hydroxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 372); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-sideoxypiperyl -2-Methylamine (compound 373); 4-Amino-5-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)amino)-5-tefoxyvalerate (compound 374); 1-Methyl-6-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazine -2-Methylamine (compound 375); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(1H-pyrazol-4-yl)pyrrolidine-2-methamide (compound 376); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(1H-pyrazol-4-yl)pyrrolidine-2-methamide (compound 377); 1-(3-amino-3-sideoxypropyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methamide (compound 378); (2S,4S)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 379); 1-Imine-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)hexahydro-1λ6-thiopiperan-4-methamide 1-oxide (compound 380); N-(4-fluoro-2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 381); 1,4-Dimethyl-6-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazine -2-Methylamine (compound 382); N-(5-(4-amino-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 383); N-(5-(4-chloro-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 384); N-(5-(3-ethoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methoxyamine (compound 385); N-(5-(3-ethoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methoxyamine (compound 386); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-sideoxy-2,3-dihydro Azoxyl-4-methoxylamine (compound 387); N-(3-(3,4-difluorophenoxy)-6-methoxy-2-methylphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 388); N-(5-(3-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 389); N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 390); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1H-tetrazole-5-methamide (compound 391); (R)-N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 392); (S)-N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 393); N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 394); N-(5-(4-cyano-3-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 395); N-(5-(3-cyano-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 396); (S)-N-(5-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 397); (N-(5-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 398); N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 399); (S)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 400); (R)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 401); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 402); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-2-sideoxyimidazolidine-4-methamide (compound 403); (R,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 404); (S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 405); (S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 406); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-methoxyamine (compound 407); ((S,E)-N-(6-(2-(4,4-difluorocyclohexyl)vinyl)benzo[d][1,3]m-dioxacyclopenten-4-yl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 408); N-(2-hydroxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 409); N-(5-(2-hydroxy-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 410); 1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidone-3-methamide (compound 411); 1-Ethyl-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)pyrrolidone-3-methamide (compound 412); 1-Glycinyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methoxyamine, HCl (compound 413); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidone-2-methamide (compound 414); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)pyrrolidone-2-methamide (compound 415); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-N,1-dimethyl-5-sideoxypyrrolidone-2-methamide (compound 416); And its medically acceptable salts and tautomers.

[0071] The compounds of this invention can be administered to patients in therapeutically effective amounts, typically ranging from about 0.5 to about 2000 mg daily, more typically from about 1 to about 500 mg, for example from about 2 to about 100 mg, depending on the patient's age, sex, weight, race, condition, symptoms to be treated, route of administration, and active ingredient used. The compounds of this invention can be formulated into dosage forms using principles known in the art. The compounds can be provided to patients as is or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. Selecting suitable ingredients for the composition is routine work for those skilled in the art. Suitable carriers, solvents, gel-forming agents, dispersion-forming agents, antioxidants, pigments, sweeteners, wetting compounds, and other ingredients commonly used in the art can also be used. Compositions containing active compounds can be administered enterically or non-enterally, with oral administration being preferred. The composition contains about 0.5% to 100% of the active compound by weight of the total composition, typically about 0.5% to about 20%.

[0072] The compounds of the present invention may be provided to an individual in the form of a single active ingredient or in combination with one of a plurality of other active ingredients for the treatment of a specific disease.

[0073] In the treatment of diseases and symptoms requiring suppression of TEAD, such as various cancers or chronic pain, a combination of therapeutic agents and / or other treatments (e.g., radiation therapy) is often advantageous. The second (or third) agent to be administered may have the same or different mechanism of action as the primary therapeutic agent.

[0074] Therefore, the compounds of the present invention can be administered in combination with other anticancer therapies suitable for treating cancer. For example, the compounds of the present invention can be packaged together with a specification stating that the compound is to be combined with other anticancer agents and therapies to treat cancer. Similarly, the compounds of the present invention can be administered in combination with other pain relievers suitable for treating chronic pain. For example, the compounds of the present invention can be packaged together with a specification stating that the compound is to be combined with other anticancer agents and therapies to treat cancer, or with other pain relievers and therapies to treat chronic pain. The present invention further includes combinations of the compounds of the present invention in kit form with one or more other pharmaceutical agents, for example, wherein they are packaged together or placed in individual packages for sale as kits, or wherein they are packaged together for formulation.

[0075] According to a specific example of the present invention, a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt system is co-administered with one or more anticancer agents or pain relievers.

[0076] Other anticancer agents that may be administered as needed, besides compounds of formula (I) or their pharmaceutically acceptable salts, include (but are not limited to) those that are appropriate to the patient. - Chemotherapy agents (such as docetaxel and paclitaxel) - Tyrosine kinase inhibitors, including EGFR inhibitors (such as gefitinib and osimertinib), VEGFR inhibitors (such as bevacizumab), and FGFR inhibitors (such as erdafitinib); - Immune checkpoint inhibitors (e.g., nivolumab and pembrolizumab) - Epigenetic regulators (e.g., BET inhibitors and HDAC inhibitors) - mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alpharadin); - GnRH / LHRH analogs (such as leuprorelin); - PI3K inhibitors (such as idelalisib); and - CDK4 / 6 inhibitors (e.g., ribocyclib) - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate and seviteronel); and - Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and darolutamide).

[0077] According to yet another specific example, the present invention provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional active ingredient selected from the list of the following: - Chemotherapy agents (such as docetaxel and paclitaxel), - Tyrosine kinase inhibitors, including EGFR inhibitors (such as gefitinib and osimertinib), VEGFR inhibitors (such as bevacizumab), and FGFR inhibitors (such as erdatinib); - Immune checkpoint inhibitors (e.g., nivolumab and pelizumab) - Epigenetic regulators (e.g., BET inhibitors and HDAC inhibitors) - mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radioactive drugs (e.g., levamisole); - GnRH / LHRH analogs (such as leuprolide); - PI3K inhibitors (such as edecoxib); and - CDK4 / 6 inhibitors (e.g., ribociclib) - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate and sevetenline); and - Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and daloulamide), Used for simultaneous, separate, or sequential delivery.

[0078] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used in equal amounts, for example, as indicated in the Physicians' Desk Reference (PDR) or otherwise determined by those of ordinary knowledge in the art to which they pertain.

[0079] The compounds of this invention can be prepared using suitable starting materials via various synthetic routes similar to those known in the literature. The invention will be explained in more detail by the following experiments and examples. The experiments and examples are intended for illustrative purposes only and do not limit the scope of the invention as defined in the claims. [] [Example:]

[0080] Purification method used: A) Reversed-phase HPLC (water / acetonitrile, 2-8 min 0-65%, 30 mL / min, column: SunFire 100*19 mm). B) Reversed-phase HPLC (water / methanol, 2-8 min 0-65%, 30 mL / min, column: SunFire 100*19 mm). C) Reverse-phase HPLC (water / acetonitrile / formic acid, 2-10 min 0-40%, 30 mL / min, column: SunFire 100*19 mm). D) Reversed-phase HPLC (water / acetonitrile / ammonia, 2-8 min 0-65%, 30 mL / min, column: SunFire 100*19 mm). E) Reversed-phase HPLC (water / methanol / ammonia, 2-10 min 40-50%, 30 mL / min, column: SunFire 100*19 mm). F) Reverse-phase HPLC (water / acetonitrile / trifluoroacetic acid, 2-10 min 0-50%, 30 mL / min, column: SunFire 100*19 mm). G) Reverse-phase HPLC (water / methanol / trifluoroacetic acid, 2-10 min 10-50%, 30 mL / min, column: SunFire 100*19 mm). H) Preparative palmar HPLC (methanol / isopropanol, 50-50, 12 mL / min, column: Chiralpak AD-H (250*20 mm)). I) Preparative HPLC (methanol / IPA / hexane, 25-25-50, 0.6 mL / min, column: Chiralpak IC (250*4.6 mm)). J) Preparative HPLC (methanol / CO 2, 50-50, 2 mL / min, column: Chiralpak AD-H (250*4.6 mm)). [Intermediate substance] [1.] 5-Bromo-2-fluoro-4-methoxyphenyl formate

[0081] 3-Chloroperoxybenzoic acid (1.851 g, 2.5 eq., 10.73 mmol) was added to a solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (1.000 g, 1 eq., 4.291 mmol) in CHCl3 (20 mL) at 4 °C, followed by stirring for 30 min. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with saturated NaHCO3 solution (2 × 10 mL) and brine (10 mL), dehydrated with sodium sulfate, filtered, and concentrated to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ: 8.57 (s, 1H), 7.69 (dd, 1H), 7.29 (dd, 1H), 3.86 (d, 3H).

[0082] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described for intermediate 1. Data will not be displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-2 244 [M] + 7-Bromobenzo[d][1,3]m-dioxacyclopentene-5-carboxaldehyde Int-3 - 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxaldehyde Int-4 - 7-Bromo-2-methyl-2,3-dihydrobenzofuran-5-carboxaldehyde [Intermediate substance] [5.]5-Bromo-2-fluoro-4-methoxyphenol []

[0083] Sodium hydroxide (1.606 g, 2.5 eq., 40.15 mmol) was added to a solution of 5-bromo-2-fluoro-4-methoxyphenyl formic acid (4.000 g, 1 eq., 16.06 mmol) in methanol (100 mL). The mixture was stirred at 25 °C for 12 h. The mixture was then concentrated, diluted with 50 mL of water, acidified to pH 1, and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dehydrated and concentrated with Na₂SO₄. The crude product was purified twice by column chromatography using a hexane-MTBE and chloroform-acetonitrile system to give the title compound (1.4 g, 6.0 mmol, 37%, 95% purity). 1H NMR (500 MHz, DMSO -d6) δ: 9.66 (s, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 3.73 (s, 3H). []

[0084] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described for intermediate 4. Data will not be displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-6 - 7-Bromobenzo[d][1,3]m-dioxacyclopenten-5-yl formic acid Int-7 - 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-yl formic acid Int-8 - 7-Bromo-2-methyl-2,3-dihydrobenzofuran-5-yl ester of formic acid [Intermediate substance] [9.]5-Methoxy-7-nitrobenzofuran

[0085] 5-Methoxy-7-nitrobenzofuran-2-carboxylic acid (1 g, 1 eq., 4.22 mmol) and copper (201 mg, 0.75 eq., 3.16 mmol) were refluxed in quinoline (20 mL) for 30 min. After cooling to RT, the mixture was filtered, and the filtrate was poured into 2 N hydrochloric acid and filtered again. The precipitate obtained was concentrated three times with acetonitrile to give the title compound (710 mg, 3.5 mmol). ¹H NMR (500 MHz, DMSO-d6) δ: 8.20 (s, 1H), 7.66 (d, 1H), 7.10 (s, 1H), 3.86 (s, 3H). [] [Intermediate substance] [10a.]3-(4-methoxy-2-nitrophenyl)-1-methyl-1H-pyrazole

[0086] 1-Bromo-4-methoxy-2-nitrobenzene (0.272 g, 1.17 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole (244 mg, 1.17 mmol), and potassium phosphate (746 mg, 3.52 mmol) were mixed in an argon atmosphere. The mixture was heated to 100 °C in dioxane (4 mL) and water (0.4 mL). Then, di(1-adamantyl)-n-butylphosphine (21.0 mg, 0.05 eq., 58.6 µmol) and (2'-amino-[1,1'-biphenyl]-2-yl)((methanesulfonyl)oxy)palladium (21.7 mg, 0.05 eq., 58.6 µmol) were added, and the mixture was stirred at 100 °C for 14 h. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (5 mL), washed with brine (2 × 5 mL), dehydrated with sodium sulfate, filtered, and concentrated under vacuum to give the crude title compound (0.2 g, 0.73 mmol), which was used in the next step without further purification. LCMS: m / z 234.2 [M+H]+. [Intermediate substance] [10b.]4-(1-Methyl-1H-pyrazole-3-yl)-3-nitrophenol

[0087] 3-(4-methoxy-2-nitrophenyl)-1-methyl-1H-pyrazole (1.2 g, 1 eq., 5.145 mmol) was mixed with pyridine hydrochloride (2.973 g, 5 eq., 25.73 mmol) and stirred at 200 °C for 30 h. After cooling to RT, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dehydrated with sodium sulfate, filtered, and concentrated to give the title compound (0.90 g, 3.7 mmol). 1H NMR (400 MHz, DMSO- d 6) δ: 10.42 (s, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 7.05 (dd, 1H), 6.33 (d, 1H), 3.81 (s, 3H).

[0088] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 10b. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-11 LCMS: m / z 177.8 [MH] -. 5-Methoxy-7-nitrobenzofuran [Intermediate substance] [12a.](4-fluoro-3-methoxyphenoxy)triisopropylsilane

[0089] Trichlorotriisopropylsilane (8.546 g, 9.487 mL, 1.05 Eq, 44.33 mmol) was added to a stirred solution of 4-fluoro-3-methoxyphenol (6 g, 1 eq., 42.21 mmol) and imidazole (5.748 g, 2 eq., 84.43 mmol) in DCM (60 mL) under RT. The mixture was stirred for 16 h and then poured into a saturated aqueous solution of NH4Cl (40 mL), followed by extraction with DCM (3 × 50 mL). The combined extracts were washed with brine (30 mL), dehydrated with Na2SO4, and concentrated under vacuum to give the title compound (10.00 g, 30 mmol). 1H NMR (400 MHz, chloroform-d) δ: 6.87 (dd, 1H), 6.48 (dd, 1H), 6.34 (dt, 1H), 3.82 (s, 3H), 1.23 (dh, 3H), 1.08 (d, 21H). [Intermediate substance] [12b.](4-Fluoro-3-iodo-5-methoxyphenoxy)triisopropylsilane

[0090] (4-fluoro-3-methoxyphenoxy)triisopropylsilane (6.544 g, 1 eq., 21.93 mmol) and potassium 2-methylprop-2-oxide (2.706 g, 1.1 Eq, 24.12 mmol) were mixed in THF (60 mL) under an argon atmosphere and cooled to -78 °C. Butyllithium (1.545 g, 9.647 mL, 2.5 mol, 1.1 eq., 24.12 mmol) was added dropwise at -78 °C. The mixture was then stirred at the same temperature for 1 h. Iodine (6.678 g, 1.2 eq., 26.31 mmol) was added dropwise in THF (20 mL) at -78 °C. After stirring overnight at RT, the mixture was cooled to -20 °C and ammonium chloride aqueous solution (20 mL) was added dropwise. The solution was then heated to RT. EtOAc (70 mL) was added, and the organic layer was washed with brine (2 × 30 mL), dehydrated with sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (hexane / MTBE) to give the title compound (2.0 g, 3.3 mmol). GCMS: m / z 424 [M]+. [Intermediate substance] [12c.]4-Fluoro-3-iodo-5-methoxyphenol

[0091] (4-fluoro-3-iodo-5-methoxyphenoxy)triisopropylsilane (2.3 g, 1 Eq, 5.420 mmol) was dissolved in THF (10 mL), and tetrabutylammonium fluoride (3.543 g, 13.55 mL, 1 mol, 2.5 eq., 13.55 mmol) was added dropwise. The mixture was stirred at RT for 16 h and then concentrated under vacuum. The residue was dissolved in EtOAc (20 mL), washed with water (2 × 5 mL), dehydrated with sodium sulfate, and concentrated under vacuum. The residue was purified by rapid chromatography (hexane / MTBE) to give the title compound (0.575 g, 1.9 mmol). 1H NMR (400 MHz, chloroform-d) δ: 6.72 (t, 1H), 6.45 (dd, 1H), 4.86 (s, 1H), 3.82 (s, 3H). [Intermediate substance] [13.]1-Methoxy-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene

[0092] 4-Methoxy-3-nitrophenol (1 g, 1 Eq., 6 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2 g, 2 eq., 0.01 mol), pyridine (0.9 g, 1 mL, 2 eq., 0.01 mol), diethoxycopper (1 g, 1.05 eq., 6 mmol), and powdered molecular sieve 4 Å (1 g) were suspended in dichloromethane (10 mL). Air was bubbled through the resulting solution for 30 min, and the mixture was stirred overnight at RT. The mixture was filtered. The filtrate was washed with water (2 × 30 mL), dehydrated with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by method A to give the title compound. LCMS: m / z 314.0 [M+H]+.

[0093] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described for intermediate 13. Data will not be displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-14 264.2 [M+H] + 4-Methoxy-3-nitrophenol and (3-fluorophenyl)boronic acid Int-15 314.0 [M+H] + 4-Methoxy-3-nitrophenol and (3-(trifluoromethyl)phenyl)boronic acid Int-16 284.2 [M+H] + 3-Nitrophenol and (3-(trifluoromethyl)phenyl)boronic acid Int-17 376.2 [M+H] + 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-ol and (3-(trifluoromethyl)phenyl)boronic acid Int-18 323.1 [M] + 7-Nitrobenzofuran-5-ol and (3-(trifluoromethyl)phenyl)boronic acid Int-19 359.93 [M] + 7-Bromobenzo[d][1,3]m-dioxacyclopenten-5-ol and (3-(trifluoromethyl)phenyl)boronic acid Int-20 320.0 [M+H] + 2,4-Difluoro-5-nitrophenol and (3-(trifluoromethyl)phenyl)boronic acid Int-21 301.0 [M] + 4-Fluoro-3-nitrophenol and (3-(trifluoromethyl)phenyl)boronic acid Int-22 236.0 [M] + (4-Methoxyphenyl)boronic acid and 2,4-difluorophenol Int-23 282.0 [M+H] + 4-Methoxy-3-nitrophenol and (3,4-Difluorophenyl)boronic acid Int-24 390.2 [M+H] + 8-Bromo-5-methyl-2,3-dihydrobenzo[b][1,4]dioxane-6-ol and (3-(trifluoromethyl)phenyl)boronic acid Int-25 376.2 [M+H] + 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-ol and (4-(trifluoromethyl)phenyl)boronic acid Int-26 313.2 [M+H] + 4-Methoxy-3-nitroaniline and (4-(trifluoromethyl)phenyl)boronic acid Int-27 302.2 [M+H] + 4-Fluoro-3-nitrophenol and (4-(trifluoromethyl)phenyl)boronic acid Int-28 358.0 [M] + 7-Bromo-2,3-dihydrobenzofuran-5-ol and (4-(trifluoromethyl)phenyl)boronic acid Int-29 282.2 [M+H] + 4-Methoxy-3-nitrophenol and (3,5-Difluorophenyl)boronic acid Int-30 326.0 [M] + 7-Bromo-2,3-dihydrobenzofuran-5-ol and (3,4-difluorophenyl)boronic acid Int-31 344.2 [M+H] + 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-ol and (3,4-difluorophenyl)boronic acid Int-32 326.0 [M+H] + 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-ol and (4-fluorophenyl)boronic acid Int-33 332.0 [M+H] + 4-(1-Methyl-1H-pyrazole-3-yl)-3-nitrophenol and (3,4-difluorophenyl)boronic acid Int-34 - 4-Fluoro-3-methoxyphenol and (4-(trifluoromethyl)phenyl)boronic acid Int-35 - 4-Fluoro-3-iodo-5-methoxyphenol and (3,4-difluorophenyl)boronic acid Int-36 355.0 [M+H] + 7-Hydroxyl-5-nitro-2H-benzo[b][1,4]-3(4H)-one and (3-(trifluoromethyl)phenyl)boronic acid Int-37 296.0 [M] + 4-Methoxy-3-nitrophenol and (4-(difluoromethyl)phenyl)boronic acid Int-38 - 7-Nitrobenzofuran-5-ol and (4-(trifluoromethyl)phenyl)boronic acid Int-39 - 7-Bromobenzo[d][1,3]m-dioxanepenten-5-ol and (4-(trifluoromethyl)phenyl)boronic acid Int-40 - 7-Bromo-2,3-dihydrobenzofuran-5-ol and (4-(difluoromethyl)phenyl)boronic acid Int-41 - methyl 5-hydroxy-2-methoxybenzoate and (4-(trifluoromethyl)phenyl)boronic acid Int-42 271.2 [M+H] + 4-Methoxy-3-nitrophenol and 3-cyanophenylboronic acid Int-43 315.9 [M+H]+ 4-Methoxy-3-nitrophenol and 3,4-dichlorophenylboronic acid Int-44 297.9 [M+H]+ 4-Methoxy-3-nitrophenol and 3-chloro-4-fluorophenylboronic acid Int-45 344.3 [M+H]+ 4-Methoxy-3-nitrophenol and 3-Methoxy-4-(trifluoromethyl)phenylboronic acid Int-46 338.9 [M+H]+ 4-Methoxy-3-nitrophenol and (4-cyano-3-(trifluoromethyl)phenyl)boronic acid Int-47 288.6 [M+H]+ 4-Methoxy-3-nitrophenol and 3-cyano-4-fluorophenylboronic acid [Intermediate substance] [48.]2-Fluoro-1-iodo-3-methoxy-5-(4-(trifluoromethyl)phenoxy)benzene

[0094] 1-Fluoro-2-methoxy-4-(4-(trifluoromethyl)phenoxy)benzene (4.000 g, 1 eq., 13.97 mmol) and potassium 2-methylprop-2-oxide (1.725 g, 1.1 eq., 15.37 mmol) were mixed in THF (60 mL) and cooled to -78 °C under an argon atmosphere. Butyllithium (984.7 mg, 6.149 mL, 2.5 mol, 1.1 eq., 15.37 mmol) was added dropwise at -78 °C, and the mixture was stirred for 2 h at the same temperature. Iodine (4.256 g, 1.2 eq., 16.77 mmol) was added dropwise to a solution of THF (20 mL) at -78 °C. After stirring overnight at RT, the mixture was cooled to -20 °C, and an aqueous solution of ammonium chloride (10 mL) was added dropwise. The solution was then heated to ambient temperature. EtOAc (100 mL) was added and the organic layer was washed with brine (2 × 25 mL), dehydrated with sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (hexane / MTBE) to give the title compound (0.900 g, 2.0 mmol, 14%, 90% purity). [Intermediate substance] [49.]6-Hydroxy-8-nitro-octan-4-one

[0095] 6-Bromo-8-nitro-octamethyl-4-one (2.00 g, 1 eq., 7.35 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboron) (2.24 g, 1.2 eq., 8.82 mmol) and potassium acetate (2.16 g, 3 eq., 22.1 mmol) were mixed in 1,4-dioxo-4-one. In alkyl (20 mL). Argon gas was bubbled in the solution at 25 °C for 1 h to remove any excess oxygen. PdCl₂(dppf)CH₂Cl₂ (180 mg, 0.03 eq., 221 µmol) was added to the mixture under an argon atmosphere. The reaction mixture was heated to 80 °C and stirred for 3 h until TLC showed complete reaction. The mixture was cooled to 25 °C and then filtered. The precipitate was washed with alkane (15 mL). The filtered solutions were combined, concentrated, and then transferred to a reactor. Hydrogen peroxide (4.29 g, 4.29 mL, 35 w-%, 6 eq., 44.1 mmol) was added, and the mixture was heated to 50 °C and stirred for 40 min until TLC showed complete reaction. Water (10 mL) was added to the mixture, and the mixture was extracted with DCM (2 × 50 mL). The organic phase was collected, washed with 15% brine (2 × 15 mL), and extracted with 15% Na₂CO₃ (2 × 25 mL). The aqueous phase was collected, and the pH was adjusted to 4–5 with 3 M HCl. The aqueous phase was then extracted with ethyl acetate (2 × 50 mL). The organic phase was collected, dehydrated with Na₂SO₄, and concentrated under reduced pressure to give the title compound (810 mg, 3.6 mmol). LCMS: m / z 208.0 [M+H]⁺

[0096] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described for intermediate 49. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-50 210.2 [M+H] +. 7-Bromo-5-nitro-2H-benzo[b][1,4]-3(4H)-one [Intermediate substance] [51.](7-nitrobenzo[d][1,3]m-dioxacyclopenten-5-yl)methanol

[0097] 7-Nitrobenzo[d][1,3]m-dioxacyclopentene-5-carboxaldehyde (1000 mg, 1 Eq, 5.125 mmol) was dissolved in anhydrous methanol (40 mL). The mixture was cooled to 0 °C and sodium borohydride (232.6 mg, 1.2 eq., 6.150 mmol) was added fractionally over 10 min. The mixture was stirred at RT for 18 h and then concentrated under reduced pressure. The residue was treated with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (3 × 20 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.693 g, 3.29 mmol, 64.1%, 93.46% purity). 1H NMR (500 MHz, DMSO-d6) δ: 7.50 (s, 1H), 7.21 (s, 1H), 6.28 (s, 2H), 5.41 (s, 1H), 4.45 (s, 2H).

[0098] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described for intermediate 51. Data will not be displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-52 201.03 [M] + 3-Fluoro-4-methoxy-5-nitrobenzaldehyde Int-53 - 8-Nitro-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxaldehyde Int-54 - 7-Bromo-2,3-dihydrobenzofuran-5-carboxaldehyde Int-55 212.0 [M+H] + 6-Hydroxy-8-nitro-octan-4-one [Intermediate substance] [56.]1-(chloromethyl)-2,4-dimethoxy-5-nitrobenzene

[0099] 2,4-Dimethoxy-1-nitrobenzene (1 g, 1 Eq, 5 mmol), formaldehyde (0.3 g, 2 eq., 0.01 mol, aq. 40%), and zinc(II) chloride (0.07 g, 0.1 eq., 0.5 mmol) were dissolved in an aqueous hydrochloric acid solution (37%) (10 mL), and the mixture was stirred at 100 °C for 12 h. After cooling to RT, the reaction mixture was extracted with dichloromethane (2 × 50 mL), the organic layers were combined, washed with water (2 × 100 mL), dehydrated with sodium sulfate, filtered, and concentrated under vacuum to give the crude title compound (312 mg, 1.46 mmol, 30%, 100% purity), which was purified by method A. 1H NMR (400 MHz, DMSO- d 6) δ: 7.97 (s, 1H), 6.81 (d, 1H), 4.43 (d, 2H), 4.01 (d, 1H), 3.96 (dd, 6H).

[0100] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described for intermediate 56. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-57 218.98 [M] + 4-Fluoro-2-methoxy-1-nitrobenzene [Intermediate substance] [58.]5-(chloromethyl)-1-fluoro-2-methoxy-3-nitrobenzene

[0101] (3-fluoro-4-methoxy-5-nitrophenyl)methanol (610 mg, 1 eq., 3.03 mmol) was dissolved in dichloromethane (7 mL) and DMF (2.22 mg, 2.35 µL, 0.01 eq., 30.3 µmol) was added. The resulting solution was cooled to 0 °C, and thionyl chloride (722 mg, 443 µL, 2 eq., 6.07 mmol) was added dropwise to the mixture at the same temperature. The solution was stirred at 0 °C for 10 min, then heated to ambient temperature and stirred overnight. The solution was then poured into a 10% sodium bicarbonate aqueous solution (10 mL) and stirred for 10 min. The aqueous layer was then extracted with dichloromethane (10 mL). The combined organic layers were dehydrated with sodium sulfate, filtered, and the solvent was evaporated under vacuum to give the title compound (602 mg, 2.4 mmol, 80%, 88% purity), which was used in the next step without further purification. LCMS: m / z 219.8 [M+H] +.

[0102] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described in section 58. Data will not be displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-59 215.8 [M+H] + (7-Nitrobenzo[d][1,3]m-dioxacyclopenten-5-yl)methanol Int-60 230.2 [M+H] + (8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methanol Int-61 - (7-Bromo-2,3-dihydrobenzofuran-5-yl)methanol [Intermediate substance] [62.](3-Fluorophenyl)(4-methoxy-3-nitrophenylmethyl)aminocarbamate, tributyl ester

[0103] Sodium hydride (238.1 mg, 60%, 1.2 eq., 5.952 mmol) was added to a solution of tributyl (3-fluorophenyl)aminocarbamate (1.048 g, 1 eq., 4.960 mmol) in DMF (20 mL) at 0 °C, and the mixture was stirred at RT for 30 min. 4-(chloromethyl)-1-methoxy-2-nitrobenzene (1.000 g, 1 Eq, 4.960 mmol) was added in a single addition, and the reaction mixture was stirred at RT for 18 h. The resulting mixture was filtered, and the filtrate was diluted with water (50 mL) and ethyl acetate (50 mL). The layers were separated, the organic phase was washed with brine (4 × 30 mL), dehydrated with sodium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound, which was used in the next step without further purification.

[0104] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 62. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-63 293.2 [M+H] + 6-(chloromethyl)-4-nitrobenzo[d][1,3]m-dioxanepentene and 3-fluorophenol Int-64 328.2 [M+H] + 4-(chloromethyl)-1-methoxy-2-nitrobenzene and 3-(trifluoromethyl)phenol Int-65 328.2 [M+H] + 4-Methoxy-3-nitrophenol and 1-(bromomethyl)-3-(trifluoromethyl)benzene Int-66 307.2 [M+H] + 7-(chloromethyl)-5-nitro-2,3-dihydrobenzo[b][1,4]dioxane and 3-fluorophenol Int-67 315.0 [M+H] + 4-Methoxy-3-nitrophenol and 5-Fluoro-2-(trifluoromethyl)pyridine Int-68 378.0 [M+H] + 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-ol and 2-fluoro-5-(trifluoromethyl)pyridine [Intermediate substance] [69.]4-((3,4-difluorophenoxy)methyl)-1-methoxy-2-nitrobenzene

[0105] 3,4-Difluorophenol (2.00 g, 1 eq., 15.4 mmol) was dissolved in DMF (20 mL), and sodium hydride (676 mg, 60%, 1.1 eq., 16.9 mmol) was added at RT, while the mixture was stirred for 30 min at this temperature. 4-(chloromethyl)-1-methoxy-2-nitrobenzene (3.41 g, 1.1 eq., 16.9 mmol) was added, and the mixture was heated at 100 °C for 16 h. The solution was cooled to RT and concentrated. The residue was dissolved in ethyl acetate (60 mL), washed with brine (3 × 50 mL), dehydrated with sodium sulfate, filtered, and evaporated to give the title compound (4.5 g, 14 mmol, 94%, 95% purity). The crude product was used in the next step without further purification.

[0106] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 69. Data is not displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-70 - 7-(chloromethyl)-5-nitro-2,3-dihydrobenzo[b][1,4]dioxane and 4,4-difluorocyclohexane-1-ol Int-71 281.0 [M+H] + 4-Methoxy-3-nitrophenol and 5-chloro-2-fluoropyridine Int-72 279.0 [M+H] + 5-Hydroxy-2-methoxyphenylammonium chloride and 1,2-difluoro-4-nitrobenzene Int-73 - 4,4-Difluorocyclohexane-1-ol and 4-(chloromethyl)-1-methoxy-2-nitrobenzene Int-74 325.0 [M+H] + 7-Nitrobenzofuran-5-ol and 2-fluoro-5-(trifluoromethyl)pyridine [Intermediate substance] [75.]4-(2,5-difluorophenoxy)-1-methoxy-2-nitrobenzene

[0107] 1,2,4-Trifluorobenzene (2.4 g, 1 eq., 18 mmol), 4-methoxy-3-nitrophenol (3.1 g, 1 eq., 18 mmol), and potassium 2-methylprop-2-oxide (2.2 g, 1.1 eq., 20 mmol) were dissolved in DMF (50 mL), and the resulting mixture was stirred at 80 °C for 10 h. EtOAc (50 mL) was then added, and the organic layer was washed with brine (5 × 30 mL), dehydrated, and evaporated under reduced pressure to give the title compound, which was used in the next step without further purification. GCMS: m / z 281 [M] + [Intermediate substance] [76.](E)-2-methoxy-5-(2-(tetrahydro-2H-piperan-4-yl)vinyl)aniline

[0108] 5-Bromo-2-methoxyaniline (730 mg, 1 eq., 3.61 mmol), (E)-4,4,5,5-tetramethyl-2-(2-(tetrahydro-2H-piperan-4-yl)vinyl)-1,3,2-dioxoboron (1.29 g, 1.5 eq., 5.42 mmol), sodium carbonate (383 mg, 1 eq., 3.61 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (295 mg, 0.1 eq., 361 µmol) were suspended in degassed 1,4-dioxoaniline. The mixture was placed in alkane (12 mL) and water (2.4 mL). The mixture was heated overnight at 90 °C under argon. After cooling to RT, the solvent was evaporated under vacuum, and the residue was dissolved in ethyl acetate (30 mL), washed with brine (20 mL), dehydrated with sodium sulfate, filtered, concentrated under vacuum, and purified by method A to give the title compound (205 mg, 839 µmol, 23.2%, 95.5% purity). LCMS: m / z 234.2 [M+H]+.

[0109] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 76. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-77 268.0 [M+H] + 5-Bromo-2-methoxyaniline and (E)-2-(2-(4,4-difluorocyclohexyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron [Intermediate substance] [78.]7-Bromo-5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran

[0110] 7-Bromo-2,3-dihydrobenzofuran-5-ol (0.500 g, 1 eq., 2.33 mmol) was dissolved in N,N-dimethylformamide (5 mL) and cesium carbonate (1.52 g, 2 eq., 4.65 mmol) was added. The mixture was stirred at RT for 10 min, and 4-(chloromethyl)-1,2-difluorobenzene (378 mg, 1 eq., 2.33 mmol) was added. The mixture was stirred at RT for 12 h. The resulting solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL). The solution was washed with brine (20 mL) and water (20 mL), dehydrated with sodium sulfate, filtered, and evaporated to give the title compound. The crude product was used in the next step without further purification. 1H NMR (400 MHz, CDCl 3) δ: 7.22 - 7.02 (m, 3H), 6.85 (s, 1H), 6.75 (s, 1H), 4.90 (s, 2H), 4.61 (t, 2H), 3.26 (t, 2H).

[0111] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described in section 78. Data will not be displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-79 308.2 [M] + 1-(chloromethyl)-2,4-dimethoxy-5-nitrobenzene and 3-fluorophenol Int-80 322.0 [M] + 7-Bromo-5-(chloromethyl)-2,3-dihydrobenzofuran and 3-fluorophenol Int-81 295.04 [M] + 5-(chloromethyl)-1-fluoro-2-methoxy-3-nitrobenzene and 3-fluorophenol Int-82 371.6 [MH] - 7-Bromo-2,3-dihydrobenzofuran-5-ol and 1-(chloromethyl)-3-(trifluoromethyl)benzene Int-83 - 7-Bromo-5-(chloromethyl)-2,3-dihydrobenzofuran and 3,4-difluorophenol [intermediate] [84.]1-Fluoro-2-((3-fluorophenoxy)methyl)-5-methoxy-4-nitrobenzene

[0112] 1-(chloromethyl)-2-fluoro-4-methoxy-5-nitrobenzene (0.306 g, 1 eq., 1.39 mmol) was dissolved in acetonitrile (3 mL), and cesium carbonate (908 mg, 2 eq., 2.79 mmol) and sodium iodide (209 mg, 1 eq., 1.39 mmol) were added. The mixture was stirred for 10 min, and 3-fluorophenol (141 mg, 114 µL, 0.9 eq., 1.25 mmol) was added. The mixture was stirred at RT for 10 h. The resulting solution was filtered and concentrated to give the title compound (0.362 g, 0.61 mmol, 44%, 50% purity), which was used in the next step without further purification. LCMS: m / z 297.2 [M+H]+ [Intermediate substance] [85.] 1-Fluoro-5-methoxy-4-nitro-2-(3-(trifluoromethyl)phenoxy)benzene

[0113] 1,5-Difluoro-2-nitro-4-(3-(trifluoromethyl)phenoxy)benzene (150 mg, 1 eq., 470 µmol) was dissolved in toluene (2 mL). The solution was cooled to 0 °C, and then methanol (15.1 mg, 19.0 µL, 1 eq., 470 µmol) was added at 0 °C. Potassium terbutoxide (52.7 mg, 1 eq., 470 µmol) was added to the resulting solution at 0 °C. The mixture was stirred at 0 °C for 10 min, then the temperature was raised to RT, and then stirred for 12 h. The reaction mixture was quenched with water (15 mL), and then stirred for 15 min. Toluene (10 mL) was added to the mixture. The layers were separated, and the aqueous layer was extracted with toluene (2 × 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), and dehydrated with sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound, which was used in the next step without further purification. GCMS: m / z331.0 [M] +. [Intermediate substance] [86.]7-Bromo-5-((3-fluorophenoxy)methyl)benzofuran

[0114] A solution of (7-bromobenzofuran-5-yl)methanol (3.110 g, 1 eq., 13.70 mmol) and triphenylphosphine (4.311 g, 1.2 eq., 16.44 mmol) in THF (100 mL) was cooled to 0 °C under an inert atmosphere. Diethyl (E)-diazepine-1,2-dicarboxylate (2.863 g, 2.58 mL, 1.2 eq., 16.44 mmol) was slowly added while stirring the mixture for 30 min, followed by the addition of 3-fluorophenol (1.612 g, 1.302 mL, 1.05 eq., 14.38 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 17 h. Tetrahydrofuran was evaporated, and the mixture was dissolved in MTBE (10 mL), washed with NaOH (3 mL, 10%) and water (3 mL), dehydrated with Na₂SO₄, and concentrated under vacuum. The residue was purified by rapid chromatography (MTBE / hexane, flow rate 30 mL / min) to give the title compound (1.42 g, 4.2 mmol, 31%, 95% purity). ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.03 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.33–7.23 (m, 1H), 7.03 (d, 1H), 6.83 (d, 2H), 6.75–6.65 (m, 1H), 5.17 (s, 2H).

[0115] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in section 86. Data is not displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-87 320.0 [M+H] + 4-Methoxy-3-nitrophenol and (trans)-4-(trifluoromethyl)cyclohexyl-1-ol Int-88 - 7-Bromo-2,3-dihydrobenzofuran-5-ol and (cis)-4-(trifluoromethyl)cyclohexane-1-ol Int-89 364 [M] + 7-Bromo-2,3-dihydrobenzofuran-5-ol and (trans)-4-(trifluoromethyl)cyclohexane-1-ol Int-90 333.8 [M+H] + 7-Bromo-2,3-dihydrobenzofuran-5-ol and 4,4-difluorocyclohexane-1-ol Int-91 348 [M] + 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-ol and 4,4-difluorocyclohexane-1-ol Int-92 302.0 [M+H] + (4,4-Difluorocyclohexyl)methanol and 4-methoxy-3-nitrophenol Int-93 - (trans)-4-(trifluoromethyl)cyclohexyl-1-ol and 4-methoxy-3-nitrophenol Int-94 - 4-Methoxy-3-nitrophenol and 4,4-difluorocycloheptane-1-ol Int-95 252.1 [M+H] + 4-Methoxy-3-nitrophenol and cyclohexanol Int-96 250.1 [M+H] + 4-Methoxy-3-nitrophenol and cyclohexyl-2-en-1-ol [Intermediate substance] [97.]2-(4-methoxy-3-nitrophenoxy)bicyclo[2.2.1]heptane

[0116] 4-Methoxy-3-nitrophenol (5.00 g, 1 eq., 29.6 mmol), triphenylphosphine (15.5 g, 2 eq., 59.1 mmol), and bicyclo[2.2.1]hepta-2-ol (3.32 g, 1 eq., 29.6 mmol) were dissolved in THF (50 mL). The mixture was cooled to 4 °C and diisopropyl diazepine-1,2-dicarboxylate (12.0 g, 11.5 mL, 2 eq., 59.1 mmol) was added. The mixture was stirred at RT for 16 h, then concentrated and purified by rapid chromatography (MTBE / hexane, flow rate 30 mL / min) to give the title compound.

[0117] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in section 97. Data is not displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-98 - 4-Methoxy-3-nitrophenol and 4,4-difluorocyclohexyl-1-ol [Intermediate substance] [99.]4-(2,4-difluorophenoxy)-1-methoxy-2-nitrobenzene

[0118] 2,4-Difluoro-1-(4-methoxyphenoxy)benzene (0.180 g, 1 eq., 762 µmol) was dissolved in acetic acid (1 mL) and the solution was cooled to 0 °C. Nitric acid (144 mg, 102 µL, 3 eq., 2.29 mmol) was then added dropwise to the mixture, and the solution was stirred at RT for 10 h. The mixture was then poured into an ice-cooled saturated sodium carbonate solution (5 mL) and EtOAc (5 mL) was added. The organic layer was separated, dehydrated with sodium sulfate, and concentrated under vacuum to give the title compound, which was used in the next step without further purification. GCMS: m / z 281 [M] + [Intermediate substance] [100.]8-Nitrochloroalkyl-6-ol

[0119] 8-Nitro-octan-4,6-diol (135 mg, 1 eq., 639 µmol) was dissolved in TFA (2 mL) and triethylsilane (372 mg, 0.511 mL, 5.00 eq., 3.20 mmol) was added. The mixture was stirred at 23 °C for 16 h, then concentrated, mixed with hexane (10 mL), and filtered. The precipitate obtained by dehydration under reduced pressure gave the title compound (100 mg, 0.49 mmol). The crude product was used in the next step without further purification. LCMS: m / z 196.0 [M+H]+ [Intermediate substance]

[0101] [and] [102.] 4-Bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole and 7-bromo-5-methoxy-1-methyl-1H-benzo[d]imidazole

[0120] 7-Bromo-5-methoxy-1H-benzo[d]imidazole (0.3 g, 1 eq., 1.32 mmol) was dissolved in DMF (5 mL). The mixture was cooled to 5 °C and sodium hydride (58.1 mg, 60 w-%, 1.1 eq., 1.45 mmol) was added dropwise. The mixture was stirred at 5 °C for 30 min and iodomethane (206 mg, 90.9 µL, 1.1 eq., 1.45 mmol) was added dropwise at the same temperature. The resulting mixture was heated to 20 °C and stirred for 12 h, poured into ice-cold water (10 mL), and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (4 × 5 mL), dehydrated, and concentrated to obtain a mixture of crude products. This mixture was separated by HPLC (Method A) to yield two regiomeric isomers: 7-bromo-5-methoxy-1-methyl-1H-benzo[d]imidazole (0.0467 g, 194 µmol) and 4-bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole (0.0868 g, 360 µmol). LCMS: m / z 243.0 [M+H]+. [Intermediate substance] [103.]4-Bromo-1-methyl-1H-benzo[d]imidazol-6-ol

[0121] 4-Bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole (80 mg, 1 eq., 0.33 mmol) was dissolved in DCM (2 mL), and tribromoborane (0.83 g, 0.32 mL, 10 eq., 3.3 mmol) was added dropwise to the mixture at 4 °C. The resulting mixture was stirred at 28 °C for 18 h, and MeOH (5 mL) was added dropwise to the mixture at 4 °C. The mixture was concentrated under reduced pressure, and the residue was poured into a saturated sodium carbonate aqueous solution (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated to give crude 4-bromo-1-methyl-1H-benzo[d]imidazole-6-ol (80 mg, 0.26 mmol), which was used in the next step without further purification. LCMS: m / z 227.0 [M+H]+ [Intermediate substance] [104.]2-(5-bromo-2-fluoro-4-methoxyphenoxy)-5-(trifluoromethyl)pyridine

[0122] A mixture of 5-bromo-2-fluoro-4-methoxyphenol (4.75 g, 1 eq., 21.49 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (3.548 g, 1 eq., 21.49 mmol), and cesium carbonate (14 g, 2 eq., 42.98 mmol) in DMF (100 mL) was stirred at 60 °C for 18 h. Water (100 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (100 × 20 mL). The combined organic layers were washed with brine (4 × 100 mL), dehydrated with sodium sulfate, filtered, and evaporated to give the crude title compound (6.35 g, 14.8 mmol), which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ: 8.38 (s, 1H), 7.91 (dd, 1H), 7.42 (d, 1H), 7.07 (d, 1H), 6.78 (d, 1H), 3.88 (s, 3H). [Intermediate substance] [105.]Methyl 4-(3,4-difluorophenoxy)-2-nitrobenzoate

[0123] Methyl 4-fluoro-2-nitrobenzoate (5.000 g, 1 eq., 25.11 mmol), 3,4-difluorophenol (3.593 g, 1.1 eq., 27.62 mmol), and potassium carbonate (6.940 g, 2 eq., 50.22 mmol) were mixed in acetonitrile (100 mL) and heated at reflux for 14 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure, extracted with EtOAc (100 mL), and washed with water (20 mL), K₂CO₃ solution (20 mL, 15% in water), and brine (20 mL). The organic phase was dehydrated with Na₂SO₄ and concentrated under vacuum to give the title compound (6.68 g, 19 mmol, 77%, 90% purity). 1H NMR (500 MHz, DMSO-d6) δ: 7.89 (d, 1H), 7.63 (d, 1H), 7.59 - 7.50 (m, 1H), 7.47 (dq, 1H), 7.33 (dd, 1H), 7.12 - 7.03 (m, 1H), 3.81 (s, 3H).

[0124] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 105. Data will not be displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-106 341.1 [M] + 4-Fluoro-2-nitrobenzene methyl ester and 4-(trifluoromethyl)phenol Int-107 341.1 [M] + 4-Fluoro-2-nitrobenzoate and 3-(trifluoromethyl)phenol Int-108 294.2 [M+H] + 1-(4-fluoro-2-nitrophenyl)ethyl-1-one and 3,4-difluorophenol Int-109 331.0 [M+H] + 2-Fluoro-5-(trifluoromethoxy)pyridine and 4-methoxy-3-nitrophenol Int-110 299.0 [MH] - 4-Methoxy-3-nitrophenol and 2-fluoro-5-(trifluoromethyl)pyridine Int-111 - 2-Chloro-5-(trifluoromethyl)pyridine and 7-bromo-2,3-dihydrobenzofuran-5-ol Int-112 341.0 [M] + 8-Nitro-6-ol and 2-Fluoro-5-(trifluoromethyl)pyridine Int-113 265.0 [M] + 4-Methoxy-3-nitrophenol and 2,5-difluoropyridine Int-114 297.0 [M+H] + 4-Methoxy-3-nitrophenol and 5-(difluoromethyl)-2-fluoropyridine Int-115 371.8 [M+H] + 4-Bromo-1-methyl-1H-benzo[d]imidazol-6-ol and 2-fluoro-5-(trifluoromethyl)pyridine [intermediate] [116.]4-(3,4-difluorophenoxy)-2-nitrobenzo[a]hydrazine

[0125] Hydrazine hydrate (2.266 g, 7 eq., 45.28 mmol) was added to a solution of methyl 4-(3,4-difluorophenoxy)-2-nitrobenzene (2.000 g, 1 eq., 6.468 mmol) in ethanol (20 mL). The mixture was heated under reflux overnight. The solvent was then evaporated under reduced pressure, and water (20 mL) was added to the residue. The resulting solid was filtered, washed with water and hexane, and dehydrated under vacuum to give the title compound (1.900 g, 5.5 mmol, 85%, 90% purity). 1H NMR (500 MHz, DMSO-d6) δ: 9.77 (s, 1H), 7.59 (d, 1H), 7.59 - 7.49 (m, 2H), 7.47- 7.42 (m, 1H), 7.33 (dd, 1H), 7.07 - 6.99 (m, 1H), 4.32 (s, 1H).

[0126] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 116. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-117 342.2 [M+H] + 2-Nitro-4-(4-(trifluoromethyl)phenoxy)benzoate methyl ester and hydrazine hydrate Int-118 342.4 [M+H] + 2-Nitro-4-(3-(trifluoromethyl)phenoxy)benzoate methyl ester and hydrazine hydrate [Intermediate substance] [119.]2-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1,3,4- diazole

[0127] 4-(3,4-difluorophenoxy)-2-nitrobenzo[a]hydrazine (1.000 g, 1 eq., 3.234 mmol), 4-methylbenzenesulfonic acid (111.4 mg, 0.2 eq., 646.8 µmol), and triethoxymethane (20 mL) were heated at reflux for 14 h. The mixture was then concentrated under vacuum to give the title compound (1.00 g, 2.2 mmol, 69%, 71% purity). LCMS: m / z 320.0 [M+H]+.

[0128] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 119. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-120 352.0 [M+H] + 2-Nitro-4-(4-(trifluoromethyl)phenoxy)benzo[a]hydrazine and triethoxymethane Int-121 352.2 [M+H] + 2-Nitro-4-(3-(trifluoromethyl)phenoxy)benzo[a]hydrazine and triethoxymethane [intermediate] [122.](E)-1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one

[0129] A solution of 1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)ethyl-1-one (0.300 g, 1 Eq, 1.02 mmol), DMF-DMA (244 mg, 272 µL, 2 Eq, 2.05 mmol), and toluene (3 mL) was stirred and heated at reflux for 16 h, then cooled to RT. The resulting solid was filtered, washed with toluene and hexane, and dehydrated under vacuum to give the title compound (0.246 g, 706 µmol, 69.0%) as a yellow solid. LCMS: m / z 349.2 [M+H]+. [intermediate] [123.]5-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1-methyl-1H-pyrazole

[0130] (E)-1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one (0.246 g, 1 eq., 706 µmol) and methylhydrazine sulfate (112 mg, 1.1 eq., 777 µmol) were mixed in 2-propanol (4 mL) and heated at reflux for 18 h. The mixture was cooled to RT, concentrated under vacuum, and purified by method C to give the title compound (0.109 g, 329 µmol, 46.6%, 100% purity). LCMS: m / z 332.0 [M+H]+. [Intermediate substance] [124.]7-Nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole

[0131] A solution of sodium nitrite (369.2 mg, 1.1 eq., 5.352 mmol) in water (2.4 mL) was added to a stirred solution of 2-methyl-6-nitro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline (1.524 g, 1 eq., 4.865 mmol) in acetic acid (70.5 mL), and the mixture was stirred for 1 h. After the reaction was complete, acetic acid was distilled off, and the resulting residue was mixed with ice water (200 mL) and extracted with MTBE (3 × 30 mL). The combined organic phases were washed with water (2 × 10 mL), dehydrated with sodium sulfate, and concentrated under reduced pressure to give the title compound (1.5 g, 3.9 mmol, 80%, 84% purity). LCMS: m / z 325.0 [M+H]+.

[0132] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 124. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-125 358.0 [M+H] + 4-(2-chloro-4-(trifluoromethyl)phenoxy)-2-methyl-6-nitroaniline [Intermediate substance] [126.]5-(4-(trifluoromethyl)phenoxy)-1H-indazole-7-amine

[0133] 5-(2-chloro-4-(trifluoromethyl)phenoxy)-7-nitro-1H-indazole (0.093 g, 1 eq., 0.26 mmol) was dissolved in methanol (15 mL). Ammonium formate (0.33 g, 20 eq., 5.2 mmol) and palladium (0.22 g, 10 w-%, 0.8 eq., 0.21 mmol) were added. The resulting mixture was stirred at 65 °C for 16 h, cooled to RT, and filtered. The filtrate was concentrated under reduced pressure and treated with EtOAc (10 mL). The precipitate was filtered and dehydrated under reduced pressure to give the title compound (0.044 g, 0.15 mmol, 58%, 100% purity), which was used in the next step without further purification. 1H NMR (500 MHz, DMSO -d6) δ: 7.87 (s, 1H), 7.65 (d, 2H), 7.06 (d, 2H), 6.62 (s, 1H), 6.18 (s, 1H), 5.69 (s, 2H). [Intermediate substance] [127.] 1-Methyl-7-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole

[0134] Sodium hydride (14.8 mg, 60 w-%, 1.2 eq., 370 µmol) was added to a solution of 7-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole (0.1 g, 1 eq., 308 µmol) in THF (4 mL) cooled to 0 °C. After stirring at 23 °C for 1 h, iodomethane (46.0 mg, 20.3 µL, 1.05 eq., 324 µmol) was added dropwise at 0 °C. The mixture was stirred at 23 °C for 16 h. Water (1 mL) was added and the mixture was concentrated under reduced pressure. The crude material was dissolved in EtOAc (10 mL), washed with water and brine, dehydrated by MgSO4, and the solvent was removed under reduced pressure to give the title compound (0.129 g, 310 µmol, 100%, 81.2% purity), which was used in the next step without further purification. LCMS: m / z339.2 [M+H] +. [Intermediate substance] [128.]1-(3,4-difluorophenoxy)-4-methoxy-2-methyl-3-nitrobenzene

[0135] 1-Bromo-4-methoxy-2-methyl-3-nitrobenzene (0.384 g, 1.5 mmol), 3,4-difluorophenol (0.13 g, 1.0 mmol), Cs₂CO₃ (0.652 g, 2.0 mmol), CuI (0.057 g, 0.3 mmol), and N,N-dimethylglycine (0.031 g, 0.3 mmol) were prepared in a 2... The mixture in alkane (5 mL) was heated at 130 °C for 24 hours. The mixture was evaporated and the residue was purified by normal phase chromatography to give 0.175 g of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ: 2.07 (³H, s), 3.87 (³H, s), 6.71–6.79 (¹H, m), 7.12–7.19 (¹H, m), 7.19–7.27 (²H, m), 7.38–7.49 (¹H, m). [Intermediate substance] [129.]2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline

[0136] 1-Methoxy-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (558 mg, 1 eq., 1.78 mmol) was dissolved in methanol (20 mL) and treated with Pd / C (37.9 mg, 0.2 eq., 356 µmol). The resulting mixture was hydrogenated overnight at 1 atm under RT. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give the crude title product, which was used in the next step without further purification. LCMS: m / z 284.2 [M+H]+.

[0137] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 129. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-130 234.2 [M+H] + 4-(3-Fluorophenoxy)-1-methoxy-2-nitrobenzene Int-131 279.2 [M+H] + 1-((3-fluorophenoxy)methyl)-2,4-dimethoxy-5-nitrobenzene Int-132 284.2 [M+H] + 1-Methoxy-2-nitro-4-(3-(trifluoromethyl)phenoxy)benzene Int-133 254.2 [M+H] + 1-Nitro-3-(3-(trifluoromethyl)phenoxy)benzene Int-134 347.2 [M+H] + (3-Fluorophenyl)(4-methoxy-3-nitrophenylmethyl)aminocarbamate tributyl ester Int-135 294.0 [M+H] + 7-Nitro-5-(3-(trifluoromethyl)phenoxy)benzofuran Int-136 266.0 [M+H] + 1-Fluoro-5-((3-fluorophenoxy)methyl)-2-methoxy-3-nitrobenzene Int-137 302.0 [M+H] + 1-Fluoro-5-methoxy-4-nitro-2-(3-(trifluoromethyl)phenoxy)benzene Int-138 272.0 [M+H] + 1-Fluoro-2-nitro-4-(3-(trifluoromethyl)phenoxy)benzene Int-139 252.0 [M+H] + 4-(2,4-Difluorophenoxy)-1-methoxy-2-nitrobenzene Int-140 251.0 [M+H] + 4-(3,4-Difluorophenoxy)-1-methoxy-2-nitrobenzene Int-141 286.0 [M+H] + 5-(4-methoxy-3-nitrophenoxy)-2-(trifluoromethyl)pyridine Int-142 266.2 [M+H] + 1-Fluoro-2-((3-fluorophenoxy)methyl)-5-methoxy-4-nitrobenzene Int-143 271.07 [M] + 1-Fluoro-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene Int-144 252.2 [M+H] + 4-(2,5-Difluorophenoxy)-1-methoxy-2-nitrobenzene Int-145 290.2 [M+H] + 2-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1,3,4- diazole Int-146 290.2 [M+H] + 1-Methoxy-2-nitro-4-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-147 325.0 [M+H] + 5-Nitro-7-(3-(trifluoromethyl)phenoxy)-2H-benzo[b][1,4]-3(4H)-one Int-148 301.0 [M+H] + 2-(4-methoxy-3-nitrophenoxy)-5-(trifluoromethoxy)pyridine Int-149 300.2 [M+H] + 7-(((4,4-difluorocyclohexyl)oxy)methyl)-5-nitro-2,3-dihydrobenzo[b][1,4]dioxane Int-150 285.0 [M+H] + 2-(4-methoxy-3-nitrophenoxy)-5-(trifluoromethyl)pyridine Int-151 294.2 [M+H] + 7-Nitro-5-(4-(trifluoromethyl)phenoxy)benzofuran Int-152 295.0 [M+H] + 7-Nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole Int-153 309.0 [M+H] + 1-Methyl-7-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole Int-154 235.2 [M+H] + 5-Fluoro-2-(4-methoxy-3-nitrophenoxy)pyridine Int-155 290.2 [M+H] + 1-Methoxy-2-nitro-4-((cis)-4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-156 295.0 [M+H] + 2-((7-nitrobenzofuran-5-yl)oxy)-5-(trifluoromethyl)pyridine Int-157 272.2 [M+H] + 1,1-Difluoro-4-(4-methoxy-3-nitrophenoxy)cycloheptane [Intermediate substance] [158.]2-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)pyridine

[0138] A mixture of 2-chloro-4-(trifluoromethyl)pyridine (2.72 g, 15.0 mmol), 4-methoxy-3-nitrophenol (2.80 g, 15.8 mmol), and Cs₂CO₃ (5.68 g, 17.3 mmol) in DMF (20 ml) was heated at 100 °C for 7 hours. Water (50 ml) was added, and the mixture was extracted with EtOAc (3 × 50 ml). The organic layers were combined and evaporated to give 4.71 g of the crude title compound, which was used in the next reaction without further purification. 1H NMR (400 MHz, DMSO- d 6) δ: 3.96 (3 H, s), 7.44 (1 H, d), 7.50 - 7.59 (3 H, m), 7.84 (1 H, d), 8.41 (1 H, d). LCMS: m / z 315.4 [M+H] +

[0139] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 158. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-159 332.0 [M+H] + 4-Methoxy-3-nitrophenol and 2,4-difluoro-1-(trifluoromethyl)benzene Int-160 332.0 [M+H]+ 4-Methoxy-3-nitrophenol and 3,4-difluorotrifluorotoluene (DMSO solvent, 120℃, 4 h) Int-161 333.2 [M+H]+ 4-Methoxy-3-nitrophenol and 3,5-difluoro-2-(trifluoromethyl)-pyridine Int-162 332.9 [M+H]+ 4-Methoxy-3-nitrophenol and 2,6-difluoro-3-trifluoromethylpyridine [Intermediate substance] [163.]2-Methoxy-5-((3-(trifluoromethyl)benzyl)oxy)aniline hydrochloride

[0140] 1-Methoxy-2-nitro-4-((3-(trifluoromethyl)benzyl)oxy)benzene (8.70 g, 1 eq., 26.6 mmol), water (7.43 g, 7.4 mL, 15.5 eq., 412 mmol), ammonium hydrochloride (142 mg, 0.1 eq., 2.66 mmol), and hydrogen chloride (266 mg, 226 µL, 36.5% aqueous solution, 0.1 eq., 2.66 mmol) were mixed in 1,4-di(methoxy-2-nitro-4-((3-(trifluoromethyl)benzyl)oxy)benzene (8.70 g, 1 eq., 26.6 mmol), water (7.43 g, 7.4 mL, 15.5 eq., 412 mmol), ammonium hydrochloride (142 mg, 0.1 eq., 2.66 mmol), and hydrogen chloride (266 mg, 226 µL, 36.5% aqueous solution, 0.1 eq., 2.66 mmol) in 1,4-di(methoxy-2-nitro-4-((3-(trifluoromethyl)benzyl)oxy)benzene (8.70 g, 1 eq., 26.6 mmol), water (7.43 g, 7.4 mL, 15.5 eq., 412 mmol), ammonium hydrochloride (142 mg, 0.1 eq., 2.66 mmol), water (266 mg, 226 µL, 36.5% aqueous solution, 0.1 eq., 2.66 mmol), water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water The mixture was added to alkane (200 mL), followed by the addition of iron (7.42 g, 5 eq., 133 mmol). The mixture was stirred at 110 °C for 5 h and then at RT for 16 h. The mixture was filtered through a silica thin-layer filter, concentrated, and the residue was added to a volume saturated with hydrochloric acid (30 mL). In an alkane. The solution was evaporated under reduced pressure. The residue was washed with ethyl acetate and dehydrated to give the title compound. LCMS: m / z 334.2 [M+H]+.

[0141] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 163. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-164 262.0 [M+H] + 6-((3-fluorophenoxy)methyl)-4-nitrobenzo[d][1,3]m-dioxane Int-165 298.2 [M+H] + 1-Methoxy-2-nitro-4-((3-(trifluoromethyl)phenoxy)methyl)benzene Int-166 276.0 [M+H] + 7-((3-fluorophenoxy)methyl)-5-nitro-2,3-dihydrobenzo[b][1,4]dioxane Int-167 283.2 [M+H] + 4-Methoxy-3-nitro-N-(4-(trifluoromethyl)phenyl)aniline Int-168 252.2 [M+H] + 4-(3,5-Difluorophenoxy)-1-methoxy-2-nitrobenzene Int-169 322.0 [M+H] + 2-(2-nitro-4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,4- diazole Int-170 322.2 [M+H] + 2-(2-nitro-4-(3-(trifluoromethyl)phenoxy)phenyl)-1,3,4- diazole Int-171 302.0 [M+H] + 3-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1-methyl-1H-pyrazole Int-172 302.2 [M+H] + 5-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1-methyl-1H-pyrazole Int-173 302.2 [M+H] + 4-((3,4-difluorophenoxy)methyl)-1-methoxy-2-nitrobenzene Int-174 334.0 [M+H] + 2-(4-methoxy-3-nitrophenoxy)bicyclo[2.2.1]heptane Int-175 258.2 [M+H] + 4-((4,4-difluorocyclohexyl)oxy)-1-methoxy-2-nitrobenzene Int-176 266.2 [M+H] + 4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene Int-177 311.2 [M+H] + 2-((8-nitrochloroalkyl-6-yl)oxy)-5-(trifluoromethyl)pyridine Int-178 267.0 [M+H] + 5-(difluoromethyl)-2-(4-methoxy-3-nitrophenoxy)pyridine Int-179 285.0 [M+H] + 2-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)pyridine Int-180 272.0 [M+H] + 4-(((4,4-difluorocyclohexyl)oxy)methyl)-1-methoxy-2-nitrobenzene Int-181 272.2 [M+H] + 4-((4,4-difluorocyclohexyl)methoxy)-1-methoxy-2-nitrobenzene [Intermediate substance] [182.]5-((5-chloropyridin-2-yl)oxy)-2-methoxyaniline

[0142] 5-Chloro-2-(4-methoxy-3-nitrophenoxy)pyridine (197 mg, 1 eq., 702 µmol) was dissolved in methanol (5 mL) and platinum (20.5 mg, 0.15 eq., 105 µmol) was added. The mixture was degassed and stirred in a hydrogen atmosphere for 12 h, then filtered and the solvent was evaporated to give the title compound (175 mg, 0.66 mmol, 94%, 95% purity), which was used in the next step without further purification. LCMS: m / z 251.0 [M+H]+. [Intermediate substance] [183.]1,1-Diphenyl-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)methylimine

[0143] 4-Bromo-6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopentene (1.20 g, 1 eq., 3.32 mmol), diphenylmethyleneimine (663 mg, 1.1 eq., 3.66 mmol), sodium 2-methylprop-2-ol (335 mg, 1.05 eq., 3.49 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (207 mg, 0.1 eq., 332 µmol) were dissolved in toluene (20 mL). Argon gas was bubbled through the solution for 1 min, followed by the addition of diethoxypalladium (37.3 mg, 0.05 eq., 166 µmol), and the mixture was stirred at 110 °C under an argon atmosphere for 12 h. The mixture was filtered, and the solid was washed with ethyl acetate (2 × 20 mL). The ethyl acetate solution was then washed with brine (2 × 50 mL). The organic phase was dehydrated with sodium sulfate and filtered. The solvent was evaporated to give the title compound, which was used in the next step without further purification. LCMS: m / z 462.0 [M+H]+.

[0144] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 183. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-184 422.2 [M+H] + 7-Bromo-5-((3-fluorophenoxy)methyl)benzofuran and diphenylmethylimine Int-185 425.2 [M+H] + 7-Bromo-5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran and diphenylmethylimine Int-186 463.0 [M+H] + 2-((7-bromobenzo[d][1,3]m-dioxacyclopenten-5-yl)oxy)-5-(trifluoromethyl)pyridine and diphenylmethylene Int-187 462.2 [M+H] + 4-Bromo-6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopentene and diphenylmethyleneimine Int-188 475.2 [M+H] + 2-((7-bromo-2-methyl-2,3-dihydrobenzofuran-5-yl)oxy)-5-(trifluoromethyl)pyridine and diphenylmethyleneimine [Intermediate substance] [189.](7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)aminocarbamate tributyl ester

[0145] XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethyldibenzo[b][1,4]dioxane (326.2 mg, 0.15 eq., 563.8 µmol)) and tributyl carbamate (660.5 mg, 1.5 eq., 5.638 mmol) and cesium carbonate (3.674 g, 3 eq., 11.28 mmol) in toluene (40 mL) were added under argon atmosphere to a mixture of 5-bromo-7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane (326.2 mg, 0.15 eq., 563.8 µmol) and triphenylmethyleneacetone (172.1 mg, 0.05 eq., 187.9 µmol), and the mixture was heated at 110 °C for 18 h. After cooling to RT, the mixture was filtered and concentrated. The residue was diluted with ethyl acetate (10 mL) and washed with brine (2 × 50 mL). The organic phase was dehydrated with Na₂SO₄, filtered, and concentrated under vacuum. The residue was recrystallized from acetonitrile to give the title compound. LCMS: m / z 412.2 [M+H]⁺.

[0146] The following intermediates were prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 189. Data is not displayed if the LCMS / GCMS data does not provide useful information. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-190 380.0 [M+H] + 5-Bromo-7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane and tributyl carbamate Int-191 364.2 [M+H] + 7-Bromo-5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran and tributyl carbamate Int-192 402.0 [M+H] + 7-Bromo-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran and tributyl carbamate Int-193 396.0 [M+H] + 7-Bromo-5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran and tributyl carbamate Int-194 303.0 [M+H] + 2-(5-bromo-2-fluoro-4-methoxyphenoxy)-5-(trifluoromethyl)pyridine and tributyl carbamate Int-195 - 7-Bromo-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran and tributyl carbamate Int-196 336.0 [M+H] + 1-Bromo-5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxybenzene and tributyl carbamate Int-197 - 2-((7-bromo-2,3-dihydrobenzofuran-5-yl)oxy)-5-(trifluoromethyl)pyridine and tributyl carbamate Int-198 411.0 [M+H] + 2-((8-bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)oxy)-5-(trifluoromethyl)pyridine and tributyl carbamate Int-199 268.8 [MH] - 7-Bromo-5-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzofuran and tributyl carbamate Int-200 387.2 [M+H] + 5-Bromo-7-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane and tributyl carbamate Int-201 278.0 [M+H] + 7-Bromo-5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran and tributyl carbamate [Intermediate substance] [202.]7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine hydrochloride

[0147] Trimethylchlorosilane (1.320 g, 1.54 mL, 5 eq., 12.15 mmol) was added dropwise to methanol (25 mL) at 0 °C. The mixture was stirred for 30 min, and tributyl 7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)aminocarbamate (1 g, 1 eq., 2.431 mmol) was added, and the solution was stirred at RT for 48 h. The mixture was concentrated under vacuum to give the crude title compound (808 mg, 2.11 mmol, 86.9%, 90.93% purity). LCMS: m / z 312.2 [M+H]+.

[0148] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 202. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-203 280.0 [M+H] + (7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)tributyl aminocarboxylate Int-204 264.2 [M+H] + (5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)aminocarbamate tributyl ester Int-205 302.2 [M+H] + (5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)aminocarbamate tributyl ester Int-206 296.0 [M+H] + (5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)aminocarbamate tributyl ester Int-207 303.0 [M+H] + (4-Fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)aminocarboxylic acid tributyl ester Int-208 302.0 [M+H] + (5-((((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)aminocarbamate tributyl ester Int-209 313.0 [M+H] + (7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)aminocarbamate tributyl ester Int-210 270.2 [M+H] + (5-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)aminoformate tributyl ester Int-211 286.2 [M+H] + (7-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)tributyl aminocarboxylate Int-212 278.2 [M+H] + (5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)aminocarbamate tributyl ester Int-213 297.0 [M+H] + (5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)aminocarbamate tributyl ester [Intermediate substance] [214.]6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-amine

[0149] 1,1-Diphenyl-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)methylimine (0.800 g, 1 eq., 1.73 mmol) was dissolved in THF (10 mL), and HCl solution (253 mg, 6.93 mL, 1 mol, 4 eq., 6.93 mmol) was added under RT. The mixture was stirred under RT for 10 min and then evaporated under vacuum to give the title compound (640 mg, 1.1 mmol, 62%, 50% purity), which was used in the next step without further purification. LCMS: m / z 298.0 [M+H]+.

[0150] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 214. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-215 258.2 [M+H] + N-(5-((3-fluorophenoxy)methyl)benzofuran-7-yl)-1,1-diphenylmethylene Int-216 260.2 [M+H] + N-(5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-1,1-diphenylmethylene Int-217 299.1 [M+H] + 1,1-Diphenyl-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)methylimine Int-218 298.0 [M+H] + 1,1-Diphenyl-N-(6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)methylimine Int-219 311.1 [M+H] + N-(2-Methyl-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)-1,1-diphenylmethylene [Intermediate substance] [220.]5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyaniline hydrochloride

[0151] (0.185 g, 1 eq., 425 µmol) of tributyl 5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxy-phenyl)aminocarbamate was dissolved in methanol (5 mL), and HCl (155 mg, 104 µL, 10 w-%, 1 eq., 425 µmol) was added dropwise at 25 °C. Solution in alkane. The mixture was stirred at 25 °C for 56 h and then concentrated under reduced pressure to give the title compound (0.150 g, 0.32 mmol, 76%, 80% purity), which was used in the next step without further purification. ¹H NMR (500 MHz, DMSO-d6) δ: 8.00 (s, 1H), 7.66 (d, 1H), 7.21 (d, 1H), 6.97 (m, 2H), 3.85 (s, 3H). LCMS: m / z 336.0 [M+H]+. [Intermediate substance] [221a.] Methyl N-methylpropionate 1,1-dioxide

[0152] Methyl propionate 1,1-dioxide (350 mg, 1 eq., 2.12 mmol) and potassium carbonate (879 mg, 3 eq., 6.36 mmol) were mixed in anhydrous DMF (5 mL), followed by a single addition of methyl iodoforme (1.50 g, 660 µL, 5 eq., 10.6 mmol). The mixture was stirred at 27 °C for 18 h. The mixture was concentrated under vacuum, the residue was treated with water (5 mL), and the resulting suspension was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (2 × 15 mL), dehydrated with sodium sulfate, filtered, and concentrated under vacuum to give the title compound (116 mg, 0.39 mmol, 18%, 60% purity), which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ: 4.56 - 4.46 (m, 1H), 4.38 (m, 1H), 3.95 (m, 1H), 3.71 (s, 3H), 2.67 (s, 3H). [Intermediate substance] [221b.] Lithium N-methylpropionate 1,1-dioxide

[0153] Methyl N-methylpropionate 1,1-dioxide (100 mg, 1 eq., 558 µmol) and lithium hydroxide (23.4 mg, 1 eq., 558 µmol) were dissolved in methanol (2 mL) and stirred at RT for 16 h. The mixture was concentrated and the residue was concentrated three times with acetonitrile to give the title compound (77 mg, 0.43 mmol, 77%, 95% purity), which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d6) δ: 4.10–3.96 (m, 2H), 3.13 (t, 1H), 2.61 (s, 3H). [Intermediate substance] [222a.]1-Methyl-5-thionylpyrrolidone-2-carboxylic acid tributyl ester

[0154] Phosphorus sulfide (V) (262 mg, 0.5 eq., 1.18 mmol) was added to a solution of 1-methyl-5-semi-oxypyrrolidone-2-carboxylic acid tributyl ester (470 mg, 1 eq., 2.36 mmol) in tetrahydrofuran (3 mL). The mixture was refluxed with stirring for 24 h. The solution was cooled and filtered. Chloroform (20 mL) was added, and the organic phase was washed with saturated sodium bicarbonate (20 mL). The aqueous phase was extracted with chloroform (20 mL). The combined organic phases were dehydrated and concentrated under vacuum to give the title compound (500 mg, 1.8 mmol, 76%, 77% purity), which was used in the next step without further purification. GCMS: m / z 216.1 [M]+. [Intermediate substance] [222b.]1-Methyl-5-thionopyrrolidin-2-carboxylic acid

[0155] Tributyl 1-methyl-5-thionylpyrrolidone-2-carboxylic acid (500 mg, 1 eq., 2.32 mmol) was dissolved in trifluoroacetic acid (2.65 g, 1.79 mL, 10 eq., 23.2 mmol), and the solution was stirred at RT for 12 h. The solvent was then evaporated, and the residue was dissolved in toluene (5 mL) and concentrated to remove excess TFA, giving the title compound (370 mg, 1.2 mmol, 50%, 50% purity), which was used in the next step without further purification. [Intermediate substance] [223.]N-(5-hydroxy-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide []

[0156] 1-Methyl-5-sideoxypyrrolidone-2-carboxylic acid (0.5 g, 1.2 eq., 3.49 mmol) was dissolved in N,N-dimethylformamide (5 mL) and HATU (1.33 g, 1.2 eq., 3.49 mmol) was added. The solution was stirred at RT for 5 min. 3-amino-4-methoxyphenol hydrochloride (511 mg, 1 eq., 2.91 mmol) was added to this solution, followed by DIPEA (1.05 g, 1.42 mL, 2.8 eq., 8.15 mmol). The mixture was then stirred at RT for 2 h. The solvent was removed under vacuum. The crude substance was dissolved in ethyl acetate (10 mL), washed with brine (50 mL) and water (50 mL), dehydrated, and the solvent was evaporated. The residue was purified using method B to give the title compound (0.0667 g). 1H NMR (400 MHz, DMSO-d6) δ: 9.34 (s, 1H), 8.96 (s, 1H), 7.54 (s, 1H), 6.85 (d, 1H), 6.45 (d, 1H), 4.42 (d, 1H), 3.32 (s, 2H), 2.66 (s, 3H), 2.37 - 2.11 (m, 3H), 1.87 (s, 1H). LCMS: m / z 265.2 [M+H]+.

[0157] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 223. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-224 479.5 [MH] - 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid Int-225 586.192 (M+H)+ 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-(((benzoxy)carbonyl)glycinyl)-5-sideoxypyrrolidone-2-carboxylic acid [Intermediate substance] [226.](3-Fluorophenyl)(4-methoxy-3-(5-sideoxypyrrolidone-2-methamido)benzyl)aminocarbamate tributyl ester []

[0158] N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (243 mg, 1.5 eq., 866 µmol) was added to a mixture of (3-amino-4-methoxybenzyl)(3-fluorophenyl)aminocarbamate (200 mg, 1 eq., 577 µmol), 5-sideoxypyrrolidone-2-carboxylic acid (74.5 mg, 1 eq., 577 µmol), and 1-methyl-1H-imidazolium (237 mg, 5 eq., 2.89 mmol) in acetonitrile (4 mL). The mixture was stirred at RT for 18 h and then concentrated under vacuum. Water (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dehydrated with sodium sulfate, filtered, and evaporated to give the title compound (0.3 g), which was used in the next step without further purification. LCMS: m / z 358.0 [M+H] +. [Intermediate substance] [227a.]Methyl 4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-carboxylate

[0159] At 0 °C, methyl 4-hydroxy-2,3-dihydrobenzofuran-6-carboxylate (2 g, 1 eq., 10.30 mmol) and N-ethyl-N-isopropylpropyl-2-amine (3.994 g, 5.38 mL, 3 eq., 30.90 mmol) in DCM (80 mL) were added to a solution of chloro(methoxy)methane (1.309 g, 1.24 mL, 95 w-%, 1.5 eq., 15.45 mmol), and the mixture was stirred at 20 °C for 18 h. The mixture was washed with brine (3 × 10 mL), dehydrated with sodium sulfate, filtered, and evaporated to give the title compound (2.3 g, 8.834 mmol, 85.78%, 90.75% purity), which was used in the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ: 7.29 (s, 1H), 7.13 (s, 1H), 5.23 (s, 2H), 4.63 (t, 2H), 3.87 (s, 3H), 3.49 (s, 3H), 3.20 (t, 2H). [Intermediate substance] [227b.](4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-yl)methanol

[0160] A solution of LiAlH₄ (127 mg, 2 eq., 3.36 mmol) in THF (5 mL) was cooled to 0 °C, and a solution of methyl 4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-carboxylate (400 mg, 1 eq., 1.68 mmol) in THF (5 mL) was added dropwise. The cooling bath was removed, and the mixture was stirred at 20 °C for 18 h. The mixture was cooled to 0 °C, and a 30% solution of K₂CO₃ (4 × 130 µL) was added dropwise. The mixture was filtered, and the residue was washed with THF (5 mL). The organic layer was separated and concentrated to give a crude title compound (340 mg, 1.48 mmol, 88.0%, 91.31% purity) as a yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ: 6.59 (s, 1H), 6.48 (s, 1H), 5.17 (s, 2H), 4.66 - 4.48 (m, 4H), 3.47 (s, 3H), 3.14 (t, 2H). [Intermediate substance] [227c.]5-((3,4-difluorophenoxy)methyl)-4-(methoxymethoxy)-2,3-dihydrobenzofuran

[0161] Tributylphosphine (385 mg, 0.48 mL, 2 eq., 1.90 mmol) was added to a mixture of (7-(methoxymethoxy)-2,3-dihydrobenzofuran-5-yl)methanol (200 mg, 1 eq., 951 µmol) and 3,4-difluorophenol (124 mg, 1 eq., 951 µmol) in THF (40 mL) at 0 °C under an Ar atmosphere, followed by the addition of (E)-diazepine-1,2-diylbis(piperidin-1-yl methyl ketone) (480 mg, 2 eq., 1.90 mmol). The mixture was stirred at 20 °C for 18 h. The solvent of the mixture was evaporated under reduced pressure. The residue was purified by reversed-phase HPLC (water-acetonitrile) to give the title compound (178 mg, 552 µmol, 58.1%). ¹H NMR (500 MHz, chloroform-d) δ: 7.04 (q, ¹H), 6.83 - 6.71 (m, ¹H), 6.64 (s, 2H), 6.54 (s, ¹H), 5.19 (s, 2H), 4.92 (s, 2H), 4.60 (t, 2H), 3.49 (s, 3H), 3.17 (t, 2H). [Intermediate substance] [227d.]5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-ol

[0162] Trimethylchlorosilane (146 mg, 170 µL, 2 eq., 1.34 mmol) was added dropwise to MeOH (4 mL) at 0 °C. The mixture was stirred for 30 min, and a solution of 5-((3,4-difluoro-phenoxy)methyl)-4-(methoxymethoxy)-2,3-dihydrobenzofuran (216 mg, 1 eq., 670 µmol) in MeOH (1 mL) was added. The mixture was then stirred at 20 °C for 18 h. The mixture was concentrated under reduced pressure to give a crude title compound (178 mg, 623 µmol, 92.9%, 97.37% purity) as a beige solid. 1H NMR (500 MHz, DMSO -d6) δ: 9.50 (s, 1H), 7.34 - 7.27 (m, 1H), 7.14 - 7.01 (m, 1H), 6.83 - 6.73 (m, 1H), 6.34 (s, 1H), 6.28 (s, 1H), 4.92 (s, 2H), 4.47 (t, 2H), 2.99 (t, 2H). [Intermediate substance] [227e.] 6-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-yl ester of trifluoromethanesulfonic acid

[0163] Trifluoromethanesulfonic anhydride (199 mg, 118 μL, 1.1 eq., 704 μmol) was added dropwise to a solution of 5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-ol (178 mg, 1 eq., 640 µmol) and triethylamine (84.2 mg, 116 µL, 1.3 eq., 832 µmol) in DCM (5 mL) at 0 °C, and the mixture was stirred at 20 °C for 18 h. DCM (10 mL) was added to the mixture, and the solution was washed with NaHSO₄ solution (2 × 5 mL), dehydrated with sodium sulfate, filtered, and evaporated to give the title compound (238 mg, 0.52 mmol, 82%, 90% purity) as a brown oil, which was used in the next step without further purification. ¹H NMR (500 MHz, chloroform-d) δ: 7.06 (q, ¹H), 6.84 (s, ¹H), 6.80 (s, ¹H), 6.79 - 6.72 (m, ¹H), 6.66 - 6.60 (m, ¹H), 4.96 (s, 2H), 4.68 (t, 2H), 3.34 (t, 2H). [Intermediate substance] [228.]2-Methoxy-5-(4-(trifluoromethyl)phenoxy)benzoic acid

[0164] A solution of potassium hydroxide (51.6 mg, 1.5 eq., 919 µmol) in water (0.6 mL) was added to a solution of methyl 2-methoxy-5-(4-(trifluoromethyl)phenoxy)benzoate (0.200 g, 1 eq., 613 µmol) in methanol (5 mL). The mixture was stirred at 25 °C for 16 h and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and washed with EtOAc (2 × 2 mL). The aqueous mixture was acidified with NaHSO4 (5 mL, 15% in water). The resulting mixture was extracted with EtOAc (2 × 8 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure to give the title compound (0.08 g, 0.26 mmol, 42%). LCMS: m / z 311.0 [MH] -. [Intermediate substance] [229.] 1-Methoxy-3-nitro-5-(4-(trifluoromethyl)phenoxy)benzene

[0165] 3-Methoxy-5-nitrophenol (0.5 g, 1 eq., 2.96 mmol), 4-trifluorophenylboronic acid (0.7 g, 1.5 eq., 4.43 mol), pyridine (1.2 g, 1.2 mL, 5 eq., 14.8 mol), copper acetylacetonate (0.54 g, 1 eq., 2.96 mmol), and 4 Å (1 g) of powdered molecular sieve were suspended in dichloromethane (15 mL). Air was bubbled through the resulting solution for 30 min, and the mixture was stirred overnight at RT. The mixture was filtered, the filtrate was washed with water (2 × 30 mL), dehydrated with sodium sulfate, filtered again, and the solvent was removed under reduced pressure. The residue was purified by method A to give the title compound. LCMS: m / z 314.2 [M+H]+.

[0166] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 229. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-230 317.1 [M] + 4-(trifluoromethyl)phenylboronic acid and 4-chloro-3-nitrophenol Int-231 312.0 [M+H] + 4-(trifluoromethyl)phenylboronic acid and (2-methoxy-5-nitrophenol) Int-232 264.0 [M+H] + 4-Methoxy-3-nitrophenol and 4-fluorophenylboronic acid Int-233 279.1 [M+H] + 4-Methoxy-3-nitrophenol and (6-fluoro-5-methylpyridin-3-yl)boronic acid Int-234 314.2 [M+H] + 3-Bromo-5-nitrobenzene and 3-(trifluoromethyl)phenol Int-235 346.3 [M+H] + 3-Bromo-5-nitrobenzene and 4-chloro-3-(trifluoromethyl)phenol Int-236 315.1 [M+H] + 4-Methoxy-3-nitrophenol and 2-chloro-5-(trifluoromethyl)pyridine Int-237 316.1 [M+H] + 3-Methoxy-5-nitrophenol and 2-chloro-5-(trifluoromethyl)pyridine Int-238 337.1 [M+H] + 8-Nitroquinoline-6-ol and 2-Chloro-5-(trifluoromethyl)pyridine Int-239 283.1 [M+H] + 3,4-Difluorophenylboronic acid and 3-methoxy-5-nitrophenol [intermediate] [240.]1-Methoxy-2-nitro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzene

[0167] DEAD (0.28 ml, 1.77 mmol) was added dropwise to a mixture of 4-methoxy-3-nitrophenol (0.25 g, 1.47 mmol), 4-trifluoromethyl-1-hydroxycyclohexane (0.20 ml, 1.47 mmol), and triphenylphosphine (465 mg, 1.77 mmol) in anhydrous THF (10 mL) under nitrogen atmosphere at RT, while stirring the mixture for 24 h. The mixture was diluted with Et₂O (30 ml) and washed with NaOH (2 × 10⁻⁸ ml), water (10 ml), and brine (10 ml). The organic phase was dehydrated with sodium sulfate, filtered, and concentrated. The crude residue was further purified by purification method A to give 0.1 g of the title compound. LCMS: m / z 320.28 [M+H]⁺

[0168] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 240. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-241 320.1 [M+H] + 3-Methoxy-5-nitrophenol and 4-trifluoromethyl-1-hydroxycyclohexane Int-242 320.1 [M+H] + 4-Methoxy-3-nitrophenol and 4-trifluoromethyl-1-hydroxycyclohexane Int-243 320.2 [M+H] + A mixture of cis / trans isomers of 4-methoxy-3-nitrophenol and 3-(trifluoromethyl)cyclohexanol. Int-244 320.2 [M+H] + 4-Fluoro-3-nitrophenol and 4-trifluoromethyl-1-hydroxycyclohexane Int-245 320.3 [M+H] + 2-Methoxy-5-nitrophenol and 4-trifluoromethyl-1-hydroxycyclohexane Int-246 320.3 [M+H] + 2-Methoxy-5-nitrophenol and 4-trifluoromethyl-1-hydroxycyclohexane Int-247 288.1 [M+H] + 3-Methoxy-5-nitrophenol and 1,1-difluoro-4-hydroxycyclohexane [Intermediate substance] [248.](E)-4-(3-fluorostyryl)-1-methoxy-2-nitrobenzene

[0169] Triethylphosphine (5.6 mL, 32.6 mmol) was added to 3-fluorobenzyl bromide (2.0 mL, 16.3 mmol) at RT under N2. The resulting mixture was heated at 150 °C for 2 h. The mixture was cooled and purified by rapid chromatography to give diethyl (3-fluorobenzyl)phosphonate. NaH (0.27 g, 11.0 mmol) was added to a mixture of diethyl (3-fluorobenzyl)phosphonate (0.82 g, 3.3 mmol) in anhydrous THF (10 mL) at 0 °C–5 °C. After 30 min, a solution of 4-methoxy-3-nitrobenzaldehyde (0.5 g, 2.8 mmol) in anhydrous THF (10 mL) was added dropwise to the mixture, followed by stirring at RT for 3 h. The mixture was cooled, quenched with ice water (20 mL), acidified with 2 M HCl, and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, dehydrated, evaporated, and subsequently purified by rapid chromatography to obtain the title compound. LCMS m / z 274.2 [M+H]+. 1H NMR (chloroform-d, 400 MHz) δ: 8.0-8.0 (m, 1H), 7.6-7.7 (m, 1H), 7.2-7.4 (m, 4H), 6.9-7.1 (m, 3H), 3.99 (s, 3H). [Intermediate substance] [249.] 1-Methoxy-2-nitro-4-(3-(trifluoromethyl)benzyl)benzene

[0170] 3-(trifluoromethyl)benzaldehyde (0.20 ml, 1.4 mmol) and toluenesulfonamide (0.27 g, 1.4 mmol) were mixed in a 1,4-didicarbonyl chloride solution. The mixture in alkane (10 ml) was heated at 60 °C for 90 min. K₂CO₃ (0.24 g, 1.8 mmol) and 4-methoxy-3-nitrophenylboronic acid (0.23 g, 1.2 mmol) were added to the obtained crude product (E)-4-methyl-N'-(3-(trifluoromethyl)benzylmethyl)benzenesulfonamide (0.4 g, 1.168 mmol). The mixture was heated at 110 °C for 4 h under nitrogen atmosphere, then cooled to RT. The mixture was quenched with 2 M NaHCO₃ (5 ml) and subsequently extracted with ethyl acetate (2 × 10⁻⁶ ml). The combined organic layers were washed with water, dehydrated, evaporated, and purified by rapid chromatography to give the title compound. LCMS m / z 312.3 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ: 3.89 - 4.00 (m, 3 H), 4.02 (s, 2 H), 7.03 (d, 1 H), 7.27 - 7.35 (m, 3 H), 7.49 - 7.62 (m, 2 H), 7.65 - 7.70 (m, 1 H). [Intermediate substance] [250.]1-Methoxy-2-nitro-4-(4-(trifluoromethyl)benzyl)benzene

[0171] 1-Methoxy-2-nitro-4-(4-(trifluoromethyl)benzene)benzene was prepared using 4-(trifluoromethyl)benzaldehyde as the starting material, following the procedure described for intermediate 234. LCMS m / z 312.3 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ: 3.90–4.04 (m, 5H), 6.99–7.26 (m, 1H), 7.32–7.34 (m, 1H), 7.39–7.63 (m, 4H), 7.69 (d, 1H). [Intermediate substance] [251.] 1-Methoxy-2-nitro-4-(4-(trifluoromethyl)benzyl)benzene

[0172] A mixture of 1-methoxy-3-nitro-5-(4-(trifluoromethyl)phenoxy)benzene (0.1 g, 1 eq., 0.32 mmol), zinc (0.21 g, 10 eq., 3.2 mmol), and ammonium chloride (0.17 g, 10 equiv., 3.2 mmol) in THF (5 ml), MeOH (2.5 ml), and water (2.5 ml) was stirred at RT for 4 h. The mixture was filtered through diatomaceous earth. The filtrate was washed with water (2 × 30 mL), dehydrated with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by rapid chromatography to give the title compound. LCMS m / z 284.1 [M] +

[0173] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 251. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-252 244.2 [M+H] + (E)-4-(3-fluorostyryl)-1-methoxy-2-nitrobenzene Int-253 290.6 [M+H] + 1-Methoxy-2-nitro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-254 282.2 [M+H] + 1-Methoxy-2-nitro-4-(3-(trifluoromethyl)benzene)benzene Int-255 286.1 [M] + 1-Chloro-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene Int-256 284.1 [M+H] + 1-Methoxy-4-nitro-2-(4-(trifluoromethyl)phenoxy)benzene Int-257 234.1 [M+H] + 4-(4-fluorophenoxy)-1-methoxy-2-nitrobenzene Int-258 284.1 [M+H] + 1-Methoxy-3-nitro-5-(4-(trifluoromethyl)phenoxy)benzene Int-259 249.3 [M+H] + 2-Fluoro-5-(4-methoxy-3-nitro-phenoxy)-3-methylpyridine Int-260 291.1 [M+H] + 1-Methoxy-3-nitro-5-((4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-261 291.1 [M+H] + 1-Methoxy-2-nitro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-262 291.2 [M+H] + 1-Methoxy-2-nitro-4-((3-(trifluoromethyl)cyclohexyl)oxy)benzene Int-263 278.1 [M+H] + 1-Fluoro-2-nitro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-264 290.1 ​​[M+H] + 1-Methoxy-4-nitro-2-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-265 290.1 ​​[M+H] + 1-Methoxy-4-nitro-2-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)oxy)benzene Int-266 284.3 [M+H] + 1-Methoxy-3-nitro-5-(3-(trifluoromethyl)phenoxy)benzene Int-267 318.2 [M+H] + 1-Chloro-4-(3-methoxy-5-nitrophenoxy)-2-(trifluoromethyl)benzene Int-268 259.1 [M+H] + 1-((4,4-difluorocyclohexyl)oxy)-3-methoxy-5-nitrobenzene Int-269 286.1 [M+H] + 2-(3-Methoxy-5-nitrophenoxy)-5-(trifluoromethyl)pyridine Int-270 284.1 [M+H] + 1-Methoxy-3-nitro-5-(4-(trifluoromethyl)phenoxy)benzene Int-271 306.0 [M+H] + 8-Nitro-6-((5-(trifluoromethyl)-pyridin-2-yl)oxy)quinoline Int-272 254.0 [M+H] + 1,2-Difluoro-4-(3-methoxy-5-nitrophenoxy)benzene Int-273 265.6 [M+H] + 1-(3,4-Difluorophenoxy)-4-methoxy-2-methyl-3-nitro-benzene Int-274 241.5 [M+H]+ 3-(4-methoxy-3-nitrophenoxy)benzonitrile Int-275 285.1 [M+H]+ 1,2-Dichloro-4-(4-methoxy-3-nitrophenoxy)benzene Int-276 267.1 [M+H]+ 2-Chloro-1-fluoro-4-(4-methoxy-3-nitrophenoxy)benzene Int-277 314.5 [M+H]+ 2-Methoxy-4-(4-Methoxy-3-nitrophenoxy)-1-(trifluoromethyl)benzene Int-278 284.4 [M+H]+ 1-Methoxy-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene Int-279 285.5 [M+H]+ 2-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)pyridine Int-280 302.5 [M+H]+ 2-Fluoro-4-(4-methoxy-3-nitro-phenoxy)-1-(trifluoromethyl)benzene Int-281 314.5 [M+H]+ 2-Methoxy-4-(4-Methoxy-3-nitrophenoxy)-1-(trifluoromethyl)benzene Int-282 309.5 [M+H]+ 4-(4-methoxy-3-nitrophenoxy)-2-(trifluoromethyl)benzonitrile Int-283 259.5 [M+H]+ 2-Fluoro-5-(4-methoxy-3-nitrophenoxy)benzonitrile Int-284 302.4 [M+H]+ 2-Fluoro-1-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)benzene Int-285 303.3 [M+H]+ 3-Fluoro-5-(4-methoxy-3-nitrophenoxy)-2-(trifluoromethyl)pyridine Int-286 303.3 [M+H]+ 2-Fluoro-6-(4-methoxy-3-nitrophenoxy)-3-(trifluoromethyl)pyridine Int-287 285.4 [M+H]+ 2-(4-methoxy-3-nitrophenoxy)-5-(trifluoromethyl)pyridine Int-288 222.2 [M+H] + 4-(cyclohexyloxy)-1-methoxy-2-nitrobenzene Int-289 220.2 [M+H] + 4-(cyclohexyl-2-en-1-yloxy)-1-methoxy-2-nitrobenzene [Intermediate substance] [290.]2-Methoxy-5-(3-(trifluoromethoxy)phenoxy)aniline

[0174] A mixture of 1-methoxy-2-nitro-4-(3-(trifluoromethoxy)phenoxy)benzene (0.050 g, 0.152 mol), zinc powder (0.050 g, 0.759 mmol), NH₄Cl (0.041 g, 0.759 mmol), ethanol (1.5 ml), and water (0.5 ml) was stirred at 50 °C until the reaction was complete (analyzed by LCMS). The mixture was filtered through a diatomaceous earth filter. The diatomaceous earth layer was further washed with ethanol and the filtrate was evaporated to give 0.040 g of the title compound. LCMS: m / z 299.8 [M+H]⁺. [Intermediate substance] [291.]5-(4-Isopropoxyphenoxy)-2-methoxyaniline

[0175] Following the procedure for intermediate 257, the compound was prepared from 4-(4-isopropoxyphenoxy)-1-methoxy-2-nitrobenzene (0.22 g, 0.725 mmol) using 4 eq. zinc powder and 4 eq. NH4Cl. The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.044 g. LCMS: m / z 273.9 [M+H]+. [Intermediate substance] [292.]2-Methoxy-5-(4-(trifluoromethoxy)phenoxy)aniline

[0176] A mixture of 1-methoxy-2-nitro-4-(4-(trifluoromethoxy)phenoxy)benzene (0.12 g, 0.364 mol), iron powder (0.061 g, 1.093 mmol), anhydrous CaCl₂ (0.040 g, 0.364 mmol), ethanol (1.0 ml), and water (0.25 ml) was stirred at 60 °C until the reaction was complete (analyzed by LCMS). The mixture was filtered through a diatomaceous earth filter. The diatomaceous earth layer was washed with EtOAc. The filtrate was washed with water (2×), dehydrated, and evaporated to give 0.090 g of the title compound. LCMS: m / z 299.7 [M] +

[0177] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 292. [serial number] [structure] [LCMS] m / z [Starting material] Int-293 287.9 ​​[M] + 1-Fluoro-2-nitro-4-(4-(trifluoromethoxy)phenoxy)benzene Int-294 265.6 [M] + 4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene Int-295 263.6 [M] + 1-Fluoro-2-methoxy-4-(4-methoxy-3-nitrophenoxy)benzene Int-296 304.5 [M+H] + 1-Chloro-2-nitro-4-(4-(trifluoromethoxy)phenoxy)benzene [Intermediate substance] [297.]2-amino-4-(4-(trifluoromethyl)phenoxy)benzamide

[0178] The compound was prepared from 2-nitro-4-(4-(trifluoromethyl)phenoxy)benzonitrile (0.36 g, 1.168 mmol) as the starting material, following the procedure for intermediate 292. The crude product was purified by rapid chromatography to give the title compound. Yield: 0.21 g. LCMS: m / z 296.8 [M]+. [Intermediate substance] [298.]5-(cyclohexylmethoxy)-2-methoxyaniline

[0179] A mixture of 4-(cyclohexylmethoxy)-1-methoxy-2-nitrobenzene (0.26 g, 0.98 mol), zinc powder (0.32 g, 4.90 mmol, 5.0 eq.), NH₄Cl (0.262 g, 4.90 mmol, 5.0 eq.), THF (3.0 ml), methanol (0.75 ml), and water (0.75 ml) was stirred at RT until the reaction was complete (analyzed by LCMS). The mixture was filtered through a diatomaceous earth filter. The diatomaceous earth layer was washed with EtOAc. The filtrate was washed with water (2×), dehydrated, and evaporated. The crude compound was purified by rapid chromatography to give 0.15 g of the title compound. LCMS: m / z 235.4 [M] +

[0180] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 298. [serial number] [structure] [purification;] [LCMS m / z] [Starting material] Int-299 crude matter; 263.6 [M] + 2-Fluoro-1-methoxy-4-(4-methoxy-3-nitrophenoxy)benzene Int-300 crude matter; 249.4 [M] + 4-((4,4-dimethylcyclohexyl)oxy)-1-methoxy-2-nitrobenzene Int-301 Rapid chromatography; 267.7 [M] + (3,4-Difluorophenyl)(4-methoxy-3-nitrophenyl)thione Int-302 crude matter; 244.6 [M+H] + 4-((3,3-difluorocyclobutyl)-methoxy)-1-methoxy-2-nitrobenzene Int-303 Rapid chromatography; 269.5 [M+H] + 5-(4-methoxy-3-nitrophenoxy)-1-methyl-1H-indole Int-304 Rapid chromatography; 258.5 [M+H] + 5-(4-methoxy-3-nitrophenoxy)-2,3-dihydrobenzofuran Int-305 crude matter; 251.1 [M+H] + 4-(3-Chlorophenoxy)-1-methoxy-2-nitrobenzene [Intermediate substance] [306.]5-(3-bromophenoxy)-2-methoxyaniline

[0181] The compound was prepared using the procedure described with respect to intermediate 298, starting with 4-(3-bromophenoxy)-1-methoxy-2-nitrobenzene (0.46 g, 1.419 mmol), with 7.5 eq. zinc powder and 7.5 eq. NH4Cl. Yield: 0.34 g. LCMS: m / z 294.2 [M]+.

[0182] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 306. [serial number] [structure] [purification;] [LCMS m / z] [Starting material] Int-307 Rapid chromatography; 332.2 [M] + 1-Bromo-2-nitro-4-(3-(trifluoromethyl)phenoxy)benzene Int-308 crude matter; 272.4 [M+H] + 1-(4-fluorophenoxy)-3-nitro-5-(trifluoromethyl)benzene Int-309 crude matter; 251.2 [M+H] + 4-(4-Chlorophenoxy)-1-methoxy-2-nitrobenzene Int-310 crude matter; 269.2 [M+H] + 1-Chloro-2-fluoro-4-(4-methoxy-3-nitrophenoxy)benzene Int-311 crude matter; 248.6 [M+H] + 4-(4-(fluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene [Intermediate substance] [312.]5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyaniline

[0183] Following the procedure for intermediate 298, the compound was prepared from 3-fluoro-2-(4-methoxy-3-nitrophenoxy)-5-(trifluoromethyl)pyridine (0.50 g, 1.505 mmol) as the starting material, using 10 eq. zinc powder and 10 eq. NH4Cl. Yield: 0.43 g. LCMS: m / z 303.5 [M+H]+.

[0184] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 312. [serial number] [structure] [purification;] [LCMS m / z] [Starting material] Int-313 crude matter; 289.5 [M+H] + 2-(3-chloro-5-nitrophenoxy)-5-(trifluoromethyl)pyridine Int-314 Rapid chromatography; 273.6 [M+H] + 2-(3-fluoro-5-nitrophenoxy)-5-(trifluoromethyl)pyridine [Intermediate substance] [315.]3-amino-5-(4-(trifluoromethyl)phenoxy)benzonitrile

[0185] 3-Nitro-5-(4-(trifluoromethyl)phenoxy)benzonitrile (0.22 g, 0.714 mmol) was reacted with 1,4-dioxane. Add 0.805 g (3.57 mmol) of stannous(II) dihydrate dissolved in 1.0 ml of 37% HCl aqueous solution to the mixture of alkane (3.5 ml). Stir the mixture at RT until the reaction is complete (analyzed by LC-MS). Make the mixture alkaline with 6 M NaOH solution. Add DCM and filter the mixture through a short diatomaceous earth stopper. Wash the diatomaceous earth with DCM. Dehydrate the filtrate and evaporate the solvent to give the title compound. Yield: 0.14 g. LCMS: m / z 279.3 [M+H]+.

[0186] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 315. [serial number] [structure] [purification;] [LCMS m / z] [Starting material] Int-316 crude matter; 276.2 [M+H] + 2-Chloro-4-(4-methoxy-3-nitrophenoxy)benzonitrile Int-317 Rapid chromatography; 279.2 [M+H] + 2-Nitro-4-(4-(trifluoromethyl)-phenoxy)benzonitrile Int-318 crude matter; 255.5 [M+H] + 4-(4-methoxy-3-nitrophenoxy)-2-methylbenzonitrile [Intermediate substance] [319.]1-Methoxy-2-nitro-4-(3-(trifluoromethoxy)phenoxy)benzene

[0187] DIPEA (0.871 ml, 5.00 mmol) was added to a mixture of 4-methoxy-3-nitrophenol (0.169 g, 1.00 mmol), 3-(trifluoromethoxy)phenylboronic acid (0.448 g, 2.18 mmol), anhydrous Cu(OAc)₂ (0.182 g, 1.00 mmol), and powdered 4 Å molecular sieve (0.25 g) in anhydrous DCM (7.5 ml). The mixture was stirred at RT until maximum conversion was achieved, as analyzed by LCMS (48 h). The mixture was filtered through a diatomaceous earth plug and the diatomaceous earth layer was washed with EtOAc. The filtrate was washed with 5% NH₄OH aqueous solution, dehydrated, and evaporated. The crude compound was purified by reversed-phase rapid chromatography to give 0.050 g of the title compound. LCMS: m / z 330.2 [M+H]⁺. [Intermediate substance] [320.]1-Methoxy-2-nitro-4-(4-(trifluoromethoxy)phenoxy)benzene

[0188] Pyridine (0.809 ml, 10.0 mmol) was added to a mixture of 4-methoxy-3-nitrophenol (0.338 g, 2.00 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.618 g, 3.00 mmol), anhydrous Cu(OAc)₂ (0.363 g, 2.00 mmol), and powdered 4 Å molecular sieve (0.25 g) in anhydrous DCM (15 ml). The mixture was stirred at RT until maximum conversion was achieved, as analyzed by LCMS (24–48 h). The mixture was filtered through a diatomaceous earth plug and the diatomaceous earth layer was washed with DCM. The filtrate was washed with 5% NH₄OH aqueous solution, dehydrated, and evaporated. The crude material was purified by rapid chromatography to give 0.33 g of the title compound. LCMS: m / z 330.2 [M+H]⁺.

[0189] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 320. [serial number] [structure] [LCMS m / z, / , , 1 , H NMR (400 MHz, CDCl , 3, ) , , ] [Starting material] Int-321 δ: 7.63-7.69 (m,1H), 7.23-7.32 (m, 4H), 7.01-7.08 (m, 2H) 4-Fluoro-3-nitrophenol and 4-(trifluoromethoxy)phenylboronic acid (2.2 eq) Int-322 294.0 [M+H] + 4-Methoxy-3-nitrophenol and 4-fluoro-3-methoxyphenylboronic acid (2.2 eq) Int-323 294.1 [M+H] + 4-Methoxy-3-nitrophenol and 3-fluoro-4-methoxyphenylboronic acid (1.8 eq.) Int-324 δ: 7.55 (d, 1H), 7.19-7.29 (m, 3H), 7.07-7.14 (m, 2H), 6.92 (ddd, 1H), 3.97 (s,3H) 4-Methoxy-3-nitrophenol and 3-bromophenylboronic acid (2.2 eq) Int-325 304.1 [M+H] + 4-Methoxy-3-nitrophenol and (4-isopropoxyphenyl)boronic acid (1.5 eq) Int-326 δ: 7.51 (d, 1H), 7.47 (d, 1H), 7.24-7.30 (m, 2H), 7.16 (dd, 1H), 7.05-7.11 (m, 2H) 4-Chloro-3-nitrophenol and (4-(trifluoromethoxy)phenyl)boronic acid (1.5 eq) Int-327 δ: 7.70 (d, 1H), 7.47-7.57 (m, 2H), 7.47 (d, 1H), 7.30-7.33 (m, 1H), 7.21-7.25 (m, 1H), 7.09 (dd, 1H) 4-Bromo-3-nitrophenol and (3-(trifluoromethyl)phenyl)boronic acid (2.2 eq) Int-328 279.9 [M] + 4-Methoxy-3-nitrophenol and (4-chlorophenyl)boronic acid (1.5 eq.) Int-329 δ: 7.55 (d, 1H), 7.35 (t, 1H), 7.25 (dd, 1H), 7.11 (d, 1H), 6.79 (dd, 1H), 6.72 (ddd, 1H), 3.97 (s, 3H) 4-Methoxy-3-nitrophenol and (4-chloro-3-fluorophenyl)boronic acid (1.5 eq.) Int-330 299.1 [M+H] + 4-Methoxy-3-nitrophenol and (1-methyl-1H-indol-5-yl)boronic acid (1.5 eq.) Int-331 287.8 [M] + 4-Methoxy-3-nitrophenol and (2,3-dihydrobenzofuran-5-yl)boronic acid (1.5 eq.) Int-332 279.9 [M] + 4-Methoxy-3-nitrophenol and (3-chlorophenyl)boronic acid [intermediate] [333.]4-(cyclohexylmethoxy)-1-methoxy-2-nitrobenzene

[0190] Diisopropyl azodicarbonate (0.738 ml, 3.75 mmol) was added to a mixture of cyclohexylmethanol (0.285 g, 2.50 mmol), 4-methoxy-3-nitrophenol (0.423 g, 2.50 mmol), and triphenylphosphine (0.984 g, 3.75 mmol) in anhydrous THF (17 ml) under cooling (0°C–5°C). The mixture was stirred overnight at RT. THF was evaporated and the residue was dissolved in DCM. The organic phase was washed with water and brine, dehydrated, and evaporated. The crude product was purified by rapid chromatography to give 0.26 g of the title compound. LCMS: m / z 266.2 [M+H]+

[0191] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 333. [serial number] [structure] [LCMS] m / z [Starting material] Int-334 280.0 [M+H] + 4-Fluoro-3-nitrophenol and 4,4-Dimethylcyclohexyl-1-ol Int-335 273.8 [M] + 4-Methoxy-3-nitrophenol and (3,3-difluorocyclobutyl)methanol [Intermediate substance] [336.]4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene a) 4-(4-methoxy-3-nitrophenoxy)benzaldehyde

[0192] A mixture of 4-fluorobenzaldehyde (0.215 ml, 2.00 mmol), 4-methoxy-3-nitrophenol (0.338 g, 2.00 mmol), and potassium carbonate (0.553 g, 4.00 mmol) in anhydrous DMA (4.0 ml) was stirred at 120 °C until the reaction was complete (analyzed by LCMS). Water was added to the cooled mixture and extracted with EtOAc. The organic phase was washed with water, dehydrated, and evaporated to give 0.49 g of the title compound. LCMS: m / z 274.1 [M+H]+. b) 4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene

[0193] 4-(4-methoxy-3-nitrophenoxy)benzaldehyde (0.49 g, 1.793 mmol) was dissolved in anhydrous DCM (5.5 ml) and cooled to 0-5 °C. Diethylaminosulfur trifluoride (0.521 ml, 3.95 mmol) was added in small amounts, and the mixture was stirred at RT for 24 h. The mixture was diluted with DCM and saturated NaHCO3 solution was added in small amounts. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with water and brine, dehydrated, and evaporated. The crude compound was purified by rapid chromatography to give 0.37 g of the title compound. LCMS: m / z 296.0 [M+H]+. [Intermediate substance] [337.](3,4-Difluorophenyl)(4-methoxy-3-nitrophenyl)thion

[0194] A mixture of 3,4-difluorothiophenol (0.155 ml, 1.40 mmol), 4-methoxy-3-nitrophenylboronic acid (0.197 g, 1.00 mmol), copper(II) sulfate (8.0 mg, 0.05 mmol), and 1,10-phenanthroline (9.0 mg, 0.05 mmol) in ethanol (1.0 ml) (bubbled with oxygen before use) was mixed with 40% tetrabutylammonium hydroxide aqueous solution (1.0 ml, 3.82 mmol). The mixture was stirred overnight at RT. The mixture was then diluted with EtOAc and filtered through a diatomaceous earth mat. The diatomaceous earth layer was further washed with EtOAc. The filtrate was evaporated and the crude substance was purified by rapid chromatography to give 0.17 g of the title compound. 1H NMR (400 MHz, CDCl 3): δ 7.88 (d, 1H), 7.56 (dd, 1H), 7.00-7.16 (m, 4H), 3.98 (s, 3H). [Intermediate substance] [338.]2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline a) 2-Chloro-1-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)benzene

[0195] A mixture of 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (0.397 g, 2.00 mmol), 4-methoxy-3-nitrophenol (0.372 g, 2.20 mmol), and potassium carbonate (0.608 g, 4.40 mmol) in anhydrous DMF (4.0 ml) was stirred at 120 °C until the reaction was complete (analyzed by LCMS). Water was added to the cooled mixture, and the mixture was stirred at RT for 1 h. The precipitate was filtered, washed with water, and dehydrated under reduced pressure to give 0.62 g of the title compound. LCMS: m / z 348.1 [M+H]+. b) 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline

[0196] 10 wt% palladium / carbon (0.253 g, 0.237 mmol) was added to a mixture of 2-chloro-1-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)benzene (0.66 g, 1.898 mmol) and ammonium formate (1.197 g, 18.98 mmol) in anhydrous methanol (35 ml). The mixture was stirred vigorously at RT until the reaction was complete (analyzed by LCMS). The mixture was filtered through a diatomaceous earth stopper and the diatomaceous earth layer was washed with methanol. The filtrate was evaporated and the residue was dissolved in EtOAc. The organic phase was washed with water, dehydrated, and evaporated to give 0.52 g of the title compound. LCMS: m / z 284.5 [M+H]+. [Intermediate substance] [339.]2-Chloro-4-(4-methoxy-3-nitrophenoxy)benzonitrile

[0197] A mixture of 4-methoxy-3-nitrophenol (0.677 g, 4.00 mmol, 1.0 eq.), 2-chloro-4-fluorobenzonitrile (0.622 g, 4.00 mmol, 1.0 eq.), and potassium carbonate (1.216 g, 8.80 mmol, 2.2 eq.) in anhydrous DMF (5.5 ml) was stirred at 100–120 °C until the reaction was complete (analyzed by LCMS). The cooled reaction mixture was treated with water, and the precipitate was filtered and dehydrated to give the title compound. Yield: 1.06 g. LCMS: m / z 304.5 [M+H]+. If the product did not precipitate from water, it was extracted with EtOAc. The organic phase was washed with water, dehydrated, and evaporated to give the title compound, which was used as is or purified by rapid chromatography.

[0198] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 339. [serial number] [structure] [purification] [LCMS] m / z [Starting material()] [eq.] [), base () [eq.] [)] Int-340 Rapid chromatography; 309.0 [M+H] + 4-(trifluoromethyl)phenol (1.1) and 4-fluoro-2-nitrobenzene (1.0); K₂CO₃ (2.2) Int-341 precipitation; 285.0 [M+H] + 4-Methoxy-3-nitrophenol (1.0) and 4-fluoro-2-methylbenzonitrile (1.0); K₂CO₃ (2.2) Int-342 precipitation; 319.2 [M+H] + 3-Chloro-5-nitrophenol (1.1) and 2-chloro-5-(trifluoromethyl)pyridine (1.0); K₂CO₃ (1.5) Int-343 crude matter; 303.2 [M+H] + 3-Fluoro-5-nitrophenol (1.0) and 2-chloro-5-(trifluoromethyl)pyridine (1.0); K₂CO₃ (1.5) Int-344 precipitation; 4-Methoxy-3-nitrophenol (1.1) and 2-chloro-5-(trifluoromethyl)pyridine (1.0); K₂CO₃ (1.5) Int-345 precipitation; 315.3 [M+H] + 4-Methoxy-3-nitrophenol (1.1) and 2,3-dichloro-5-(trifluoromethyl)pyridine (1.0); K₂CO₃ (1.5) Int-346 crude matter; 306.5 [M+H] + 4-Fluoro-3-nitrophenol (1.1) and 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (1.0); K₂CO₃ (1.5) Int-347 Rapid chromatography; 333.0 [M+H] + 4-Methoxy-3-nitrophenol (1.0) and 2,3-difluoro-5-(trifluoromethyl)pyridine (1.0); Cs₂CO₃ (1.25) [Intermediate substance] [348.]2-Nitro-4-(4-(trifluoromethyl)phenoxy)benzonitrile

[0199] A mixture of 4-(trifluoromethyl)phenol (0.40 g, 2.467 mmol), 4-fluoro-2-nitrobenzenenitrile (0.40 g, 2.408 mmol), and potassium carbonate (0.666 g, 4.82 mmol) in anhydrous N-methylacetamide (DMA) (5.0 ml) was stirred at 100 °C until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc. The organic phase was dehydrated and evaporated. The crude substance was purified by rapid chromatography to give the title compound. Yield: 0.40 g. ¹H NMR (400 MHz, CDCl₃) δ: 7.89 (d, 1H), 7.87 (d, 1H), 7.74–7.79 (m, 2H), 7.36 (dd, 1H), 7.20–7.25 (m, 2H). [Intermediate substance] [349.]3-Nitro-5-(4-(trifluoromethyl)phenoxy)benzonitrile

[0200] A mixture of 4-(trifluoromethyl)phenol (0.324 g, 2.00 mmol), 3,5-dinitrobenzonitrile (0.463 g, 2.40 mmol), and potassium phosphate (0.849 g, 4.00 mmol) in anhydrous DMA (3.0 ml) was stirred at 100 °C until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc. The organic phase was dehydrated and evaporated. The crude substance was purified by rapid chromatography to give the title compound. Yield: 0.42 g. LCMS: m / z 309.2 [M+H]+. [Intermediate substance] [350.]4-(4-(fluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene a)(4-(4-methoxy-3-nitrophenoxy)phenyl)methanol

[0201] A small amount of NaBH4 (0.204 g, 5.38 mmol) was added to a mixture of 4-(4-methoxy-3-nitrophenoxy)benzaldehyde (0.98 g, 3.59 mmol) in MeOH (15 ml) and the mixture was stirred at RT until the reaction was complete. The solvent was evaporated and the residue was treated with water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine, dehydrated, and evaporated to give the title compound. Yield: 0.97 g. LCMS: m / z 258.3 [MH2O+H]+. b) 4-(4-(fluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene

[0202] Add 0.25 ml (1.892 mmol) of diethylaminosulfur trifluoride (DAST) to a cooled (-78°C) solution of (4-(4-methoxy-3-nitrophenoxy)phenyl)methanol (0.48 g, 1.744 mmol) in anhydrous DCM (5.0 ml). Remove the cooling bath and heat the mixture to RT with stirring until the reaction is complete. Dilute the mixture with DCM (15 ml) and cool to 0°C to 5°C. Add saturated NaHCO3 solution (5 ml) to adjust the pH to 7–8. Separate the phases and extract the aqueous phase with DCM. Wash the combined organic phases with water and brine, dehydrate and evaporate. Purify the crude product by rapid chromatography to give the title compound. Yield: 0.26 g. 1H NMR (400 MHz, CDCl 3) δ: 7.53 (d, 1H), 7.36-7.41 (m, 2H), 7.25 (dd, 1H), 7.08 (d, 1H), 6.98-7.03 (m, 2H), 5.35 (d, 2H), 3.96 (s, 3H). [Intermediate substance] [351.]2,4-Difluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline

[0203] A mixture of 5-amino-2,4-difluorophenol (0.218 g, 1.50 mmol) and potassium tributoxide (0.185 g, 1.65 mmol) in anhydrous DMSO (3.0 ml) was stirred at RT for 1 h. 2-chloro-5-(trifluoromethyl)pyridine (0.272 g, 1.50 mmol) and K₂CO₃ (0.104 g, 0.75 mmol) were added, and stirring was continued at 120 °C until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc. The organic phase was washed with 1 M NaOH and water, dehydrated, and evaporated. The crude product was purified by filtration through a short silicone stopper and elution with EtOAc-heptane (4:1). The filtrate was evaporated and the residue was dehydrated under vacuum to give the title compound. Yield: 0.25 g. LCMS: m / z 291.5 [M+H]⁺. [Intermediate substance] [352.](2S, 4R)-4-hydroxy-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)aminomethyl)pyrrolidone-1-carboxylic acid methyl ester

[0204] To a mixture of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (0.085 g, 0.30 mmol), (2S,4R)-1-((benzyloxy)-carbonyl)-4-hydroxypyrrolidone-2-carboxylic acid (0.080 g, 0.30 mmol), EtOAc (0.40 ml), and pyridine (0.20 ml), 1-propane phosphate cyclic anhydride and 50 wt% EtOAc solution (0.30 ml, 0.509 mmol) were added. The mixture was stirred overnight at RT. The reaction mixture was quenched with 0.5% HCl solution and diluted with water and EtOAc. The phases were separated, and the organic phase was washed with 0.5% HCl solution, water, and brine, dehydrated, and evaporated to give the title compound. Yield: 0.111 g. LC-MS: m / z = 531.3 [M+H]+. The crude product was used as is or purified by reverse-phase rapid chromatography to obtain the pure compound.

[0205] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described with respect to intermediate 352. [serial number] [structure] [purification] [LCMS] m / z [Starting material] Int-353 crude matter; 481.4 [M+H] + 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (S)-1-(tert-butoxycarbonyl)-5-sideoxypyrrolidone-2-carboxylic acid Int-354 crude matter; 500.4 [M+H] + 5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyaniline and (tert-butoxycarbonyl)-L-proline Int-355 Reverse-phase rapid chromatography; 253.3 [M+H]+ 3-Amino-4-fluorophenol and 1-Methyl-5-sideoxypyrrolidone-2-carboxylic acid Int-356 crude matter; 498.4 [M+H] + 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (tertiary butyoxycarbonyl)glycine glycine [Intermediate substance] [357.]1-(2-methoxyacetylated)-5-sideoxypyrrolidone-2-carboxylic acid tributyl ester

[0206] A mixture of 0.37 g (2.00 mmol) of tributyl 5-side-oxypyrrolidone-2-carboxylic acid (THF) in anhydrous THF (5.0 ml) and cooled (0 °C–5 °C) was mixed with an oil solution of 60 wt% NaH (0.10 g (2.50 mmol) and stirred at 0 °C–5 °C for 30 min. 2-Methoxyacetyl chloride (0.26 g (2.40 mmol)) dissolved in anhydrous THF (2.5 ml) was added and stirring continued overnight at RT. The solvent was evaporated and the residue was treated with DCM and water. The phases were separated and the organic phase was washed with water and brine. The organic phase was dehydrated and evaporated to give the title compound. Yield: 0.51 g. LCMS: m / z 258.0 [M+H]+. The crude product was used as is or purified by reversed-phase rapid chromatography to obtain the pure compound.

[0207] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 357. [serial number] [structure] [purification] [LCMS] m / z [Starting material()] [eq.] [), base () [eq.] [)] Int-358 Reverse-phase rapid chromatography; 244.2 [M+H]+ 5-Side-oxypyrrolidone-2-carboxylic acid tributyl ester (1.0) and 1-iodo-2-methoxyethylene (1.38); NaH (1.75) Int-359 crude matter; 257.1 [M] + (S)-5-S-oxypyrrolidone-2-carboxylic acid tributyl ester (1.0) and 2-methoxyacetyl chloride (1.25); NaH (1.35) Int-360 crude matter; 243.3 [M+H] + (S)-1-methyl-2-sideoxyimidazolidine-4-carboxylic acid tributyl ester (1.0) and acetyl chloride (2.0); NaH (1.75) Int-361 Reverse-phase rapid chromatography; 258.2 [M+H]+ 1-(2-methoxy-2-sideoxyethyl)-5-sideoxypyrrolidone-2-carboxylic acid tributyl ester (1.0) and methyl 2-bromoacetate (2.5); NaH (2.0) [Intermediate substance] [362.](2-Methoxyacetyl)-L-proline tributyl ester

[0208] 2-Methoxyacetyl chloride (0.239 g, 2.20 mmol) was added to a mixture of L-proline tributyl ester (0.342 g, 2.00 mmol) and triethylamine (0.558 ml, 4.00 mmol) cooled (0 °C–5 °C) in anhydrous DCM (10 ml). The reaction mixture was stirred overnight at RT. The mixture was filtered, and the filtrate was washed with saturated NH₄Cl solution, saturated NaHCO₃ solution, and brine. The filtrate was dehydrated and evaporated to give the title compound. Yield: 0.34 g. LCMS: m / z 244.2 [M+H]⁺. [Intermediate substance] [363.](2-Methoxyacetyl)-L-proline tributyl ester

[0209] A mixture of L-proline tributyl ester (0.342 g, 2.00 mmol), 2-bromoacetamide (0.331 g, 2.40 mmol), and potassium bicarbonate (0.30 g, 3.00 mmol) in anhydrous ACN (10 ml) was stirred at 80 °C until the reaction was complete. The cooled mixture was filtered and the filtrate was evaporated. The residue was treated with water and DCM. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dehydrated and evaporated to give the title compound. Yield: 0.34 g. LCMS: m / z 229.4 [M+H]+. [Intermediate substance] [364.](S)-1-(2-methoxyacetylated)-5-sideoxypyrrolidone-2-carboxylic acid

[0210] Trifluoroacetic acid (2.50 ml, 32.4 mmol, 10.8 eq) was added to a mixture of (S)-1-(2-methoxyacetyl)-5-syloxypyrrolidone-2-carboxylic acid tributyl ester (0.77 g, 2.99 mmol) in anhydrous DCM (15 ml), and the mixture was stirred overnight at RT. The solvent was evaporated, and the residue was treated with toluene and evaporated again. This procedure was repeated, and the residue was dehydrated under vacuum to give the title compound. Crude product: (a) used as is in the next step, or (b) extracted with DCM after alkalization with saturated Na₂CO₃ solution, followed by dehydration and evaporation of the organic phase. LCMS: m / z 201.9 [M+H]⁺

[0211] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 364. [serial number] [structure] [Processor] [LCMS] m / z [Starting material()] [eq.] [);] [TFA] [(] [eq.] [)] Int-365 (a) / 202.0 [M+H] + 1-(2-methoxyacetyl)-5-sideoxypyrrolidone-2-carboxylic acid tributyl ester; TFA (10.5) Int-366 (a) / 188.0 [M+H] + 1-(2-methoxyethyl)-5-sideoxypyrrolidone-2-carboxylic acid tributyl ester; TFA(12.5) Int-367 (a) / 187.9 [M+H] + (2-Methoxyacetyl)-L-proline tributyl ester; TFA(11.2) Int-368 (a) / 173.0 [M+H] + (2-amino-2-sideoxyethyl)-L-proline tributyl ester; TFA (10.5) Int-369 (a) / 187.0 [M+H] + (S)-3-acetylated-1-methyl-2-semi-oxyimidazolidine-4-carboxylic acid tributyl ester; TFA (10.3) Int-370 (a) / 202.1 [M+H] + 1-(2-methoxy-2-sideoxyethyl)-5-sideoxypyrrolidone-2-carboxylic acid tributyl ester; TFA(10.4) [Intermediate substance] [371.](E)-5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-amine

[0212] 5-bromo-2,3-dihydrobenzofuran-7-amine (0.158 g, 0.738 mmol), 2-[(E)-2-(4,4-difluorocyclohexyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboron (0.243 g, 1.15 mmol), K₃PO₄ (0.313 g, 2.0 mmol), and SPhos Pd G₂ (0.040 g, 0.075 mmol) were prepared in a two-phase system. The mixture of alkane (1 ml) and water (1 ml) was heated at 85 °C for 8 h under a nitrogen atmosphere. The mixture was extracted with ethyl acetate (2 × 4 ml). The combined organic layers were evaporated and subsequently purified by normal-phase chromatography to give 0.144 g of the title compound. 1H NMR (400 MHz, DMSO- d 6) δ: 1.34 - 1.46 (2 H, m), 1.76 - 1.95 (4 H, m), 1.97 - 2.09 (2 H, m), 2.20 - 2.29 (1 H, m), 3.08 (2 H, t), 4.47 (2 H, t), 4.57 (2 H, s), 5.88 - 5.95 (1 H, m), 6.21 (1 H, d), 6.50 (1 H, d), 6.53 (1 H, br s). LCMS: m / z 280.7 [M+H] +

[0213] The following intermediates are prepared from the starting materials indicated in the table according to the procedure described in relation to intermediate 371. [serial number] [structure] [LCMS / GCMS] m / z [Starting material] Int-372 282.5 [M+H]+ 6-Bromo-1,3-dioxane-4-amine and 2-[(E)-2-(4,4-difluorocyclohexyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboron [Intermediate substance] [373.] 1-(((benzooxy)carbonyl)glycinyl)-5-sideoxypyrrolidone-2-carboxylic acid a)((benzooxy)carbonyl)glycine 4-nitrobenzene ester

[0214] Triethylamine (290 mg, 2.87 mmol, 1.2 eq.) was added to a suspension of N-benzyloxycarbonylglycine (1 eq.) in anhydrous CH₂Cl₂ (12 mL). The stirred mixture was cooled to 0 °C and 4-nitrobenzene chloroformate (578 mg, 2.87 mmol, 1.2 eq.) was added. After 10 min, DMAP (29.2 mg, 0.239 mmol, 0.1 eq.) was added and the mixture was stirred at 0 °C for 1 h. The mixture was further diluted with CH₂Cl₂ (20 mL) and washed with saturated NaHCO₃ solution (10 mL), 0.1 M HCl solution (10 mL), and brine (10 mL), followed by dehydration (Na₂SO₄), filtration, and vacuum evaporation to give the crude product. The crude residue was further purified by reversed-phase chromatography to obtain the title compound. LCMS: m / z 331.068 (M+H)+. b) 1-(((benzooxy)carbonyl)glycinyl)-5-sideoxypyrrolidone-2-carboxylic acid tributyl ester

[0215] LiHMDS (896 μL, 0.896 mmol, 1.06 eq.) was added dropwise to a solution of 5-sideoxy-2-pyrrolidone carboxylic acid tributyl ester (157 mg, 0.845 mmol, 1 eq.) in anhydrous THF (3 mL) at -78 °C under nitrogen atmosphere. The mixture was stirred at RT for 15 min, followed by the addition of ((benzyloxy)carbonyl)glycine 4-nitrophenyl ester in anhydrous THF (4 mL) at -78 °C. The mixture was stirred at this temperature for 1 h. The mixture was diluted with ethyl acetate (20 mL) and washed with NH4Cl (10 mL) and brine (10 mL), then dehydrated (Na2SO4), filtered, and the solvent was evaporated under vacuum to give the crude product. The crude residue was further purified by reversed-phase chromatography to obtain the title compound. LCMS: m / z 377.155 (M+H)+. c) 1-(((benzoxy)carbonyl)glycinyl)-5-sideoxypyrrolidone-2-carboxylic acid (intermediate 287)

[0216] Trifluoroacetic acid was added dropwise to a solution of 1-(((benzyloxy)carbonyl)glycinyl)-5-sideoxypyrrolidone-2-carboxylic acid tributyl ester (285 mg, 0.76 mmol, 1 eq.) in anhydrous DCM at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. The DCM and trifluoroacetic acid residues were removed under vacuum to give the crude product. The crude residue was further purified by reversed-phase chromatography to obtain the title compound. LCMS: m / z 321.031 (M+H)+. [Example] [1.]N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methylamine (Compound 1)

[0217] To a solution of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (215 mg, 1 eq., 759 µmol) in anhydrous acetonitrile (5 mL), 5-side-oxypyrrolidone-2-carboxylic acid (98.0 mg, 1 eq., 759 µmol) and 1-methyl-1H-imidazolium (312 mg, 5 eq., 3.80 mmol) were added. The mixture was stirred at RT for 10 min, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (319 mg, 1.5 eq., 1.14 mmol) was added in a single batch. The resulting solution was stirred at RT overnight, and the mixture was purified directly by method A to give the title compound (0.194 g). 1H NMR (400 MHz, DMSO- d 6) δ: 9.35 (s, 1H), 7.91 (d, 2H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.91 (dd, 1H), 4.38 (dd, 1H), 3.88 (s, 3H), 2.38 - 2.27 (m, 1H), 2.26 - 2.07 (m, 2H), 2.02 - 1.90 (m, 1H). LCMS: m / z395.0 [M+H]+.

[0218] The following compounds were prepared according to the procedure described for compound 1. Compound codes, structures, starting materials, purification methods, and characterization information are indicated in the table. [serial number] [Structure and Starting Materials] [Purification methods and characterization information] 2 Starting material: 5-(3-fluoro-phenoxy)-2-methoxyaniline and 1-Acetyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.73 (s, 1H), 7.84 (d, 1H), 7.41-7.29 (m, 1H), 7.10 (d, 1H), 6.94-6.80 (m, 2H), 6.80-6.69 (m, 2H), 5.07 (d, 1H), 2.65-2.51 (m, 2H), 2.37 (s, 3H), 2.34-2.19 (m, 1H), 1.97-1.83 (m, 1H). LCMS: m / z 387.2 [M+H] + 3 Starting materials: 5-((3-fluorophenoxy)methyl)-2-methoxyaniline and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.62 (s, 1H), 8.09 (d, 1H), 7.36-7.25 (m, 1H), 7.18 (d, 1H), 7.11-6.99 (m, 1H), 6.91-6.79 (m, 2H), 6.79-6.68 (m, 1H), 5.05 (dd, 1H), 4.99 (s, 2H), 3.86 (s, 3H), 2.71-2.53 (m, 2H), 2.34-2.23 (m, 1H), 1.99-1.84 (m, 1H). LCMS: m / z 401.4 [M+H] + 4 Starting materials: 5-((3-fluorophenoxy)methyl)-2,4-methoxyaniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.11 (s, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.37-7.22 (m, 1H), 6.89-6.71 (m, 4H), 4.96 (s, 2H), 4.34-4.19 (m, 1H), 3.87 (d, 6H), 2.31-2.04 (m, 3H), 2.01-1.90 (m, 1H). LCMS: m / z 389.2 [M+H] + 5 Starting materials: 5-((3-fluorophenoxy)methyl)-2-methoxyaniline HCl and 1-(2-fluoroethyl)azacyclobutane-3-carboxylate lithium Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.26 (s, 1H), 8.11 (s, 1H), 7.35-7.26 (m, 1H), 7.16 (d, 1H), 7.04 (d, 1H), 6.94-6.81 (m, 2H), 6.79-6.71 (m, 1H), 5.01 (s, 2H), 4.45 (t, 1H), 4.33 (t, 1H), 3.83 (s, 3H), 3.56-3.41 (m, 3H), 3.28-3.21 (m, 2H), 2.70 (t, 1H), 2.62 (t, 1H). LCMS: m / z 377.2 [M+H] + 6 Starting materials: 5-((3-fluorophenoxy)methyl)-2-methoxyaniline HCl and racemic-(trans)-3-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.28 (d, 1H), 8.09 - 8.00 (m, 1H), 7.86 (d, 1H), 7.34-7.25 (m, 1H), 7.19 (d, 1H), 7.07 (d, 1H), 6.91-6.80 (m, 2H), 6.80-6.69 (m, 1H), 5.02 (s, 2H), 4.36 (d, 1H), 3.85 (s, 3H), 2.24-1.84 (m, 1H), 1.07 (dd, 3H). LCMS: m / z 373.2 [M+H] + 7 Starting materials: 3-(3-(trifluoromethyl)phenoxy)aniline and 4-side-oxyazinon-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 10.31 (s, 1H), 8.23 ​​(s, 1H), 7.68-7.61 (m, 1H), 7.51 (d, 1H), 7.47-7.30 (m, 5H), 6.82 (d, 1H), 4.12 (d, 1H), 3.16 (dd, 1H), 2.91-2.78 (m, 1H). LCMS: m / z 351.2 [M+H] + 8 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 4-sideoxyazinon-2-carboxylic acid Purification method A. 1H NMR (500 MHz, DMSO- d 6) δ: 9.48 (s, 1H), 8.25 (s, 1H), 7.89 (s, 1H), 7.61-7.55 (m, 1H), 7.42 (d, 1H), 7.25-7.18 (m, 2H), 7.11 (d, 1H), 6.88 (dd, 1H), 4.37-4.31 (m, 1H), 3.86 (s, 3H), 3.15 (dd, 1H), 2.83 (d, 1H). LCMS: m / z 281.0 [M+H] + 9 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 2-(5-sideoxypyrrolidin-2-yl)acetic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.32 (s, 1H), 7.88 (s, 1H), 7.63-7.53 (m, 2H), 7.42 (d, 1H), 7.25-7.18 (m, 2H), 7.09 (d, 1H), 6.85 (dd, 1H), 3.88 (d, 1H), 3.86 (s, 3H), 2.69-2.57 (m, 2H), 2.22-2.02 (m, 3H), 1.74-1.60 (m, 1H). LCMS: m / z 409.2 [M+H] + 10 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.34 (s, 1H), 7.95-7.87 (m, 2H), 7.58 (dd, 1H), 7.43 (d, 1H), 7.26-7.19 (m, 2H), 7.12 (d, 1H), 6.88 (dd, 1H), 4.38 (dd, 1H), 3.87 (s, 3H), 2.39-2.27 (m, 1H), 2.27-2.03 (m, 2H), 2.02-1.88 (m, 1H). LCMS: m / z 395.0 [M+H] + 11 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 1-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.63 (s, 1H), 7.85 (d, 1H), 7.63-7.55 (m, 1H), 7.43 (d, 1H), 7.25-7.19 (m, 2H), 7.13 (d, 1H), 6.90 (dd, 1H), 4.52-4.41 (m, 1H), 3.88 (s, 3H), 2.64 (s, 3H), 2.33-2.15 (m, 3H), 1.93-1.85 (m, 1H). LCMS: m / z 409.2 [M+H] + 12 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 1,1-dioxide of tetrahydrothiophene-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.61 (s, 1H), 7.85 (d, 1H), 7.63-7.54 (m, 1H), 7.43 (d, 1H), 7.21 (s, 2H), 7.12 (d, 1H), 6.89 (dd, 3.0 Hz, 1H), 3.69-3.59 (m, 1H), 3.40-3.33 (m, 1H), 3.29-3.20 (m, 1H), 3.17-3.01 (m, 2H), 2.45-2.37 (m, 1H), 2.21-2.07 (m, 1H). LCMS: m / z 430.0 [M+H] + 13 Starting materials: 5-((3-fluorophenoxy)methyl)-2-methoxyaniline HCl and 1,1-dioxide of 2-methylisothiazolidin-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.36 (s, 1H), 8.11 (s, 1H), 7.37-7.26 (m, 1H), 7.22 (d, 1H), 7.08 (d, 1H), 6.93-6.80 (m, 2H), 6.80-6.72 (m, 1H), 5.03 (s, 2H), 4.02 (t, 1H), 3.86 (s, 3H), 3.41-3.33 (m, 1H), 3.29-3.20 (m, 1H), 2.64 (s, 3H), 2.63-2.58 (m, 1H), 2.32-2.20 (m, 1H). LCMS: m / z 409.2 [M+H] + 14 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 2-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (500 MHz, DMSO- d 6) δ: 8.85 (s, 1H), 8.36 (s, 1H), 7.90 (d, 1H), 7.62-7.54 (m, 1H), 7.43 (d, 1H), 7.25-7.18 (m, 2H), 7.13 (d, 1H), 6.88 (dd, 1H), 3.86 (s, 3H), 2.31-2.26 (m, 1H), 2.22 (t, 2H), 2.00-1.89 (m, 1H), 1.40 (s, 3H). LCMS: m / z 409.2 [M+H] + 15 Starting material: 5-(3-fluorophenoxy)-2-methoxyaniline and 2-Methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (500 MHz, DMSO- d 6) δ: 8.83 (s, 1H), 8.36 (s, 1H), 7.89 (d, 1H), 7.40-7.33 (m, 1H), 7.11 (d, 1H), 6.94-6.88 (m, 1H), 6.85 (dd, 1H), 6.80-6.70 (m, 2H), 3.86 (s, 3H), 2.32-2.25 (m, 1H), 2.25-2.20 (m, 2H), 2.00-1.91 (m, 1H), 1.40 (s, 3H). LCMS: m / z 359.2 [M+H] + 16 Starting materials: 3-(3-(trifluoromethyl)phenoxy)aniline and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 10.15 (s, 1H), 7.84 (s, 1H), 7.68 - 7.59 (m, 1H), 7.51 (d, 1H), 7.45-7.28 (m, 5H), 6.81 (d, 1H), 4.15 (dd, 1H), 2.36-2.27 (m, 1H), 2.22-2.04 (m, 2H), 2.03-1.90 (m, 1H). LCMS: m / z 364.2 [M+H] + 17 Starting materials: 5-((3-fluorophenoxy)methyl)benzofuran-7-amine and 5-sideoxypyrrolidone-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 10.20 (s, 1H), 8.07 (s, 1H), 7.90 (d, 2H), 7.53 (s, 1H), 7.35-7.27 (m, 1H), 7.04-7.00 (m, 1H), 6.95-6.85 (m, 2H), 6.82-6.73 (m, 1H), 5.18 (d, 2H), 4.41 (dd, 1H), 2.38 (q, 1H), 2.29-2.12 (m, 2H), 2.11-1.99 (m, 1H). LCMS: m / z 369.0 [M+H] + 18 Starting materials: 5-(3-fluorophenoxy)-2-methoxyaniline and 5-sideoxytetrahydropyrrolo[2,1-b]thiazole-7a(5H)-formic acid Purification method A. 1H NMR (400 MHz, methanol-d 4) δ: 7.83 (d, 1H), 7.36-7.26 (m, 1H), 7.09 (d, 1H), 6.87 (dd, 1H), 6.84-6.72 (m, 2H), 6.71-6.60 (m, 1H), 4.59 (s, 1H), 4.47-4.38 (m, 1H), 3.94 (s, 3H), 3.26-3.19 (m, 3H), 2.89-2.70 (m, 2H), 2.67-2.52 (m, 2H). LCMS: m / z 403.2 [M+H] + 19 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 5-sideoxytetrahydropyrrolo[2,1-b]thiazole-7a(5H)-formic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.19 (s, 1H), 7.70 (d, 1H), 7.63-7.55 (m, 1H), 7.44 (d, 1H), 7.23 (d, 2H), 7.15 (d, 1H), 6.94 (dd, 1H), 4.38-4.23 (m, 1H), 3.87 (s, 3H), 3.18-3.00 (m, 3H), 2.75-2.56 (m, 3H), 2.47-2.38 (m, 1H). LCMS: m / z 453.0 [M+H] + 20 Starting materials: 5-((3-fluorophenoxy)methyl)-2-methoxyaniline HCl and racemic-(cis)-3-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.32 (s, 1H), 8.04 (d, 1H), 7.81 (s, 1H), 7.37-7.26 (m, 1H), 7.19 (dd, 1H), 7.07 (d, 1H), 6.92-6.80 (m, 2H), 6.80-6.69 (m, 1H), 5.02 (s, 2H), 4.36 (d, 1H), 3.85 (s, 3H), 2.70-2.62 (m, 1H), 2.20 (dd, 1H), 1.91 (dd, 1H), 0.99 (d, 3H). LCMS: m / z 373.2 [M+H] + twenty one Starting materials: (E)-5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyaniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.19 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.12 (d, 1H), 7.00 (d, 1H), 6.35 (d, 1H), 6.05 (dd, 1H), 4.35 (d, 1H), 3.83 (s, 3H), 2.35-1.79 (m, 11H), 1.43 (q, 2H). LCMS: m / z 379.2 [M+H] + twenty two Starting materials: (E)-5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyaniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.47 (s, 1H), 8.01 (s, 1H), 7.13 (d, 1H), 7.00 (d, 1H), 6.35 (d, 1H), 6.06 (dd, 1H), 4.48-4.39 (m, 1H), 3.83 (s, 3H), 2.67 (s, 3H), 2.39-2.15 (m, 4H), 2.09-1.97 (m, 2H), 1.97-1.74 (m, 5H), 1.43 (q, 2H). LCMS: m / z 393.2 [M+H] + twenty three Starting material: racemic-(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide Purification method A, followed by method H. Retention time = 17.42 min; ee 98%. ¹H NMR (400 MHz, DMSO-d 6) δ: 9.49 (s, 1H), 8.02 (d, 1H), 7.13 (dd, 1H), 7.00 (d, 1H), 6.34 (d, 1H), 6.06 (dd, 1H), 4.51–4.35 (m, 1H), 3.83 (s, 3H), 2.67 (s, 3H), 2.28–2.20 (m, 4H), 2.14–1.75 (m, 7H), 1.50–1.32 (m, 2H). LCMS: m / z 393.2 [M+H]+ twenty four Starting material: racemic-(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide Purification method A, followed by method H. Retention time = 20.55 min; ee 100%. ¹H NMR (400 MHz, DMSO-d 6) δ: 9.49 (s, 1H), 8.02 (d, 1H), 7.13 (dd, 1H), 7.00 (d, 1H), 6.34 (d, 1H), 6.06 (dd, 1H), 4.51–4.36 (m, 1H), 3.83 (s, 3H), 2.67 (s, 3H), 2.34–2.17 (m, 4H), 2.11–1.98 (m, 2H), 1.98–1.76 (m, 5H), 1.51–1.32 (m, 2H). LCMS: m / z 393.2 [M+H] + 25 Starting material: 5-(3-fluorophenoxy)-2-methoxyaniline and (R)-5-Syne-5-O-pyrrolidone-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.33 (s, 1H), 7.91 (s, 1H), 7.87 (d, 1H), 7.44-7.34 (m, 1H), 7.10 (d, 1H), 6.93-6.88 (m, 1H), 6.85 (dd, 1H), 6.80-6.72 (m, 2H), 4.38 (dd, 1H), 3.86 (s, 3H), 2.35-2.25 (m, 1H), 2.24-2.03 (m, 2H), 2.03-1.82 (m, 1H). LCMS: m / z 354.2 [M+H] + 26 Starting materials: 5-((3-fluorophenoxy)methyl)-2-methoxyaniline HCl and 3-methyl-2-sideoxypyrrolidone-3-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 10.11 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.37-7.24 (m, 1H), 7.14 (d, 1H), 7.05 (d, 1H), 6.95-6.80 (m, 2H), 6.80-6.71 (m, 1H), 5.02 (s, 2H), 3.29-3.12 (m, 2H), 2.58-2.52 (m, 1H), 2.05-1.89 (m, 1H), 1.41 (s, 3H). LCMS: m / z 373.0 [M+H] + 27 Starting materials: 6-((3-fluorophenoxy)methyl)benzo[d][1,3]m-dioxane-4-amine and 5-sideoxypyrrolidone-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.84 (s, 1H), 7.88 (s, 1H), 7.36 (d, 1H), 7.35-7.25 (m, 1H), 6.91-6.80 (m, 3H), 6.80-6.73 (m, 1H), 6.07 (d, 2H), 4.99 (s, 2H), 4.28 (dd, 1H), 2.38-2.27 (m, 1H), 2.27-2.05 (m, 2H), 2.05-1.89 (m, 1H). LCMS: m / z 374.2 [M+H] + 28 Starting materials: 5-(3-(trifluoromethyl)phenoxy)benzofuran-7-amine and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 10.61 (s, 1H), 8.14 (d, 1H), 7.70 (d, 1H), 7.63-7.57 (m, 1H), 7.46 (d, 1H), 7.31-7.24 (m, 2H), 7.19 (d, 1H), 7.01 (d, 1H), 4.51-4.43 (m, 1H), 2.68 (s, 3H), 2.34-2.22 (m, 3H), 2.00-1.92 (m, 1H). LCMS: m / z 419.0 [M+H] + 29 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.74 (s, 1H), 7.85 (d, 1H), 7.61-7.53 (m, 1H), 7.42 (d, 1H), 7.20 (d, 2H), 7.12 (d, 1H), 6.88 (dd, 1H), 5.07 (d, 1H), 3.89 (s, 3H), 3.37-3.32 (m, 1H), 2.47-2.40 (m, 1H), 2.37 (s, 3H), 2.35-2.22 (m, 1H), 1.99-1.87 (m, 1H). LCMS: m / z 437.0 [M+H] + 30 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A, followed by method I. Retention time 23.52 min; ee 100%. 1H NMR (400 MHz, DMSO-d 6) δ: 9.74 (s, 1H), 7.85 (d, 1H), 7.61-7.53 (m, 1H), 7.42 (d, 1H), 7.20 (d, 2H), 7.12 (d, 1H), 6.88 (dd, 1H), 5.07 (d, 1H), 3.89 (s, 3H), 3.37-3.32 (m, 1H), 2.47-2.40 (m, 1H), 2.37 (s, 3H), 2.35-2.22 (m, 1H), 1.99-1.87 (m, 1H). LCMS: m / z 437.0 [M+H] + 31 Starting materials: 5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-amine and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.49 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.36-7.25 (m, 1H), 7.11 (s, 1H), 6.91-6.80 (m, 2H), 6.80-6.69 (m, 1H), 4.98 (s, 2H), 4.61 (t, 2H), 4.32 (dd, 1H), 3.23 (t, 2H), 2.35-2.25 (m, 1H), 2.25-2.06 (m, 2H), 2.06-1.89 (m, 1H). LCMS: m / z 371.2 [M+H] + 32 Starting materials: 5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-amine and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 9.77 (s, 1H), 7.73 (s, 1H), 7.32-7.24 (m, 1H), 7.10 (s, 1H), 6.89-6.79 (m, 2H), 6.74 (dd, 1H), 4.96 (s, 2H), 4.60 (t, 2H), 4.39-4.31 (m, 1H), 3.22 (t, 2H), 2.64 (s, 3H), 2.31-2.17 (m, 3H), 1.94-1.84 (m, 1H). LCMS: m / z 385.2 [M+H] + 33 Starting materials: 6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxane-4-amine and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.95 (s, 1H), 7.83 (s, 1H), 7.64-7.54 (m, 1H), 7.45 (d, 1H), 7.25 (d, 2H), 7.13 (d, 1H), 6.68 (d, 1H), 6.12 (s, 2H), 4.29 (dd, 1H), 2.35-2.25 (m, 1H), 2.22-2.06 (m, 2H), 2.00-1.86 (m, 1H). LCMS: m / z 409.2 [M+H] + 34 Starting materials: 6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-amine and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 10.19 (s, 1H), 7.63-7.54 (m, 1H), 7.44 (d, 1H), 7.24 (d, 2H), 7.15 (d, 1H), 6.73-6.66 (m, 1H), 6.13 (d, 2H), 4.34 (dd, 1H), 2.69-2.60 (m, 3H), 2.31-2.14 (m, 3H), 1.94-1.83 (m, 1H). LCMS: m / z 423.0 [M+H] + 35 Starting materials: 3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyaniline and 1-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 9.80 (s, 1H), 7.88 (s, 1H), 7.35-7.26 (m, 1H), 7.15 (dd, 1H), 6.90-6.86 (m, 1H), 6.85-6.80 (m, 1H), 6.80-6.74 (m, 1H), 5.03 (s, 2H), 4.48-4.43 (m, 1H), 3.85 (s, 3H), 2.66 (s, 3H), 2.32-2.17 (m, 3H), 1.95-1.89 (m, 1H). LCMS: m / z 391.2 [M+H] + 36 Starting materials: 3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyaniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 9.52 (s, 1H), 7.91 (s, 2H), 7.36-7.25 (m, 1H), 7.13 (dd, 1H), 6.89-6.85 (m, 1H), 6.83 (dd, 1H), 6.79-6.72 (m, 1H), 5.04 (s, 2H), 4.39 (dd, 1H), 3.84 (s, 3H), 2.38-2.30 (m, 1H), 2.25-2.16 (m, 1H), 2.16-2.06 (m, 1H), 2.03-1.94 (m, 1H). LCMS: m / z 377.1 [M+H] + 37 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 1-ethyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.66 (s, 1H), 7.85 (d, 1H), 7.63-7.55 (m, 1H), 7.43 (d, 1H), 7.24-7.18 (m, 2H), 7.13 (d, 1H), 6.90 1.00 (t, 3H). LCMS: m / z 423.0 [M+H] + 38 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 1-(cyclopropanecarbonyl)-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.70 (s, 1H), 7.85 (d, 1H), 7.61-7.54 (m, 1H), 7.42 (d, 1H), 7.23-7.15 (m, 2H), 7.12 (d, 1H), 6.87 (dd, 1H), 5.06 (dd, 1H), 3.88 (s, 3H), 3.18-3.07 (m, 1H), 2.70-2.54 (m, 2H), 2.36-2.24 (m, 1H), 1.98-1.86 (m, 1H), 0.99-0.76 (m, 4H). LCMS: m / z 463.0 [M+H] + 39 Starting materials: 4-fluoro-2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.77 (s, 1H), 7.93 (d, 1H), 7.62-7.54 (m, 1H), 7.44 (d, 1H), 7.28-7.15 (m, 4H), 5.03 (d, 1H), 3.92 (s, 3H), 2.65-2.57 (m, 2H), 2.37 (s, 3H), 2.31-2.22 (m, 1H), 1.99-1.88 (m, 1H). LCMS: m / z 455.1 [M+H] + 40 Starting materials: 2-fluoro-5-(3-(trifluoromethyl)phenoxy)aniline and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 10.29 (s, 1H), 7.80 (dd, 1H), 7.64-7.56 (m, 1H), 7.48 (d, 1H), 7.41-7.22 (m, 3H), 6.96-6.87 (m, 1H), 4.98 (dd, 1H), 2.68-2.52 (m, 2H), 2.38 (s, 3H), 2.35-2.25 (m, 1H), 2.01-1.93 (m, 1H). LCMS: m / z 383.2 [M+H] + 41 Starting materials: 2-fluoro-5-(3-(trifluoromethyl)phenoxy)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, methanol-d 4) δ: 7.81 (dd, 1H), 7.59-7.52 (m, 1H), 7.41 (d, 1H), 7.30-7.19 (m, 3H), 6.93-6.84 (m, 1H), 4.42 (dd, 1H), 2.83 (s, 3H), 2.57-2.32 (m, 3H), 2.13-2.05 (m, 1H). LCMS: m / z 397.0 [M+H] + 42 Starting materials: 5-(2,4-difluorophenoxy)-2-methoxyaniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 9.27 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H), 7.47-7.39 (m, 1H), 7.19-7.12 (m, 1H), 7.09-7.05 (m, 1H), 7.03 (d, 1H), 6.71 (dd, 1H), 4.35 (dd, 1H), 3.82 (s, 3H), 2.33-2.25 (m, 1H), 2.20-2.13 (m, 1H), 2.12-2.05 (m, 1H), 1.95-1.89 (m, 1H). LCMS: m / z 363.2 [M+H] + 43 Starting materials: 5-(2,4-difluorophenoxy)-2-methoxyaniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.57 (s, 1H), 7.80 (d, 1H), 7.50-7.42 (m, 1H), 7.21-7.11 (m, 1H), 7.07 (dd, 2H), 6.74 (dd, 1H), 4.50-4.40 (m, 1H), 3.84 (s, 3H), 2.64 (s, 3H), 2.29-2.11 (m, 3H), 1.92-1.83 (m, 1H). LCMS: m / z 377.2 [M+H] + 44 Starting materials: 5-(2,4-difluorophenoxy)-2-methoxyaniline and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.67 (s, 1H), 7.81 (d, 1H), 7.50-7.39 (m, 1H), 7.17-7.10 (m, 1H), 7.10-7.02 (m, 2H), 6.72 (dd, 1H), 5.06 (dd, 1H), 3.85 (s, 3H), 2.66-2.54 (m, 2H), 2.38 (s, 3H), 2.33-2.20 (m, 1H), 1.97-1.85 (m, 1H). LCMS: m / z 405.0 [M+H] + 45 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A, followed by method I. Retention time 4.29 min; ee 100%. ¹H NMR (400 MHz, DMSO-d 6) δ: 9.35 (s, 1H), 7.91 (d, 2H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.91 (dd, 1H), 4.38 (dd, 1H), 3.88 (s, 3H), 2.38–2.27 (m, 1H), 2.26–2.07 (m, 2H), 2.02–1.90 (m, 1H). LCMS: m / z 395.2 [M+H]+. 46 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A, followed by method I. Retention time 7.87 min; ee 99%. ¹H NMR (400 MHz, DMSO-d 6) δ: 9.35 (s, 1H), 7.91 (d, 2H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.91 (dd, 1H), 4.38 (dd, 1H), 3.88 (s, 3H), 2.38–2.27 (m, 1H), 2.26–2.07 (m, 2H), 2.02–1.90 (m, 1H). LCMS: m / z 395.0 [M+H]+. 47 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 9.73 (s, 1H), 7.85 (d, 1H), 7.68 (d, 2H), 7.12 (d, 1H), 7.04 (d, 2H), 6.88 (dd, 1H), 5.05 (dd, 1H), 2.64-2.53 (m, 2H), 2.35 (s, 3H), 2.33-2.20 (m, 1H), 1.95-1.86 (m, 1H). LCMS: m / z 437.0 [M+H] + 48 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.64 (s, 1H), 7.87 (d, 1H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.92 (dd, 1H), 4.47 (d, 1H), 3.89 (s, 3H), 2.64 (s, 3H), 2.31-2.16 (m, 3H), 1.94-1.80 (m, 1H). GCMS m / z 409.13 [M] + 49 Starting materials: 2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)aniline HCl and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.23 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.57-7.47 (m, 1H), 7.32-7.24 (m, 3H), 7.21 (d, 1H), 7.08 (d, 1H), 5.10 (s, 2H), 4.36 (d, 1H), 3.85 (s, 3H), 2.34-1.96 (m, 4H). LCMS: m / z 409.2 [M+H] + 50 Starting materials: 2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)aniline HCl and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 9.60 (s, 1H), 8.10 (d, 1H), 7.52-7.45 (m, 1H), 7.31-7.24 (m, 3H), 7.18 (dd, 1H), 7.05 (d, 1H), 5.06 (s, 2H), 5.04 (dd, 1H), 3.85 (s, 3H), 2.64-2.50 (m, 2H), 2.38 (s, 3H), 2.32-2.23 (m, 1H), 1.95-1.89 (m, 1H). LCMS: m / z 452.1 [M+H] + 51 Starting materials: 2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)aniline HCl and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.58 (s, 1H), 7.86-7.56 (m, 5H), 6.98 (d, 1H), 6.74 (dd, 1H), 5.12 (s, 2H), 5.10-5.03 (m, 1H), 3.81 (s, 3H), 2.72-2.56 (m, 1H), 2.40 (s, 3H), 2.36-2.18 (m, 1H), 1.98-1.86 (m, 1H). LCMS: m / z 451.0 [M+H] + 52 Starting materials: 2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)aniline HCl and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (500 MHz, DMSO- d 6) δ: 9.17 (s, 1H), 7.93 (s, 1H), 7.87-7.57 (m, 5H), 6.96 (d, 1H), 6.73 (dd, 1H), 5.12 (s, 2H), 4.35 (dd, 1H), 3.78 (s, 3H), 2.37-2.26 (m, 1H), 2.24-2.02 (m, 2H), 2.01-1.86 (m, 1H). LCMS: m / z 409.2 [M+H] + 53 Starting materials: 2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)aniline HCl and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.49 (s, 1H), 7.84-7.60 (m, 5H), 6.99 (d, 1H), 6.77 (d, 1H), 5.14 (s, 2H), 4.49-4.43 (m, 1H), 3.80 (s, 3H), 2.66 (s, 3H), 2.28-2.16 (m, 3H), 1.93-1.88 (m, 1H). LCMS: m / z 423.0 [M+H] + 54 Starting materials: 7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and isothiazolidine-3-carboxylic acid 1,1-dioxide Purification method D. 1H NMR (600 MHz, acetonitrile-d 3) δ: 9.03 (s, 1H), 7.65 (d, 1H), 7.57-7.51 (m, 1H), 7.42 (d, 1H), 7.27 (d, 1H), 7.23 (dd, 1H), 6.45 (d, 1H), 4.39-4.30 (m, 4H), 4.25 (dd, 1H), 3.30-3.21 (m, 1H), 3.08-2.99 (m, 1H), 2.91-2.80 (m, 1H), 2.46-2.37 (m, 1H). LCMS: m / z 458.9 [M+H] + 55 Starting materials: 7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.38 (s, 1H), 7.89 (s, 1H), 7.63-7.55 (m, 1H), 7.47-7.38 (m, 2H), 7.27-7.16 (m, 2H), 6.48 (d, 1H), 4.39-4.25 (m, 5H), 2.35-2.26 (m, 1H), 2.23-2.07 (m, 2H), 2.01-1.89 (m, 1H). LCMS: m / z 423.2 [M+H] + 56 Starting materials: 7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.79 (s, 1H), 7.64-7.55 (m, 1H), 7.50-7.38 (m, 2H), 7.28-7.14 (m, 2H), 6.47 (d, 1H), 5.06 (dd, 1H), 4.41-4.27 (m, 4H), 2.64-2.52 (m, 2H), 2.37 (s, 3H), 2.32-2.20 (m, 1H), 1.95 - 1.86 (m, 1H). LCMS: m / z 465.0 [M+H] + 57 Starting materials: 7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine and 5-sideoxypyrrolidone-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.26 (s, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 7.35-7.27 (m, 1H), 6.91-6.80 (m, 2H), 6.80-6.73 (m, 2H), 4.97 (s, 2H), 4.41-4.21 (m, 5H), 2.38-2.27 (m, 1H), 2.27-2.04 (m, 2H), 2.01-1.90 (m, 1H). LCMS: m / z 388.0 [M+H] + 58 Starting materials: 7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.57 (s, 1H), 7.61 (s, 1H), 7.34-7.25 (m, 1H), 6.88-6.81 (m, 2H), 6.81-6.67 (m, 2H), 4.97 (s, 2H), 4.43 (s, 1H), 4.30 (dd, 4H), 2.66 (s, 3H), 2.36-2.17 (m, 3H), 1.95-1.84 (m, 1H). LCMS: m / z 401.0 [M+H] + 59 Starting materials: 5-(3,4-difluorophenoxy)-2-methoxyaniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.32 (s, 1H), 7.95-7.83 (m, 2H), 7.47-7.36 (m, 1H), 7.09 (d, 2H), 6.83 (dd, 1H), 6.76 (d, 1H), 4.38 (dd, 1H), 3.86 (s, 3H), 2.39-2.05 (m, 3H), 2.01-1.92 (m, 1H). LCMS: m / z 363.2 [M+H] + 60 Starting materials: 5-(3,4-difluorophenoxy)-2-methoxyaniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 9.58 (s, 1H), 7.81 (d, 1H), 7.45-7.36 (m, 1H), 7.11-7.03 (m, 2H), 6.82 (dd, 1H), 6.79-6.65 (m, 1H), 4.45 (dd, 1H), 3.85 (s, 3H), 2.62 (s, 3H), 2.29-2.12 (m, 3H), 1.92-1.81 (m, 1H). LCMS: m / z 377.2 [M+H] + 61 Starting materials: 8-methyl-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine hydrochloride and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.32 (s, 1H), 7.87 (s, 1H), 7.62-7.51 (m, 2H), 7.45-7.35 (m, 2H), 7.16 (d, 1H), 7.13-7.06 (m, 1H), 4.40-4.28 (m, 5H), 2.34-2.26 (m, 1H), 2.23-2.02 (m, 2H), 1.93 (s, 3H), 1.92-1.87 (m, 1H). LCMS: m / z 437.0 [M+H] + 62 Starting materials: 2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)aniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.40 (s, 1H), 8.51 (d, 1H), 7.97-7.89 (m, 2H), 7.87 (d, 1H), 7.46 (dd, 1H), 7.16 (d, 1H), 6.98 (dd, 1H), 4.39 (dd, 1H), 3.89 (s, 3H), 2.38-2.26 (m, 1H), 2.26-2.05 (m, 2H), 2.05-1.87 (m, 1H). LCMS: m / z 396.2 [M+H] + 63 Starting materials: 2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.68 (s, 1H), 8.50 (d, 1H), 7.92 (d, 1H), 7.87 (d, 1H), 7.46 (dd, 1H), 7.16 (d, 1H), 6.99 (dd, 1H), 4.53-4.39 (m, 1H), 3.89 (s, 3H), 2.36-2.14 (m, 3H), 1.97-1.83 (m, 1H). LCMS: m / z 410.2 [M+H] + 64 Starting materials: (E)-2-methoxy-5-(2-(tetrahydro-2H-piperan-4-yl)vinyl)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.47 (s, 1H), 8.02 (d, 1H), 7.12 (dd, 1H), 7.00 (d, 1H), 6.31 (d, 1H), 6.04 (dd, 1H), 4.47-4.42 (m, 1H), 3.90-3.85 (m, 2H), 3.83 (s, 3H), 2.67 (s, 3H), 2.37-2.21 (m, 3H), 1.97-1.87 (m, 1H), 1.64 (d, 2H), 1.49-1.34 (m, 2H). LCMS: m / z 359.2 [M+H] + 65 Starting materials: (E)-2-methoxy-5-(2-(tetrahydro-2H-piperan-4-yl)vinyl)aniline and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.19 (s, 1H), 8.06 (d, 1H), 7.94 (s, 1H), 7.11 (dd, 1H), 6.99 (d, 1H), 6.31 (d, 1H), 6.03 (dd, 1H), 3.91-3.84 (m, 2H), 3.83 (s, 3H), 2.40-2.30 (m, 2H), 2.30-2.04 (m, 2H), 2.04-1.93 (m, 1H), 1.64 (d, 2H), 1.49-1.32 (m, 2H). LCMS: m / z 345.2 [M+H] + 66 Starting materials: 7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 5-sideoxypyrrolidone-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.38 (s, 1H), 7.89 (s, 1H), 7.71 (d, 2H), 7.44 (d, 1H), 7.09 (d, 2H), 6.51 (d, 1H), 4.39-4.30 (m, 5H), 2.25-1.85 (m, 4H). LCMS: m / z 423.1 [M+H] + 67 Starting materials: 7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO- d 6) δ: 9.70 (s, 1H), 7.71 (d, 2H), 7.42 (s, 1H), 7.09 (d, 2H), 6.52 (d, 1H), 4.48-4.43 (m, 1H), 4.37-4.29 (m, 4H), 2.63 (s, 3H), 2.28-2.15 (m, 3H), 1.93-1.82 (m, 1H). LCMS: m / z 437.2 [M+H] + 68 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-ethyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.67 (s, 1H), 7.86 (d, 1H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.92 (dd, 1H), 4.67-4.58 (m, 1H), 3.89 (s, 3H), 3.53-3.44 (m, 1H), 2.86-2.76 (m, 1H), 2.35-2.13 (m, 3H), 1.98-1.84 (m, 1H), 1.00 (t, 3H). LCMS: m / z 423.1 [M+H] + 69 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (R)-1-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.66 (s, 1H), 7.87 (d, 1H), 7.71 (d, 2H), 7.14 (d, 1H), 7.07 (d, 2H), 6.92 (dd, 1H), 4.52-4.43 (m, 1H), 3.88 (s, 3H), 2.64 (s, 3H), 2.30-2.13 (m, 3H), 1.93-1.82 (m, 1H). LCMS: m / z 409.2 [M+H] + 70 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.65 (s, 1H), 7.87 (d, 1H), 7.70 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.92 (dd, 1H), 4.51-4.41 (m, 1H), 3.89 (s, 3H), 2.64 (s, 3H), 2.31-2.15 (m, 3H), 1.95-1.82 (m, 1H). LCMS: m / z 409.2 [M+H] + 71 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and lithium N-methylpropanoate 1,1-dioxide Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.68 (s, 1H), 7.91 (d, 1H), 7.71 (d, 2H), 7.17 (d, 1H), 7.09 (d, 2H), 6.95 (dd, 1H), 4.51 (dd, 1H), 4.37 (dd, 1H), 4.07 (dd, 1H), 2.70 (s, 3H). LCMS: m / z 431.2 [M+H] + 72 Starting materials: 2-methoxy-5-(3-(trifluoromethyl)phenoxy)aniline and lithium N-methylpropanoate 1,1-dioxide Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 9.68 (s, 1H), 7.91 (d, 1H), 7.71 (d, 2H), 7.17 (d, 1H), 7.09 (d, 2H), 6.95 (dd, 1H), 4.51 (dd, 1H), 4.37 (dd, 1H), 4.07 (dd, 1H), 2.70 (s, 3H). LCMS: m / z 431.0 [M+H] + 73 Starting materials: 4-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyaniline and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.16 (s, 1H), 7.87 (s, 1H), 7.72 (d, 1H), 7.01-6.91 (m, 2H), 6.56-6.46 (m, 2H), 4.28 (dd, 1H), 3.81 (s, 3H), 3.76 (s, 2H), 2.31-2.04 (m, 3H), 2.00-1.88 (m, 1H). LCMS: m / z 375.0 [MH] - 74 Starting materials: 4-methoxy-N1-(4-(trifluoromethyl)phenyl)benzene-1,3-diamine and methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.52 (s, 1H), 8.48 (s, 1H), 7.90 (d, 1H), 7.46 (d, 2H), 7.02 (dd, 3H), 6.94 (dd, 1H), 4.51-4.41 (m, 1H), 3.84 (s, 3H), 2.65 (s, 3H), 2.34-2.15 (m, 3H), 1.98-1.82 (m, 1H). LCMS: m / z 408.2 [M+H] + 75 Starting materials: 2-fluoro-5-(4-(trifluoromethyl)phenoxy)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, chloroform-d) δ: 8.12 (dd, 1H), 7.72 (s, 1H), 7.59 (d, 2H), 7.19-7.12 (m, 1H), 7.05 (d, 2H), 6.82 (dd, 1H), 4.14 (dd, 1H), 2.95 (s, 3H), 2.64-2.40 (m, 3H), 2.22-2.13 (m, 1H). LCMS: m / z 397.2 [M+H] + 76 Starting materials: 2-fluoro-5-(4-(trifluoromethyl)phenoxy)aniline and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, chloroform-d) δ: 8.12 (dd, 1H), 7.72 (s, 1H), 7.59 (dd, 2H), 7.20-7.12 (m, 1H), 7.05 (d, 2H), 6.82 (dd, 1H), 4.14 (dd, 1H), 2.65-2.39 (m, 3H), 2.22-2.12 (m, 1H). LCMS: m / z 383.2 [M+H] + 77 Starting materials: 5-(3,5-difluorophenoxy)-2-methoxyaniline HCl and 1-acetyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.76 (s, 1H), 7.85 (d, 1H), 7.12 (d, 1H), 6.98-6.85 (m, 2H), 6.67-6.58 (m, 2H), 5.07 (d, 1H), 3.89 (s, 3H), 2.61-2.55 (m, 1H), 2.38 (s, 3H), 2.34-1.82 (m, 3H). LCMS: m / z 405.2 [M+H] + 78 Starting materials: 5-(3,5-difluorophenoxy)-2-methoxyaniline HCl and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.67 (s, 1H), 7.86 (d, 1H), 7.13 (d, 1H), 6.98-6.88 (m, 2H), 6.64 (dd, 2H), 4.47 (d, 1H), 3.88 (s, 3H), 2.64 (s, 3H), 2.32-2.17 (m, 3H), 1.93-1.79 (m, 1H). LCMS: m / z 377.0 [M+H] + 79 Starting materials: 5-(2,5-difluorophenoxy)-2-methoxyaniline and 5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.32 (s, 1H), 7.97-7.82 (m, 2H), 7.53-7.35 (m, 1H), 7.09 (d, 1H), 7.06-6.97 (m, 1H), 6.96-6.88 (m, 1H), 6.83 (dd, 1H), 4.38 (dd, 1H), 3.86 (s, 3H), 2.35-2.25 (m, 1H), 2.25-2.03 (m, 2H), 2.02-1.87 (m, 1H). LCMS: m / z 363.0 [M+H] + 80 Starting materials: 7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 3-sideoxytetrahydro-1H-pyridine-7a(5H)-carboxylate lithium Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ: 8.90 (s, 1H), 7.70 (d, 2H), 7.32 (d, 1H), 7.08 (d, 2H), 6.53 (d, 1H), 4.35-4.24 (m, 4H), 3.60-3.50 (m, 1H), 3.10-3.01 (m, 1H), 2.71-2.63 (m, 1H), 2.35-2.24 (m, 3H), 2.21-2.14 (m, 1H), 1.97-1.87 (m, 1H), 1.86-1.77 (m, 1H), 1.73-1.65 (m, 1H). LCMS: m / z 463.2 [M+H] + 81 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-isopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, acetonitrile-d 3) δ: 8.51 (s, 1H), 8.06 (d, 1H), 7.68 (d, 2H), 7.09 (dd, 3H), 6.88 (dd, 1H), 4.38 (dd, 1H), 4.22-4.12 (m, 1H), 2.58-2.44 (m, 1H), 2.36-2.20 (m, 3H), 1.22 (d, 3H), 1.10 (d, 3H). LCMS: m / z 437.2 [M+H] + 82 Starting materials: 5-(3,4-difluorophenoxy)-2-methoxyaniline and 1-isopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, acetonitrile-d 3) δ: 8.49 (s, 1H), 8.02 (dd, 1H), 7.31-7.18 (m, 1H), 7.04 (dd, 1H), 6.99-6.88 (m, 1H), 6.85-6.73 (m, 2H), 4.42-4.34 (m, 1H), 4.24-4.10 (m, 1H), 3.92 (d, 3H), 2.54-2.43 (m, 1H), 2.40 -.24 (m, 1H), 1.25-1.18 (m, 3H), 1.13-1.04 (m, 3H). LCMS: m / z 405.2 [M+H] + 83 Starting materials: 2-(1,3,4-diazol-2-yl)-5-(4-(trifluoromethyl)phenoxy)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 10.91 (s, 1H), 9.42 (s, 1H), 8.07 (s, 1H), 8.01 (d, 1H), 7.83 (d, 2H), 7.34 (d, 2H), 7.07 (dd, 1H), 4.29 (dd, 1H), 2.72 (s, 3H), 2.45-2.20 (m, 3H), 2.07-1.95 (m, 1H). LCMS: m / z 447.0 [M+H] + 84 Starting material: 2-(1,3,4- diazol-2-yl)-5-(3-(trifluoromethyl)phenoxy)aniline and 1-methyl-5-sideoxypyrrolidin-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 10.91 (s, 1H), 9.41 (s, 1H), 8.08-7.97 (m, 2H), 7.76-7.67 (m, 1H), 7.63 (d, 1H), 7.54 (s, 1H), 7.48 (d, 1H), 7.01 (dd, 1H), 4.28 (d, 1H), 2.72 (s, 3H), 2.39-2.21 (m, 3H), 2.05-1.94 (m, 1H). LCMS: m / z 447.0 [M+H] + 85 Starting materials: 5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazole-3-yl)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 11.79 (s, 1H), 8.34 (d, 1H), 7.90-7.79 (m, 2H), 7.55-7.44 (m, 1H), 7.35-7.25 (m, 1H), 6.98-6.90 (m, 1H), 6.87-6.77 (m, 2H), 4.20 (dd, 1H), 3.94 (s, 3H), 2.79 (s, 3H), 2.44-2.24 (m, 3H), 2.02-1.89 (m, 1H). LCMS: m / z 427.0 [M+H] + 86 Starting materials: 5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazole-5-yl)aniline and 1-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method C. 1H NMR (600 MHz, DMSO- d 6) δ: 9.61 (s, 1H), 7.55-7.46 (m, 1H), 7.44 (d, 1H), 7.37 (d, 1H), 7.35-7.31 (m, 1H), 7.28 (d, 1H), 7.01-6.92 (m, 2H), 6.21 (d, 1H), 4.10-4.03 (m, 1H), 3.63 (s, 3H), 2.17-2.09 (m, 3H), 1.75-1.66 (m, 1H). LCMS: m / z 427.0 [M+H] + 87 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 3-methyl-2-sideoxy Azodin-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.83 (s, 1H), 7.91 (d, 1H), 7.71 (d, 2H), 7.15 (d, 1H), 7.08 (d, 2H), 6.97-6.89 (m, 1H), 4.68 (dd, 1H), 4.42 (t, 1H), 4.18 (dd, 1H), 3.89 (s, 3H), 2.73 (s, 3H). LCMS: m / z 411.0 [M+H] + 88 Starting materials: 5-(3,4-difluorophenoxy)-2-methoxyaniline and 3-methyl-2-sideoxy Azodin-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.79 (s, 1H), 7.86 (d, 1H), 7.47-7.35 (m, 1H), 7.15-7.05 (m, 2H), 6.86 (dd, 1H), 6.80-6.72 (m, 1H), 4.68 (dd, 1H), 4.42 (t, 1H), 4.18 (dd, 1H), 3.87 (s, 3H), 2.73 (s, 3H). LCMS: m / z 379.0 [M+H] + 89 Starting materials: 5-((3,4-difluorophenoxy)methyl)-2-methoxyaniline HCl and 3-methyl-2-sideoxy Azodin-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.71 (s, 1H), 8.09 (d, 1H), 7.41-7.30 (m, 1H), 7.29-7.17 (m, 1H), 7.17-7.11 (m, 1H), 7.08 (d, 1H), 6.87-6.78 (m, 1H), 5.00 (s, 2H), 4.66 (dd, 1H), 4.44 (t, 1H), 4.18 (dd, 1H), 3.86 (s, 3H), 2.75 (s, 3H). LCMS: m / z 391.0 [MH] - 90 Starting materials: 5-((3-fluorophenoxy)methyl)-2-methoxyaniline HCl and 3-methyl-2-sideoxy Azodin-4-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 9.71 (s, 1H), 8.10 (s, 1H), 7.31 (d, 1H), 7.25-7.20 (m, 1H), 7.08 (d, 1H), 6.91-6.82 (m, 2H), 6.80-6.72 (m, 1H), 5.02 (s, 2H), 4.69-4.63 (m, 1H), 4.49-4.41 (m, 1H), 4.23-4.15 (m, 1H), 3.86 (s, 3H), 2.75 (s, 3H). LCMS: m / z 375.2 [M+H] + 91 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-methyl-5-thionylpyrrolidine-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 9.84 (s, 1H), 7.90-7.82 (m, 1H), 7.71 (d, 2H), 7.15 (d, 1H), 7.07 (d, 2H), 6.94 (dd, 1H), 5.00-4.92 (m, 1H), 3.89 (s, 3H), 3.07 (s, 3H), 2.94-2.83 (m, 2H), 2.36-2.29 (m, 1H), 2.06-1.91 (m, 1H). LCMS: m / z 425.0 [M+H] + 92 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 5-thionylpyrrolidine-2-carboxylate Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 10.30 (s, 1H), 9.61 (s, 1H), 7.91-7.85 (m, 1H), 7.71 (d, 2H), 7.13 (s, 1H), 7.08 (d, 2H), 6.92 (dd, 1H), 4.84-4.72 (m, 1H), 3.88 (s, 3H), 2.75 (q, 2H), 2.44-2.31 (m, 1H), 2.13-2.01 (m, 1H). LCMS: m / z 411.1 [M+H] + 93 Starting materials: 5-(3,4-difluorophenoxy)-2-methoxyaniline and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.62 (s, 1H), 7.83 (d, 1H), 7.48-7.36 (m, 1H), 7.14-7.05 (m, 2H), 6.84 (dd, 1H), 6.76 (d, 1H), 4.50-4.41 (m, 1H), 3.86 (s, 3H), 2.64 (s, 3H), 2.35-2.13 (m, 3H), 1.94-1.81 (m, 1H). LCMS: m / z 377.2 [M+H] + 94 Starting materials: 5-(3,4-difluorophenoxy)-2-methoxyaniline and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.62 (s, 1H), 7.83 (d, 1H), 7.47-7.38 (m, 1H), 7.12-7.04 (m, 2H), 6.84 (dd, 1H), 6.76 (d, 1H), 4.50-4.41 (m, 1H), 3.86 (s, 3H), 2.64 (s, 3H), 2.30-2.14 (m, 3H), 1.92-1.77 (m, 1H). LCMS: m / z 377.2 [M+H] + 95 Starting materials: 5-((3,4-difluorophenoxy)methyl)-2-methoxyaniline HCl and 5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (500 MHz, DMSO- d 6) δ: 9.50 (s, 1H), 8.03 (d, 1H), 7.38-7.25 (m, 1H), 7.18 (dd, 1H), 7.15-7.09 (m, 1H), 7.05 (d, 1H), 6.82-6.75 (m, 1H), 4.98 (s, 2H), 4.46-4.38 (m, 1H), 3.84 (s, 3H), 2.65 (s, 3H), 2.33-2.12 (m, 3H), 1.93-1.82 (m, 1H). LCMS: m / z 391.2 [M+H] + 96 Starting materials: 5-(bicyclo[2.2.1]hept-2-yloxy)-2-methoxyaniline HCl and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.45 (s, 1H), 7.68-7.61 (m, 1H), 6.94 (d, 1H), 6.60 (dd, 1H), 4.50-4.38 (m, 1H), 4.11 (d, 1H), 3.78 (s, 3H), 2.66 (s, 3H), 2.36-2.15 (m, 5H), 1.96-1.84 (m, 1H), 1.80-1.67 (m, 1H), 1.61-1.33 (m, 4H), 1.24-1.02 (m, 3H). LCMS: m / z 359.2 [M+H] + 97 Starting materials: 7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.52 (s, 1H), 7.46-7.28 (m, 2H), 7.12-7.01 (m, 1H), 6.79 (d, 1H), 6.41 (d, 1H), 4.44 (dd, 1H), 4.35-4.24 (m, 4H), 2.65 (s, 3H), 2.34-2.13 (m, 3H), 1.96-1.85 (m, 1H). LCMS: m / z 405.0 [M+H] + 98 Starting materials: 7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO- d 6) δ 9.64 (s, 1H), 7.44-7.37 (m, 1H), 7.35 (d, 1H), 7.14-6.99 (m, 1H), 6.77 (dd, 1H), 6.41 (d, 1H), 4.43 (dd, 1H), 4.36-4.22 (m, 4H), 2.61 (s, 3H), 2.28-2.14 (m, 3H), 1.90-1.81 (m, 1H). LCMS: m / z 405.0 [M+H] + 99 Starting materials: 5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-amine HCl and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.95 (s, 1H), 7.70 (d, 2H), 7.57 (d, 1H), 7.07 (d, 2H), 6.88 (s, 1H), 4.65 (t, 2H), 4.40 (d, 1H), 3.25 (t, 2H), 2.63 (s, 3H), 2.24-2.17 (m, 3H), 1.90-1.80 (m, 1H). LCMS: m / z 421.2 [M+H] + 100 Starting materials: 5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-amine HCl and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method F. 1H NMR (400 MHz, DMSO- d 6) δ: 9.91 (s, 1H), 7.52 (d, 1H), 7.40 (q, 1H), 7.14-6.97 (m, 1H), 6.81 (d, 1H), 6.78-6.70 (m, 1H), 4.63 (t, 2H), 4.43-4.36 (m, 1H), 3.28-3.19 (m, 2H), 2.63 (s, 3H), 2.29-2.13 (m, 3H), 1.93-1.81 (m, 1H). LCMS: m / z 389.0 [M+H] + 101 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (R)-3-methyl-2-sideoxy Lithium azolidinium-4-carboxylate Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.83 (s, 1H), 7.94-7.88 (m, 1H), 7.71 (d, 2H), 7.15 (d, 1H), 7.08 (d, 2H), 6.94 (dd, 1H), 4.73-4.65 (m, 1H), 4.42 (t, 1H), 4.18 (dd, 1H), 2.73 (s, 3H). LCMS: m / z 411.0 [M+H] + 102 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (S)-3-methyl-2-sideoxy Lithium azolidinium-4-carboxylate Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.83 (s, 1H), 7.96-7.86 (m, 1H), 7.71 (d, 2H), 7.15 (d, 1H), 7.08 (d, 2H), 6.94 (dd, 1H), 4.68 (dd, 1H), 4.42 (t, 1H), 4.18 (dd, 1H), 3.89 (s, 3H), 2.73 (s, 3H). LCMS: m / z 411.0 [M+H] + 103 Starting materials: 2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)aniline and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 9.46 (s, 1H), 7.65 (d, 1H), 6.95 (d, 1H), 6.71 (dd, 1H), 4.50-4.41 (m, 1H), 4.19-4.08 (m, 1H), 2.66 (s, 3H), 2.37-2.15 (m, 4H), 2.10 (d, 2H), 1.97-1.84 (m, 3H), 1.49-1.31 (m, 4H). LCMS: m / z 415.0 [M+H] + 104 Starting materials: 5-((4,4-difluorocyclohexyl)oxy)-2-methoxyaniline HCl and 3-methyl-2-sideoxy Azodin-4-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 9.68 (s, 1H), 7.74 (s, 1H), 6.98 (d, 1H), 6.77 (d, 1H), 4.74-4.62 (m, 1H), 4.49-4.37 (m, 2H), 4.19 (dd, 1H), 3.80 (s, 3H), 2.74 (s, 3H), 2.06-1.76 (m, 8H). LCMS: m / z 385.2 [M+H] + 105 Starting materials: 2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)aniline and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 9.46 (s, 1H), 7.65 (d, 1H), 6.95 (d, 1H), 6.71 (dd, 1H), 4.49-4.41 (m, 1H), 4.22-4.09 (m, 1H), 3.78 (s, 3H), 2.66 (s, 3H), 2.35-2.16 (m, 4H), 2.10 (d, 2H), 1.95-1.84 (m, 3H), 1.39 (q, 4H). LCMS: m / z 415.0 [M+H] + 106 Starting materials: 5-amino-7-(3-(trifluoromethyl)phenoxy)-2H-benzo[b][1,4]-3(4H)-one and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 10.40 (s, 1H), 9.65 (s, 1H), 7.65-7.58 (m, 2H), 7.47 (d, 2H), 7.28 (d, 3H), 7.11 (d, 1H), 6.68 (d, 1H), 4.61 (s, 3H), 4.32-4.26 (m, 1H), 2.67 (s, 3H), 2.33-2.11 (m, 5H), 2.07-1.94 (m, 1H). LCMS: m / z 450.0 [M+H] + 107 Starting materials: 5-((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.75 (s, 1H), 7.37 (d, 1H), 6.70 (d, 1H), 4.55 (t, 2H), 4.46-4.34 (m, 2H), 3.18 (t, 2H), 2.65 (s, 3H), 2.40-2.16 (m, 4H), 2.03-1.83 (m, 3H), 1.69-1.49 (m, 6H). LCMS: m / z 427.2 [M+H] + 108 Starting materials: 5-((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.75 (s, 1H), 7.37 (d, 1H), 6.70 (d, 1H), 4.55 (t, 2H), 4.48-4.32 (m, 2H), 3.18 (t, 2H), 2.65 (s, 3H), 2.39-2.17 (m, 5H), 1.97 (d, 2H), 1.89 (d, 1H), 1.68-1.54 (m, 6H). LCMS: m / z 427.2 [M+H] + 109 Starting materials: 5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-amine HCl and 1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.93 (s, 1H), 7.70 (d, 2H), 7.60 (d, 1H), 7.07 (d, 2H), 6.87 (s, 1H), 4.66 (t, 2H), 4.40 (d, 1H), 3.29-3.20 (m, 2H), 2.36-2.05 (m, 2H), 1.92-1.76 (m, 1H), 0.77-0.40 (m, 4H). LCMS: m / z 447.0 [M+H] + 110 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.65 (s, 1H), 7.95-7.84 (m, 1H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.92 (dd, 1H), 4.54-4.42 (m, 1H), 3.89 (s, 3H), 2.44-2.37 (m, 1H), 2.32-2.24 (m, 1H), 2.24-2.10 (m, 2H), 1.94-1.78 (m, 1H), 0.74-0.46 (m, 4H). LCMS: m / z 435.2 [M+H] + 111 Starting materials: 5-(3,4-difluorophenoxy)-2-methoxyaniline and 1-cyclopropyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method E. 1H NMR (400 MHz, DMSO- d 6) δ: 9.61 (s, 1H), 7.87-7.82 (m, 1H), 7.47-7.35 (m, 1H), 7.13-7.04 (m, 2H), 6.84 (dd, 1H), 6.81-6.70 (m, 1H), 4.51-4.42 (m, 1H), 3.87 (s, 3H), 2.44-2.37 (m, 1H), 2.37-2.22 (m, 1H), 2.22-2.09 (m, 2H), 1.92-1.80 (m, 1H), 0.75-0.48 (m, 4H). LCMS: m / z 403.2 [M+H] + 112 Starting materials: 2-methoxy-5-((5-(trifluoromethoxy)pyridin-2-yl)oxy)aniline and 3-methyl-2-sideoxy Azodin-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.79 (s, 1H), 8.23 ​​(d, 1H), 7.99-7.93 (m, 1H), 7.89 (d, 1H), 7.19-7.08 (m, 2H), 6.95 (dd, 1H), 4.68 (dd, 1H), 4.43 (t, 1H), 4.18 (dd, 1H), 3.87 (s, 3H), 2.73 (s, 3H). LCMS: m / z 428.2 [M+H] + 113 Starting materials: 7-(((4,4-difluorocyclohexyl)oxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine and 1-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.54 (s, 1H), 7.49 (s, 1H), 6.64 (s, 1H), 4.47-4.39 (m, 1H), 4.35 (s, 2H), 4.32-4.23 (m, 4H), 3.58-3.52 (m, 1H), 2.66 (s, 3H), 2.33-2.14 (m, 3H), 1.98-1.64 (m, 9H). LCMS: m / z 425.0 [M+H] + 114 Starting materials: 7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method C. 1H NMR (400 MHz, DMSO- d 6) δ: 9.70 (s, 1H), 7.71 (d, 2H), 7.45 (d, 1H), 7.09 (d, 2H), 6.52 (d, 1H), 4.47 (d, 1H), 4.41-4.27 (m, 4H), 2.41-2.11 (m, 4H), 1.90-1.75 (m, 1H), 0.78-0.43 (m, 4H). LCMS: m / z 463.2 [M+H] + 115 Starting materials: 2-methoxy-5-((5-(trifluoromethoxy)pyridin-2-yl)oxy)aniline and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method E. 1H NMR (400 MHz, DMSO- d 6) δ: 9.62 (s, 1H), 8.23 ​​(d, 1H), 7.98-7.90 (m, 1H), 7.85 (d, 1H), 7.11 (dd, 2H), 6.93 (dd, 1H), 4.53-4.41 (m, 1H), 3.88 (s, 3H), 2.65 (s, 3H), 2.31-2.16 (m, 3H), 1.95-1.81 (m, 1H). LCMS: m / z 426.2 [M+H] + 116 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1,1-dioxide of tetrahydrothiophene-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.62 (s, 1H), 8.23 ​​(d, 1H), 7.98-7.90 (m, 1H), 7.85 (d, 1H), 7.11 (dd, 2H), 6.93 (dd, 1H), 4.53-4.41 (m, 1H), 3.88 (s, 3H), 2.65 (s, 3H), 2.31-2.16 (m, 3H), 1.95-1.81 (m, 1H). LCMS: m / z 430.2 [M+H] + 117 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.51 (s, 1H), 7.89 (s, 1H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.49-6.44 (m, 1H), 4.41-4.35 (m, 1H), 3.88 (s, 3H), 3.19-3.09 (m, 1H), 2.62 (s, 3H). LCMS: m / z 410.2 [M+H] + 118 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and 3-methyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.49 (s, 1H), 8.55 (s, 1H), 8.21 (d, 1H), 7.90 (s, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 6.96 (d, 1H), 6.47 (s, 1H), 4.43-4.33 (m, 1H), 3.88 (s, 3H), 3.58-3.48 (m, 1H), 3.20-3.10 (m, 1H), 2.62 (s, 3H). LCMS: m / z 411.0 [M+H] + 119 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (S)-6-sideoxypiperidine-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.44 (s, 1H), 7.89-7.84 (m, 1H), 7.70 (d, 2H), 7.48 (d, 1H), 7.09 (dd, 3H), 6.89 (dd, 1H), 3.87 (s, 3H), 3.30-3.18 (m, 2H), 3.09-2.94 (m, 1H), 2.24-2.16 (m, 2H), 1.97-1.90 (m, 1H), 1.86-1.77 (m, 1H). LCMS: m / z 409.2 [M+H] + 120 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (R)-6-sideoxypiperidine-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 9.45 (s, 1H), 7.91-7.84 (m, 1H), 7.70 (d, 2H), 7.48 (d, 1H), 7.09 (dd, 3H), 6.89 (dd, 1H), 3.87 (s, 3H), 3.31-3.17 (m, 2H), 3.05-2.92 (m, 1H), 2.25-2.15 (m, 2H), 2.00-1.87 (m, 1H), 1.87 - 1.69 (m, 1H). LCMS: m / z 409.2 [M+H] + 121 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 3-methyl-6-sideoxypiperidine-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 8.85 (s, 1H), 7.71 (d, 2H), 7.60 (dd, 1H), 7.52 (s, 1H), 7.13 (d, 1H), 7.08 (d, 2H), 6.95 (dd, 1H), 3.85 (s, 3H), 3.55 (d, 1H), 3.04 (d, 1H), 2.24-2.14 (m, 3H), 1.86-1.75 (m, 1H), 1.26 (s, 3H). LCMS: m / z 423.0 [M+H] + 122 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 6-sidekto-1,6-dihydropyridine-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO- d 6) δ: 12.06 (s, 1H), 9.39 (s, 1H), 8.14 (d, 1H), 7.90 (dd, 1H), 7.72 (d, 2H), 7.62 (dd, 1H), 7.15 (d, 1H), 7.10 (d, 2H), 6.97 (dd, 1H), 6.38 (d, 1H), 3.86 (s, 3H). LCMS: m / z 423.0 [M+H] + 123 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and 3,4-dimethyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ 8.90 (s, 1H), 8.55 (s, 1H), 8.22 (dd, 1H), 7.83 (d, 1H), 7.17 (dd, 2H), 6.97 (dd, 1H), 3.88 (s, 3H), 3.43 (d, 1H), 3.20 (d, 1H), 2.67 (s, 3H), 1.43 (s, 3H). LCMS: m / z 425.2 [M+H] + 124 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and (R)-3-methyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.47 (s, 1H), 8.55 (s, 1H), 8.23-8.17 (m, 1H), 7.89 (d, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 7.02-6.86 (m, 1H), 6.46 (s, 1H), 4.45-4.25 (m, 1H), 3.88 (s, 3H), 3.54 (t, 1H), 3.18-3.09 (m, 1H), 2.62 (d, 3H). LCMS: m / z 411.0 [M+H] + 125 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and (S)-3-methyl-2-sideoxy Lithium azolidinium-4-carboxylate Purification method A 1H NMR (400 MHz, acetonitrile-d3) δ: 8.59 (s, 1H), 8.33 (d, 1H), 8.12 (d, 1H), 7.35 (d, 1H), 7.28 (s, 1H), 7.10 (d, 1H), 6.95 (dd, 1H), 4.54-4.44 (m, 2H), 4.31-4.21 (m, 1H). LCMS: m / z 412.0 [M+H] + 126 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and (R)-3-methyl-2-sideoxy Lithium azolidinium-4-carboxylate Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.79 (s, 1H), 8.38 (d, 1H), 7.90 (d, 1H), 7.46 (d, 1H), 7.42 (s, 1H), 7.12 (d, 1H), 6.96 (dd, 1H), 4.68 (dd, 1H), 4.43 (t, 1H), 4.18 (dd, 1H), 3.89 (s, 3H), 2.73 (s, 3H). LCMS: m / z 412.0 [M+H] + 127 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and 3-ethyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (500 MHz, DMSO -d6) δ: 9.46 (s, 1H), 8.36 (d, 1H), 7.87 (d, 1H), 7.44 (d, 1H), 7.39 (s, 1H), 7.10 (d, 1H), 6.93 (dd, 1H), 6.43 (s, 1H), 4.49 (dd, 1H), 3.86 (s, 3H), 3.51 (t, 1H), 3.18-3.13 (m, 1H), 2.87 (dq, 1H), 0.98 (t, 3H). LCMS: m / z 425.0 [M+H] + 128 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and (R)-1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method F. 1H NMR (400 MHz, acetonitrile-d 3) δ: 8.51-8.41 (m, 2H), 8.13 (d, 1H), 8.09-8.03 (m, 1H), 7.13 (d, 1H), 7.09 (s, 1H), 6.96-6.89 (m, 1H), 4.30-4.20 (m, 1H), 3.96 (s, 3H), 2.60-2.45 (m, 1H), 2.45-2.35 (m, 1H), 2.35-2.20 (m, 2H), 2.07-2.03 (m, 1H), 0.86 - 0.68 (m, 2H), 0.67 - 0.48 (m, 2H). LCMS: m / z 436.1 [M+H] + 129 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and (S)-1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.62 (s, 1H), 8.55 (s, 1H), 8.27-8.15 (m, 1H), 7.90 (d, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 7.00-6.91 (m, 1H), 4.52-4.42 (m, 1H), 3.89 (s, 3H), 2.45-2.38 (m, 2H), 2.36-2.26 (m, 1H), 2.22-2.10 (m, 2H), 1.95-1.75 (m, 1H), 0.79-0.67 (m, 1H), 0.67-0.47 (m, 3H). LCMS: m / z 436.2 [M+H] + 130 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and (S)-3-methyl-2-sideoxy-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.47 (s, 1H), 8.55 (s, 1H), 8.23-8.17 (m, 1H), 7.89 (d, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 7.02-6.86 (m, 1H), 6.46 (s, 1H), 4.45-4.25 (m, 1H), 3.88 (s, 3H), 3.54 (t, 1H), 3.18-3.09 (m, 1H), 2.62 (d, 3H). LCMS: m / z 411.0 [M+H] + 131 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and 3-cyclopropyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A 1H NMR (400 MHz, DMSO -d6) δ: 9.49 (s, 1H), 8.55 (d, 1H), 8.21 (dd, 1H), 7.92 (d, 1H), 7.16 (dd, 2H), 6.95 (dd, 1H), 6.45 (s, 1H), 4.44 (dd, 1H), 3.89 (s, 3H), 3.46 (t, 1H), 3.14 (dd, 1H), 2.43-2.30 (m, 1H), 0.66-0.44 (m, 4H). LCMS: m / z 437.2 [M+H] + 132 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and 1-(cyclopropylmethyl)-5-sideoxypyrrolidone-2-carboxylic acid (racemic) Purification method A, followed by method I. Retention time 14.3 min. 1H NMR (600 MHz, DMSO -d6) δ: 9.65 (s, 1H), 8.52 (d, 1H), 8.26-8.13 (m, 1H), 7.82 (d, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 6.98-6.92 (m, 1H), 4.77-4.55 (m, 1H), 2.62 (d, 1H), 2.33-2.13 (m, 2H), 1.94-1.74 (m, 1H), 0.81 (dq, 1H), 0.49-0.43 (m, 1H), 0.39-0.27 (m, 1H), 0.19-0.12 (m, 1H), 0.12-0.04 (m, 1H). LCMS: m / z 450.2 [M+H] + 133 Starting materials: 2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline and 1-(cyclopropylmethyl)-5-sideoxypyrrolidone-2-carboxylic acid (racemic) Purification method A, followed by method I. Retention time 16.9 min. 1H NMR (600 MHz, DMSO -d6) δ: 9.65 (s, 1H), 8.52 (d, 1H), 8.26-8.13 (m, 1H), 7.82 (d, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 6.98-6.92 (m, 1H), 4.77-4.55 (m, 1H), 2.62 (d, 1H), 2.33-2.13 (m, 2H), 1.94-1.74 (m, 1H), 0.81 (dq, 1H), 0.49-0.43 (m, 1H), 0.39-0.27 (m, 1H), 0.19-0.12 (m, 1H), 0.12-0.04 (m, 1H). LCMS: m / z 450.2 [M+H] + Int-279 (Intermediate) Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 4-(tri-butoxycarbonyl)-1-methyl-6-sideoxypiperidine Lithium 2-formate LCMS: m / z 523.5 [M+H] + 134 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (R)-1,2-dimethyl-5-sideoxypyrrolidone-2-carboxylate Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 8.83 (s, 1H), 7.72 (d, 2H), 7.62 (dd, 1H), 7.15 (d, 1H), 7.08 (d, 2H), 6.97 (dd, 1H), 3.85 (s, 3H), 2.69 (s, 3H), 2.30 (d, 2H), 2.00-1.87 (m, 1H), 1.48 (s, 3H). LCMS: m / z 423.2 [M+H] + Int-280 (Intermediate) Starting materials: (R)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-sideoxypyrrolidine-2-carboxylic acid and 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline LCMS: m / z 479.0 [MH] - 135 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (S)-1,2-dimethyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 8.82 (s, 1H), 7.71 (d, 2H), 7.61 (d, 1H), 7.14 (d, 1H), 7.08 (d, 2H), 7.01-6.90 (m, 1H), 3.85 (s, 3H), 2.69 (s, 3H), 2.33-2.17 (m, 3H), 2.02-1.85 (m, 1H), 1.48 (s, 3H). LCMS: m / z 423.2 [M+H] + Int-281 (Intermediate) Starting materials: (S)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-sideoxypyrrolidine-2-carboxylic acid and 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline LCMS: m / z 579.2 [MH] - Int-282 (Intermediate) Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-(2-cyanoethyl)-5-sideoxypyrrolidine-2-carboxylic acid LCMS: m / z 446.0 [MH] - 136 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-(2-amino-2-sideoxyethyl)-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.75 (s, 1H), 7.82 (s, 1H), 7.71 (d, 2H), 7.43 (s, 1H), 7.23-7.03 (m, 4H), 6.93 (d, 1H), 4.68-4.58 (m, 1H), 4.15 (d, 1H), 3.86 (s, 3H), 3.24 (d, 1H), 2.42-2.21 (m, 3H), 1.96-1.85 (m, 1H). LCMS: m / z 552.0 [M+H] + 137 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-(1-methyl-1H-pyrazol-4-yl)-5-sideoxypyrrolidine-2-carboxylic acid HCl Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.82 (s, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.69 (d, 2H), 7.45 (s, 1H), 7.15 (d, 1H), 7.06 (d, 2H), 6.92 (dd, 1H), 4.98 (d, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 2.49-2.30 (m, 3H), 2.06 (q, 1H). LCMS: m / z 475.0 [M+H] + 138 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 5-sideoxy-1-(tetrahydrofuran-3-yl)pyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.65 (d, 1H), 7.84 (t, 1H), 7.71 (d, 2H), 7.19-7.10 (m, 1H), 7.07 (d, 2H), 6.96-6.87 (m, 1H), 4.76-4.59 (m, 1H), 4.38 (m, 1H), 3.78-3.44 (m, 4H), 2.41-2.04 (m, 4H), 2.01-1.76 (m, 2H). LCMS: m / z 465.0 [M+H] + 139 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1,3-dimethyl-2-sideoxyimidazolidine-4-carboxylate Purification method D. 1H NMR (400 MHz, DMSO -d6) δ: 9.57 (s, 1H), 7.88 (d, 1H), 7.71 (d, 2H), 7.11 (dd, 3H), 6.93 (dd, 1H), 4.33 (dd, 1H), 3.88 (s, 3H), 3.54 (t, 1H), 3.19 (dd, 1H), 2.64 (d, 6H). LCMS: m / z 424.0 [M+H] + 140 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (R)-3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.52 (s, 1H), 7.93-7.83 (m, 1H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.93 (dd, 1H), 6.47 (s, 1H), 4.46-4.28 (m, 1H), 3.88 (s, 3H), 3.53 (t, 1H), 3.22-3.09 (m, 2H), 2.62 (s, 3H). LCMS: m / z 410.0 [M+H] + 141 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.52 (s, 1H), 7.89 (t, 1H), 7.71 (d, 2H), 7.11 (dd, 3H), 6.93 (dd, 1H), 6.47 (s, 1H), 4.47-4.29 (m, 1H), 3.88 (s, 3H), 3.53 (t, 1H), 3.17 (d, 2H), 2.62 (s, 3H). LCMS: m / z 410.1 [M+H] + 142 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 3-acetyl-1-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.79 (s, 1H), 7.89 (d, 1H), 7.70 (d, 2H), 7.14 (d, 1H), 7.06 (d, 2H), 6.91 (dd, 1H), 5.03 (dd, 1H), 3.90 (s, 3H), 3.64 (t, 1H), 3.30 (dd, 1H), 2.74 (s, 3H), 2.35 (s, 3H). LCMS: m / z 452.0 [M+H] + Int-283 (Intermediate) Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (2S,4S)-4-((tributyldimethylsilyl)oxy)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid LCMS: m / z 539.2 [M+H] + Int-284 (Intermediate) Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-oxide of tetrahydro-2H-thiopiperan-4-carboxylic acid LCMS: m / z 428.2 [M+H] + 143 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and (2S)-4-methoxy-1-methyl-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, acetonitrile-d 3) δ: 8.72-8.48 (m, 1H), 8.13-8.01 (m, 1H), 7.68 (d, 2H), 7.18-7.03 (m, 2H), 6.95-6.80 (m, 1H), 4.37-4.26 (m, 1H), 4.19-4.06 (m, 1H), 3.94 (s, 3H), 3.50 (s, 2H), 2.84-2.75 (m, 3H), 2.75-2.67 (m, 1H), 2.52-2.36 (m, 1H). LCMS: m / z 439.2 [M+H] + 144 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 2-sideoxyimidazolidine-4-carboxylic acid Purification method A. H NMR (400 MHz, DMSO -d6) δ: 9.27 (s, 1H), 7.98 (d, 1H), 7.71 (d, 2H), 7.15 (d, 1H), 7.08 (d, 2H), 6.95-6.84 (m, 1H), 6.80 (s, 1H), 6.49 (s, 1H), 4.38-4.28 (m, 1H), 3.63 (t, 1H), 3.30-3.24 (m, 1H). LCMS: m / z 396.0 [M+H] + 145 Starting materials: 2-methoxy-4-(4-(trifluoromethyl)phenoxy)aniline and 1-(2-(methylamino)-2-sideoxyethyl)-5-sideoxypyrrolidine-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.73 (s, 1H), 7.88 (d, 1H), 7.83 (s, 1H), 7.70 (d, 2H), 7.13 (d, 1H), 7.07 (d, 2H), 6.92 (dd, 1H), 4.67-4.58 (m, 1H), 4.16 (d, 1H), 3.86 (s, 3H), 3.26 (d, 1H), 2.60-2.55 (m, 3H), 2.41-2.22 (m, 3H), 1.95-1.84 (m, 1H). LCMS: m / z 466.2 [M+H] + 146 Starting materials: 2-methoxy-4-(4-(trifluoromethyl)phenoxy)aniline and 1-(2-(dimethylamino)-2-sideoxyethyl)-5-sideoxypyrrolidine-2-carboxylic acid Purification method F. 1H NMR (400 MHz, DMSO -d6) δ: 9.67 (s, 1H), 7.84 (s, 1H), 7.71 (d, 2H), 7.12 (d, 1H), 7.07 (d, 2H), 6.91 (dd, 1H), 4.71-4.58 (m, 1H), 4.42 (d, 1H), 3.86 (s, 3H), 3.57 (d, 1H), 2.92 (s, 3H), 2.80 (s, 3H), 2.41-2.20 (m, 3H), 1.99-1.82 (m, 1H). LCMS: m / z 480.2 [M+H] + 147 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-(cyclopropylmethyl)-5-sideoxypyrrolidine-2-carboxylic acid Purification method A, followed by method I. Retention time 16.48 min. 1H NMR (600 MHz, DMSO -d6) δ: 9.67 (s, 1H), 7.81 (d, 1H), 7.69 (d, 2H), 7.12 (d, 1H), 7.06 (d, 2H), 6.94-6.84 (m, 1H), 4.72-4.66 (m, 1H), 2.65-2.60 (m, 1H), 2.32-2.15 (m, 2H), 1.96-1.74 (m, 1H), 0.87-0.77 (m, 0H), 0.48-0.41 (m, 1H), 0.40-0.33 (m, 1H), 0.18-0.12 (m, 1H), 0.11-0.05 (m, 1H). LCMS: m / z 449.2 [M+H] + 148 Starting materials: 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline and 1-(cyclopropylmethyl)-5-sideoxypyrrolidine-2-carboxylic acid Purification method A, followed by method I. Retention time 26.11 min. 1H NMR (600 MHz, DMSO -d6) δ: 9.67 (s, 1H), 7.81 (d, 1H), 7.69 (d, 2H), 7.12 (d, 1H), 7.06 (d, 2H), 6.94-6.84 (m, 1H), 4.72-4.66 (m, 1H), 2.65-2.60 (m, 1H), 2.32-2.15 (m, 2H), 1.96-1.74 (m, 1H), 0.87-0.77 (m, 0H), 0.48-0.41 (m, 1H), 0.40-0.33 (m, 1H), 0.18-0.12 (m, 1H), 0.11-0.05 (m, 1H). LCMS: m / z 449.2 [M+H] + 149 Starting materials: 5-(4-(difluoromethyl)phenoxy)-2-methoxyaniline and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, acetonitrile-d3) δ: 8.60 (s, 1H), 8.06 (d, 1H), 7.56 (d, 2H), 7.07 (d, 3H), 6.87 (dd, 1H), 6.79 (t, 1H), 5.01 (s, 1H), 4.19 (dd, 1H), 3.68 (t, 1H), 3.32 (t, 1H), 2.78 (s, 3H). LCMS: m / z 390.1 [MH] - 150 Starting materials: 5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.74 (s, 1H), 7.33 (s, 1H), 6.70 (s, 1H), 4.55 (t, 2H), 4.37 (m, 1H), 4.17-3.89 (m, 1H), 3.18 (t, 2H), 2.31 (s, 3H), 2.09 (m, 4H), 1.89 (m, 2H), 1.55-1.20 (m, 4H). LCMS: m / z 427.2 [M+H] + 151 Starting materials: 5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.74 (s, 1H), 7.33 (s, 1H), 6.70 (s, 1H), 4.54 (t, 2H), 4.37 (m, 1H), 4.16-4.01 (m, 1H), 3.18 (t, 2H), 2.63 (s, 3H), 2.36-2.13 (m, 4H), 2.10 (m, 2H), 1.89 (s, 3H), 1.51-1.20 (m, 4H). LCMS: m / z 427.2 [M+H] + 152 Starting materials: 4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline HCl and 3-methyl-2-sideoxy Azodin-4-carboxylic acid Purification method A. 1H NMR (500 MHz, DMSO -d6) δ: 9.80 (s, 1H), 8.53 (s, 1H), 8.24 (d, 1H), 7.95 (d, 1H), 7.32 (d, 1H), 7.22 (d, 1H), 4.69-4.59 (m, 1H), 4.41 (t, 1H), 4.21-4.10 (m, 1H), 3.88 (s, 3H), 2.71 (s, 3H). LCMS: m / z 430.0 [M+H] + 153 Starting materials: 4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline HCl and 3-methyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.53 (s, 1H), 8.55 (s, 1H), 8.26 (dd, 1H), 7.95 (dd, 1H), 7.34 (d, 1H), 7.23 (d, 1H), 6.45 (s, 1H), 4.43-4.26 (m, 1H), 3.89 (s, 3H), 3.53 (t, 1H), 3.16 (t, 1H), 2.62 (s, 3H). LCMS: m / z 429.2 [M+H] + 154 Starting materials: 4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline HCl and (R)-3-methyl-2-sideoxy Lithium azolidinium-4-carboxylate Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.82 (s, 1H), 8.57-8.50 (m, 1H), 8.26 (dd, 1H), 7.97 (d, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 4.66-4.61 (m, 1H), 4.43 (t, 1H), 4.21-4.15 (m, 1H), 3.90 (s, 3H), 2.73 (s, 3H). LCMS: m / z 430.0 [M+H] + 155 Starting materials: 4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline HCl and (R)-3-methyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO -d6) δ: 9.50 (s, 1H), 8.53 (d, 1H), 8.24 (dd, 1H), 7.92 (d, 1H), 7.32 (d, 1H), 7.21 (d, 1H), 6.42 (s, 1H), 4.33 (dd, 1H), 3.87 (s, 3H), 3.51 (t, 1H), 3.15 (t, 1H), 2.60 (s, 3H). LCMS: m / z 429.2 [M+H] + 156 Starting materials: 4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline HCl and (S)-3-methyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.50 (s, 1H), 8.55 (s, 1H), 8.26 (dd, 1H), 7.94 (d, 1H), 7.34 (d, 1H), 7.23 (d, 1H), 6.44 (s, 1H), 4.39-4.31 (m, 1H), 3.89 (s, 3H), 3.53 (t, 1H), 3.21-3.13 (m, 1H), 2.62 (s, 3H). LCMS: m / z 429.0 [M+H] + 157 Starting materials: 4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline HCl and (S)-3-methyl-2-sideoxy Lithium azolidinium-4-carboxylate Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.82 (s, 1H), 8.58 - 8.49 (m, 1H), 8.26 (d, 1H), 7.97 (d, 1H), 7.34 (d, 1H), 7.23 (d, 1H), 4.69-4.61 (m, 1H), 4.43 (t, 1H), 4.22-4.13 (m, 1H), 3.90 (s, 3H), 2.73 (s, 3H). LCMS: m / z 430.0 [M+H] + 158 Starting materials: 5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyaniline HCl and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.58 (s, 1H), 8.02 (s, 1H), 7.96 (d, 1H), 7.67 (d, 1H), 7.32 (d, 1H), 6.97 (d, 1H), 6.44 (s, 1H), 4.36 (dd, 1H), 3.90 (s, 3H), 3.52 (t, 1H), 3.21-3.10 (m, 1H), 2.61 (s, 3H). LCMS: m / z 462.0 [M+H] + 159 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.76 (s, 1H), 8.55 (s, 1H), 8.20 (d, 1H), 7.56 (s, 1H), 7.18 (d, 1H), 6.90 (s, 1H), 6.39 (s, 1H), 4.65 (t, 2H), 4.35 (dd, 1H), 3.51 (t, 1H), 3.25 (t, 2H), 3.18-3.10 (m, 1H), 2.60 (s, 3H). LCMS: m / z 423.0 [M+H] + 160 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and 2-sideoxypiperidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.62 (s, 1H), 8.55 (s, 1H), 8.19 (d, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.16 (d, 1H), 6.85 (s, 1H), 4.63 (t, 2H), 3.24 (t, 2H), 3.19-2.89 (m, 3H), 2.24 (d, 2H), 2.02-1.57 (m, 2H). LCMS: m / z 422.2 [M+H] + 161 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and 6-sideoxypiperidine-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.65 (s, 1H), 8.53 (s, 1H), 8.17 (d, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.14 (d, 1H), 6.84 (s, 1H), 4.62 (t, 2H), 3.22 (m, 4H), 2.96-2.85 (m, 1H), 2.23-2.07 (m, 2H), 1.97-1.70 (m, 2H). LCMS: m / z 422.2 [M+H] + 162 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.91 (s, 1H), 8.55 (s, 1H), 8.19 (d, 1H), 7.57 (s, 1H), 7.17 (d, 1H), 6.89 (s, 1H), 4.65 (t, 2H), 4.40 (s, 1H), 3.25 (t, 2H), 2.63 (s, 3H), 2.36-2.10 (m, 3H), 1.99-1.73 (m, 1H). LCMS: m / z 422.0 [M+H] + 163 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and (S)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.91 (s, 1H), 8.55 (s, 1H), 8.19 (d, 1H), 7.57 (s, 1H), 7.17 (d, 1H), 6.89 (s, 1H), 4.65 (t, 1H), 4.40 (s, 1H), 3.24 (d, 1H), 2.63 (s, 3H), 2.33-2.14 (m, 3H), 1.86 (m, 1H). LCMS: m / z 422.0 [M+H] + 164 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and 3-cyclopropyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.79 (s, 1H), 8.55 (d, 1H), 8.20 (dd, 1H), 7.60 (t, 1H), 7.18 (d, 1H), 6.89 (d, 1H), 6.40 (s, 1H), 4.65 (t, 2H), 4.44-4.35 (m, 1H), 3.43 (t, 1H), 3.25 (t, 2H), 3.16-3.09 (m, 1H), 2.34 (s, 1H), 0.62-0.52 (m, 2H), 0.49 (m, 2H). LCMS: m / z 449.0 [M+H] + 165 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine and (S)-1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylate Purification method A. 1H NMR (400 MHz, acetonitrile-d 3) δ: 8.47 (s, 1H), 8.16 (s, 1H), 8.06 (d, 1H), 7.72 (s, 1H), 7.11 (d, 1H), 6.87 (s, 1H), 4.70 (t, 2H), 4.22 (d, 1H), 3.31 (t, 2H), 2.60-2.22 (m, 4H), 0.89-0.66 (m, 2H), 0.60 (m, 2H). LCMS: m / z 448.0 [M+H] + 166 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine and (R)-1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylate Purification method A. 1H NMR (400 MHz, acetonitrile-d 3) δ: 8.47 (s, 1H), 8.16 (s, 1H), 8.06 (d, 1H), 7.72 (s, 1H), 7.11 (d, 1H), 6.87 (s, 1H), 4.70 (t, 2H), 4.22 (d, 1H), 3.31 (t, 2H), 2.60-2.22 (m, 4H), 0.89-0.66 (m, 2H), 0.60 (m, 2H). LCMS: m / z 448.2 [M+H] + 167 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and 3-ethyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.80 (s, 1H), 8.55 (s, 1H), 8.20 (d, 1H), 7.56 (s, 1H), 7.18 (d, 1H), 6.90 (s, 1H), 6.39 (s, 1H), 4.65 (t, 2H), 4.49 (dd, 1H), 3.49 (t, 1H), 3.38-3.20 (m, 3H), 3.20-3.11 (m, 1H), 2.84 (dq, 1H), 0.98 (t, 3H). LCMS: m / z 437.2 [M+H] + 168 Starting materials: (S)-3-methyl-2-sideoxyimidazolidine-4-carboxylic acid and 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine Purification method A. 1H NMR (600 MHz, DMSO -d6) δ: 9.75 (s, 1H), 8.53 (d, 1H), 8.18 (dd, 1H), 7.54 (d, 1H), 7.16 (d, 1H), 6.92-6.82 (m, 1H), 6.38 (s, 1H), 4.63 (t, 2H), 4.33 (dd, 1H), 3.49 (t, 1H), 3.23 (t, 2H), 3.17-3.08 (m, 1H), 2.59 (s, 4H). LCMS: m / z 423.0 [M+H] + 169 Starting materials: (R)-3-methyl-2-sideoxyimidazolidine-4-carboxylic acid and 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine Purification method A. 1H NMR (600 MHz, DMSO -d6) δ: 9.75 (s, 1H), 8.53 (d, 1H), 8.18 (dd, 1H), 7.54 (d, 1H), 7.16 (d, 1H), 6.92-6.83 (m, 1H), 6.38 (s, 1H), 4.63 (t, 2H), 4.33 (dd, 1H), 3.49 (t, 1H), 3.23 (t, 3H), 3.13 (dd, 1H), 2.58 (s, 3H). LCMS: m / z 423.0 [M+H] + 170 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine and (R)-1-ethyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO -d6) δ: 9.91 (s, 1H), 8.67-8.48 (m, 1H), 8.18 (dd, 1H), 7.55 (d, 1H), 7.15 (d, 1H), 6.88 (d, 1H), 4.64 (t, 1H), 4.53-4.39 (m, 1H), 3.45 (m, 1H), 3.23 (t, 2H), 2.78 (m, 1H), 2.33-2.05 (m, 3H), 1.97-1.75 (m, 1H), 0.98 (t, 3H). LCMS: m / z 436.2 [M+H] + 171 Starting materials: 5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine and 1-(S)-1-ethyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO -d6) δ: 9.91 (s, 1H), 8.53 (t, 1H), 8.18 (dd, 1H), 7.55 (d, 1H), 7.15 (d, 1H), 6.88 (s, 1H), 4.64 (t, 2H), 4.51 (m, 1H), 3.46 (m, 1H), 3.23 (t, 2H), 2.78 (m, 1H), 2.32-2.05 (m, 3H), 1.86 (m, 1H), 0.98 (t, 3H). LCMS: m / z 436.2 [M+H] + 172 Starting materials: 2-methyl-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A, followed by method I. Retention time 7.23 min. 1H NMR (600 MHz, DMSO -d6) δ: 9.85 (s, 1H), 8.53 (s, 1H), 8.17 (d, 1H), 7.56 (s, 1H), 7.15 (d, 1H), 6.84 (s, 1H), 5.02 (q, 1H), 4.40 (d, 1H), 3.39-3.33 (m, 1H), 2.88-2.80 (m, 1H), 2.61 (s, 3H), 2.29-2.12 (m, 3H), 1.91-1.82 (m, 1H), 1.46 (d, 3H). LCMS: m / z 436.2 [M+H] + 173 Starting materials: 2-methyl-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-amine and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A, followed by method I. Retention time 11.33 min. 1H NMR (600 MHz, DMSO -d6) δ: 9.84 (s, 1H), 8.53 (s, 1H), 8.17 (d, 1H), 7.56 (s, 1H), 7.15 (d, 1H), 6.83 (s, 1H), 5.02 (q, 1H), 4.40 (d, 1H), 3.39-3.33 (m, 1H), 2.85 (dd, 1H), 2.62 (s, 3H), 2.28-2.15 (m, 3H), 1.90-1.81 (m, 1H), 1.45 (d, 3H). LCMS: m / z 436.2 [M+H] + 174 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy) octocarbamate-8-amine and (S)-1-methyl-5-syloxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, methanol-d4) δ: 8.42 (s, 1H), 8.07 (dd, 1H), 7.76 (d, 1H), 7.09 (d, 1H), 6.71 (d, 1H), 4.45 (dd, 1H), 4.32 (t, 2H), 2.85 (m, 5H), 2.55-2.34 (m, 3H), 2.13-2.00 (m, 3H). LCMS: m / z 436.0 [M+H] + 175 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy) octocarbamate-8-amine and (R)-1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, methanol-d4) δ: 8.42 (s, 1H), 8.07 (dd, 1H), 7.76 (d, 1H), 7.09 (d, 1H), 6.71 (d, 1H), 4.45 (dd, 1H), 4.32 (t, 2H), 2.85 (m, 5H), 2.55-2.34 (m, 3H), 2.13-2.00 (m, 3H). LCMS: m / z 436.0 [M+H]+ 176 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy) oxo-8-amine and 3-methyl-2-yl-imidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.37 (s, 1H), 8.55 (s, 1H), 8.20 (dd, 1H), 7.72 (d, 1H), 7.18 (d, 1H), 6.72 (d, 1H), 6.46 (s, 1H), 4.37 (dd, 1H), 4.26 (t, 2H), 3.53 (t, 1H), 3.14 (t, 1H), 2.76 (t, 2H), 2.61 (s, 3H), 1.96 (t, 2H). LCMS: m / z 437.2 [M+H] + 177 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy) octocarbamate-8-amine and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, methanol-d4) δ: 8.42 (s, 1H), 8.06 (dd, 1H), 7.76 (d, 1H), 7.08 (d, 1H), 6.71 (d, 1H), 4.45 (dd, 1H), 4.35-4.28 (m, 2H), 2.83 (m, 5H), 2.55-2.33 (m, 3H), 2.11-2.00 (m, 3H). LCMS: m / z 436.4 [M+H] + 178 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxane-4-amine and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 10.10 (s, 1H), 8.57 (d, 1H), 8.25-8.16 (m, 1H), 7.26-7.11 (m, 2H), 6.74 (d, 1H), 6.43 (s, 1H), 6.12 (s, 2H), 4.35-4.24 (m, 1H), 3.57-3.47 (m, 1H), 3.22-3.11 (m, 1H), 2.61 (s, 3H). LCMS: m / z 425.0 [M+H] + 179 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxane-4-amine and 1-cyclopropyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 10.17 (s, 1H), 8.57 (d, 1H), 8.27-8.14 (m, 1H), 7.27-7.14 (m, 2H), 6.74 (d, 1H), 6.14 (d, 2H), 4.47-4.17 (m, 1H), 2.46-2.36 (m, 1H), 2.35-2.23 (m, 1H), 2.23-2.12 (m, 2H), 1.93-1.82 (m, 1H), 0.77-0.67 (m, 1H), 0.66-0.58 (m, 1H), 0.57-0.46 (m, 2H). LCMS: m / z 450.2 [M+H] + 180 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxane-4-amine and (S)-3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 10.06 (s, 1H), 8.64-8.53 (m, 1H), 8.25-8.08 (m, 1H), 7.28-7.11 (m, 2H), 6.74 (d, 1H), 6.41 (s, 1H), 6.12 (s, 2H), 4.47-4.14 (m, 1H), 3.69-3.47 (m, 1H), 3.21-3.11 (m, 1H), 2.61 (s, 3H). LCMS: m / z 425.0 [M+H] + 181 Starting materials: 6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxane-4-amine and (R)-3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 10.08 (s, 1H), 8.57 (d, 1H), 8.29-8.10 (m, 1H), 7.28-7.07 (m, 2H), 6.74 (d, 1H), 6.42 (s, 1H), 6.12 (s, 2H), 4.35-4.21 (m, 1H), 3.51 (d, 1H), 3.16 (t, 1H), 2.61 (s, 3H). LCMS: m / z 425.5 [M+H] + 182 Starting materials: 7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method B. 1H NMR (400 MHz, DMSO -d6) δ: 9.53 (s, 1H), 8.56 (s, 1H), 8.21 (d, 1H), 7.45 (s, 1H), 7.18 (d, 1H), 6.58 (s, 1H), 6.46 (s, 1H), 4.43-4.26 (m, 5H), 3.59-3.45 (m, 1H), 3.20-3.08 (m, 1H), 2.61 (s, 3H). LCMS: m / z 439.0 [M+H] + 183 Starting materials: 7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method B, followed by method H. Retention time 8.02 min. LCMS: m / z 439.0 [M+H]+ 184 Starting materials: 7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method B, followed by method H. Retention time: 12.86 min. LCMS: m / z 439.0 [M+H]+ 185 Starting materials: 5-(4-(trifluoromethyl)phenoxy)benzofuran-7-amine and 1-methyl-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 10.62 (s, 1H), 8.15 (d, 1H), 7.77-7.65 (m, 3H), 7.23 (d, 1H), 7.12 (d, 2H), 7.02 (d, 1H), 4.52-4.44 (m, 1H), 2.68 (s, 3H), 2.35-2.19 (m, 3H), 2.01-1.90 (m, 1H). LCMS: m / z 419.2 [M+H] + 186 Starting materials: 6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-amine and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 10.10 (s, 1H), 7.71 (d, 2H), 7.15 (s, 1H), 7.11 (d, 2H), 6.71 (d, 1H), 6.42 (s, 1H), 6.13 (s, 2H), 4.36-4.20 (m, 1H), 3.51 (t, 1H), 3.16 (t, 1H), 2.60 (s, 3H). LCMS: LCMS: m / z 424.0 [M+H] + Int-285 (Intermediate) Starting materials: 5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-amine HCl and 4-(tert-butoxycarbonyl)-1-methyl-6-sideoxypiperyl Lithium 2-formate LCMS: m / z 534.2 [MH] - 187 Starting materials: 5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-amine HCl and 2-sideoxypiperidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.65 (s, 1H), 7.69 (d, 2H), 7.57 (s, 1H), 7.48 (s, 1H), 7.06 (d, 2H), 6.84 (s, 1H), 4.64 (t, 2H), 3.24 (t, 2H), 3.16-2.92 (m, 3H), 2.25 (d, 2H), 2.03-1.80 (m, 1H), 1.74-1.55 (m, 1H). LCMS: m / z 421.2 [M+H] + 188 Starting materials: 5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-amine HCl and 1-(2-(methylamino)-2-sideoxyethyl)-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.99 (s, 1H), 7.94-7.81 (m, 1H), 7.70 (d, 2H), 7.52 (s, 1H), 7.07 (d, 2H), 6.87 (s, 1H), 4.64 (t, 2H), 4.59-4.51 (m, 1H), 4.15 (d, 1H), 3.28-3.20 (m, 3H), 2.57 (d, 3H), 2.36-2.22 (m, 3H), 1.95-1.83 (m, 1H). LCMS: m / z 478.0 [M+H] + 189 Starting materials: 5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-amine HCl and 1-(2-amino-2-sideoxyethyl)-5-sideoxypyrrolidone-2-carboxylic acid Purification method A. 1H NMR (600 MHz, DMSO -d6) δ: 9.99 (s, 1H), 7.68 (d, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.12-7.02 (m, 3H), 6.85 (s, 1H), 4.62 (t, 2H), 4.58-4.51 (m, 1H), 4.12 (d, 1H), 3.27-3.15 (m, 3H), 2.34-2.17 (m, 3H), 1.93-1.80 (m, 1H). LCMS: m / z 464.0 [M+H] + 190 Starting materials: 5-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzofuran-7-amine HCl and 6-sideoxypiperidine-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.52 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1H), 6.70 (s, 1H), 4.54 (t, 2H), 4.36 (s, 1H), 3.25 (s, 2H), 3.17 (t, 2H), 2.91 (m, 1H), 2.27-1.62 (m, 12H). LCMS: m / z 395.2 [M+H] + 191 Starting materials: 7-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 6-sideoxypiperidine-3-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.30 (s, 1H), 7.48 (s, 1H), 7.23 (s, 1H), 6.33 (s, 1H), 4.39 (s, 1H), 4.24 (s, 4H), 3.28-3.17 (m, 2H), 2.95 (m, 1H), 2.20 (m, 2H), 2.08-1.67 (m, 8H). LCMS: m / z 411.2 [M+H] + 192 Starting materials: 7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-amine HCl and 3-methyl-2-sideoxyimidazolidine-4-carboxylic acid Purification method A. 1H NMR (400 MHz, DMSO -d6) δ: 9.57...

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein A is phenyl, pyridyl, or cyclohexyl; L is -O-; R1 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR36R37, or a 5- to 6-membered heterocycle having 1 to 3 heteroatoms independently selected from O, S, and N as ring atoms, substituted as desired; R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen; R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, or cyano, or R1 and R3 together with the attached carbon atom form a 5- to 6-membered ring having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms, substituted as desired; R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl; R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the attached carbon atom form a 5- to 6-membered heterocycle having 1 to 3 independently selected heteroatoms selected from O, S, and N as ring atoms, which may be substituted as required; wherein B is any of the following groups: , , , , , , , , , , , , , , , , , , and; the restriction is that when B is a ring (2), (4), (20), (21), (23), or (25), then R1 is a C1-7 alkoxy; R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-7 alkyl, -C(O)-RX, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxycarbonyl-C1-7 alkyl, -SO2-C1-7 alkyl, -C1-7 alkyl-C(O)-NR23R24, or a 4- to 6-membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms, which are substituted as needed; RX is C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkyl-NR36R37, or a 4- to 6-membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms, which are substituted as needed; R7, R8, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, hydroxyl, C1-7 alkoxy, or C1-7 alkyl carbonyl; R11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl; R23, R24, R27, R28, R29, R31, R33, R34, R35, R36, R37, R40, R41, R42, R43, and R44 are independently hydrogen or C1-7 alkyl; R30 is C1-7 alkyl, C1-7 alkyl carbonyl, or -SO2C1-7 alkyl;R38 is hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxy C1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR23R24; R39 is hydrogen, C1-7 alkyl, or hydroxyl; wherein the substitutions selected as needed are 1 to 2 independently selected from the following substituents each time they appear: C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy, and lateral oxy; the limitation is that the compound of formula (Ia) is not N-[4-methyl-3-[(4-methyl-2-pyridyl)oxy]phenyl]-5-lateral oxy-2-pyrrolidinemethylamine; 1-ethyl-5-lateral oxy-N-(3-phenoxyphenyl)-3-pyrrolidinemethylamine; N-[4-methoxy-3-(4-methoxyphenoxy)phenyl]-1-(2-methylpropyl)-5-sideoxy-3-pyrrolidinemethylamine; or 6-sideoxy-N-(3-phenoxyphenyl)-2-piperazine.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein B is a ring (1a), (3), (4), (6), (8), (9), (10), (11), (12), (13), (16), (17) or (18).

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein B is a ring (1a), (4), (10), (11), (12), (13), (16) or (17).

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein B is a ring (1a), (10), (11) or (12).

5. The compound of claim 4 or its pharmaceutically acceptable salt, wherein B is a ring (1a) or (12).

6. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1-5, wherein R7 and R8 are hydrogen.

7. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, a C1-7 alkyl or a C3-7 cycloalkyl.

8. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R6 is -C(O)-RX, wherein RX is a C1-7 alkyl group or a 4- to 6-membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms, substituted as desired.

9. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1-5, wherein R20 is hydrogen and R18 is a C1-7 alkyl or C3-7 cycloalkyl.

10. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R21 is hydrogen or a C1-7 alkyl group.

11. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1-5, wherein R1 is hydrogen, C1-7 alkoxy, or halogen.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-7 alkoxy or halogen.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-7 alkoxy group.

14. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1-5, wherein R2 is hydrogen, a C1-7 alkoxy group, or a halogen.

15. The compound of claim 14 or its pharmaceutically acceptable salt, wherein R2 is hydrogen or a halogen.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

17. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, halogen or C1-7 alkoxy.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen or C1-7 alkoxy.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.

20. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1-5, wherein R1 and R3 together with the attached carbon atom form a substituted 5- to 6-membered ring having 0-3 independently selected heteroatoms chosen as ring atoms from O, S and N.

21. The compound of claim 20 or its pharmaceutically acceptable salt, wherein R1 and R3 together with the attached carbon atom form a 5- or 6-membered ring having 1-2 independent heteroatoms selected from O and N as ring atoms.

22. The compound of claim 21 or its pharmaceutically acceptable salt, wherein R1 and R3 together with the attached carbon atom form a 5- or 6-membered ring having 1-2 heteroatoms, wherein the heteroatom is O.

23. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1-5, wherein R4 is hydrogen, halogen, C1-7 alkyl, C1-7 alkoxy, halogenated C1-7 alkyl, or halogenated C1-7 alkoxy, and R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, cyano, amino, or halogen.

24. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein A is phenyl or pyridyl; L is -O-; R1 is C1-7 alkoxy; R2, R3, R5, R33 and R42 are hydrogen; Z is cyclo(1a) or (12); and R4 is halogenated C1-7 alkyl.

25. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carboxamide (compound 1); 1-methyl-5-sideoxy-N-(5-(3-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidone-2-carboxamide (compound 28); 5-sideoxy-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxanepenten-4-yl)pyrrolidone-2-carboxamide (compound 33); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carboxamide (compound 45); 1-Ethyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carboxamide (Compound 47); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 48); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-sideoxypyrrolidone-2-carboxamide (Compound 59); 5-sideoxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-carboxamide (Compound 66); 1-Methyl-5-sideoxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-carboxamide (Compound 67); 1-Ethyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carboxamide (Compound 68); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 69); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 70); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carbinolamine (Compound 75); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carbinolamine (Compound 76); 1-isopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carbinolamine (Compound 81); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyazolidone-4-carbinolamine (Compound 87); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyazolidone-4-carbinolamine (Compound 88);N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-thionoylpyrrolidone-2-carboxamide (Compound 91); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-thionoylpyrrolidone-2-carboxamide (Compound 92); (R)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 93); (R)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 97); (R)-1-methyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-carboxamide (Compound 99); (S)-N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 100); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyazolidine-4-carboxamide (Compound 101); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyazolidine-4-carboxamide (Compound 102); (R)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 103); (S)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 105); (S)-1-methyl-5-sideoxy-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-carboxamide (Compound 107); 1-Cyclopropyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-carboxamide (Compound 109); 1-Cyclopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carboxamide (Compound 110); 1-Cyclopropyl-5-sideoxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-carboxamide (Compound 114); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (Compound 117);N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (compound 118); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-sideoxypiperidine-3-carboxamide (compound 119); (R)-1-cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidine-2-carboxamide (compound 128); (S)-1-cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidine-2-carboxamide (compound 129); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (Compound 130); 3-cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-sideoxyimidazolidine-4-carboxamide (Compound 131); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-sideoxypyrrolidine-2-carboxamide, mirror isomer 2 (Compound 133); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-sideoxypyrrolidine-2-carboxamide (Compound 134); 1-(2-amino-2-sideoxyethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carboxamide (Compound 136); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-carboxamide (Compound 139); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (Compound 141); (2S)-4-methoxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (Compound 143); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (compound 149); (S)-1-methyl-5-sideoxy-N-(5-((((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 150); (R)-1-methyl-5-sideoxy-N-(5-(((((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 151);N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyazolidin-4-carboxamide (Compound 152); N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyazolidin-4-carboxamide (Compound 153); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyazolidin-4-carboxamide (Compound 154); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (Compound 156); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (Compound 157); 3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (Compound 159); (R)-1-Methyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 162); (S)-1-Methyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 163); 3-Cyclopropyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (Compound 164); (S)-1-Cyclopropyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 165); (R)-1-Cyclopropyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 166); 3-Ethyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (Compound 167); (S)-3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-methamide (compound 168);(R)-1-Ethyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methylamine (Compound 170); (S)-1-Ethyl-5-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methylamine (Compound 171); (R)-1-Methyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy) octocarbazin-8-yl)pyrrolidone-2-methylamine (Compound 175); 3-Methyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy) Compound 176: 1-Methyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy) 1-Methyl-8-yl)pyrrolidine-2-methylamine (Compound 177); 3-Methyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-methylamine (Compound 178); 1-Cyclopropyl-5-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)pyrrolidine-2-methylamine (Compound 179); (S)-3-methyl-2-sideoxy-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-methylamine (Compound 180); 3-methyl-2-sideoxy-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxacyclohexen-5-yl)imidazolidine-4-methylamine (Compound 182); 3-methyl-2-sideoxy-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxacyclohexen-5-yl)imidazolidine-4-methylamine, mirror isomer 2 (Compound 184); 1-Methyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidin-2-carboxamide (Compound 185); 3-Methyl-2-sideoxy-N-(6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-carboxamide (Compound 186); 2-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperidine-4-carboxamide (Compound 187);1-(2-amino-2-sideoxyethyl)-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-methamide (Compound 189); 3-methyl-2-sideoxy-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)imidazolidine-4-methamide (Compound 192); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (Compound 196); N-(5-((4,4-difluorocyclohexyl)methoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 206); (R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-3-methyl-2-sideoxyazolidine-4-carboxamide (compound 208); (R)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 209); (S)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 210); N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (compound 213); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidine-2-carboxamide (compound 214); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidine-2-carboxamide (compound 215); (S)-3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-carboxamide (compound 216); (R)-3-methyl-2-sideoxy-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-carboxamide (compound 217); N-(5-(3,4-dichlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidine-2-carboxamide (compound 222); N-(5-(3-chloro-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidine-2-carboxamide (compound 223); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-carboxamide (compound 226);(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-sideoxyimidazolidine-4-carboxamide (compound 227); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(5-sideoxypyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (compound 229); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-5-sideoxypyrrolidine-2-carbonyl)-5-sideoxypyrrolidine-2-carboxamide (compound 230); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(4-sideoxyazacyclobutane-2-carbonyl)pyrrolidone-2-carboxylamine (compound 231); 1-methyl-5-sideoxy-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)pyrrolidone-2-carboxylamine, mirror isomer 1 (compound 234); 1-methyl-5-sideoxy-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidone-2-carboxylamine (compound 237); N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 239); N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 240); N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-carboxamide (compound 253); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 255); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 264); (R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 265); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 276); (R)-N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 278); N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 279);(R)-N-(3-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (Compound 282); (R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (Compound 283); (R)-N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (Compound 290); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (Compound 292); N-(5-((4,4-dimethylcyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 296); N-(5-(3-bromophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 299); N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methylamine (compound 300); N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 304); N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 305); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (Compound 307); (R)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (Compound 308); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (Compound 312); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (Compound 313); N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 316); N-(5-(4-cyano-3-methylphenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 317); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyethyl)-5-sideoxypyrrolidone-2-methamide (compound 318); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methamide (compound 319);N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-sideoxypiperidine-2-methamide (compound 320); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-sideoxypiperidine-4-methamide (compound 322); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidine-3-methamide (compound 335); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 338); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 339); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 340); (S)-N-(5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 345); (S)-N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methamide (compound 348); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-3-carboxamide (compound 349); (S)-N-(3-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (compound 351); N-(3-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 352); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-3-carboxamide (compound 355); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-sideoxyimidazolidine-4-methoxyamine (compound 356); (S)-N-(2,4-difluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methoxyamine (compound 361); (S)-N-(3-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-methoxyamine (compound 362); (S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidine-2-methoxyamine (compound 363);(S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (Compound 365); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxy-1-(1H-pyrazol-4-yl)pyrrolidine-2-carboxamide (Compound 376); N-(4-fluoro-2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-sideoxyimidazolidine-4-carboxamide (Compound 381); N-(5-(4-chloro-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxyimidazolidine-2-carboxamide (Compound 384); N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 390); N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 394); (S)-N-(5-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 397); (N-(5-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-carboxamide (compound 398); N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 399); (S)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 400); (R)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 401); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-sideoxypyrrolidone-2-methylamine (compound 402); 1-glycinyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-sideoxypyrrolidone-2-methylamine, HCl (compound 413); or their tautomers.

26. Use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for the preparation of a medicine for treating a disease or symptom requiring inhibition of TEAD, wherein A is phenyl, pyridyl, or cyclohexyl; L is -O-; R1 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR36R37, or a 5- to 6-membered heterocycle having 1 to 3 heteroatoms independently selected from O, S, and N as ring atoms, substituted as desired; R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen; R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogen C1-7 alkyl, or cyano, or R1 and R3 together with the attached carbon atom form a 5- to 6-membered ring having 0 to 3 heteroatoms independently selected from O, S, and N as ring atoms, substituted as desired; R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl; R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the attached carbon atom form a 5- to 6-membered heterocycle having 1 to 3 independently selected heteroatoms selected from O, S, and N as ring atoms, which may be substituted as required; wherein B is any of the following groups: , , , , , , , , , , , , , , , , , , and; the restriction is that when B is a ring (2), (4), (20), (21), (23), or (25), then R1 is a C1-7 alkoxy; R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-7 alkyl, -C(O)-RX, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxycarbonyl-C1-7 alkyl, -SO2-C1-7 alkyl, -C1-7 alkyl-C(O)-NR23R24, or a 4- to 6-membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms, which are substituted as needed; RX is C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkyl-NR36R37, or a 4- to 6-membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms, which are substituted as needed; R7, R8, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, hydroxyl, C1-7 alkoxy, or C1-7 alkyl carbonyl; R11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl; R23, R24, R27, R28, R29, R31, R33, R34, R35, R36, R37, R40, R41, R42, R43, and R44 are independently hydrogen or C1-7 alkyl;R30 is a C1-7 alkyl, C1-7 alkyl carbonyl, or -SO2C1-7 alkyl; R38 is hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxyC1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR23R24; R39 is hydrogen, C1-7 alkyl, or hydroxyl; wherein the substitutions selected as needed are, in each occurrence, one or two independent substituents selected from the following: C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy, and side-oxy.

27. As requested in claim 26, wherein the disease is cancer or chronic pain.

28. As claimed in claim 27, wherein the cancer is mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, stomach cancer, liver cancer, lung cancer, and colorectal cancer.

29. As requested in claim 27, wherein the chronic pain is chronic neuralgia or chronic musculoskeletal pain.

30. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.