TEAD inhibitor

Abstract

This invention provides therapeutically active compounds useful for inhibiting the transcription-promoting domain (TEAD). [Solution] This invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound of formula (I) has utility as an inhibitor of TEAD. This compound is useful as a pharmaceutical in the treatment of diseases or conditions in which inhibition of TEAD is desired, such as cancer and chronic pain. TIFF2026086790000344.tif3158

Description

[Technical Field]

[0001] The present invention relates to therapeutically active compounds useful for inhibiting transcription-promoting domains (TEADs), and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of diseases or disorders associated with increased TEAD activity or expression, such as various cancers and chronic pain. [Background technology]

[0002] TEAD domain transcription factors (TEAD1-4) are a family of DNA-binding transcription factors that regulate the expression of genes involved in cell proliferation, cell fate, cell differentiation, organ abnormal growth, and organ regeneration. YAP and TAZ are coactivators of TEAD transcription that can travel back and forth between the cytoplasm and the nucleus. Alterations in actin dynamics and the Hippo signaling pathway promote phosphorylation, cytoplasmic retention, and proteasomal degradation of YAP and TAZ, resulting in decreased nuclear levels of YAP and TAZ and reduced TEAD transcriptional activity.

[0003] The evolutionarily conserved Hippo signaling pathway consists of large tumor suppressor 1 / 2 (LATS1 / 2), serine / threonine kinase, Sterile20-like kinase 1 / 2 (MST1 / 2), and the adapter proteins Salvador homolog 1 (SAV1) and MOB kinase activator 1A / B (MOB1A / B). The tumor suppressor neurofibromin 2 (NF2) (also known as merlin) is involved upstream of these kinases and inhibits YAP and TAZ activity by promoting the activation of the pathway. The Hippo pathway is associated with many aspects of tumorigenesis, including cell proliferation, cell differentiation, cancer metastasis, and cancer treatment resistance. Therefore, dysregulation of Hippo pathway signaling has been shown to lead to carcinogenesis across various cancer types. Furthermore, YAP and TAZ have been reported to be core mechanisms underlying the pathogenesis of chronic pain, such as chronic neuropathic pain and chronic musculoskeletal pain.

[0004] Compounds having TEAD inhibitory activity are disclosed, for example, in Patent Documents 1, 2, and 3. The antitumor effect of the TEAD inhibitor K-975 on malignant pleural mesothelioma in vivo is reported in Non-Patent Document 1.

[0005] Compounds targeting diseases associated with dysregulation of Hippo pathway components, such as those targeting the YAP-TEAD interaction, are needed. Such compounds would be useful in treating diseases or conditions where TEAD inhibition is desired, including chronic pain such as neuropathic pain, and various cancers, including cancers that are resistant to other treatments such as chemotherapy, immunotherapy, and targeted therapy. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2020 / 081572 [Patent Document 2] International Publication No. 2020 / 070181 [Patent Document 3] International Publication No. 2020 / 051099 [Non-patent literature]

[0007] [Non-Patent Document 1] Am J Cancer Res, 2020; 10(12): 4399-4415. [Overview of the project]

[0008] It has been found that the compound of formula (I) is a potent inhibitor of the YAP-TEAD interaction. The present compound is therefore useful for the treatment of conditions or diseases where inhibition of TEAD is desired. Such conditions or diseases include, but are not particularly limited to, chronic pain, particularly chronic neuropathic pain and chronic musculoskeletal pain, and cancer, particularly cancers associated with deregulation in components of the Hippo pathway including YAP-TEAD. Specific cancers include, but are not particularly limited to, mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, gastric cancer, liver cancer, lung cancer and colon cancer.

[0009] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Chemical formula

[0010] According to one embodiment, the present invention relates to a method for treating a disease or condition in which inhibition of TEAD is desired, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. [ka] (In the formula, A is a pyridyl, tetrahydropyranyl, 4-10 membered carbon ring; L stands for -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- is; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 , or an optionally substituted 5-6 membered heterocycle having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; R2 is hydrogen, C 1-7 Alkyl, C 1-7 It is an alkoxy or halogen; R3 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 They are alkyl or cyano, or R1 and R3, together with the carbon atoms to which they are bonded, form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R4 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, cyano, or C 1-7 It is an alkylcarbonyl; R5 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, or R4 and R5, together with the carbon atoms to which they are bonded, form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; Z is -CH(NHR 25)-(CH2)2-COOH, or formula [ka] (In the formula, B is one of the following groups) [ka] however, If B is a ring (2), then L is -O- or -OC 1-7 It is alkyl, and R1 is C 1-7 It is an alkoxy; If B is a ring (3), then L is -O-; If B is a ring (4), then L is -O- and R1 is C 1-7 It is an alkoxy; If B is a ring (20), (21), (23), (25), or (26), then L is -O- and R1 is C 1-7 (It is an alkoxy) It is the basis of; L is -C 1-7 In the case of alkyl-O-, R1 is C 1-7 It is an alkoxy, or R1 and R3, together with the carbon atoms to which they are bonded, form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; If A is a 4-membered, 5-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbon ring, then R1 is C 1-7 It is an alkoxy; R6 and R9 are independently hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-7 Alkyl, -C(O)-Rx, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, -SO2C 1-7 Alkyl, -C 1-7 Alkyl-C(O)-NR 23 R 24, or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; Rx is C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl-NR 36 R 37 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R7, R8, R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 26 These are, independently, hydrogen and C 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxyl, C 1-7 Alkoxy or C 1-7 It is an alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 It is an alkylcarbonyl; R 23 , R 24 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 and R 45 These are, independently, hydrogen, or C 1-7It is alkyl; R 25 C 1-7 It is alkyl; R 30 C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO2C 1-7 It is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy C 1-7 Alkylcarbonyl or -C 1-7 Alkyl-C(O)-NR 23 R 24 and; R 39 is hydrogen, C 1-7 Alkyl or hydroxyl; In each existence, any permutation is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 (One or two substituents independently selected from alkoxy and oxo.)

[0011] According to one embodiment, diseases or conditions in which TEAD inhibition is desired include cancers such as mesothelioma, squamous cell carcinoma, gynecological cancers, bladder cancer, gastric cancer, liver cancer, lung cancer, and colon cancer.

[0012] According to one embodiment, diseases or conditions for which TEAD inhibition is desired include chronic pain, such as chronic neuropathic pain and chronic musculoskeletal pain.

[0013] According to one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier. [Modes for carrying out the invention]

[0014] This application provides a novel compound of formula (I) or a pharmaceutically acceptable salt thereof that is useful as a TEAD inhibitor.

[0015] One embodiment of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. [ka] (In the formula, A is a pyridyl, tetrahydropyranyl, 4-10 membered carbon ring; L stands for -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- is; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 , or an optionally substituted 5-6 membered heterocycle having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; R2 is hydrogen, C 1-7 Alkyl, C 1-7 It is an alkoxy or halogen; R3 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 They are alkyl or cyano, or R1 and R3, together with the carbon atoms to which they are bonded, form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R4 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, cyano, or C 1-7 It is an alkylcarbonyl; R5 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogen C 1-7 Alkyl, halogen C1-7 Alkoxy, or R4 and R5, together with the carbon atoms to which they are bonded, form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; Z is -CH(NHR 25 )-(CH2)2-COOH, or formula [ka] (In the formula, B is one of the following groups) [ka] however, If B is a ring (2), then L is -O- or -OC 1-7 It is alkyl, and R1 is C 1-7 It is an alkoxy; If B is a ring (3), then L is -O-; If B is a ring (4), then L is -O- and R1 is C 1-7 It is an alkoxy; If B is a ring (20), (21), (23), (25), or (26), then L is -O- and R1 is C 1-7 (It is an alkoxy) It is the basis of; L is -C 1-7 In the case of alkyl-O-, R1 is C 1-7 It is an alkoxy, or R1 and R3, together with the carbon atoms to which they are bonded, form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; If A is a 4-membered, 5-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbon ring, then R1 is C 1-7 It is an alkoxy; R6 and R9 are independently hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-7 Alkyl, -C(O)-Rx, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C1-7 Alkyl, -SO2C 1-7 Alkyl, -C 1-7 Alkyl-C(O)-NR 23 R 24 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; Rx is C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl-NR 36 R 37 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R7, R8, R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 26 These are, independently, hydrogen and C 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxyl, C 1-7 Alkoxy or C 1-7 It is an alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 It is an alkylcarbonyl; R 23 , R 24 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41, R 42 , R 43 , R 44 and R 45 These are, independently, hydrogen, or C 1-7 It is alkyl; R 25 C 1-7 It is alkyl; R 30 C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO2C 1-7 It is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy C 1-7 Alkylcarbonyl or -C 1-7 Alkyl-C(O)-NR 23 R 24 and; R 39 is hydrogen, C 1-7 Alkyl or hydroxyl; In each existence, any permutation is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 One or two substituents independently selected from alkoxy and oxo; However, the compound of formula (I) N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-2-pyrrolidinecarboxamide; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide; N-[3-[(4-chlorophenyl)methyl]phenyl]-5-oxo-2-pyrrolidinecarboxamide; N-[3-[(chlorohexyloxy)methyl]phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide; N-[4-methyl-3-[(4-methyl-2-pyridinyl)oxy]phenyl]-5-oxo-2-pyrrolidinecarboxamide; N-[3-(cyclopentylamino)phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide; N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-oxo-3-piperidinecarboxamide; 1-Ethyl-5-oxo-N-(3-phenoxyphenyl)-3-pyrrolidinecarboxamide; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-2-pyrrolidinecarboxamide; 1-(1-ethylpropyl)-N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-5-oxo-3-pyrrolidinecarboxamide; N-[3-[(4-chlorophenyl)methyl]phenyl]-1,6-dihydro-6-oxo-3-pyridinecarboxamide; 1,6-dihydro-N-[4-methoxy-3-(phenylmethyl)phenyl]-6-oxo-3-pyridinecarboxamide; 1,6-dihydro-6-oxo-N-[3-[2-(2-pyridinyl)ethenyl]phenyl]-3-pyridinecarboxamide; N-[3-[(3-fluorophenoxy)methyl]phenyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide; 1-Methyl-N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-3-pyrrolidinecarboxamide; N-[3-[(1,3-benzodioxol-5-yloxy)methyl]phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide; 1,6-dihydro-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]6-oxo-3-pyridinecarboxamide; N-[3-[(cyclohexyloxy)methyl]phenyl]-1-ethyl-5-oxo-3-pyrrolidinecarboxamide; 1-Methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-5-oxo-3-pyrrolidinecarboxamide; 2,3-dihydro-3-methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]2-oxo-1H-imidazole-4-carboxamide; 2,3-dihydro-1,3-dimethyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-oxo-1H-imidazole-4-carboxamide; 1-Ethyl-N-[4-Methoxy-3-(4-pyridinylmethoxy)phenyl]-5-oxo-3-pyrrolidinecarboxamide; N-[4-Methoxy-3-(4-Methoxyphenoxy)phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide, or 6-Oxo-N-(3-phenoxyphenyl)-2-piperazinecarboxamide isn't it.)

[0016] It should be understood that the left bond in the variant of linker L is bonded to ring A in formula (I), and the right bond is bonded to the phenyl group. The wavy lines in the variant of group B indicate the position of the bond to the carboxamide group.

[0017] According to one embodiment, a compound of formula (I) is provided, specifically in which A is phenyl, pyridyl, or cyclohexyl. In the subgroup of the embodiments described above, A is phenyl or cyclohexyl. In 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.

[0018] Furthermore, according to one embodiment, specifically, R 42 A compound according to any of the above embodiments is provided, wherein the compound is hydrogen.

[0019] According to one embodiment, specifically, a compound according to formula (Ia) or a pharmaceutically acceptable salt thereof is provided. [ka] (In the formula, A, L, B, R1, R2, R3, R4, R5, R 33 and R 42 (This is as defined above.)

[0020] Furthermore, according to one embodiment, specifically, a compound is provided which is a compound according to any of the above embodiments, wherein B is a ring (1a), (3), (4), (6), (8), (9), (10), (11), (12), (13), (16), (17), or (18). In the subgroup of the embodiments described above, B is a ring (1a), (4), (10), (11), (12), (13), (16), or (17). In 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).

[0021] In the subgroup of compounds where B is (1a), R7 and R8 are hydrogen compounds. In yet another subgroup of the embodiments described above, R6 is hydrogen, C 1-7 Alkyl or C 3-7 It is a cycloalkyl compound. According to another subgroup, R6 is -C(O)-Rx, where Rx is C 1-7 An optionally substituted 4-6 membered ring having 1-3 heteroatoms independently selected from O, S, and N as alkyl or ring atoms. A specific example of such a ring is C 1-7 The pyrrolidine and azetidine rings are optionally substituted with one or two substituents independently selected from alkyl or oxo groups.

[0022] In the subgroup of compounds where B is a ring (12), R 20 is hydrogen and R 18 C 1-7 Alkyl or C 3-7 It is a cycloalkyl compound. In yet another subgroup of the embodiments described above, R 21 However, hydrogen or C1-7 It is a compound that is alkyl.

[0023] According to another embodiment, specifically, L is -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, or -O-C 1-7 alkyl-. Compounds according to any of the above embodiments are provided. In a subgroup of the above embodiments, L is -O-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, or -O-C 1-7 alkyl-. In a subgroup of the above embodiments, L is -O-, -C 2-7 alkenyl- or -O-C 1-7 alkyl-. In another subgroup, L is -O- or -C 2-7 alkenyl-. In yet another subgroup, L is -O-. Specific examples of C 1-7 alkyl as L is a -CH2- group. Specific examples of -C 2-7 alkenyl- as L is a -CH=CH- group. Specific examples of -C 1-7 alkyl-O- as L is a -CH2-O- group. Specific examples of -O-C 1-7 alkyl- as L is a -O-CH2- group.

[0024] According to one embodiment, specifically, compounds are provided in which R1 is hydrogen, C 1-7 alkoxy or halogen. In a subgroup of the above embodiments, R1 is C 1-7 alkoxy or halogen. In a subgroup of the above embodiments, R1 is C 1-7 alkoxy, particularly methoxy. According to one embodiment, R1 is an optionally substituted 5- to 6-membered heterocycle having 1 to 3 heteroatoms independently selected from O, S, and N as ring atoms. Specific examples of such rings include oxadiazolyl and pyrazolyl optionally substituted by 1 to 2 C 1-7 alkyl or oxo substituents.

[0025] According to one embodiment, specifically, R2 is hydrogen, C 1-7 A compound according to any of the above embodiments where R2 is alkoxy or halogen is provided. In a subgroup of the above embodiments, the compound is one where R2 is hydrogen or halogen. In a subgroup of the above embodiments, the compound is one where R2 is hydrogen.

[0026] According to one embodiment, specifically, a compound is provided where R3 is hydrogen, halogen or C 1-7 A compound where R3 is alkoxy is provided. In a subgroup, the compound is one where R3 is hydrogen or C 1-7 A compound where R3 is alkoxy. In a subgroup, the compound is one where R3 is hydrogen.

[0027] According to one embodiment, specifically, a compound according to any of the above embodiments is provided where R1 and R3 together with the carbon atom to which they are attached form an optionally substituted 5- to 6-membered ring having 0 to 3 heteroatoms independently selected from O, S and N as ring atoms. In a subgroup, the compound is one where R1 and R3 together with the carbon atom to which they are attached form an optionally substituted 5- to 6-membered ring having 1 to 2 heteroatoms independently selected from O and N as ring atoms. In a subgroup, the compound is one where R1 and R3 together with the carbon atom to which they are attached form an optionally substituted 5- to 6-membered ring having 1 to 2 heteroatoms where the heteroatom is O. Specific examples of such rings are furanyl, dihydrofuranyl, tetrahydrofuranyl, dioxanyl, dioxolanyl, oxazinyl, pyridinyl, 2,3-dihydro-1,4-dioxinyl, 2,3-dihydro-1,4-oxazinyl rings optionally substituted by 1 to 2 C 1-7 alkyl or oxo substituents.

[0028] According to one embodiment, specifically, R1 and R3 together with the phenyl ring to which they are attached are the following groups: [Chemical formula] (In the formula, the wavy line on the left indicates the bond position to the L group, and the wavy line on the right indicates the bond position to the carboxamide group.) Compounds according to any of the above embodiments are provided, which form an optionally substituted condensed ring represented by any of the following: 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 It can consist of one or two substituents independently selected from alkoxy and oxo.

[0029] According to one embodiment, specifically, R4 is hydrogen, halogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen C 1-7 Alkyl or halogen C 1-7 It is an alkoxy, and R5 is hydrogen, C 1-7 Alkyl, C 1-7 Compounds according to any of the above embodiments are provided, which are alkoxy, cyano, amino, or halogen. In the subgroup, R4 is a halogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or halogen C 1-7 It is an alkoxy, and R5 is hydrogen, C 1-7 These are compounds that are alkyl, cyano, or halogen. In the subgroup, R4 is halogen C 1-7 Alkyl or halogen C 1-7 A compound that is an alkoxy and in which R5 is hydrogen or a halogen. In the subgroup, R4 is a halogen C 1-7 Alkyl or halogen C 1-7 These are compounds that are alkoxy and have R5 as hydrogen. In another subgroup, both R4 and R5 are C 1-7 These are compounds where R4 and R5 are alkyl, for example, methyl. In another subgroup, these are compounds where both R4 and R5 are halogens, for example, fluoro. Halogen C 1-7 Specific examples of alkyl R4 groups are the -CF3 and CHF2 groups. Halogen C 1-7A specific example of an alkoxy R4 is the -OCF3 group.

[0030] According to one embodiment, specifically, ring A, together with R4 and R5, forms the following group: [ka] (In the formula, X is a halogen, and the dashed line indicates the bond position to the L group.) A compound according to any of the above embodiments represented by any of the above is provided.

[0031] In one embodiment, specifically, a compound according to any of the above embodiments is provided, wherein A, together with R4 and R5, is the group (1'), (2'), (3'), (4'), (7'), (8'), (10'), (11'), or (13'). In a subgroup, a compound according to any of the above embodiments is provided, wherein A, together with R4 and R5, is the group (1'), (4'), (7'), (8'), (10'), or (11').

[0032] According to one embodiment, specifically, A together with R4 and R5, the following base: [ka] (In the formula, the wavy line indicates the bond position to the L group.) A compound according to any of the above embodiments represented by is provided.

[0033] In one embodiment, specifically, a compound according to any of the above embodiments is provided, wherein A, together with R4 and R5, is the 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 embodiments is provided, wherein A, together with R4 and R5, is the group (1''), (2''), (4''), (7''), (11''), (12''), (15''), or (21'').

[0034] According to one embodiment, specifically, A is phenyl or pyridyl, L is -O-, R1 is C 1-7 alkoxy, and R2, R3, R5, R 33 and R 42 are hydrogen, Z is ring (1a) or (12), and R4 is halogen C 1-7 alkyl. A compound according to any of the above embodiments is provided.

[0035] According to one embodiment, specifically, Z may be -CH(NHR 25 )-(CH2)2-COOH. A compound according to any of the above embodiments is provided.

[0036] According to one embodiment, specifically, a compound of formula (Ib) or a pharmaceutically acceptable salt thereof is provided. [Chemical formula] (In the formula, D is CH or N; R2 is H or halogen; R4 is H, halogen or cyano; R5 is halogen or halogen C 1-7 alkyl; R1 is -OCH3 or halogen, or R1 and R3 together with the phenyl ring to which they are attached form the following group: [Chemical formula] a condensed ring represented by any of them. )

[0037] According to one embodiment, specifically, a compound of formula (Ic) or a pharmaceutically acceptable salt thereof is provided. [Chemical formula] (In the formula, L is -O- or -CH=CH-; R2 is H or halogen; R4 is H, C 1-7 It is an alkyl or halogen; R5 is hydrogen, C 1-7 Alkyl or halogen C 1-7 It is alkyl; B is a ring (1a), (10), or (12); R1 is either -OCH3 or a halogen, or R1 and R3, along with the phenyl ring to which they are bonded, are the following groups: [ka] (Forms a fused ring represented by one of the following:)

[0038] According to one embodiment, the present invention provides a method for treating diseases or conditions in which inhibition of TEAD is desired, such as cancer and chronic pain, comprising administering a therapeutically effective amount of a compound of formula (I) as defined in any of the above embodiments to a subject in need thereof.

[0039] The compounds of the present invention can be prepared using appropriate starting materials by a variety of synthetic routes similar to those known in the literature. Compounds of formula (I) can be prepared, for example, in the same way as or according to the following reaction scheme. Some of the compounds included in formula (I) can be obtained by transforming the functional groups of other compounds of formula (I) obtained according to the following scheme by oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, and other well-known reaction steps. It should be noted that any suitable leaving group, such as an N-protecting group such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, can be used in the synthesis in well-known ways to improve the selectivity of the reaction steps.

[0040] The compound of formula (I) can be prepared, for example, by scheme 1, in scheme 1, A, L, Z, R1, R2, R3, R4, R5, R 23 and R 42The above definition is used. In the method of Scheme 1, the aniline compound of formula [1] is coupled with the carboxylic acid derivative of formula [2] in a suitable solvent such as anhydrous acetonitrile or DMF in the presence of a suitable coupling reagent such as a combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methyl-1H-imidazole, or hexafluorophosphate azabenzotriazole tetramethyluranium (HATU) and N,N-diisopropylethylamine (DIPEA) to produce the compound of formula (I). [ka]

[0041] Alternatively, R 42 Compounds of formula (I) where is H can be prepared by scheme 2, where A, L, Z, R1, R2, R3, R4, R5 and R 33 is as defined above, where X is a halogen, for example, bromo. In the method of Scheme 2, the compound of formula [3] is coupled with the carboxamide compound of formula [4] in a suitable solvent such as toluene in the presence of a base such as cesium carbonate and a combination of Pd2(dba) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(xanthophos), or copper iodide and N1,N2-dimethylcyclohexane-1,2-diamine to produce the compound of formula (I). [ka]

[0042] The compound of formula (I), where L is -O-, can also be prepared, for example, according to scheme 3, in which A, Z, R1, R2, R3, R4 and R5 are as defined above. In the method of scheme 3, the compound of formula [3] is condensed with the compound of formula [4] in a suitable solvent such as tetrahydrofuran in the presence of Mitsunobu reagents such as triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD) to produce the compound of formula (I). [ka]

[0043] The intermediate compounds may be prepared according to the methods disclosed in the literature or as described in this disclosure.

[0044] For example, the intermediate compound of formula [1a] where L is -O- can be prepared according to scheme 4, in scheme 4, A, R1, R2, R3, R4, R5 and R 33 This is defined above. In the method of Scheme 4, the compound of formula [7] is coupled with the compound of formula [8] in a suitable solvent such as dichloromethane in the presence of a base such as pyridine and a catalyst such as copper diacetoxy to produce the compound of formula [8], which is then reduced by hydrogenation in the presence of a suitable catalyst such as palladium carbon to obtain the intermediate of formula [Ia]. [ka]

[0045] The intermediate compound of formula [3a], in which L is -O-, can be prepared, for example, according to scheme 5, in scheme 5, A, R1, R2, R3, R4, R5 and R 33 The compound is as defined above, where X is a halogen. In the method of Scheme 5, the compound of formula [9] is coupled with the compound of formula

[10] in a suitable solvent such as dichloromethane in the presence of a base such as pyridine and a catalyst such as copper diacetoxy to produce the compound of formula [3a]. [ka]

[0046] The intermediate compound of formula [5] can be prepared, for example, according to scheme 6, in which Z, R1, R2, and R3 are as defined above. In the method of scheme 6, the compound of formula

[11] is coupled with the compound of formula

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

[0047] Alternatively, the compound of formula (I) can be prepared as disclosed in the specific examples of this disclosure.

[0048] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those with ordinary skill in the art to which the subject matter herein pertains. The following definitions, used herein, are provided to facilitate understanding of the invention.

[0049] As used herein, the term "subject" means human and animal.

[0050] In this specification, the term "halo" or "halogen" as used by itself or as part of another group means chlorine, bromine, fluorine, or iodine. Preferred halogens are chlorine and fluorine.

[0051] The term "C" as used in this specification, either by itself or as part of another group. 1-7"Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. 1-7 Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and n-hexyl. 1-7 One preferred embodiment of "alkyl" is C 1-3 It is alkyl. Term "C 1-3 "Alkyl" refers to a group of atoms that have one, two, or three carbon atoms. 1-7 This means the "alkyl" embodiment. 1-3 Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, and iso-propyl. One preferred "C" 1-7 "Alkyl" refers to a methyl group.

[0052] The term "C" as used in this specification, either by itself or as part of another group. 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. Typical examples include, but are not limited to, ethenyl, propenyl, and hexenyl. 2-7 One preferred embodiment of "Alkenil" is C 2-4 It is an alkenil. Term "C 2-4 "Alkenyl" is a "C" which has 2, 3, or 4 carbon atoms. 2-7 This refers to an embodiment of "alkenyl". Typical examples include, but are not limited to, ethenyl, propenyl, and butenyl. One preferred "C 2-7 The "alkenyl" group is a -CH=CH- group.

[0053] The term "C" as used in this specification, either by itself or as part of another group. 3-7"Cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3, 4, 5, 6, or 7 carbon atoms. Typical examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. One preferred "C" 3-7 "Cycloalkyl" refers to a cyclopropyl group.

[0054] In this specification, the term "hydroxy" as used by itself or as part of another group means the -OH group.

[0055] In this specification, the term "cyano" as used by itself or as part of another group means the -CN group.

[0056] In this specification, the term "carboxyl" as used by itself or as part of another group means the -COOH group.

[0057] In this specification, the term "carbonyl," as used by itself or as part of another group, means a carbon atom (C=O) double-bonded to an oxygen atom.

[0058] In this specification, the term "oxo," as used by itself or as part of another group, refers to an oxygen atom (=O) bonded to another atom by a double bond.

[0059] The term "C" as used in this specification, either by itself or as part of another group. 1-7 "Alkoxy" is a C molecule as defined herein, which is added to the parent molecule via an oxygen atom. 1-7 It means alkyl. 1-7 Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. 1-7 One preferred embodiment of "alkoxy" is C 1-3 It is an alkoxy. Term "C 1-3"Alkoxy" is a "C" which has 1, 2, or 3 carbon atoms. 1-7 This refers to an embodiment of "alkoxy". 1-3 Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy. One preferred "C 1-7 The "alkoxy" group is methoxy.

[0060] The term "hydroxy C" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 This means at least one hydroxyl group as defined herein, which is added through an alkyl group. 1-7 Typical examples of 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.

[0061] The term "halogen C" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 This means at least one halogen as defined herein, which is added through an alkyl group. Halogen C 1-7 Typical examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl. Preferred "halogen C 1-7 The alkyl group is trifluoromethyl or difluoromethyl.

[0062] The term "halogen C" as used herein 1-7 "Alkoxy" is defined as C in the parent molecule portion. 1-7 This means at least one halogen as defined herein, which is added through an alkoxy group.

[0063] The term "C" as used in this specification, either by itself or as part of another group. 1-7 Alkoxy C 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 At least one C as defined herein is added through an alkyl group. 1-7 It means an alkoxy group.

[0064] 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 solely of carbon atoms. One embodiment of a "4-10 membered carbocyclic ring" is a "5-6 membered carbocyclic ring," which refers to a saturated, partially saturated, or aromatic ring having 5 to 6 ring atoms consisting solely of carbon atoms. Typical examples of 4-10 membered carbocyclic rings include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

[0065] As used herein in relation to various residues, the term "substituted" refers, unless otherwise specified, to halogen substituents such as fluorine, chlorine, bromine, iodine, or C 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxy, amino, nitro, cyano, thiol C 1-7 Alkyl, methylsulfonyl, C 1-7 Alkoxy, Halo C 1-7 Alkyl, hydroxy C 1-7 Alkyl, or amino C 1-7 This refers to alkyl substituents. Preferred substituents are halogens and C 1-7 Alkyl, hydroxy, amino, halo C 1-7 Alkyl, C 1-7 These are alkoxy and methylsulfonyl substituents. One group of preferred substituents is C 1-7 One or two substituents selected from alkyl or halogen substituents, particularly C 1-3 These are alkyl or halogen substituents, particularly methyl, ethyl, chloro, fluoro, and bromo substituents.

[0066] Unless otherwise specified, the "substituted" group may include 1 to 3, preferably 1 or 2, of the above substituents.

[0067] Optically active enantiomers or diastereomers of the compound of formula (I) can be prepared, for example, by the resolution of the final product of a racemic compound by known methods, or by using a suitable optically active starting material. Similarly, the racemic compound of formula (I) can be prepared using a racemic starting material. The resolution of the racemic compound of formula (I) or its racemic starting material can be carried out, for example, by converting the racemic compound into a mixture of salts of its diastereomers by reaction with an optically active acid, and then separating the diastereomers by crystallization. Typical examples of such optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography may be used to resolve the racemic mixture.

[0068] Pharmaceutically acceptable salts are well known in the field of pharmaceutical formulations. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with 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 with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfons, methanesulfons, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbicates, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, where applicable, can be prepared by known methods using pharmaceutically acceptable acids commonly used in the field of medicine, and retain the pharmacological properties of their free forms. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl esters. Phosphate esters and carbonate esters are also within the scope of the present invention.

[0069] The definition of formula (I) above includes all possible isotopes and stereoisomers of the compound, including geometric isomers such as Z and E isomers (cis and trans isomers), optical isomers such as diastereomers and enantiomers, and all prodrug esters such as phosphate esters and carbonate esters.

[0070] It will be understood by those skilled in the art that the compounds of the present invention may have at least one chiral center. Therefore, the compounds may exist in an optically active form or a racemic mixture. Formula (I) should be understood to include any racemic or optically active form or mixtures thereof. In one embodiment, the compound is a pure (R)-isomer. In another embodiment, the compound is a pure (S)-isomer. In yet another embodiment, the compound is a mixture of the (R)-isomer and the (S)-isomer. In yet another embodiment, the compound is a racemic mixture containing an equimolar mixture of the (R)-isomer and the (S)-isomer. The compound may also have two chiral centers. In such a case, according to one embodiment, the compound is a mixture of diastereomers. According to another embodiment, the compound of the present invention is a mixture of enantiomers. According to yet another embodiment, the compound is a pure enantiomer. Individual isomers may be obtained using the corresponding isomers of the starting materials, or they may be separated after the preparation of the final compound according to conventional separation methods. Conventional separation methods, such as fractional crystallization, may be used to separate optical isomers, such as enantiomers or diastereomers, from their mixtures.

[0071] The compounds of the present invention may exist as tautomers or as equimolar mixtures thereof in which the proton of the compound shifts from one atom to another. Examples of tautomerism include, but are not limited to, amide-imide, keto-enol, phenol-keto, oxime-nitroso, nitro-ac, imine-enamine, and heterocyclic tautomerism such as pyrosol rings. It is intended that tautomers should be encompassed by the compound of formula (I), even if only one tautomer is shown.

[0072] Examples of preferred compounds in one group of formula (I) include: N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 1); 1-Acetyl-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 2); 1-Acetyl-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 3); N-(5-((3-fluorophenoxy)methyl)-2,4-dimethoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 4); 1-(2-fluoroethyl)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)azetidine-3-carboxamide (compound 5); rac-(trans)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-5-oxopyrrolidine-2-carboxamide (compound 6); 4-Oxo-N-(3-(3-(trifluoromethyl)phenoxy)phenyl)azetidine-2-carboxamide (compound 7); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-4-oxoazetidine-2-carboxamide (compound 8); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-(5-oxopyrrolidine-2-yl)acetamide (compound 9); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 10); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 11); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)tetrahydrothiophene-3-carboxamide 1,1-dioxide (compound 12); N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-2-methylisothiazolidine-3-carboxamide 1,1-dioxide (compound 13); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-methyl-5-oxopyrrolidine-2-carboxamide (compound 14); N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-2-methyl-5-oxopyrrolidine-2-carboxamide (compound 15); 5-Oxo-N-(3-(3-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 16); N-(5-((3-fluorophenoxy)methyl)benzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide (compound 17); N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-carboxamide (compound 18); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-carboxamide (compound 19); rac-(cis)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-5-oxopyrrolidine-2-carboxamide (compound 20); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 21); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 22); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 23); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 24); (R)-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 25); N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxopyrrolidine-3-carboxamide (compound 26); N-(6-((3-fluorophenoxy)methyl)benzo[d][1,3]dioxol-4-yl)-5-oxopyrrolidine-2-carboxamide (compound 27); 1-Methyl-5-oxo-N-(5-(3-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidine-2-carboxamide (compound 28); 1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 29); 1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 30); N-(5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide (compound 31); N-(5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 32); 5-Oxo-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)pyrrolidine-2-carboxamide (compound 33); 1-Methyl-5-oxo-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)pyrrolidine-2-carboxamide (compound 34); N-(3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 35); N-(3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 36); 1-Ethyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 37); 1-(cyclopropanecarbonyl)-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 38); 1-Acetyl-N-(4-fluoro-2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 39); 1-Acetyl-N-(2-fluoro-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 40); N-(2-fluoro-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 41); N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 42); N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 43); 1-Acetyl-N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 44); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 45); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 46); 1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 47); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 48); N-(2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 49); 1-Acetyl-N-(2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 50); 1-Acetyl-N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 51); N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 52); N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 53); N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)isothiazolidine-3-carboxamide 1,1-dioxide (compound 54); 5-Oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 55); 1-Acetyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 56); N-(7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-oxopyrrolidine-2-carboxamide (compound 57); N-(7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 58); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 59); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 60); N-(8-methyl-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-oxopyrrolidine-2-carboxamide (compound 61); N-(2-methoxy-5-((6-(trifluoromethyl)pyridine-3-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 62); N-(2-Methoxy-5-((6-(trifluoromethyl)pyridine-3-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 63); (E)-N-(2-Methoxy-5-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 64); (E)-N-(2-Methoxy-5-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 65); 5-Oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 66); 1-Methyl-5-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 67); 1-Ethyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 68); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 69); (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 70); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-methyl-1,2-thiazetidine-3-carboxamide 1,1-dioxide (compound 71); N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-methyl-1,2-thiazetidine-3-carboxamide 1,1-dioxide (compound 72); N-(4-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 73); N-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 74); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 75); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 76); 1-Acetyl-N-(5-(3,5-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 77); N-(5-(3,5-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 78); N-(5-(2,5-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 79); 3-Oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxamide (compound 80); 1-Isopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 81); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-isopropyl-5-oxopyrrolidine-2-carboxamide (compound 82); N-(2-(1,3,4-oxadiazol-2-yl)-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 83); N-(2-(1,3,4-oxadiazol-2-yl)-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 84); N-(5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazole-3-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 85); N-(5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 86); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (Compound 87) N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 88); N-(5-((3,4-difluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 89); N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 90); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-thioxopyrrolidine-2-carboxamide (compound 91); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-thioxopyrrolidine-2-carboxamide (compound 92); (R)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 93); (S)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 94); N-(5-((3,4-difluorophenoxy)methyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 95); N-(5-(bicyclo[2.2.1]heptan-2-yloxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 96); (R)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 97); (S)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 98); (R)-1-methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 99); (S)-N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 100); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (Compound 101); (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 102); (R)-N-(2-Methoxy-5-(((Trans)-4-(Trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 103); N-(5-((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 104); (S)-N-(2-Methoxy-5-(((Trans)-4-(Trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 105); 1-Methyl-5-oxo-N-(3-oxo-7-(3-(trifluoromethyl)phenoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)pyrrolidine-2-carboxamide (compound 106); (S)-1-methyl-5-oxo-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 107); (R)-1-methyl-5-oxo-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 108); 1-Cyclopropyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 109); 1-Cyclopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 110); 1-Cyclopropyl-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 111); N-(2-methoxy-5-((5-(trifluoromethoxy)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 112); N-(7-(((4,4-difluorocyclohexyl)oxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 113); 1-Cyclopropyl-5-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 114); N-(2-methoxy-5-((5-(trifluoromethoxy)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 115); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)tetrahydrothiophene-3-carboxamide 1,1-dioxide (compound 116); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 117); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 118); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-oxopiperidine-3-carboxamide (compound 119); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-oxopiperidine-3-carboxamide (Compound 120); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-6-oxopiperidine-3-carboxamide (compound 121); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 122); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3,4-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 123); (R)-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 124); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 125); (R)-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 126); 3-Ethyl-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (Compound 127); (R)-1-Cyclopropyl-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 128); (S)-1-Cyclopropyl-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 129); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 130); 3-Cyclopropyl-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (Compound 131); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 132); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 133); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-oxopyrrolidine-2-carboxamide (compound 134); (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-oxopyrrolidine-2-carboxamide (Compound 135); 1-(2-amino-2-oxoethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 136); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-1H-pyrazol-4-yl)-5-oxopyrrolidine-2-carboxamide (compound 137); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(tetrahydrofuran-3-yl)pyrrolidine-2-carboxamide (compound 138); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 139); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (Compound 140); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 141); 3-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 142); (2S)-4-methoxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 143); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 144); N-(2-Methoxy-4-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-(methylamino)-2-oxoethyl)-5-oxopyrrolidine-2-carboxamide (Compound 145); 1-(2-(dimethylamino)-2-oxoethyl)-N-(2-methoxy-4-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 146); 1-(cyclopropylmethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 147); 1-(cyclopropylmethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 148); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 149); (S)-1-methyl-5-oxo-N-(5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 150); (R)-1-methyl-5-oxo-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)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 152); N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 153); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 154); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 155); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 156); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 157); N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 158); 3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidined-4-carboxamide (compound 159); 2-Oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidine-4-carboxamide (compound 160); 6-Oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidine-3-carboxamide (compound 161); (R)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 162); (S)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 163); 3-Cyclopropyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidined-4-carboxamide (compound 164); (S)-1-Cyclopropyl-5-Oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (Compound 165); (R)-1-Cyclopropyl-5-Oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (Compound 166); 3-Ethyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidined-4-carboxamide (compound 167); (S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidined-4-carboxamide (compound 168); (R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidined-4-carboxamide (compound 169); (R)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 170); (S)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 171); (2R)-1-methyl-N-(2-methyl-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 172); (2R)-1-methyl-N-(2-methyl-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 173); (S)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 174); (R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 175); 3-Methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)chroman-8-yl)imidazolidined-4-carboxamide (compound 176); 1-Methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 177); 3-Methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 178); 1-Cyclopropyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)pyrrolidine-2-carboxamide (compound 179); (S)-3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 180); (R)-3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 181); 3-Methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazolidine-4-carboxamide (compound 182); 3-Methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazolidine-4-carboxamide, enantiomer 1 (compound 183); 3-Methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazolidine-4-carboxamide, enantiomer 2 (compound 184); 1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidine-2-carboxamide (compound 185); 3-Methyl-2-oxo-N-(6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 186); 2-Oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperidine-4-carboxamide (compound 187); 1-(2-(methylamino)-2-oxoethyl)-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 188); 1-(2-amino-2-oxoethyl)-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 189); N-(5-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)-6-oxopiperidine-3-carboxamide (compound 190); N-(7-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-oxopiperidine-3-carboxamide (compound 191); 3-Methyl-2-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazolidine-4-carboxamide (compound 192); 3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-imidazol-7-yl)imidazolidine-4-carboxamide (compound 193); 1-Methyl-N-(1-methyl-5-((5-(trifluoromethyl)pyridine-4-yl)oxy)-1H-imidazol-7-yl)-5-oxopyrrolidine-2-carboxamide (compound 194); (S)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 195); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 196); N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 197); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 198); (S)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 199); N-(2-methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 200); N-(2-methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 201); N-(5-((5-fluoropyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 202); N-(5-((5-chloropyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 203); N-(5-(2-fluoro-4-nitrophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 204); N-(5-(((4,4-difluorocyclohexyl)oxy)methyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 205); N-(5-((4,4-difluorocyclohexyl)methoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 206); (2S)-N-(5-((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 207); (R)-N-(2-Methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 208); (R)-N-(2-Methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 209); (S)-N-(2-Methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 210); N-(5-((5-(difluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 211); N-(5-((5-(difluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 212); N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 213); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 214); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 215); (S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzofuran-7-yl)imidazolidined-4-carboxamide (compound 216); (R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzofuran-7-yl)imidazolidined-4-carboxamide (compound 217); (S)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-oxoimidazolidine-4-carboxamide (compound 218); (R)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-oxoimidazolidine-4-carboxamide (compound 219); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 220); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 221); N-(5-(3,4-dichlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 222); N-(5-(3-chloro-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 223); N-(5-(3,4-difluorophenoxy)-2-(1,3,4-oxadiazol-2-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 224); 1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-1H-indazol-7-yl)pyrrolidine-2-carboxamide (compound 225); (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 226); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (Compound 227); 4-Hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (compound 228); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (compound 229); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-5-oxopyrrolidine-2-carbonyl)-5-oxopyrrolidine-2-carboxamide (compound 230); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(4-oxoazetidine-2-carbonyl)pyrrolidine-2-carboxamide (compound 231); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-oxo-1-(4-oxoazetidine-2-carbonyl)pyrrolidine-2-carboxamide (compound 232); 1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 233); 1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide, enantiomer 1 (compound 234); 1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide, enantiomer 2 (compound 235); 1-Methyl-N-(8-methyl-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-oxopyrrolidine-2-carboxamide (compound 236); 1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 237); 1-Methyl-5-oxo-N-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 238); N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 239); N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 240); N-(7-(4-fluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 241); N-(5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 242); N-(6-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 243); 1-Methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 244); 1-Methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 245); N-(5-(((3-fluorophenyl)amino)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 246); N-(5-((4,4,-difluorocyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 247) N-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 248); N-(5-((3-fluorophenoxy)methyl)benzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 249); N-(2-fluoro-3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 250); N-(5-(3,4-difluorophenoxy)-2-fluoro-3-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 251); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazol-7a(5H)-carboxamide 1,1-dioxide (compound 252); N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 253); (E)-N-(5-(3-fluorostyryl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 254); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 255); N-(2-Methoxy-5-(3-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 256); N-(2-Methoxy-5-(4-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 257); N-(2-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 258); N-(4-Methoxy-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 259); N-(5-(4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 260); N-(3-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 261); N-(5-((6-fluoro-5-methylpyridine-3-yl)oxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 262); (R)-N-(5-((6-fluoro-5-methylpyridine-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 263); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 264); (R)-N-(2-Methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 265); N-(2-Methoxy-5-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 266); N-(2-methoxy-5-(((1S,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 267); (R)-N-(2-Methoxy-5-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 268); (R)-N-(2-Methoxy-5-(((1S,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 269); N-(2-fluoro-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 270); (R)-N-(4-Methoxy-3-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 271); (R)-N-(4-Methoxy-3-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 272); N-(3-Methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 273); N-(3-(4-chloro-3-(trifluoromethyl)phenoxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 274); (R)-N-(3-((4,4-difluorocyclohexyl)oxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 275); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 276); N-(3-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 277); (R)-N-(3-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 278); N-(3-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 279); 1-Methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)quinoline-8-yl)pyrrolidine-2-carboxamide (compound 280); (R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)quinoline-8-yl)pyrrolidine-2-carboxamide (compound 281); (R)-N-(3-Methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 282); (R)-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 283); N-(3-(3,4-difluorophenoxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 284); (R)-N-(3-(3,4-difluorophenoxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 285); N-(5-(cyclohexyloxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 286); N-(5-(cyclohex-2-en-1-yloxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 287); (S)-N-(5-((5-cyclopyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 288); 1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)azetidine-3-carboxamide (compound 289); (R)-N-(2-Methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 290); N-(2-Methoxy-5-(3-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 291); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 292); (R)-N-(5-(4-fluoro-3-methoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 293); N-(5-(cyclohexylmethoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 294); N-(5-(3-fluoro-4-methoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 295); N-(5-((4,4-dimethylcyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 296); N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 297); N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 298); N-(5-(3-bromophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 299); N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 300); N-(5-(4-isopropylphenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 301); N-(5-((3,3-difluorocyclobutyl)methoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 302); N-(3-(4-fluorophenoxy)-5-(trifluoromethyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 303); N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 304); N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 305); N-(3-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 306); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 307); (R)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 308); N-(5-(3-chloro-4-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 309); (S)-N-(5-(3-chloro-4-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 310); (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxamide (compound 311); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 312); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 313); N-(2-methoxy-5-((1-methyl-1H-indol-5-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 314); N-(5-((2,3-dihydrobenzofuran-5-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 315); N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 316); N-(5-(4-cyano-3-methylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 317); N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyethyl)-5-oxopyrrolidine-2-carboxamide (compound 318); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 319); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-oxopiperidine-2-carboxamide (compound 320); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-6-oxopiperidine-2-carboxamide (compound 321); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopiperidine-4-carboxamide (compound 322); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxopiperidine-4-carboxamide (compound 323); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-2-oxopiperidine-4-carboxamide, enantiomer 1 (compound 324); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-2-oxopiperidine-4-carboxamide, enantiomer 2 (compound 325); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-3-carboxamide (compound 326); N-(2-methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-2-oxopiperidine-4-carboxamide, enantiomer 1 (compound 327); N-(2-fluoro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 328); N-(2-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 329); N-(2-carbamoyl-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 330); N-(2-methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (compound 331); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 332); (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (compound 333); N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (compound 334); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 335); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-carboxamide (compound 336); (S)-1-(2-amino-2-oxoethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 337); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 338); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 339); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 340); 2-(1,3-dimethyl-2,5-dioxoimidazolidine-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-oxoimidazolidine-4-carboxamide (compound 342); (S)-3-acetyl-N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 343); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 344); (S)-N-(5-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 345); (S)-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 346); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-carboxamide (compound 347); (S)-N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 348); N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (Compound 349); N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 350); (S)-N-(3-chloro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 351); N-(3-chloro-5-((5-trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 352); (S)-N-(5-(4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 353); Methyl 2-(2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-5-oxopyrrolidine-1-yl)acetate (compound 354); (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 355); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 356); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (Compound 357); (S)-1-acetyl-N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (compound 358); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 359); (S)-1,3-dimethyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 360); (S)-N-(2,4-difluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 361); (S)-N-(3-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 362); (S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 363); (S)-1,3-dimethyl-2-oxo-N-(5-((5-trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidined-4-carboxamide (compound 364); (S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 365); N-(2-bromo-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 366); N-(2-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 367); N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 368); N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 369); (2S,4R)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 370); (S)-1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 371); N-(2-hydroxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 372); (S)-N-(2-hydroxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 373); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-oxopiperazine-2-carboxamide (compound 374); 4-amino-5-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)amino)-5-oxopentanoic acid (compound 375); 1-Methyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazine-2-carboxamide (compound 376); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazole-4-yl)pyrrolidine-2-carboxamide (compound 377); (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazole-4-yl)pyrrolidine-2-carboxamide (compound 378); 1-(3-amino-3-oxopropyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 379); (2S,4S)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 380); 1-Imino-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)hexahydro-1λ6 - Thiopyran-4-carboxamide 1 oxide (compound 381); N-(4-fluoro-2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 382); 1,4-dimethyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazine-2-carboxamide (compound 383); N-(5-(4-amino-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 384); N-(5-(4-chloro-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 385); N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 386); N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 387); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxo-2,3-dihydroxazole-4-carboxamide (compound 388); N-(3-(3,4-difluorophenoxy)-6-methoxy-2-methylphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 389); N-(5-(3-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 390); N-(2-Methoxy-5-(3-Methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 391); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1H-tetrazole-5-carboxamide (compound 392); (R)-N-(2-Methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 393); (S)-N-(2-Methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 394); N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 395); N-(5-(4-cyano-3-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 396); N-(5-(3-cyano-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 397); (S)-N-(5-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 398); (N-(5-((5-fluoro-6-(trifluoromethyl)pyridine-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 399); N-(5-((6-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 400); (S)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 401); (R)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 402); (S)-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 403); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-2-oxoimidazolidine-4-carboxamide (compound 404); (R,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 405); (S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 406); (S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 407); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 408); ((S,E)-N-(6-(2-(4,4-difluorocyclohexyl)vinyl)benzo[d][1,3]dioxol-4-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 409); N-(2-hydroxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 410); N-(5-(2-hydroxy-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 411); 1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-3-carboxamide (compound 412); 1-Acetyl-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)pyrrolidine-3-carboxamide (compound 413); 1-Glycyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, HCl (compound 414); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 415); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (compound 416); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-N,1-dimethyl-5-oxopyrrolidine-2-carboxamide (compound 417), This also includes its tautomers and pharmaceutically acceptable salts.

[0073] The compounds of the present invention can be administered to a patient in a therapeutically effective amount ranging from about 0.5 to about 2000 mg per day, more typically about 1 to about 1500 mg, for example, about 2 to about 100 mg, depending on age, sex, weight, ethnicity, patient condition, symptoms to be treated, route of administration, and the active ingredient used. The compounds of the present invention can be formulated into dosage forms using principles known in the art. The compounds can be administered to a patient as is or in combination with appropriate pharmaceutical excipients, in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. The selection of appropriate components for a composition is a routine task for those skilled in the art. Appropriate carriers, solvents, gel-forming components, dispersion-forming components, antioxidants, colorants, sweeteners, humectants, and other components commonly used in the art can also be used. Compositions containing the active compound can be administered enterally or parenterally, with the oral route being the most preferred route. The content of the active compound in the composition is about 0.5 to 100% of the total weight of the composition, typically about 0.5 to about 20%.

[0074] The compounds of the present invention can be administered to a patient as a single active ingredient or in combination with one of other active ingredients for the treatment of a specific disease.

[0075] In the treatment of diseases or conditions where TEAD inhibition is desired, such as various cancers and chronic pain, combinations of therapeutic agents and / or other treatments (e.g., radiation therapy) are often beneficial. The second (or third) agent administered may have the same mechanism of action as the first therapeutic agent, or it may have a different mechanism of action.

[0076] Therefore, the compounds of the present invention can be administered in combination with other anticancer therapies useful in the treatment of cancer. For example, the compounds of the present invention can be packaged with instructions indicating that the compounds are to be used in combination with other anticancer agents and therapies for the treatment of cancer. Similarly, the compounds of the present invention can be administered in combination with other pain relievers useful in the treatment of chronic pain. For example, the compounds of the present invention can be packaged with instructions indicating that the compounds are to be used in combination with other anticancer agents and therapies for the treatment of cancer, or in combination with other pain relievers and therapies for the treatment of chronic pain. The present invention further includes combinations of the compounds of the present invention with one or more further agents in the form of a kit, for example, in which they are packaged together or sold together as a kit even if they are in separate packaging, or in which they are formulated and packaged together.

[0077] According to one embodiment of the present invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with one or more anticancer agents or pain relievers.

[0078] Any other anticancer agents that can be administered in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, - Chemotherapy agents (e.g., docetaxel and paciritaxel); - Tyrosine kinase inhibitors, including EGFR inhibitors (e.g., gefitinib and osimertinib), VEGFR inhibitors (e.g., bevacizumab), and FGFR inhibitors (e.g., erdafitinib); - Immune checkpoint inhibitors (e.g., nivolumab and pembrolizumab); - Epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); -GnRH / LHRH analog (e.g., leuprorelin); -PI3K inhibitors (e.g., idelalisib); - CDK4 / 6 inhibitors (e.g., ribociclib); - Steroid synthesis inhibitors (e.g., abiraterone acetate and ceviterone CYP17A1 inhibitors such as cevi); and - Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and darolutamide) These are some examples.

[0079] In another embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, - Chemotherapy agents (e.g., docetaxel and paciritaxel); - Tyrosine kinase inhibitors, including EGFR inhibitors (e.g., gefitinib and osimertinib), VEGFR inhibitors (e.g., bevacizumab), and FGFR inhibitors (e.g., erdafitinib); - Immune checkpoint inhibitors (e.g., nivolumab and pembrolizumab); - Epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); -GnRH / LHRH analog (e.g., leuprorelin); -PI3K inhibitors (e.g., idelalisib); - CDK4 / 6 inhibitors (e.g., ribociclib); - Steroid synthesis inhibitors (e.g., abiraterone acetate and ceviterone CYP17A1 inhibitors such as cevi); and - Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and darolutamide) The present invention provides a pharmaceutically acceptable combination for simultaneous, separate, or sequential administration, comprising at least one additional active ingredient selected from a list consisting of the following:

[0080] When used in combination with the compounds of the present invention, the other therapeutic agents mentioned above may be used in the amounts specified, for example, in Physicians' Desk Reference (PDR), or in amounts separately determined by those skilled in the art.

[0081] The compounds of the present invention can be produced by various synthetic routes similar to those known in the literature, using appropriate starting materials. The present invention is illustrated in more detail by the following experiments and examples. The experiments and examples are for illustrative purposes only and do not limit the scope of the present invention as defined in the claims. [Examples]

[0082] Purification method used: A) Reverse-phase HPLC (water / acetonitrile, 2-8 min, 0-65%, 30 mL / min, column: SunFire 100×19 mm) B) Reverse-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) Reverse-phase HPLC (water / acetonitrile / ammonia, 2-8 min, 0-65%, 30 mL / min, column: SunFire 100×19 mm) E) Reverse-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 chiral HPLC (methanol / isopropanol, 50-50, 12 mL / min, column: Chiralpak AD-H (250 × 20 mm)) I) Preparative chiral HPLC (methanol / IPA / hexane, 25-25-50, 0.6 mL / min, column: Chiralpak IC (250 × 4.6 mm)) I) Preparative chiral HPLC (methanol / CO2, 50-50, 2 mL / min, column: Chiralpak AD-H (250 × 4.6 mm))

[0083] Intermediate 1,5-bromo-2-fluoro-4-methoxyphenylformate [ka] To a solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (1,000 g, 1 eq., 4.291 mmol) in CHCl3 (20 mL), 3-chlorobenzoperoxoic acid (1,851 g, 2.5 eq., 10.73 mmol) was added at 4°C, and the mixture was stirred for 30 minutes. The mixture was diluted with water (50 mL), and the resulting mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with a saturated solution of NaHCO3 (2 × 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain 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).

[0084] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for Intermediate 1. LCMS / GCMS data are not shown if they were not useful.

[0085] [Table 1]

[0086] Intermediate 5,5-bromo-2-fluoro-4-methoxyphenol [ka] Sodium hydroxide (1.606 g, 2.5 eq., 40.15 mmol) was added to a methanol (100 mL) solution of 5-bromo-2-fluoro-4-methoxyphenyl formate (4.0 g, 1 eq., 16.06 mmol). The mixture was stirred at 25°C for 12 hours. 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 phase was dried over Na₂SO₄ and concentrated. The crude product was purified twice by column chromatography using hexane-MTBE and chloroformoacetonitrile systems to obtain the title compound (1.4 g, 6.0 mmol, 37%, 95% purity). 1 H NMR (500 MHz, DMSO-d6) δ: 9.66 (s, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 3.73 (s, 3H).

[0087] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 4. LCMS / GCMS data are not shown if they were not useful.

[0088] [Table 2]

[0089] Intermediate 9,5-methoxy-7-nitrobenzofuran [ka] 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 with quinoline (20 mL) for 30 minutes. After cooling to RT, the mixture was filtered, and the filtrate was poured into 2N hydrochloric acid and filtered. The resulting precipitate was concentrated three times with acetonitrile to obtain the title compound (710 mg, 3.5 mmol). 1 H NMR (500 MHz, DMSO-d6) δ: 8.20 (s, 1H), 7.66 (d, 1H), 7.10 (s, 1H), 3.86 (s, 3H).

[0090] Intermediate 10a. 3-(4-methoxy-7-nitrophenyl)-1-methyl-1H-pyrazole [ka] 1-Bromo-4-methoxy-2-nitrobenzene (0.272 g, 1.17 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (244 mg, 1.17 mmol), and potassium phosphate (746 mg, 3.52 mmol) were mixed in dioxane (4 mL) and water (0.4 mL) under an argon atmosphere, and the mixture was heated to 100°C. Then, di(1-adamantyl)-n-butylphosphine (21.0 mg, 0.05 eq., 58.6 μmol) and (2'-amino-[1,1'-biphenyl]-2-yl)((methylsulfonyl)oxy)palladium (21.7 mg, 0.05 eq., 58.6 μmol) were added, and the mixture was stirred at 100°C for 14 hours. After cooling to RT, the mixture was concentrated under vacuum. The residues were dissolved in ethyl acetate (5 mL), washed with brine (2 × 5 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the 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] + .

[0091] Intermediate 10b. 4-(1-methyl-1H-pyrazol-3-yl)-3-nitrophenol [ka] 3-(4-methoxy-2-nitrophenyl)-1-methyl-1H-pyrazole (1.2 g, 1 eq., 5.145 mmol) was mixed with pyridine HCl (2.973 g, 5 eq., 25.73 mmol), and the mixture was stirred at 200°C for 30 hours. After cooling to RT, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the title compound (0.90 g, 3.7 mmol). 1 H NMR (400 MHz, DMSO-d6) 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).

[0092] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 10b.

[0093] [Table 3]

[0094] Intermediate 12a. (4-Fluoro-3-methoxyphenoxy)triisopropylsilane [ka] 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), chlorotriisopropylsilane (8.546 g, 9.487 mL, 1.05 eq., 44.33 mmol) was added by RT. The mixture was stirred for 16 hours, then poured into a saturated aqueous solution of NH4Cl (40 mL), and subsequently extracted with DCM (3 × 50 mL). The combined extract was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound (10.00 g, 30 mmol). 1 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).

[0095] Intermediate 12b. (4-Fluoro-3-iodo-5-methoxyphenoxy)triisopropylsilane [ka] (4-Fluoro-3-methoxyphenoxy)triisopropylsilane (6.544 g, 1 eq., 21.93 mmol) and potassium 2-methylpropane-2-oleate (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 hour. A solution of iodine (6.678 g, 1.2 eq., 26.31 mmol) in THF (20 mL) was added dropwise at -78°C. After stirring overnight at RT, the mixture was cooled to -20°C and an aqueous solution of ammonium chloride (20 mL) was added dropwise. The solution was then warmed to RT. GaN (70 mL) was added, the organic layer was washed with brine (2 × 30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (hexane / MTBE) to obtain the title compound (2.0 g, 3.3 mmol). GCMS: m / z 424 [M] + .

[0096] Intermediate 12c.4-fluoro-3-iodo-5-methoxyphenol [ka] (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 hours and then concentrated under vacuum. The residue was dissolved in Depositphotos (20 mL), washed with water (2 × 5 mL), dried over sodium sulfate, and concentrated under vacuum. The resulting residue was purified by flash chromatography (hexane / MTBE) to obtain the title compound (0.575 g, 1.9 mmol). 1 ¹H NMR (400 MHz, chloroform-d) δ: 6.72 (t, 1H), 6.45 (dd, 1H), 4.86 (s, 1H), 3.82 (s, 3H).

[0097] Intermediate 13. 1-Methoxy-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene [ka] 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), copper diacetoxy (1 g, 1.05 eq., 6 mmol), and powdered molecular sieves 4 Å (1 g) were suspended in dichloromethane (10 mL). Air was bubbling through the resulting solution for 30 minutes, and the mixture was stirred overnight at RT. The mixture was filtered. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by method A to obtain the title compound. LCMS: m / z 314.0 [M+H] + .

[0098] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 13. LCMS / GCMS data are not shown if they were not useful.

[0099] [Table 4] TIFF2026086790000037.tif216151 TIFF2026086790000038.tif216151 TIFF2026086790000039.tif89151

[0100] Intermediate 48.2-Fluoro-1-iodo-3-methoxy-5-(4-(trifluoromethyl)phenoxy)benzene [ka] 1-Fluoro-2-methoxy-4-(4-(trifluoromethyl)phenoxy)benzene (4.000 g, 1 eq., 13.97 mmol) and potassium 2-methylpropane-2-olate (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 at the same temperature for 2 hours. A solution of iodine (4.256 g, 1.2 eq., 16.77 mmol) in THF (20 mL) was added dropwise 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 warmed to RT. RINKAN (100 mL) was added, the organic layer was washed with brine (2 × 25 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (hexane / MTBE) to obtain the title compound (0.900 g, 2.0 mmol, 14%, 90% purity).

[0101] Intermediate 49,6-hydroxy-8-nitrochroman-4-one [ka] 6-Bromo-8-nitrochroman-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-dioxaborolane) (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-dioxane (20 mL). Argon was bubbling through the solution at 25°C for 1 hour 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 mixture was heated to 80°C and stirred for 3 hours until the reaction was complete. The mixture was cooled to 25°C and then filtered. The precipitate was washed with dioxane (15 mL). The filtered solution was collected, concentrated, and then transferred to a reactor. Hydrogen peroxide (4.29 g, 4.29 mL, 35 wt%, 6 eq., 44.1 mmol) was added, and the mixture was heated to 50°C and stirred for 40 minutes until the reaction was complete. Water (10 mL) was added to the mixture, and the mixture was extracted with DCM (2 × 50 mL). The organic layer was collected, washed with 15% brine (2 × 15 mL), and extracted with 15% Na₂CO₃ (2 × 25 mL). The aqueous phase was collected and its 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, dried over Na₂SO₄, and concentrated under reduced pressure to obtain the title compound (810 mg, 3.6 mmol). LCMS: m / z 208.0 [M+H] +

[0102] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 49.

[0103] [Table 5]

[0104] Intermediate 51. (7-Nitrobenzo[d][1,3]dioxol-5-yl)methanol [ka] 7-Nitrobenzo[d][1,3]dioxol-5-carbaldehyde (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 in fractions over 10 minutes. The mixture was stirred at RT for 18 hours and then concentrated under reduced pressure. The resulting residue was treated with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (3 × 20 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.693 g, 3.29 mmol, 64.1%, 93.46% purity). 1 H 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).

[0105] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 51. LCMS / GCMS data are not shown if they were not useful.

[0106] [Table 6]

[0107] Intermediate 56.1-(chloromethyl)-2,4-dimethoxy-5-nitrobenzene [ka] 2,4-Dimethoxy-1-nitrobenzene (1 g, 1 eq., 5 mmol), formaldehyde (0.3 g, 2 eq., 0.01 mol, 40% aqueous solution), and zinc(II) chloride (0.07 g, 0.1 eq., 0.5 mmol) were dissolved in 10 mL of a 37% aqueous solution of hydrochloric acid, and then stirred at 100°C for 12 hours. 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), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound of the title (312 mg, 1.46 mmol, 30%, 100% purity), which was then purified by Method A. 1 H NMR (400 MHz, DMSO-d6) δ: 7.97 (s, 1H), 6.81 (d, 1H), 4.43 (d, 2H), 4.01 (d, 1H), 3.96 (dd, 6H).

[0108] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 56.

[0109] [Table 7]

[0110] Intermediate 58,5-(chloromethyl)-1-fluoro-2-methoxy-3-nitrobenzene [ka] (3-Fluoro-4-methoxy-5-nitrophenyl)methanol (610 mg, 1 eq., 3.03 mmol) was dissolved in DCM (7 mL), and DMF (2.22 mg, 2.35 μL, 0.01 eq., 30.3 mmol) 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 minutes, then heated to RT, and stirred overnight at this temperature. The solution was then poured into 10 mL of 10% sodium bicarbonate aqueous solution and stirred for 10 minutes. The aqueous layer was then extracted with DCM (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated under vacuum to obtain 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] + .

[0111] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 58. LCMS / GCMS data are not shown if they were not useful.

[0112] [Table 8]

[0113] Intermediate 62. tert-butyl(3-fluorophenyl)(4-methoxy-3-nitrobenzyl)carbamate [ka] To a solution of tert-butyl(3-fluorophenyl)carbamate (1.048 g, 1 eq., 4.960 mmol) in DMF (20 mL), sodium hydride (238.1 mg, 60%, 1.2 eq., 5.952 mmol) was added at 0°C, and the mixture was stirred at RT for 30 minutes. 4-(chloromethyl)-1-methoxy-2-nitrobenzene (1.000 g, 1 eq., 4.960 mmol) was added all at once, and the mixture was stirred at RT for 18 hours. 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), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the title compound, which was used in the next step without further purification.

[0114] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 62.

[0115] [Table 9]

[0116] Intermediate 69.4-((3,4-difluorophenoxy)methyl-1-methoxy-2-nitrobenzene [ka] 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. The mixture was stirred at this temperature for 30 minutes. 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 hours. The solution was cooled to RT and concentrated. The residue was placed in ethyl acetate (60 mL). The resulting solution was washed with brine (3 × 50 mL), dried over sodium sulfate, filtered, and evaporated to obtain the title compound (4.5 g, 14 mmol, 94%, 95% purity). The crude product was used in the next step without further purification.

[0117] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 69. LCMS / GCMS data are not shown if they were not useful.

[0118] [Table 10]

[0119] Intermediate 75.4-(2,5-difluorophenoxy)-1-methoxy-2-nitrobenzene [ka] 1,2,4-trifluorobenzene (2.4 g, 1 eq., 18 mmol), 4-methoxy-3-nitrophenol (3.1 g, 1 eq., 18 mmol), and 2-methylpropane-2-olate (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 hours. SiO2 (50 mL) was then added, the organic phase was washed with brine (5 × 30 mL), dried, and evaporated under reduced pressure to obtain the compound described in the title. This compound was used in the next step without further purification. GCMS: m / z 281 [M] +

[0120] Intermediate 76. (E)-2-methoxy-5-(2-(tetrahydro-2H-pyran-4-yl)vinyl)aniline [ka] 5-Bromo-2-methoxyaniline (730 mg, 1 eq., 3.61 mmol), (E)-4,4,5,5-tetramethyl-2-(2-(tetrahydro-2H-pyran-4-yl)vinyl-1,3,2-dioxaborolane (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) The compound was suspended in degassed 1,4-dioxane (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, the residue was dissolved in ethyl acetate (30 mL), washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated under vacuum, and the residue was purified by method A to obtain the title compound (205 mg, 839 μmol, 23.2%, 95.5% purity). LCMS: m / z 234.2 [M+H] + .

[0121] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 76. LCMS / GCMS data are not shown if they were not useful.

[0122] [Table 11]

[0123] Intermediate 78.7-bromo-5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran [ka] 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 minutes, and 4-(chloromethyl)-1,2-difluorobenzene (378 mg, 1 eq., 2.33 mmol) was added. The mixture was stirred at RT for 12 hours. The resulting solution was concentrated under reduced pressure. The residue was placed in ethyl acetate (20 mL). The resulting solution was washed with brine (20 mL) and water (20 mL), dried over sodium sulfate, filtered, and evaporated to obtain the title compound. The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) 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).

[0124] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 78. LC / GCMS data are not shown if they were not useful.

[0125] [Table 12]

[0126] Intermediate 84.1-Fluoro-2((3-fluorophenoxy)methyl)-5-methoxy-4-nitrobenzene [ka] 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 minutes, and 3-fluorophenol (141 mg, 114 μL, 0.9 eq., 1.25 mmol) was added. The mixture was stirred at RT for 10 hours. The resulting solution was filtered and concentrated to obtain 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] +

[0127] Intermediate 85.1-Fluoro-5-methoxy-4-nitro-2-(3-(trifluoromethyl)phenoxy)benzene [ka] 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 methanol (15.1 mg, 19.0 μL, 1 eq., 470 μmol) was added at 0°C. Potassium tert-butoxide (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 minutes, then the temperature was raised to RT, followed by stirring for 12 hours. The reaction mixture was quenched with water (15 mL) and then stirred for 15 minutes. 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 dried over sodium sulfate. The compound in question was obtained by evaporating the solvent under reduced pressure and used in the next step without further purification. GCMS: m / z 331.0 [M] + .

[0128] Intermediate 86,7-bromo-5-((3-fluorophenoxy)methyl)benzofuran [ka] 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)-diazene-1,2-dicarboxylate (2.863 g, 2.58 mL, 1.2 eq., 16.44 mmol) was slowly added, and the mixture was stirred for 30 minutes, 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 mixture was stirred at RT for 17 hours. The THF was evaporated, the mixture was dissolved in MTBE (10 mL), washed with NaOH (3 mL, 10%) and water (3 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (MTBE / hexane, flow rate 30 mL / min) to obtain the compound indicated in the title (1.42 g, 4.2 mmol, 31%, 95% purity). 1 H 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).

[0129] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 86. LCMS / GCMS data are not shown if they were not useful.

[0130] [Table 13]

[0131] Intermediate 97.2-(4-methoxy-3-nitrophenoxy)bicyclo[2.2.1]heptane [ka] 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]heptan-2-ol (3.32 g, 1 eq., 29.6 mmol) were dissolved in THF (50 mL). The mixture was cooled to 4°C, and diisopropyldiazene-1,2-dicarboxylate (12.0 g, 11.5 mL, 2 eq., 59.1 mmol) was added. The mixture was stirred at RT for 16 hours, then concentrated, and purified by flash chromatography (MTBE / hexane, flow rate 30 mL / min) to obtain the title compound.

[0132] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 97. LCMS / GCMS data are not shown if they were not useful.

[0133] [Table 14]

[0134] Intermediate 99.4-(2,4-difluorophenoxy)-1-methoxy-2-nitrobenzene [ka] 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 resulting solution was stirred at RT for 10 hours. The mixture was then poured into ice-cooled saturated sodium carbonate solution (5 mL), and HCl (5 mL) was added. The organic layer was separated, dried over sodium sulfate, and concentrated under vacuum to obtain the title compound, which was used in the next step without further purification. GCMS: m / z 281 [M] + .

[0135] Intermediate 100,8-nitrochroman-6-ol [ka] 8-Nitrochroman-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 hours, then concentrated, mixed with hexane (10 mL), and filtered. The resulting precipitate was dried under reduced pressure to obtain 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] + .

[0136] Intermediates 101 and 102, 4-bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole and 7-bromo-5-methoxy-1-methyl-1H-benzo[d]imidazole [ka] 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 wt%, 1.1 eq., 1.45 mmol) was added in portions. The mixture was stirred at 5°C for 30 minutes, and methyl iodide (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, stirred for 12 hours, poured into ice-cooled water (10 mL), and extracted with ELISA (2 × 20 mL). The combined organic layers were washed with brine (4 × 5 mL), dried, and concentrated to obtain a mixture of crude products. This mixture was separated by HPLC (Method A) to obtain two regioisomers: 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] + .

[0137] Intermediate 103,4-bromo-1-methyl-1H-benzo[d]imidazol-6-ol [ka] 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 hours, 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 aqueous solution of sodium carbonate (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to obtain crude 4-bromo-1-methyl-1H-benzo[d]imidazol-6-ol (80 mg, 0.26 mmol), which was used in the next step without further purification. LCMS: m / z 227.0 [M+H] + .

[0138] Intermediate 104.2-(5-bromo-2-fluoro-4-methoxyphenoxy)-5-(trifluoromethyl)pyridine [ka] 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 hours. Water (100 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (100 × 20 mL). The organic layers were combined, washed with brine (4 × 100 mL), dried over sodium sulfate, filtered, and evaporated to obtain the crude compound of the title (6.35 g, 14.8 mmol), which was used in the next step without further purification. 1¹H 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).

[0139] Intermediate 105. Methyl 4-(3,4-ditrifluorophenoxy)-2-nitrobenzoate [ka] Methyl 4-fluoro-2-nitrobenzoate (5.0 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 subsequently heated at reflux temperature for 14 hours. After cooling to RT, the mixture was concentrated under reduced pressure, extracted with SiO2 (100 mL), and washed with water (20 mL), K2CO3 solution (20 mL, 15% in water), and brine (20 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum to obtain the title compound (6.68 g, 19 mmol, 77%, 90% purity). 1 H 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).

[0140] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 105. LCMS / GCMS data are not shown if they were not useful.

[0141] [Table 15]

[0142] Intermediate 116.4-(3,4-difluorophenoxy)-2-nitrobenzohydrazide [ka] To a solution of methyl 4-(3,4-difluorophenoxy)-2-nitrobenzoate (2,000 g, 1 eq., 6,468 mmol) in ethanol (20 mL), hydrazine hydrazine (2,266 g, 7 eq., 45.28 mmol) was added. The mixture was heated overnight under reflux. 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 dried under vacuum to obtain the title compound (1,900 g, 5.5 mmol, 85%, 90% purity). 1 H 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).

[0143] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 116.

[0144] [Table 16]

[0145] Intermediate 119.2-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1,3,4-oxadiazole [ka] 4-(3,4-difluorophenoxy)-2-nitrobenzohydrazide (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 under reflux temperature for 14 hours. The mixture was then concentrated under vacuum to obtain the title compound (1.00 g, 2.2 mmol, 69%, 71% purity). LCMS: m / z 320.0 [M+H] + .

[0146] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 119. LCMS / GCMS data are not shown if they were not useful.

[0147] [Table 17]

[0148] Intermediate 122. (E)-1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one [ka] A solution of 1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)ethane-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 under reflux temperature for 16 hours, followed by cooling to RT. The resulting solid was filtered, washed with toluene and hexane, and dried under vacuum to obtain the title compound (0.246 g, 706 μmol, 69%) as a yellow solid. LCMS: m / z 349.2 [M+H] + .

[0149] Intermediate 123.5-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1-methyl-1H-pyrazole [ka] (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 under reflux temperature for 18 hours. The mixture was cooled to RT, concentrated under vacuum, and purified by method C to obtain the title compound (0.109 g, 329 μmol, 46.6%, 100% purity). LCMS: m / z 332.0 [M+H] + .

[0150] Intermediate 124.7-Nitro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-indazole [ka] To a stirred solution of 2-methyl-6-nitro-4-((5-(trifluoromethyl)pyridine-2-yl)oxyaniline (1.524 g, 1 eq., 4.865 mmol) in acetic acid (70.5 mL), a solution of sodium nitrate (369.2 mg, 1.1 eq., 5.352 mmol) in water (2.4 mL) was added, and the mixture was stirred for 1 hour. After the reaction was complete, the acetic acid was removed by distillation, and the resulting residue was mixed in ice water (200 mL) and extracted with MTBE (3 × 30 mL). The combined organic phase was washed with water (2 × 10 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.5 g, 3.9 mmol, 80%, 84% purity). LCMS: m / z 325.0 [M+H] + .

[0151] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 124. LCMS / GCMS data are not shown if they were not useful.

[0152] [Table 18]

[0153] Intermediate 126.5-(4-(trifluoromethyl)phenoxy)-1H-indazol-7-amine [ka] 5-(2-chloro-4-(trifluoromethyl)phenoxy)-7-nitro-1H-indazole (0.93 g, 1 eq., 0.26 mmol) was dissolved in methanol (15 mL). Formic acid, ammonium salt (0.33 g, 20 eq., 5.2 mmol) and palladium (0.22 g, 10 wt%, 0.8 eq., 0.21 mmol) were added. The resulting mixture was stirred at 65°C for 16 hours, cooled to RT, and filtered. The filtrate was concentrated under reduced pressure and treated with RINKAN (10 mL). The precipitate was filtered and dried under reduced pressure to obtain the title compound (0.044 g, 0.15 mmol, 58%, 100% purity), which was used in the next step without further purification. 1 H 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).

[0154] Intermediate 127.1-methyl-7-nitro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-indazole [ka] To a solution of 7-nitro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-1H-indazole (0.1 g, 1 eq., 308 μmol) cooled to 0°C in THF (4 mL), sodium hydride (14.8 mg, 60 wt%, 1.2 eq., 370 μmol) was added. After stirring at 23°C for 1 hour, methyl iodide (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 hours. Water (1 mL) was added, and the resulting mixture was concentrated under reduced pressure. The crude substance was dissolved in HCl (10 mL), washed with water and brine, and then MgSO4. SThe compound was dried and the solvent removed under reduced pressure to obtain the title compound (0.129 g, 310 μmol, 100%, 81.2% purity), which was used in the next step without further purification. LCMS: m / z 339.2 [M+H] + .

[0155] Intermediate 128.1-(3,4-difluorophenoxy)-4-methoxy-2-methyl-3-nitrobenzene [ka] A mixture of 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) in dioxane (5 mL) was heated at 130 °C for 24 hours. The mixture was evaporated, and the residue was purified by normal-phase chromatography to obtain 0.175 g of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ: 2.07 (3 H, s), 3.87 (3 H, s), 6.71 - 6.79 (1 H, m), 7.12 - 7.19 (1 H, m), 7.19 - 7.27 (2 H, m), 7.38 - 7.49 (1 H, m).

[0156] Intermediate 129.2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline [ka] 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 RT, 1 atm. The catalyst was filtered off, and the solvent was evaporated under reduced pressure to obtain the crude product described in the title, which was used in the next step without further purification. LCMS: m / z 284.2 [M+H] + .

[0157] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 129.

[0158] [Table 19] TIFF2026086790000084.tif231151 TIFF2026086790000085.tif222151

[0159] Intermediate 158.2-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)pyridine [ka] 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 RINKAN (3 × 50 mL). The organic layers were combined and evaporated to obtain the crude product described in the title. This crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0160] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 158.

[0161] [Table 20]

[0162] Intermediate 163.2-Methoxy-5-((3-(trifluoromethyl)benzyl)oxy)aniline hydrochloride [ka] 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), ammonia hydrochloride (142 mg, 0.1 eq., 2.66 mmol), and hydrogen chloride (266 mg, 226 μmol, 36.5% aqueous solution, 0.1 eq., 2.66 mmol) were mixed in 1,4-dioxane (200 mL), followed by the addition of iron (7.42 g, 5 eq., 133 mmol). The mixture was stirred at 110 °C for 5 hours and at RT for 16 hours. The mixture was filtered through a thin layer of silica, concentrated, and the residue was added to dioxane saturated with hydrochloric acid (30 mL). The solution was evaporated under reduced pressure. The resulting residue was washed with ethyl acetate and dried to obtain the title compound. LCMS: m / z 334.2 [M+H] + .

[0163] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 163.

[0164] [Table 21] TIFF2026086790000090.tif227151 TIFF2026086790000091.tif61151

[0165] Intermediate 182.5-((5-chloropyridine-2-yl)oxy)-methoxyaniline [ka] 5-Chloro-2-(4-methoxy-3-nitrophenoxy)pyridine (197 mg, 1 eq., 10⁵ μmol) was dissolved in methanol (5 mL), and platinum (20.5 mg, 0.15 eq., 10⁵ μmol) was added. The mixture was degassed, stirred under a hydrogen atmosphere for 12 hours, then filtered, and the solvent was evaporated to obtain 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] + .

[0166] Intermediate 183.1,1-diphenyl-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)methanymine [ka] 4-Bromo-6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol (120 g, 1 eq., 3.32 mmol), diphenylmethanymine (663 mg, 1.1 eq., 3.66 mmol), sodium 2-methylpropane-2-oleate (335 mg, 1.05 eq., 3.49 mmol), and 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (207 mg, 0.1 eq., 332 μmol) were dissolved in toluene (20 mL). The solution was bubbling with argon for 1 minute, then diazetoxypalladium (37.3 mg, 0.05 eq., 166 μmol) was added, and the mixture was stirred under an argon atmosphere at 110°C for 12 hours. The mixture was filtered, and the solid was washed with ethyl acetate (2 × 20 mL). The ethyl acetate solution was washed with brine (2 × 50 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the compound indicated in the title, which was used in the next step without further purification. LCMS: m / z 462.0 [M+H] + .

[0167] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 183.

[0168] [Table 22]

[0169] Intermediate 189. tert-butyl(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)carbamate [ka] A mixture of 5-bromo-7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin (1.410 g, 1 eq., 3.759 mmol), tert-butylcarbamate (660.5 mg, 1.5 eq., 5.638 mmol), and cesium carbonate (3.674 g, 3 eq., 11.28 mmol) in toluene (40 mL) was mixed with xanthophos (326.2 mg, 0.15 eq., 563.8 μmol) and tris(dibenzylideneacetone)dipalladium (172.1 mg, 0.05 eq., 187.9 μmol). The mixture was heated at 110 °C for 18 hours. 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 dried with Na2SO4, filtered, and concentrated under vacuum. The residue was recrystallized from acetonitrile to obtain the compound indicated in the title. LCMS: m / z 412.2 [M+H] + .

[0170] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 189. LCMS / GCMS data are not shown if they were not useful.

[0171] [Table 23] TIFF2026086790000097.tif238151

[0172] Intermediate 202.7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-amine hydrochloride [ka] Chlorotrimethylsilane (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 minutes, and tert-butyl(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)carbamate (1 g, 1 eq., 2.431 mmol) was added. This solution was stirred at RT for 48 hours. The mixture was concentrated under vacuum to obtain the title compound (808 mg, 2.11 mmol, 86.9%, 90.93% purity). LCMS: m / z 312.2 [M+H] + .

[0173] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 202.

[0174] [Table 24] TIFF2026086790000100.tif196151

[0175] Intermediate 214.6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-amine [ka] 1,1-Diphenyl-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)methanymine (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 minutes, and then evaporated under vacuum to obtain 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] + .

[0176] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 214.

[0177] [Table 25]

[0178] Intermediate 220.5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyaniline hydrochloride [ka] tert-butyl(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyphenyl)carbamate (0.185 g, 1 eq., 425 μmol) was dissolved in methanol (5 mL), and a solution of HCl in dioxane (155 mg, 104 μL, 10 wt%, 1 eq., 425 μmol) was added dropwise at 25°C. The mixture was stirred at 25°C for 56 hours, then concentrated under reduced pressure to obtain the title compound (0.150 g, 0.32 mmol, 76%, 80% purity), which was used in the next step without further purification. 1 H 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] + .

[0179] Intermediate 221a. Methyl N-methylalaninate 1,1-dioxide [ka] Methyl alaninate 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 the addition of iodomethane (1.50 g, 660 μL, 5 eq., 10.6 mmol) all at once. The mixture was stirred at 27°C for 18 hours. 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 phase was washed with brine (2 × 15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (116 mg, 0.39 mmol, 18%, 60% purity), which was used in the next step without further purification. 1 H 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).

[0180] Intermediate 221b. Lithium N-methylalaninate 1,1-dioxide [ka] Methyl N-methylalaninate 1,1-dioxide (100 mg, 1 eq., 558 μmol) and lithium hydroxide hydrate (23.4 mg, 1 eq., 558 μmol) were dissolved in methanol (2 mL) and stirred at RT for 16 hours. The mixture was concentrated, and the residue was concentrated three times with acetonitrile to obtain the title compound (77 mg, 0.43 mmol, 77%, 95% purity), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ: 4.10 - 3.96 (m, 2H), 3.13 (t, 1H), 2.61 (s, 3H).

[0181] Intermediate 222a. tert-butyl 1-methyl-5-thioxopyrrolidine-2-carboxylate [ka] To a solution of tert-butyl 1-methyl-5-oxopyrrolidine-2-carboxylate (470 mg, 1 eq., 2.36 mmol) in THF (3 mL), phosphorus(V) sulfide (262 mg, 0.5 eq., 1.18 mmol) was added. The mixture was refluxed with stirring for 24 hours. 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 dried and concentrated under vacuum to obtain 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] + .

[0182] Intermediate 222b. 1-Methyl-5-thioxopyrrolidine-2-carboxylic acid [ka] tert-butyl 1-methyl-5-thiooxopyrrolidine-2-carboxylate (500 mg, 1 eq., 2.32 mmol) was dissolved in trifluoroacetic acid (2.65 mg, 1.79 mL, 10 eq., 23.2 mmol), and the solution was stirred at RT for 12 hours. The solvent was then evaporated, and the residue was dissolved in toluene (5 mL). The mixture was concentrated to remove excess TFA to obtain the title compound (370 mg, 1.2 mmol, 50%, 50% purity), which was used in the next step without further purification.

[0183] Intermediate 223. N-(5-hydroxy-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide [ka] 1-Methyl-5-thioxopyrrolidine-2-carboxylic acid (0.5 mg, 1.2 eq., 3.49 mmol) was dissolved in N,N-dimethylformamide (5 mL), and HATU (1.33 mg, 1.2 eq., 3.49 mmol) was added. The solution was stirred at RT for 5 minutes. To this solution, 3-amino-4-methoxyphenol hydrochloride (511 mg, 1 eq., 2.91 mmol) was added, followed by DIPEA (1.05 mg, 1.42 mL, 2.8 eq., 8.15 mmol). The mixture was then stirred at RT for 2 hours. 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), dried, and the solvent was evaporated. The residue was purified using method B to obtain the title compound (0.0667 g). 1 H 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] + .

[0184] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 223.

[0185] [Table 26]

[0186] Intermediate 226. tert-butyl(3-fluorophenyl)(4-methoxy-3-(5-oxopyrrolidine-2-carboxamide)benzyl)carbamate [ka] To a mixture of tert-butyl(3-amino-4-methoxybenzyl)(3-fluorophenyl)carbamate (200 mg, 1 eq., 577 μmol), 5-oxopyrrolidine-2-carboxylic acid (74.5 mg, 1 eq., 577 μmol), and 1-methyl-1H-imidazole (237 mg, 5 eq., 2.89 mmol) in acetonitrile (4 mL), N-(chloro(dimethylamino)methylene)-N-methylmethaneaminium hexafluorophosphate (V) (243 mg, 1.5 eq., 866 μmol) was added. The mixture was stirred at RT for 18 hours 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 organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated to obtain the title compound (0.3 g), which was used in the next step without further purification. LCMS: m / z 358.0 [M+H] + .

[0187] Intermediate 227a. Methyl 4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-carboxylate [ka] To a solution of methyl 4-hydroxy-2,3-dihydrobenzofuran-6-carboxylate (2 g, 1 eq., 10.30 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.994 g, 5.38 mL, 3 eq., 30.90 mmol) in DCM (80 mL), chloro(methoxy)methane (1.309 g, 1.24 mL, 95% by weight, 1.5 eq., 15.45 mmol) was added at 0°C, and the mixture was stirred at 20°C for 18 hours. The mixture was washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, and evaporated to obtain the title compound (2.3 g, 8.834 mmol, 85.78%, 90.75% purity), which was used in the next step without further purification. 1¹H 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).

[0188] Intermediate 227b. (4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-yl)methanol [ka] 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 hours. The mixture was cooled to 0°C, and water (130 μL) and a 30% solution of K2CO3 (4 × 130 μL) were added dropwise. The mixture was filtered, and the residue was washed with THF (5 mL). The organic layer was separated and concentrated to obtain the title crude 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. 1 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).

[0189] Intermediate 227c. 5-((3,4-difluorophenoxy)methyl)-4-(methoxymethoxy)-2,3-dihydrobenzofuran [ka] 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), tributylphosphine (385 mg, 0.48 mL, 2 eq., 1.90 mmol) was added under an Ar atmosphere at 0°C, followed by (E)-diazene-1,2-diyrbis(piperidine-1-ylmethanone) (480 mg, 2 eq., 1.90 mmol). The mixture was stirred at 20°C for 18 hours. The solvent of the mixture was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC (water-acetonitrile) to obtain the title compound (178 mg, 552 μmol, 58.1%). 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).

[0190] Intermediate 227d. 5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-ol [ka] Chlorotrimethylsilane (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 minutes, and 5-((3,4-difluorophenoxy)methyl)-4-(methoxymethoxy)-2,3-dihydrobenzofuran (216 mg, 1 eq., 670 μmol) in MeOH (1 mL) was added, followed by stirring at 20°C for 18 hours. The mixture was concentrated under reduced pressure to obtain the 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).

[0191] Intermediate 227e.6-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-yltrifluoromethanesulfonate [ka] To a solution of 5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-ol (mg, eq., mmol) and triethylamine (mg, μL, eq., mmol) in DCM (5 mL), trifluoromethanesulfonic anhydride (mg, μL, eq., mmol) was added dropwise at 0°C, and the mixture was stirred at 20°C for 18 hours. DCM (10 mL) was added to the mixture, the solution was washed with NaHSO4 solution (2 × 5 mL), dried over sodium sulfate, filtered, and evaporated to obtain the title compound (mg, mmol, %, % purity) as a brown oil, which was used in the next step without further purification. 1 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).

[0192] Intermediate 228,2-Methoxy-5-(4-(trifluoromethyl)phenoxy)benzoic acid [ka] A solution of potassium hydroxide (51.6 mg, 1.5 eq., 919 μmol) in water (0.6 mL) was added to a solution of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)benzoic acid (0.200 g, 1 eq., 613 μmol) in methanol (5 mL). The mixture was stirred at 25°C for 16 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and washed with toluene (2 × 2 mL). The aqueous mixture was acidified with NaHSO4 (5 mL, 15% in water). The resulting mixture was extracted with toluene (2 × 8 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.08 g, 0.26 mmol, 42%). LCMS: m / z 311.0 [MH] - .

[0193] Intermediate 229.1-Methoxy-3-nitro-5-(4-(trifluoromethyl)phenoxy)benzene [ka] 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 diazetoxy (0.54 g, 1 eq., 2.96 mmol), and powdered molecular sieves 4 Å (1 g) were suspended in DCM (15 mL). Air was bubbling through the resulting solution for 30 minutes, and the mixture was stirred overnight at RT. The mixture was filtered, the filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by method A to obtain the title compound. LCMS: m / z 314.2 [M+H] + .

[0194] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 229. LC-MS / GC-MS data are not shown if they were not useful.

[0195] [Table 27]

[0196] Intermediate 240.1-Methoxy-2-nitro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzene [ka] 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 THF (10 mL) under nitrogen was to be dropwise added with DEAD (0.28 mL, 1.77 mmol) at RT, and the mixture was stirred continuously for 24 hours. The mixture was diluted with Et2O (30 mL) and washed with NaOH (2 × 10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude residue was further purified using purification method A to obtain 0.1 g of the title compound. LCMS: m / z 320.28 [M+H] +

[0197] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 240.

[0198] [Table 28] TIFF2026086790000121.tif44151

[0199] Intermediate 248. (E)-4-(3-fluorostyryl)-1-methoxy-2-nitrobenzene [ka] Triethylphosphine (5.6 mL, 32.6 mmol) was added to 3-fluorobenzyl bromide (2.0 mL, 16.3 mmol) under N2 RT. The resulting mixture was heated at 150°C for 2 hours. The mixture was cooled and purified by flash chromatography to obtain diethyl(3-fluorobenzyl)phosphonate. NaH (0.27 mg, 11.0 mmol) was added to a mixture of diethyl(3-fluorobenzyl)phosphonate (0.82 g, 3.3 mmol) in dry THF (10 mL) at 0-5°C. After 30 minutes, 4-methoxy-3-nitrobenzaldehyde (0.5 g, 2.8 mmol) in dry THF (10 mL) was added dropwise to the mixture, and the mixture was stirred at RT for 3 hours. 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, dried, evaporated, and then purified by flash chromatography to obtain the compound described in the title. LCMS m / z 274.2 [M+H] + . 1 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).

[0200] Intermediate 249. 1-Methoxy-2-nitro-4-(3-(trifluoromethyl)benzyl)benzene [ka] A mixture of 3-(trifluoromethyl)benzaldehyde (0.20 mL, 1.4 mmol) and toluenesulfonhydrazide (0.27 mL, 1.4 mmol) in 1,4-dioxane (10 mL) was heated at 60°C for 90 minutes. To the resulting crude product (E)-4-methyl-N'-(3-(trifluoromethyl)benzylidene)benzenesulfonhydrazide (0.4 g, 1.168 mmol), K2CO3 (0.24 g, 1.8 mmol) and 4-methoxy-3-nitrophenylboronic acid (0.23 g, 1.2 mmol) were added. The mixture was heated under a nitrogen atmosphere at 110°C for 4 hours, followed by cooling to RT. The mixture was quenched with 2 M NaHCO3 (5 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, dried, evaporated, and purified by flash chromatography to obtain the compound described in the title. LCMS m / z 312.3 [M+H] + . 1 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).

[0201] Intermediate 250. 1-Methoxy-2-nitro-4-(4-(trifluoromethyl)benzyl)benzene [ka] 1-Methoxy-2-nitro-4-(3-(trifluoromethyl)benzyl)benzene was prepared using 4-(trifluoromethyl)benzaldehyde as a starting material, following the procedure described for intermediate 234. LCMS m / z 312.3 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ: 3.90 - 4.04 (m, 5 H), 6.99 - 7.26 (m, 1 H), 7.32 - 7.34 (m, 1 H), 7.39 - 7.63 (m, 4 H), 7.69 (d, 1 H).

[0202] Intermediate 251.1-Methoxy-2-nitro-4-(4-(trifluoromethyl)benzyl)benzene [ka] 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 eq., 3.2 mmol) in THF (5 mL), MeOH (2.5 mL), and water (2.5 mL) was stirred at RT for 4 hours. The mixture was filtered through Celite. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography to obtain the title compound. LCMS m / z 284.1 [M] +

[0203] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 251.

[0204] [Table 29] TIFF2026086790000127.tif218151 TIFF2026086790000128.tif223151 TIFF2026086790000129.tif170151

[0205] Intermediate 290.2-Methoxy-5-(3-(trifluoromethoxy)phenoxy)aniline [ka] 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. The mixture was filtered through a celite pad. The celite layer was further washed with ethanol, and the filtrate was evaporated to obtain 0.040 g of the title compound. LCMS: m / z 299.8 [M+H] + .

[0206] Intermediate 291.5-(4-isopropoxyphenoxy)-2-methoxyaniline [ka] This compound was prepared starting with 4-(4-isopropoxyphenoxy)-1-methoxy-2-nitrobenzene (0.22 g, 0.725 mmol), followed by 4 eq. zinc powder and 4 eq. NH4Cl, according to the procedure for intermediate 257. The product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.044 g. LCMS: m / z 273.9 [M+H] + .

[0207] Intermediate 292.2-Methoxy-5-(4-(trifluoromethoxy)phenoxy)aniline [ka] 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. The mixture was filtered through a celite pad. The celite layer was washed with siRNA. The filtrate was washed with water (2 ×), dried, and evaporated to obtain 0.090 g of the title compound. LCMS: m / z 299.7 [M]+

[0208] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 292.

[0209] [Table 30]

[0210] Intermediate 297.2-amino-4-(4-(trifluoromethyl)phenoxy)benzamide [ka] This compound was prepared by starting with 2-nitro-4-(4-(trifluoromethyl)phenoxy)benzonitrile (0.36 g, 1.168 mmol) and following the procedure for intermediate 292. The product was purified by flash chromatography to obtain the title compound. Yield: 0.21 g. LCMS: m / z 296.8 [M] + .

[0211] Intermediate 298.5-(cyclohexylmethoxy)-2-methoxyaniline [ka] 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 in RT until the reaction was complete. The mixture was filtered through a celite pad. The celite layer was washed with ethyl acetate. The filtrate was washed with water (2 ×), dried, and evaporated. The crude product was purified by flash chromatography to obtain 0.15 g of the title compound. LCMS: m / z 235.4 [M] +

[0212] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 298.

[0213] [Table 31]

[0214] Intermediate 306.5-(bromophenoxy)-2-methoxyaniline [ka] This compound was prepared starting with 4-(3-bromophenoxy)-1-methoxy-2-nitrobenzene (0.46 g, 1.419 mmol), using 7.5 eq. zinc powder and 7.5 eq. NH4Cl, following the procedure described for intermediate 298. Yield: 0.34 g. LCMS: m / z 294.2 [M] + .

[0215] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 306.

[0216] [Table 32]

[0217] Intermediate 312.5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyaniline [ka] This compound was prepared starting with 3-fluoro-2-(4-methoxy-3-nitrophenoxy)-5-(trifluoromethyl)pyridine (0.50 g, 1.505 mmol), followed by 10 eq. zinc powder and 10 eq. NH4Cl, according to the procedure for intermediate 298. LCMS: m / z 303.5 [M+H] + .

[0218] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 312.

[0219] [Table 33]

[0220] Intermediate 315.3-amino-5-(4-(trifluoromethyl)phenoxy)benzonitrile [ka] To a mixture of 1,4-dioxane (3.5 mL) and 3-nitro-5-(4-(trifluoromethyl)phenoxy)benzonitrile (0.22 g, 0.714 mmol), tin(II) chloride dihydrate (0.805 g, 3.57 mmol) dissolved in 37% aqueous HCl (1.0 mL) was added. The mixture was stirred in RT until the reaction was complete. The mixture was made basic with 6 M NaOH solution. DCM was added, and the mixture was filtered through a short plug of celite. The celite was washed with DCM. The filtrate was dried, and the solvent was evaporated to obtain the title compound. Yield: 0.14 g. LCMS: m / z 279.3 [M+H] + .

[0221] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 315.

[0222] [Table 34]

[0223] Intermediate 319. 1-Methoxy-2-nitro-4-(3-(trifluoromethoxy)phenoxy)benzene [ka] A mixture of 4-methoxy-3-nitrophenol (0.169 g, 1.00 mmol), 3-(trifluoromethyl)phenylboronic acid (0.448 g, 2.18 mmol), anhydrous Cu(OAc)2 (0.182 g, 1.00 mmol), and powdered 4Å molecular sieves (0.25 g) in dry DCM (7.5 mL) was mixed with DIPEA (0.871 mL, 5.00 mmol). The mixture was stirred at RT until the maximum conversion rate was obtained (48 hours). The mixture was filtered through a celite plug, and the celite layer was washed with ethyl acetate. The filtrate was washed with 5% NH4OH aqueous solution, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain 0.050 g of the title compound. LCMS: m / z 330.2 [M+H] + .

[0224] Intermediate 320.1-Methoxy-2-nitro-4-(4-(trifluoromethoxy)phenoxy)benzene [ka] Pyridine (0.809 mL, 10.0 mmol) was added to a mixture of 4-methoxy-3-nitrophenol (0.338 g, 2.0 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.618 g, 3.00 mmol), anhydrous Cu(OAc)2 (0.363 g, 2.00 mmol), and powdered 4Å molecular sieves (0.25 g) in 15 mL of dry DCM. The mixture was stirred at RT until the maximum conversion rate was obtained (24-48 hours). The mixture was filtered through a Celite plug, and the Celite layer was washed with DCM. The filtrate was washed with 5% NH4OH aqueous solution, dried, and evaporated. The crude product was purified by flash chromatography to obtain 0.33 g of the title compound. LCMS: m / z 330.2 [M+H] + .

[0225] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 320.

[0226] [Table 35] TIFF2026086790000146.tif53151

[0227] Intermediate 333.4-(cyclohexylmethoxy)-1-methoxy-2-nitrobenzene [ka] Diisopropyl azodicarboxylate (0.738 mL, 3.75 mmol) was added to a cooled (0-5°C) 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 dry THF (17 mL). The mixture was stirred overnight at RT. The THF was evaporated, and the residue was dissolved in DCM. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to obtain 0.26 g of the title compound. LCMS: m / z 266.2 [M+H] +

[0228] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 333.

[0229] [Table 36]

[0230] Intermediate 336.4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene a) 4-(4-methoxy-3-nitrophenoxy)benzaldehyde [ka] 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 dry DMA (4.0 mL) was stirred at 120°C until the reaction was complete. Water was added to the cooled mixture, and the mixture was extracted with siRNA. The organic phase was washed with water, dried, and evaporated to obtain 0.49 g of the title compound. LCMS: m / z 274.1 [M+H] + .

[0231] b) 4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene [ka] 4-(4-methoxy-3-nitrophenoxy)benzaldehyde (0.49 g, 1.793 mmol) was dissolved in dry DCM (5.5 mL) and cooled to 0-5°C. Diethylaminosulfate trifluoride (0.521 mL, 3.95 mmol) was added in small amounts, and the mixture was stirred at RT for 24 hours. 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, dried, and evaporated. The crude product was purified by flash chromatography to obtain 0.37 g of the title compound. LCMS: m / z 296.0 [M+H] + .

[0232] Intermediate 337. (3,4-difluorophenyl)(4-methoxy-3-nitrophenyl)sulfane [ka] 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) (oxygen bubbling before use) was mixed with 40% aqueous tetrabutylammonium hydroxide (1.0 mL, 3.82 mmol). The mixture was stirred overnight at RT. The mixture was then diluted with ethyl acetate and filtered through a celite pad. The celite layer was further washed with ethyl acetate. The filtrate was evaporated, and the crude product was purified by flash chromatography to obtain 0.17 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ 7.88 (d, 1H), 7.56 (dd, 1H), 7.00-7.16 (m, 4H), 3.98 (s, 3H).

[0233] Intermediate 338.2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline a) 2-Chloro-1-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)benzene [ka] 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 dry DMF (4.0 mL) was stirred at 120 °C until the reaction was complete. Water was added to the cooled mixture, and the mixture was then stirred at RT for 1 hour. The resulting precipitate was filtered, washed with water, and dried under reduced pressure to obtain 0.62 g of the title compound. LCMS: m / z 348.1 [M+H] + .

[0234] b) 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline [ka] 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 dry methanol (35 mL) was mixed with 10 wt% palladium carbon (0.253 g, 0.237 mmol). The mixture was vigorously stirred at RT until the reaction was complete. The mixture was filtered through a Celite plug, and the Celite layer was washed with methanol. The filtrate was evaporated, and the residue was dissolved in RINKAN. The organic phase was washed with water, dried, and evaporated to obtain 0.52 g of the title compound. LCMS: m / z 284.5 [M+H] + .

[0235] Intermediate 339. 2-Chloro-4-(4-methoxy-3-nitrophenoxy)benzonitrile [ka] A mixture of 4-methoxy-3-nitrophenol (mg, mmol, eq.), 2-chloro-4-fluorobenzonitrile (mg, mmol, eq.), and potassium carbonate (mg, mmol, eq.) in dry DMF (5.5 mL) was stirred at 100–120°C until the reaction was complete. The cooled mixture was treated with water, the resulting precipitate was filtered, dried, and the title compound was obtained. Yield: 1.06 g. LCMS: m / z 304.5 [M+H] + If the product did not precipitate from water, it was extracted with RINKAN. The organic phase was washed with water, dried, and evaporated to obtain the title compound, which was used as is or purified by flash chromatography.

[0236] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 339.

[0237] [Table 37] TIFF2026086790000156.tif53151

[0238] Intermediate 348.2-Nitro-4-(4-(trifluoromethyl)phenoxy)benzonitrile [ka] A mixture of 4-(trifluoromethyl)phenol (0.40 g, 2.467 mmol), 4-fluoro-2-nitrobenzonitrile (0.40 g, 2.408 mmol), and potassium carbonate (0.666 g, 4.82 mmol) in dry DMF (5.0 mL) was stirred at 100°C until the reaction was complete. The cooled mixture was diluted with water and extracted with siRNA. The organic phase was dried and evaporated. The crude product was purified by flash chromatography to obtain the title compound. Yield: 0.40 g. 1 H 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).

[0239] Intermediate 349.3-Nitro-5-(4-(trifluoromethyl)phenoxy)benzonitrile [ka] 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 dry DMF (3.0 mL) was stirred at 100°C until the reaction was complete. The cooled mixture was diluted with water and extracted with siRNA. The organic phase was dried and evaporated. The crude product was purified by flash chromatography to obtain the title compound. Yield: 0.42 g. LCMS: m / z 309.2 [M+H] + .

[0240] Intermediate 350.4-(4-(fluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene a) (4-(4-methoxy-3-nitrophenoxy)phenyl) methanol [ka] To a mixture of 4-(4-methoxy-3-nitrophenoxy)benzaldehyde (0.98 g, 3.59 mmol) in MeOH (15 mL), NaBH4 (0.204 g, 5.38 mmol) was added in small amounts, and the mixture was stirred at RT until the reaction was complete. The solvent was evaporated, and the residue was treated with water and siRNA. The phases were separated, and the aqueous phase was extracted with siRNA. The combined organic phases were washed with water and brine, and evaporated to obtain the title compound. Yield: 0.97 g. LCMS: m / z 258.3 [M-H2O+H] + .

[0241] b) 4-(4-(fluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene [ka] To a cooled solution of (4-(4-methoxy-3-nitrophenoxy)phenyl)methanol (0.48 g, 1.744 mmol) in dry DCM (5.0 mL), diethylaminosulfate trifluoride (DAST) (0.25 mL, 1.892 mmol) was added. The cooling bath was removed, and the mixture was heated to RT and stirred until the reaction was complete. The mixture was diluted with DCM (15 mL) and cooled to 0-5°C. A saturated NaHCO3 solution (5 mL) was added to adjust the pH to 7-8. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to obtain the title compound. Yield: 0.26 g. 1H NMR (400 MHz, CDCl3) 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).

[0242] Intermediate 351.2,4-difluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)aniline [ka] A mixture of 5-amino-2,4-difluorophenol (0.218 g, 1.50 mmol) and potassium tert-butoxide (0.185 g, 1.65 mmol) in dry DMSO (3.0 mL) was stirred at RT for 1 hour. 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 siRNA. The organic phase was washed with 1 M NaOH and water, dried, and evaporated. The crude product was purified by filtration through a short-plug silica gel eluted with siRNA-heptane (4:1). The filtrate was evaporated, and the residue was dried under vacuum to obtain the title compound. Yield: 0.25 g. LCMS: m / z 291.5 [M+H] + .

[0243] Intermediate 352. Benzyl(2S,4R)-4-hydroxy-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)pyrrolidine-1-carboxylate [ka] A mixture of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (g, mmol) and (2S,4R)-1-((benzyloxy)-carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (g, mmol) in toluene (0.40 mL) and pyridine (0.20 mL) was to be mixed with 50 wt% (mL, mmol) of 1-propanephosphonic acid ring anhydride in toluene. The mixture was stirred overnight at RT. The reaction was quenched with 0.5% HCl solution and diluted with water and toluene. The phases were separated, the organic phase was washed with 0.5% HCl solution, water and brine, dried, and evaporated to obtain the title compound. Yield: 0.111 g. LC-MS: m / z = 531.3 [M+H] + The crude product was either used directly or purified by reverse-phase flash chromatography to obtain the pure compound.

[0244] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 352. LCMS / GCMS data are not shown if they were not useful.

[0245] [Table 38]

[0246] Intermediate 357. tert-butyl 1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylate [ka] To a cooled (0-5°C) mixture of tert-butyl 5-oxopyrrolidine-2-carboxylate (0.37 g, 2.00 mmol) in dry THF (5.0 mL), 60 wt% NaH in oil (0.10 g, 2.50 mmol) was added, followed by stirring at 0-5°C for 30 minutes. 2-methoxyacetyl chloride (0.26 g, 2.40 mmol) dissolved in THF (2.5 mL) was added, and stirring was 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 dried and evaporated to obtain the title compound. Yield: 0.51 g. LCMS: m / z 258.0 [M+H] + The crude product was either used directly or purified by reverse-phase flash chromatography to obtain a pure compound.

[0247] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 357.

[0248] [Table 39]

[0249] Intermediate 362. tert-butyl(2-methoxyacetyl)-L-prolinate [ka] To a cooled (0-5°C) solution of tert-butyl L-prolinate (0.342 g, 2.00 mmol) and triethylamine (0.558 g, 4.00 mmol) in 10 mL of dry DCM, 2-methoxyacetyl chloride (0.239 g, 2.20 mmol) was added. The 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 dried and evaporated to obtain the title compound. Yield: 0.34 g. LCMS: m / z 244.2 [M+H] + .

[0250] Intermediate 363. tert-butyl(2-methoxyacetyl)-L-prolinate [ka] A mixture of tert-butyl L-prolinate (0.342 g, 2.00 mmol) and potassium bicarbonate (0.30 g, 3.00 mmol) in dry acetonitrile (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 dried and evaporated to obtain the title compound. Yield: 0.34 g. LCMS: m / z 229.4 [M+H] + .

[0251] Intermediate 364. (S)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylic acid [ka] A mixture of tert-butyl(S)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylate (0.77 g, 2.99 mmol) in 15 mL of dry DCM was mixed with trifluoroacetic acid (2.5 mL, 32.4 mmol, 10.8 eq.) and stirred overnight in RT. The mixture was stirred overnight in RT. The solvent was evaporated, the residue was treated with toluene, and evaporated again. This procedure was repeated, and the residue was dried under vacuum to obtain the title compound. The crude products were either (a) used directly in the next step, or (b) basicized with saturated Na2CO3 solution, extracted in DCM, dried, and the organic phase evaporated. LCMS: m / z 201.9 [M+H] +

[0252] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 364.

[0253] [Table 40] TIFF2026086790000170.tif84151

[0254] Intermediate 371. (E)-5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-amine [ka] A mixture of 5-bromo-2,3-dihydrobenzofuran-7-amine (0.158 g, 0.738 mmol), 2-[(E)-2-(4,4-difluorocyclohexyl)ethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.243 g, 1.15 mmol), K3PO4 (0.313 g, 2.0 mmol), and SPhos Pd G2 (0.040 g, 0.075 mmol) in dioxane (1 mL) and water (1 mL) was heated at 85°C for 8 hours under a nitrogen atmosphere. The mixture was extracted with ethyl acetate (2 × 4 mL). The combined organic layer was evaporated and then purified by normal-phase chromatography to obtain the title compound in a final amount of 0.144 g. 1 H NMR (400 MHz, DMSO-d6) 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] +

[0255] The following intermediates were prepared starting from the starting materials shown in the table, following the procedure described for intermediate 371.

[0256] [Table 41]

[0257] Intermediate 373.1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylic acid a) 4-nitrophenyl((benzyloxy)carbonyl)glycinate [ka] Triethylamine (290 mg, 2.87 mmol, 1.2 eq.) was added to a suspension of N-carbobenzyloxyglycine (1 eq.) in anhydrous CH2Cl2 (12 mL). The stirred mixture was cooled to 0°C, and 4-nitrophenyl chloroformate (578 mg, 2.87 mmol, 1.2 eq.) was added. After 10 minutes, DMAP (29.2 mg, 0.239 mmol, 0.1 eq.) was added, and the mixture was stirred at 0°C for 1 hour. The mixture was further diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 solution (10 mL), 0.1 M HCl solution (10 mL), and brine (10 mL), then dried (Na2SO4), filtered, and evaporated under vacuum to obtain the crude product. The crude residue was further purified by reverse-phase chromatography to obtain the title compound. LCMS: m / z 331.068 (M+H)+.

[0258] b) tert-butyl 1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylate [ka] LiHMDS (896 μL, 0.896 mmol, 1.06 eq.) was added to a solution of tert-butyl 5-oxo-2-pyrrolidinecarboxylate (157 mg, 0.845 mmol, 1 eq.) in anhydrous THF (3 mL) at -78°C under nitrogen. The mixture was stirred at RT for 15 minutes, followed by the addition of a solution of 4-nitrophenyl ((benzyloxy)carbonyl)glycinate in anhydrous THF (4 mL) at -78°C. The mixture was stirred at this temperature for 1 hour. The mixture was diluted with ethyl acetate (20 mL), washed with NH4Cl (10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and evaporated in vacuum to obtain the crude product. The crude residue was further purified by reverse-phase chromatography to obtain the title compound. LCMS: m / z 377.155 (M+H)+.

[0259] c) 1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylic acid (intermediate 373) [ka] Trifluoroacetic acid was added dropwise to a solution of tert-butyl 1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylate (285 mg, 0.76 mmol, 1 eq.) in anhydrous DCM at 0°C under nitrogen. The mixture was stirred at 0°C for 2 hours. The DCM and trifluoroacetic acid residues were removed under vacuum to obtain the crude product. The crude residue was further purified by reverse-phase chromatography to obtain the title compound. LCMS: m / z 321.031 (M+H)+.

[0260] Example 1. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 1) [ka] To a solution of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (215 mg, 1 eq., 759 μmol) in anhydrous acetonitrile (5 mL), 5-oxopyrrolidine-2-carboxylic acid (98.0 mg, 1 eq., 759 μmol) and 1-methyl-1H-imidazole (312 mg, 5 eq., 3.80 mmol) were added. The mixture was stirred at RT for 10 minutes, and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (319 mg, 1.5 eq., 1.14 mmol) was added all at once. The resulting solution was stirred at RT overnight, and the mixture was purified by direct method A to obtain the title compound (0.194 g). 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0261] The following compounds were prepared according to the procedure described for Compound 1. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0262] [Table 42] TIFF2026086790000178.tif228151 TIFF2026086790000179.tif230151 TIFF2026086790000180.tif196151 TIFF2026086790000181.tif240151 TIFF2026086790000182.tif248150 TIFF2026086790000183.tif200151 TIFF2026086790000184.tif242151 TIFF2026086790000185.tif184151 TIFF2026086790000186.tif241151 TIFF2026086790000187.tif225151 TIFF2026086790000188.tif181151 TIFF2026086790000189.tif227151 TIFF2026086790000190.tif232151 TIFF2026086790000191.tif229151 TIFF2026086790000192.tif224151 TIFF2026086790000193.tif175151 TIFF2026086790000194.tif235151 TIFF2026086790000195.tif222151 TIFF2026086790000196.tif212151 TIFF2026086790000197.tif221151 TIFF2026086790000198.tif243151 TIFF2026086790000199.tif184151 TIFF2026086790000200.tif226151 TIFF2026086790000201.tif224151 TIFF2026086790000202.tif241150 TIFF2026086790000203.tif223151 TIFF2026086790000204.tif225151 TIFF2026086790000205.tif175151 TIFF2026086790000206.tif241151 TIFF2026086790000207.tif221151 TIFF2026086790000208.tif228151 TIFF2026086790000209.tif213151 TIFF2026086790000210.tif189151 TIFF2026086790000211.tif248151 TIFF2026086790000212.tif197151 TIFF2026086790000213.tif209151 TIFF2026086790000214.tif225151 TIFF2026086790000215.tif223151 TIFF2026086790000216.tif189151 TIFF2026086790000217.tif250147 TIFF2026086790000218.tif190151 TIFF2026086790000219.tif227151 TIFF2026086790000220.tif232151 TIFF2026086790000221.tif226151 TIFF2026086790000222.tif180151 TIFF2026086790000223.tif239151 TIFF2026086790000224.tif196151 TIFF2026086790000225.tif232151 TIFF2026086790000226.tif234151 TIFF2026086790000227.tif234151 TIFF2026086790000228.tif174151 TIFF2026086790000229.tif232151 TIFF2026086790000230.tif222151 TIFF2026086790000231.tif223151 TIFF2026086790000232.tif220151 TIFF2026086790000233.tif224151 TIFF2026086790000234.tif221151 TIFF2026086790000235.tif216151 TIFF2026086790000236.tif224151 TIFF2026086790000237.tif235151 TIFF2026086790000238.tif65151

[0263] Example 2. N-(5-(3,4-difluorophenoxy)-2-(1,3,4-oxadiazol-2-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 224) [ka] To a solution of 5-(3,4-difluorophenoxy)-2-(1,3,4-oxadiazol-2-yl)aniline (0.122 g, 1 eq., 422 μmol) in acetonitrile (3 mL), 1-methyl-5-oxopyrrolidine-2-carboxylic acid (72.5 mg, 1.2 eq., 506 μmol) and DIPEA (218 mg, 294 μL, 4 eq., 1.69 mmol) were added. HATU (321 mg, 2 eq., 844 μmol) was then added, and the mixture was stirred overnight at RT. N-(chloro(dimethylamino)methylene)-N-methylmethaneaminium hexafluorophosphate (V) (237 mg, 2 eq., 844 μmol) and 1-methyl-1H-imidazole (208 mg, 202 μL, 6 eq., 2.53 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with HCl (10 mL), washed with NaHSO4 (2 mL, 10%), K2CO3 (2 mL, 10%), and water (2 mL), and dried over Na2SO4. HCl was evaporated. The residue was purified by HPLC (2-10 min, 0-55% of MeCN, flow rate: 30 mL / min) to obtain the title compound (0.0242 g, 58.4 μmol, 13.8%, 100% purity). 1 H NMR (600 MHz, DMSO-d6) δ: 10.89 (s, 1H), 9.38 (s, 1H), 8.01 - 7.89 (m, 2H), 7.57 - 7.50 (m, 1H), 7.45 - 7.38 (m, 1H), 7.04 (dd, J = 8.0, 4.8 Hz, 1H), 6.96 (dd, J = 8.8, 2.5 Hz, 1H), 4.26 (dd, J = 9.1, 3.9 Hz, 1H), 2.70 (s, 3H), 2.38 - 2.21 (m, 3H), 2.01 - 1.93 (m, 1H). LCMS: m / z 415.0 [M+H] + .

[0264] The following compound was prepared according to the procedure described for compound 224. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0265] [Table 43]

[0266] Example 3. (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (Compound 226) [ka] 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (0.07 g, 1 eq., 0.25 mmol), (S)-1,3-dimethyl-2-oxoimidazolidine-4-carboxylic acid (39 mg, 1 eq., 0.25 mmol), and triethylamine hydrochloride (34 mg, 1 eq., 0.25 mmol) were dissolved in DMF (3 mL) and stirred for 10 minutes. Then 1-methyl-1H-imidazole (0.1 g, 99 μL, 5 eq., 1.2 mmol) was added and stirred for 10 minutes. N-(chloro(dimethylamino)methylene)-N-methylmethaneaminium hexafluorophosphate (V) (76 mg, 1.1 eq., 0.27 mmol) was then added all at once and stirred at 20°C for 10 hours. The mixture was filtered, and the filtrate was purified by HPLC (Method A) to obtain the compound indicated in the title (0.0314 g, 74.2 μmol, 30%, 100% purity). 1 H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 7.88 (t, 1H), 7.71 (d, 2H), 7.15 (d, 1H), 7.08 (d, 2H), 7.00 - 6.88 (m, 1H), 4.40 - 4.26 (m, 1H), 3.88 (s, 3H), 3.54 (t, 1H), 3.26 - 3.16 (m, 1H), 2.64 (d, 6H). LCMS: m / z 424.2 [M+H] + .

[0267] The following compounds were prepared according to the procedure described for compound 226. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0268] [Table 44]

[0269] Example 4. 4-Hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (Compound 228) [ka] 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (100 mg, 1 eq., 353 μmol), 4-acetoxy-1-methyl-5-oxopyrrolidine-3-carboxylic acid (92.3 mg, 1.3 eq., 459 μmol), and 1-methyl-1H-imidazole (174 mg, 169 μL, 6 eq., 2.12 mmol) were dissolved in acetonitrile (2 mL), and the mixture was then stirred at 22°C for 10 minutes. Next, N-(chloro(dimethylamino)methylene)-N-methylmethaneaminium hexafluorophosphate (V) (198 mg, 2 eq., 706 μmol) was added. The mixture was stirred at 22°C for 16 hours. 4-Acetoxy-1-methyl-5-oxopyrrolidine-3-carboxylic acid (92.3 mg, 1.3 eq., 459 μmol) and N-(chloro(dimethylamino)methylene)-N-methylmethaneaminium hexafluorophosphate (V) (198 mg, 2 eq., 706 μmol) were added to the mixture, and the mixture was then stirred at 22°C for 16 hours. The mixture was concentrated, and a methanol solution of ammonia (60.1 mg, 10 eq., 3.53 mmol) was added. The reaction mixture was stirred at 22°C for 16 hours. The solution was purified by reverse-phase HPLC (purification method A) to obtain the title compound (5 mg, 0.01 mmol, 3%, 95% purity). 1H NMR (400 MHz, methanol-d4) δ: 8.03 - 8.00 (m, 1H), 7.65 - 7.57 (m, 2H), 7.10 - 7.03 (m, 3H), 6.85 (m, 1H), 4.54 (dd, 1H), 3.93 (d, 3H), 3.77 - 3.67 (m, 1H), 3.58 - 3.47 (m, 2H), 3.31 - 3.25 (m, 1H), 2.88 (s, 3H). LCMS: m / z 425.1 [M+H] + .

[0270] Example 5. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (Compound 229) [ka] To a solution of N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (0.047 g, 1 eq., 0.12 mmol) in DMF (2 mL), 5-oxopyrrolidine-2-carboxylic acid (15 mg, 1 eq., 0.12 mmol) and diisopropylethylamine (46 mg, 62 μL, 3 eq., 0.36 mmol) were added. The mixture was stirred at RT for 15 minutes, and HATU (68 mg, 1.5 eq., 0.18 mmol) was added all at once. The resulting solution was stirred at RT for 10 hours. The mixture was concentrated under vacuum, diluted with ethyl acetate (10 mL), washed with NaHSO4 (2 mL, 10%), K2CO3 (2 mL, 10%), and water (2 mL), and dried over Na2SO4. Ethyl acetate was evaporated, and the residue was purified by method A to obtain the compound indicated in the title (0.0117 g). 1H NMR (400 MHz, DMSO-d6) δ: 9.78 (s, 1H), 7.87 (d, 1H), 7.77 (s, 1H), 7.69 (d, 2H), 7.14 (d, 1H), 7.06 (d, 2H), 6.90 (dd, 1H), 5.16 - 5.07 (m, 1H), 5.07 - 5.00 (m, 1H), 3.90 (s, 3H), 2.70 - 2.56 (m, 1H), 2.46 - 2.30 (m, 3H), 2.05 - 1.89 (m, 4H). LCMS: m / z 506.0 [M+H] + .

[0271] The following compounds were prepared according to the procedure described for compound 229. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0272] [Table 45]

[0273] Example 6.1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (Compound 233) [ka] Under argon, a mixture of 5-bromo-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin (217.2 mg, 1 eq., 579.0 μmol), 1-methyl-5-oxopyrrolidine-2-carboxamide (123.5 mg, 1.5 eq., 868.5 μmol), and cesium carbonate (565.9 mg, 3 eq., 1.737 mmol) in toluene (4 mL) was mixed with Pd2(dba)3 (26.51 mg, 0.05 eq., 28.95 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (50.25 mg, 0.15 eq., 86.85 μmol), and the mixture was heated at 110 °C for 18 hours. After cooling to RT, the mixture was concentrated, and the residue was purified by method A to obtain the compound indicated in the title (0.0286 g). 1 H NMR (600 MHz, DMSO-d6) δ: 9.68 (s, 1H), 7.59 - 7.54 (m, 1H), 7.42 (d, 1H), 7.39 (d, 1H), 7.25 - 7.19 (m, 2H), 6.47 (d, 1H), 4.44 (dd, 1H), 4.35 - 4.27 (m, 4H), 2.61 (s, 3H), 2.27 - 2.12 (m, 3H), 1.89 - 1.82 (m, 1H). LCMS: m / z 437.0 [M+H] + .

[0274] The following compound was prepared according to the procedure described for compound 233. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0275] [Table 46] TIFF2026086790000248.tif233151 TIFF2026086790000249.tif172151 TIFF2026086790000250.tif234151

[0276] Example 7. N-(5-(((3-fluorophenyl)amino)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (Compound 246) [ka] Chlorotrimethylsilane (210 mg, 245 μL, 5 eq., 1.93 mmol) was slowly added to methanol (5 mL) at 0°C, and the mixture was stirred at 0°C for 30 minutes. To the resulting solution, tert-butyl(3-fluorophenyl)(4-methoxy-3-(5-oxopyrrolidine-2-carboxamide)benzyl)carbamate (300 mg, 58.89%, 1 eq., 386 μmol) was added, and the mixture was stirred at RT for 18 hours. The mixture was treated with aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phase was washed with brine (2 × 15 mL), dried over sodium sulfate, filtered, concentrated, and the residue was purified by reverse-phase HPLC (water-acetonitrile) to obtain the title compound (0.0201 g). 1 H NMR (400 MHz, DMSO-d6) δ: 9.17 (s, 1H), 8.04 - 7.90 (m, 2H), 7.12 - 6.96 (m, 3H), 6.58 - 6.49 (m, 1H), 6.39 (dd, 1H), 6.32 - 6.18 (m, LCMS: m / z 358.2 [M+H] + .

[0277] Example 8. N-(5-(((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 247) [ka] N-(5-hydroxy-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.0667 g, 1 eq., 252 μmol), triphenylphosphine (86.1 mg, 1.3 eq., 328 μmol), and DEAD (54.9 mg, 49.5 μL, 1.25 eq., 315 μmol) were dissolved in THF (5.5 mL). The mixture was stirred at RT for 30 minutes. 4,4-difluorocyclohexane-1-ol (48.1 mg, 1.4 eq., 353 μmol) was added to the mixture at RT and stirred for 58 hours. The mixture was purified by column chromatography to obtain the title compound (0.0032 g, 7.9 μmol, 3.1%, 95% purity). Purification method C. 1 H NMR (400 MHz, methanol-d4) δ: 7.75 (d, 1H), 6.97 (d, 1H), 6.77 (dd, 1H), 4.48 - 4.40 (m, 2H), 3.87 (s, 3H), 2.85 (s, 3H), 2.59 - 2.47 (m, 1H), 2.47 - 2.34 (m, 2H), 2.19 - 2.04 (m, 3H), 1.99 - 1.84 (m, 6H). LCMS: m / z 383.2 [M+H] + .

[0278] Example 9. N-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 248) [ka] 7-Bromo-5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran (0.100 g, 1 eq., 293 μmol), 1-methyl-5-oxopyrrolidine-2-carboxamide (50.0 mg, 1.2 eq., 352 μmol), cesium carbonate (95.5 mg, 1 eq., 293 μmol), copper(I) iodide (16.7 mg, 0.3 eq., 87.9 μmol), and N1,N2-dimethylcyclohexane-1,2-diamine (25.0 mg, 0.6 eq., 176 μmol) were mixed in N,N-dimethylformamide (2 mL). The mixture was heated at 100 °C for 12 hours under an argon atmosphere. Next, N,N-dimethylformamide was evaporated, the residue was diluted with RINKAN (10 mL), washed with water (2 × 2 mL), dried over Na₂SO₄, and concentrated under vacuum. The reaction mixture sample was analyzed by LC-MS. The residue was purified by method A to obtain the title compound (0.0035 g). 1 ¹H NMR (400 MHz, acetonitrile-d3) δ: 8.03 (s, 1H), 7.59 (d, 1H), 7.46 - 7.36 (m, 1H), 7.36 - 7.24 (m, 2H), 6.74 (d, 1H), 5.01 (s, 2H), 4.61 (t, 2H), 4.23 (dd, 1H), 3.24 (t, 2H), 2.78 (s, 3H), 2.45 - 2.24 (m, 3H). LCMS: m / z 403.0 [M+H] + .

[0279] The following compounds were prepared according to the procedure described for compound 248. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0280] [Table 47]

[0281] Example 10. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-carboxamide 1,1-dioxide (compound 252) [ka] N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-carboxamide (100 mg, 1 eq., 221 μmol) was dissolved in acetic acid (3 mL), and potassium permanganate (55.9 mg, eq., 354 μmol) was added under RT. The mixture was stirred under RT for 24 hours. The mixture was poured into a saturated solution of sodium bicarbonate (30 mL) and subsequently extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (2 × 30 mL), dried over sodium sulfate, filtered, concentrated, and the residue was purified by purification method A to obtain the title compound (0.0079 g). 1 ¹H NMR (400 MHz, acetonitrile-d3) δ: 8.77 (s, 1H), 7.99 (d, 1H), 7.70 (d, 2H), 7.15 - 7.05 (m, 3H), 6.96 (dd, 1H), 4.52 - 4.38 (m, 1H), 3.95 (s, 3H), 3.73 - 3.64 (m, 1H), 3.45 - 3.26 (m, 2H), 2.87 - 2.66 (m, 3H), 2.57 - 2.42 (m, 1H). LCMS: m / z 485.2 [M+H] + .

[0282] Example 11. N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 253) [ka] To a solution of 5-oxopyrrolidine-2-carboxylic acid (51.1 mg, 0.40 mmol), 3-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (112 mg, 0.40 mmol), HATU (226 mg, 0.60 mmol), and dry DMF (2 mL), DIPEA (0.34 mL, 2.0 mmol) was added. The mixture was stirred overnight in RT. The reaction mixture was quenched with water (10 mL) and subsequently extracted with ethyl acetate (2 × 10 mL). The combined organic layer was washed with water, dried, evaporated, and then purified by reverse-phase chromatography to obtain the title compound in a yield of 0.074 g. 1 H NMR (600 MHz, DMSO-d6) δ: 1.93 - 2.00 (m, 1 H), 2.08 - 2.22 (m, 2 H), 2.28 - 2.36 (m, 1 H), 3.75 (s, 3 H), 4.14 (dd, 1 H), 6.48 (t, 1 H), 6.97 (t, 1 H), 7.15 - 7.21 (m, 3 H), 7.76 (d, 2 H), 7.86 (s, 1 H), 10.14 (s, 1 H). LCMS: m / z 395.2 [M+H] +

[0283] The following compounds were prepared according to the procedure described for compound 253. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0284] [Table 48] TIFF2026086790000258.tif205151 TIFF2026086790000259.tif220151 TIFF2026086790000260.tif196151 TIFF2026086790000261.tif217151 TIFF2026086790000262.tif226151 TIFF2026086790000263.tif222151 TIFF2026086790000264.tif230151 TIFF2026086790000265.tif240151 TIFF2026086790000266.tif71151

[0285] Example 12. (R)-N-(2-Methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 290) [ka] A mixture of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (0.060 g, 0.20 mmol) and HATU (0.114 g, 0.30 mmol) in dry DMF (1.0 mL) was mixed with DIPEA (0.174 mL, 1.00 mmol). The mixture was stirred overnight at RT. The mixture was diluted with ELISA and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain 0.056 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ: 8.17 (d, 1H), 8.07 (s, 1H), 7.11-7.18 (m, 2H), 6.91-6.98 (m, 2H), 6.87 (d, 1H), 6.77 (dd, 1H), 4.07-4.14 (m, 1H), 3.90 (s, 3H), 2.94 (s, 3H), 2.37-2.63 (m, 3H), 2.10-2.20 (m, 1H). LCMS: m / z 425.0 [M+H] +

[0286] The following compounds were prepared according to the procedure described for compound 290. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0287] [Table 49] TIFF2026086790000269.tif172151 TIFF2026086790000270.tif217151 TIFF2026086790000271.tif216151 TIFF2026086790000272.tif208151 TIFF2026086790000273.tif216151 TIFF2026086790000274.tif219151 TIFF2026086790000275.tif229151 TIFF2026086790000276.tif246151 TIFF2026086790000277.tif128151

[0288] Example 13. N-(2-fluoro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 328) [ka] A mixture of 2-fluoro-5-(4-(trifluoromethoxy)phenoxy)aniline (0.069 g, 0.24 mmol), 1-methyl-5-oxopyrrolidine-2-carboxylic acid (0.034 g, 0.24 mmol), and 1-methylimidazole (0.071 mL, 0.89 mmol) in dry acetonitrile (1.0 mL) was mixed with N,N,N',N'-tetramethylchloroformamidinium-hexafluorophosphate (0.081 g, 0.288 mmol). The mixture was stirred overnight at RT. The mixture was diluted with ELISA and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain 0.028 g of the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.05 (dd, 1H), 7.81 (s, 1H), 7.14-7.23 (m, 2H), 7.05-7.14 (m, 1H), 6.92-7.03 (m, 2H), 6.71-6.80 (m, 1H), 4.10-4.19 (m, 1H), 2.93 (s, 3H), 2.37-2.64 (m, 3H), 2.10-2.21 (m, 1H). LCMS: m / z 413.0 [M+H] + .

[0289] The following compound was prepared according to the procedure described for compound 328. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0290] [Table 50]

[0291] Example 14. N-(2-methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (Compound 331) [ka] To a mixture of 2-methoxy-5-((4-(trifluoromethyl)pyridine-2-yl)oxy)aniline (0.071 g, 0.25 mmol) and 1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylic acid (0.053 g, 0.25 mmol) in Depositphotos cyclic anhydride, 50 wt% (0.25 mL, 0.424 mmol) in Depositphotos cyclic anhydride, in Depositphotos cyclic anhydride. The mixture was stirred overnight at RT. The reaction was quenched with 0.5% HCl solution and diluted with water and Depositphotos. The phases were separated, and the organic phase was washed with 0.5% HCl solution, water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.046 g. 1H NMR (400 MHz, CDCl3) δ: 8.45 (s, 1H), 8.30 (d, 1H), 8.20 (s, 1H), 7.04-7.22 (m, 2H), 6.82-7.00 (m, 2H), 4.88 (d, 1H), 4.52-4.74 LCMS: m / z 468.5 [M+H] +

[0292] The following compound was prepared according to the procedure described for compound 331. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0293] [Table 51] TIFF2026086790000282.tif229151 TIFF2026086790000283.tif230151 TIFF2026086790000284.tif233151 TIFF2026086790000285.tif217151 TIFF2026086790000286.tif216151 TIFF2026086790000287.tif222151 TIFF2026086790000288.tif232151 TIFF2026086790000289.tif232151 TIFF2026086790000290.tif58151

[0294] Example 15. N-(2-bromo-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 366) [ka] To a cooled (0-5°C) mixture of 1-methyl-5-oxopyrrolidine-2-carboxylic acid (0.067 g, 0.468 mmol) in dry DCM (1.5 mL), 1-chloro-N,N,2-trimethyl-1-propenylamine (0.065 mL, 0.488 mmol) was added, and the mixture was stirred at 0-5°C for 1 hour. Then, 2-bromo-5-(3-(trifluoromethyl)phenoxy)aniline (0.18 g, 0.390 mmol) and DIPEA (0.34 mL, 1.951 mmol) dissolved in dry DMF (0.5 mL) were added, and the mixture was stirred overnight at RT. The DCM was evaporated, and the mixture was diluted with ELISA. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.019 g. 1 H NMR (600 MHZ, d6-DMSO) δ: 9.88 (s, 1H), 7.72 (d, 1H), 7.65 (t, 1H), 7.51-7.55 (m, 1H), 7.42 (d, 1H), 7.36-7.39 (m, 1H), 7.34 (dd, 1H), 6.93 (dd, 1H), 4.31-4.38 (m, 1H), 2.70 (s, 3H), 2.17-2.35 (m, 3H), 1.94-2.02 (m, 1H). LCMS: m / z 457.1 [M+H] + .

[0295] Example 16. N-(2-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 367) [ka] This compound was prepared by starting with 1-methyl-5-oxopyrrolidine-2-carboxylic acid (0.051 g, 0.359 mmol), DCM (1.5 mL), 1-chloro-N,N,2-trimethyl-1-propenylamine (0.057 mL, 0.431 mmol), 2-amino-4-(4-(trifluoromethyl)phenoxy)benzonitrile (0.10 g, 0.359 mmol), and DMF (0.75 mL), following the procedure of the previously described examples. Yield: 0.022 g. 1 H NMR (600 MHz, d6-DMSO) δ: 10.5 (s, 1H), 7.90 (d, 1H), 7.81-7.86 (m, 2H), 7-31-7.37 (m, 2H), 7.30 (d, 1H), 7.08 (dd, 1H), 4.30 (dd, 1H), 2.70 (s, 3H), 2.19-2.36 (m, 3H), 1.94-2.01 (m, 1H). LCMS: m / z 404.4 [M+H] + .

[0296] Example 17. N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 368) [ka] This compound was prepared using the procedure for intermediate 306, starting with N-(2-fluoro-5-hydroxyphenyl)-1-methyl-5-pyrrolidine-2-carboxamide (0.071 g, 0.28 mmol), 2-chloro-5-(trifluoromethyl)pyridine (0.051 g, 0.28 mmol), and K2CO3 (0.058 g, 0.42 mmol) in dry DMF (1.0 mL). The crude product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.078 g. 1H NMR (600 MHz, CDCl3) δ: 8.40-8.43 (m, 1H), 8.21 (dd, 1H), 7.92 (dd, 1H), 7.79 (s, 1H), 7.18 (dd, 1H), 7.05 (d, 1H), 6.91 (dq, 1H), 4.15 8dd, 1H), 2.93 (s, 3H), 2.54-2.62 (m, 1H), 2.39-2.53 (m, 2H), 2.11-2.18 (m, 1H). LCMS: m / z 398.6 [M+H] + .

[0297] Example 18. N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 369) [ka] This compound was prepared using the procedure for intermediate 339, starting with N-(2-fluoro-5-hydroxyphenyl)-1-methyl-5-pyrrolidine-2-carboxamide (0.071 g, 0.28 mmol), 2-chloro-5-(trifluoromethyl)pyridine (0.051 g, 0.28 mmol), and K2CO3 (0.058 g, 0.42 mmol) in dry DMF (1.0 mL). The crude product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.078 g. 1 H NMR (600 MHz, CDCl3): δ 8.40-8.43 (m, 1H), 8.21 (dd, 1H), 7.92 (dd, 1H), 7.79 (s, 1H), 7.18 (dd, 1H), 7.05 (d, 1H), 6.91 (dq, 1H), 4.15 8dd, 1H), 2.93 (s, 3H), 2.54-2.62 (m, 1H), 2.39-2.53 (m, 2H), 2.11-2.18 (m, 1H). LCMS: m / z 398.6 [M+H] + .

[0298] Example 19. (2S,4R)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (Compound 370) [ka] To a mixture of palladium (10% by weight on carbon, 0.045 g, 0.042 mmol) in methanol (15 mL), benzyl (2S,4R)-4-hydroxy-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)pyrrolidine-1-carboxylate (0.111 g, 0.209 mmol) dissolved in methanol (2.0 mL) was added. The mixture was vigorously stirred while adding ammonium formate (0.132 mg, 2.09 mmol). Stirring was continued at 50°C until the reaction was complete. The cooled mixture was filtered through a short plug of celite. The celite was washed with methanol. The filtrate was evaporated and redissolved in ethyl acetate. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.041 g. 1 H NMR (600 MHz, d6-DMSO) δ: 10.3 (s, 1H), 8.13 (d, 1H), 7.68-7.73 (m, 2H), 7.13 (d, 1H), 7.05-7.10 (m, 2H), 6.85 (dd, 1H), 4.71 (d, 1H), 4.16-4.20 (m, 1H), 3.89 (s, 3H), 3.87-3.93 (m, 1H), 3.48 (bs, 1H), 2.88 (d, 1H), 2.74 (d, 1H), 1.99-2.06 (m, 1H), 1.72-1.79 (m, 1H). LCMS: m / z 397.6 [M+H] + .

[0299] Example 20. (S)-1-acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 371) [ka] To a chilled (0-5°C) solution of (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (0.086 g, 0.225 mmol) in 2.0 mL of dry DCM, acetyl chloride (0.018 mL, 0.248 mmol) and triethylamine (0.039 mL, 0.281 mmol), dissolved in 0.25 mL of dry DCM, were added, and the mixture was stirred overnight at RT. Further addition of acetyl chloride (0.018 mL, 0.248 mmol) and triethylamine (0.039 mL, 0.281 mmol) was added, and stirring was continued until the reaction was complete. The mixture was diluted with DCM, washed with water, a saturated solution of NaHCO3, and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.072g. 1 H NMR (400 MHz, CDCl3) δ: 9.44 (s, 1H), 8.18 (s, 1H), 7.43-7.60 (m, 2H), 6.91-7.07 (m, 2H), 6.86 (d, 1H), 6.74 (d, 1H), 4.75 (d, 1H), 3.91 (s, 3H), 3.59 (t, 1H), 3.47 (dd, 1H), 2.41-2.55 (m, 1H), 2.15 (s, 3H), 1.81-2.22. (m, 3H). LCMS: m / z 423.6 [M+H] + .

[0300] Example 21. N-(2-hydroxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 372) [ka] To a solution of compound 48 (100 mg, 245 μmol) in DCM (5 mL), ammonium tetrabutyliodide (90 mg, 245 μmol) was added under RT. The solution was cooled to -50°C. Then, BCl31M (1.469 mL, 1469 μmol) in heptane was added dropwise. The mixture was stirred at -78°C for 10 minutes, then stirred under RT for 1 hour and 20 minutes. The mixture was diluted with DCM (10 mL) and poured into ice-cold 1N HCl (5 mL). The phases were separated. The aqueous phase was extracted twice with DCM. The combined organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the title compound (0.055 g). 1 H NMR (400MHz, DMSO) δ: 10.06 (br s 1H), 9.57 (s, 1H), 7.79 (d, 1H), 7.69 (d, 2H), 7.05 (d, 2H), 6.94 (d, 1H), 6.80-6.75 (m, 1H), 4.50-4.42 (m, 1H), 2.65 (s, 3H), 2.31-2.12 (m, 3H), 1.95-1.84 (m, 1H). LCMS: m / z 395.4 [M+H] +

[0301] The following compound was prepared according to the procedure described for compound 372. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0302] [Table 52]

[0303] Example 22. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-oxopiperazine-2-carboxamide (Compound 374) [ka] 30.6 mg, 58.5 μmol of tert-butyl 3-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-4-methyl-5-oxopiperazine-1-carboxylate was dissolved in HCl (dioxane solution) (2.13 g, 1.43 mL, 10% by weight, 5.85 mmol) and stirred overnight at RT. The mixture was purified by HPLC (Method D) to obtain 12.9 mg of the title compound (12.9 mg, 30.5 μmol, 52.1%, 100% purity). 1 H NMR (400 MHz, DMSO-d6) δ: 9.93 (s, 1H), 7.92 (d, 1H), 7.71 (d, 2H), 7.10 (dd, 3H), 6.91 (dd, 1H), 4.20 (s, 1H), 3.88 (d, 3H), 3.26 (s, 2H), 3.13 (s, 2H), 2.77 (s, 3H). LCMS: m / z 424.2 [M+H] + .

[0304] The following compound was prepared according to the procedure described for compound 374. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0305] [Table 53]

[0306] Example 23. 1-Methyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazine-2-carboxamide (Compound 376) [ka] tert-butyl4-methyl-3-oxo-5-((5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)carbamoyl)piperazine-1-carboxylate (0.0416 g, 1 eq., 77.7 μmol) was dissolved in methanol (3 mL). TMS-Cl (42.2 mg, 49.3 μL, 5 eq., 388 μmol) was added dropwise. The mixture was stirred at 25 °C for 16 hours and then concentrated under reduced pressure. The resulting mixture was subjected to HPLC (purification method D) to obtain the title compound (0.01 g, 0.02 mmol, 30%, 95% purity). 1 H NMR (400 MHz, DMSO-d6) δ: 7.70 (d, 2H), 7.60 (s, 1H), 7.07 (d, 2H), 6.86 (s, 1H), 4.65 (t, 2H), 4.20 (t, 1H), 3.29 - 3.20 (m, 4H), 3.18 - 3.02 (m, 2H), 2.74 (s, 3H). LCMS: m / z 436.2 [M+H] + .

[0307] Example 24. (R)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazole-4-yl)pyrrolidine-2-carboxamide (Compound 377) [ka] TFA (335 mg, 226 μL, 50 eq., 2.94 mmol) was added to (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazole-4-yl)-5-oxopyrrolidine-2-carboxamide (0.0341 g, 1 eq., 58.7 μmol), and the mixture was refluxed for 16 hours. The solvent was then evaporated, and the residue was purified by HPLC (Method G) to obtain the title compound (0.0057 g, 12 μmol, 21%, 100% purity). 1¹H NMR (400 MHz, acetonitrile-d3) δ: 8.62 (s, 1H), 8.01 (d, 1H), 7.79 (s, 2H), 7.66 (d, 2H), 7.07 (dd, 3H), 6.88 (dd, 1H), 4.75 (dd, 1H), 3.92 (s, 3H), 2.66 - 2.36 (m, 4H), 2.23 - 2.13 (m, 2H). LCMS: m / z 459.1 [MH] - .

[0308] The following compound was prepared according to the procedure described for compound 377. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0309] [Table 54]

[0310] Example 25. 1-(3-amino-3-oxopropyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 379) [ka] To a solution of 1-(2-cyanoethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (158 mg, 1 eq., 353 μmol) in DMSO (2 mL), potassium carbonate (97.6 mg, 2 eq., 706 μmol) was added, followed by hydrogen peroxide (343 mg, 309 μL, 35 wt%, 10 eq., 3.53 mmol). The mixture was stirred at 40°C for 36 hours. Water (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase HPLC (purification method B) to obtain the title compound (13.4 mg, 28.8 μmol, 8.15%, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ: 9.64 (s, 1H), 7.89 (s, 1H), 7.70 (d, 2H), 7.36 (s, 1H), 7.19 - 7.05 (m, 3H), 6.92 (d, 1H), 6.82 (s, 1H), 4.63 - 4.55 (m, 1H), 3.88 (s, 3H), 3.64 - 3.51 (m, 1H), 3.20 - 2.96 (m, 2H), 2.31 - 2.12 (m, 4H), 1.96 - 1.85 (m, 1H). LCMS: m / z 466.2 [M+H] + .

[0311] Example 26. (2S,4S)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 380) [ka] (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.185 g, 1 eq., 343 μmol) was dissolved in THF (2 mL). Then, TBAF (89.8 mg, 343 μL, 1 mol, 1 eq., 343 μmol) was added dropwise to the mixture at 0°C. The resulting mixture was stirred for 20 minutes, slowly heated to 20°C, stirred at this temperature for 10 hours, and purified by HPLC (purification method A) to obtain the title compound (0.0374 g, 88.1 μmol, 25.7%, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 7.87 (s, 1H), 7.71 (d, 2H), 7.14 (d, 1H), 7.08 (d, 2H), 6.96 - 6.88 (m, 1H), 4.31 (t, 1H), 4.12 (t, 1H), 3.88 (s, 3H), 2.67 (s, 3H), 2.65 - 2.57 (m, 1H), 1.74 - 1.57 (m, 1H). LCMS: m / z 425.0 [M+H] + .

[0312] Example 27. 1-Imino-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-hexahydro-1λ 6 - Thiopyran-4-carboxamide 1 oxide (compound 381) [ka] A mixture of N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)tetrahydro-2H-thiopyran-4-carboxamide 1 oxide (250 mg, 1 eq., 585 μmol), phenyl-λ3-iodanzyl diacetate (565 mg, 3 eq., 1.75 mmol), and ammonium carbamate (183 mg, 4 eq., 2.34 mmol) in methanol (12 mL) was stirred at 22 °C for 12 hours. The mixture was concentrated to provide a mixture of bright yellow sludge and an immiscible, colorless liquid. The mixture was washed twice by decantation with hexane (2 × 10 mL) and dried under vacuum. The residue was ground, stirred in ethyl acetate, filtered, and the recovered solid was washed with additional ethyl acetate. The filtrate was concentrated to provide a mixture of cis and trans isomers, which was purified by HPLC (purification method A) to obtain the title compound (30.5 mg, 65 μmol, 11%, 95% purity). 1H NMR (400 MHz, DMSO-d6) δ: 9.34 (d, 1H), 7.87 (t, 1H), 7.70 (d, 2H), 7.09 (dd, 3H), 6.88 (dd, 1H), 3.87 (s, 3H), 3.70 (s, 0H), 3.48 (s, 1H), 3.16 - 2.79 (m, 4H), 2.16 - 1.92 (m, 4H). LCMS: m / z 443.1 [M+H] + .

[0313] Example 28. N-(4-fluoro-2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-5-oxopyrrolidine-2-carboxamide (Compound 382) [ka] N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (0.032 g, 1 eq., 69 μmol) was dissolved in methanol (5 mL). Ammonium formate (26 mg, 6 eq., 0.42 mmol) and palladium (7.4 mg, 10 wt%, 0.1 eq., 6.9 μmol) were added. The resulting mixture was stirred at 60°C for 12 hours, cooled to RT, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), and a metal scavenger (SiliaMetS dimercaptotriazine, 50 mg) was added to the resulting solution. The mixture was stirred to RT for 3 hours and filtered. The clear filtrate was purified by HPLC (purification method B) to obtain the compound indicated in the title (0.0038 g, 8.4 μmol, 12%, 95% purity). 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 7.95 (d, 1H), 7.72 (d, 2H), 7.29 (d, 1H), 7.10 (d, 2H), 6.44 (s, 1H), 4.49 - 4.26 (m, 1H), 3.89 (s, 3H), 3.52 (t, 1H), 3.16 (t, 1H), 2.61 (s, 3H). LCMS: m / z 428.0 [M+H] +

[0314] Example 29. 1,4-dimethyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazine-2-carboxamide (compound 383) [ka] To a solution of 1-methyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazine-2-carboxamide (0.022 g, 1 eq., 51 μmol) in 1,4-dioxane (2 mL), NaCNBH4 (6.4 mg, 2 eq., 0.10 mmol) and an aqueous solution of formaldehyde (8.2 mg, 7.5 mL, 37 wt%, 2 eq., 0.10 mmol) were added. Then, HOAc (0.01 mL) was added, and the mixture was stirred at 25°C for 12 hours and evaporated. The residue was dissolved in DMSO (2 mL), and a metal scavenger (SiliaMetS dimercaptotriazine, 10 mg) was added. The resulting mixture was stirred at RT for 3 hours, filtered, and the clear solution was purified by HPLC (purification method A) to obtain the compound in question (0.0052 g, 11 μmol, 22%, 95% purity). 1H NMR (500 MHz, DMSO-d6) δ: 9.97 (s, 1H), 7.68 (d, 2H), 7.57 (s, 1H), 7.05 (d, 2H), 6.84 (s, 1H), 4.63 (t, 2H), 4.20 (t, 1H), 3.23 (t, 2H), 3.12 (d, 1H), 2.93 (dd, 1H), 2.82 - 2.64 (m, 5H), 2.17 (s, 3H). LCMS: m / z 450.2 [M+H] +

[0315] Example 30. N-(5-(4-amino-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 384) [ka] N-(5-(2-fluoro-4-nitrophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.080 g, 1 eq., 0.20 mmol) was dissolved in MeOH, and dihydroxypalladium (28 mg, 10 wt%, 0.1 eq., 20 μmol) was added. The resulting mixture was stirred under a hydrogen atmosphere for 16 hours, filtered, and concentrated to obtain the title compound (0.065 g, 0.16 mmol, 79%, 90% purity). LCMS: m / z 393.0 [M+H] +

[0316] Example 31. N-(5-(4-chloro-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 385) [ka] To a solution of N-(5-(4-amino-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.056 g, 1 eq., 0.15 mmol) in 22% hydrochloric acid (0.5 mL), a solution of sodium nitrate (12 mg, 1.2 eq., 0.18 mmol) in water (0.1 mL) was added at 0°C. The resulting mixture was stirred at the same temperature for 15 minutes, and then poured into a solution of copper(I) chloride (21 mg, 1.4 eq., 0.21 mmol) in 37% hydrochloric acid (2 mL) at 0°C. The resulting mixture was stirred at 22°C for 10 hours. The mixture was concentrated under reduced pressure and purified by HPLC (purification method A) to obtain the title compound (0.081 g, 46.1 μmol, 31%, 100% purity). 1 H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 7.83 (d, 1H), 7.69 - 7.53 (m, 1H), 7.26 (d, 1H), 7.06 (t, 2H), 6.88 - 6.70 (m, 1H), 4.55 - 4.39 (m, 1H), 3.85 (s, 3H), 2.64 (s, 3H), 2.41 - 2.11 (m, 3H), 1.95 - 1.74 (m, 1H). LCMS: m / z 393.0 [M+H] + .

[0317] Example 32. N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 386) a) 1-(4-(4-methoxy-3-nitrophenoxy)phenyl)ethane-1-one [ka] 4-Acetylphenylboronic acid (g, mmol), 4-methoxy-3-nitrophenol (0.28 g, 1.66 mmol), Cu(OAc)2 (0.451 mg, 2.48 mmol), and fresh activated powdered 4Å molecular sieves were added to dry DCM (20 mL). Et3N (1.15 mL, 8.28 mmol) was then added to the mixture. The mixture was stirred under an air atmosphere. The reaction process was monitored by LC-MS. After 24 hours, the resulting slurry was filtered through Celite and concentrated. The crude product was purified by flash chromatography (heptane: siRNA) to obtain 0.3 g of the title compound. LC-MS: m / z 288.21 [M+H] + .

[0318] b) 1-(4-(3-amino-4-methoxyphenoxy)phenyl)ethane-1-one [ka] A mixture of 1-(4-(4-methoxy-3-nitrophenoxy)phenyl)ethane-1-one (300 mg, 1.04 mmol), zinc (0.68 g, 10 eq., 10.44 mmol), and ammonium chloride (0.56 g, 10 eq., 10.44 mmol) in THF (5 mL), MeOH (3 mL), and water (3 mL) was stirred at RT for 4 hours. The mixture was filtered through Celite. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography to obtain the title compound (0.19 g). LCMS: m / z 258.65 [M+H] + .

[0319] c) N-(5-(4-acetylphenoxy)-2-methoxyphenoxy)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 386) [ka] To a solution of 1-methyl-5-oxopyrrolidine-2-carboxylic acid (22.25 mg, 0.15 mmol), 1-(4-(3-amino-4-methoxyphenoxy)phenyl)ethane-1-one (40 mg, 0.16 mmol), and TEA (0.11, 0.78 mmol) in dry DMF (2 mL) at 0°C, 1-propanephosphonic acid ring anhydride (0.73 mL, 1.24 mmol) was added. The mixture was stirred overnight at RT. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with 2 M NaHCO3, then with water, dried over sodium sulfate, evaporated, and then purified by reverse-phase chromatography to obtain the title compound (40.5 mg). 1 H NMR (600 MHz, DMSO-d6): δ: 1.86 - 1.92 (m, 1H), 2.16 - 2.30 (m, 3H), 2.52 - 2.54 (m, 3H), 2.61 - 2.65 (m, 3H), 3.89 (s, 3H), 4.47 (dd, 1H), 6.91 (dd, 1H), 6.98 - 7.01 (m, 2H), 7.14 (d, 1H), 7.87 (d, 1H), 7.94 - 8.02 (m, 2H), 9.65 (s, 1H). LCMS: m / z 383.28 [M+H] + .

[0320] Example 33. N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 387) a) 1-Methoxy-4-nitro-2-(4-(trifluoromethyl)benzyl)benzene [ka] A mixture of 2-methoxy-5-nitrobenzaldehyde (0.5 g, 2.8 mmol) and toluenesulfonhydrazide (0.51 g, 2.8 mmol) in 1,4-dioxane (5 mL) was heated at 60°C for 90 minutes. To the crude (E)-N'-(2-methoxy-5-nitrobenzylidene)-4-methylbenzenesulfonhydrazide, K2CO3 (0.53 g, 2.8 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.49 g, 2.6 mmol) were added. The mixture was heated under a nitrogen atmosphere at 110°C for 4 hours. After cooling to RT, the mixture was quenched with 2 M NaHCO3 (5 mL). The mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, evaporated, and then purified by flash chromatography to obtain the title compound (0.35 g). LCMS: m / z 312.2

[0321] b) 4-Methoxy-3-(4-(trifluoromethyl)benzyl)aniline [ka] A mixture of 1-methoxy-4-nitro-2-(4-(trifluoromethyl)benzyl)benzene (100 mg, 0.32 mmol), zinc (0.21 g, 10 eq., 3.21 mmol), and ammonium chloride (0.17 g, 10 eq., 3.21 mmol) in THF (10 mL), MeOH (3 mL), and water (3 mL) was stirred at RT for 4 hours. The mixture was filtered through Celite. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography to obtain the title compound (0.12 g). LCMS: m / z 282.05 [M+H] + .

[0322] c) N-(4-Methoxy-3-(4-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 387) [ka] To a solution of 1-methyl-5-oxopyrrolidine-2-carboxylic acid (45.8 mg, 0.32 mmol), 4-methoxy-3-(4-(trifluoromethyl)benzyl)aniline (90 mg, 0.32 mmol), and TEA (0.22, 1.60 mmol) in dry DMF (2 mL) at 0°C, 1-propanephosphonic acid ring anhydride (1.51 mL, 2.56 mmol) was added. The mixture was stirred overnight at RT. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with 2 M NaHCO3 and then with water, dried over sodium sulfate, evaporated, and then purified by reverse-phase chromatography to obtain the title compound (5 mg). 1 H NMR (400 MHz, chloroform-d) δ: 1.75 - 2.02 (m, 1H), 2.06 - 2.22 (m, 1H), 2.31 - 2.59 (m, 3H), 2.81 - 2.91 (m, 3H), 3.79 - 3.93 (m, 3H), 3.96 - 4.10 (m, 3H), 6.85 (d, 1H), 7.25 - 7.33 (m, 4H), 7.44 - 7.57 (m, 3H), 7.84 (br s, 1H). LCMS: m / z 282.05 [M+H] + .

[0323] Example 34. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxo-2,3-dihydroxazole-4-carboxamide (Compound 388) [ka] TMA (2 M, 397 μL, 0.794 mmol in chlorobenzene) was added to a mixture of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (0.075 g, 0.265 mmol) and ethyl-2-oxo-2,3-dihydroxazole-4-carboxylate (0.064 g, 0.397 mmol) in toluene (2 mL), and the mixture was subsequently heated at 90°C for 3 hours. The reaction mixture was quenched with ice-cold water. The aqueous layer was extracted with ELISA (2 × 5 mL). The combined organic layers were evaporated and then purified by reverse-phase chromatography to obtain 0.029 g of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ: 3.87 (3H, s), 7.00 (1H, m), 7.11 (2H, d), 7.17 (1H, d), 7.59 (1H, d), 7.72 (2H, d), 7.98 (1H, s), 9.46 (1H, s), 11.44 (1H, br s). LCMS: m / z 395.2 [M+H] +

[0324] Example 35. N-(3-(3,4-difluorophenoxy)-6-methoxy-2-methylphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 389) [ka] 1-methyl-5-oxopyrrolidine-2-carboxylic acid (15 mg, 0.10 mmol), 3-(3,4-difluorophenoxy)-6-methoxy-2-methylaniline (24 mg, 0.09 mmol), T3P (50% in HCl, 80 μL, 0.14 mmol), and DCM (2 mL) were mixed with DIPEA (47 μL, 0.27 mmol). After refluxing for 3 hours, additional starting materials and reagents were added (1-methyl-5-oxopyrrolidine-2-carboxylic acid 1.15 eq., T3P 1.5 eq., DIPEA 3.0 eq.), and the mixture was subsequently stirred in a closed container at 80°C for 7 hours. The reaction mixture was quenched with 2N NaOH (2 mL). The organic layer was separated, and the aqueous layer was extracted with HCl (1 × 4 mL). The combined organic layers were evaporated and then purified by reverse-phase chromatography to obtain 0.016 g of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ: 1.94 (3H, s), 1.94 - 2.03 (1H, m), 2.19 - 2.37 (3H, m), 2.71 (3H, s), 3.79 (3H, s), 4.26 - 4.33 (1H, m), 6.61 (1H, m), 6.90 - 7.02 (3H, m), 7.36 - 7.45 (1H, m), 9.66 (1H, s). LCMS: m / z 391.1 [M+H] +

[0325] The following compound was prepared according to the procedure described for compound 389. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0326] [Table 55] TIFF2026086790000320.tif223151 TIFF2026086790000321.tif223151 TIFF2026086790000322.tif207151 TIFF2026086790000323.tif224151 TIFF2026086790000324.tif71151

[0327] Example 36. N-(2-hydroxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 410) [ka] BCl3 (1 M in heptane, 798 μL, 0.798 mmol) was added dropwise to a -50°C cooled solution of N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.100 g, 0.228 mmol) in DCM (9 mL), followed by stirring at RT for 50 minutes. The reaction mixture was quenched with 1N HCl (5 mL). The organic layer was separated and evaporated. The residue was purified by reverse-phase chromatography to obtain 0.066 g of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ: 1.85 - 1.95 (1H, m), 2.13 - 2.35 (3H, m), 2.65 (3H, s), 3.84 (3H, s), 4.43 - 4.50 (1H, m), 6.42 (1H, m), 6.78 (1H, m), 6.86 (1H, d), 6.94 (1H, d), 7.53 (1H, d), 7.79 (1H, d), 9.57 (1H, s), 10.07 (1H, s). LCMS: m / z 425.2 [M+H] +

[0328] Example 37. N-(5-(2-hydroxy-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 411) [ka] NaH (60% of oil, 0.028 g, 0.704 mmol) was added to a 0°C cooled solution of N-(5-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.100 g, 0.235 mmol) in DMF (2 mL), followed by stirring at RT for 15 minutes. Then 2-(methylsulfonyl)ethanol was added, and the mixture was heated at 50°C for 2.5 hours. Additional NaH (60% of oil, 5 eq.) and 2-(methylsulfonyl)ethanol were then added twice, and the mixture was heated at 80°C for 4 hours and at 100°C for 5.5 hours, respectively. The reaction mixture was quenched with 2N HCl (2 mL) and extracted with RINKAN (3 × 3 mL). The organic layer was separated and evaporated. The residue was purified by reverse-phase chromatography to obtain 0.012 g of the compound indicated in the title. 1 H NMR (600 MHz, DMSO-d6) δ: 1.85 - 1.92 (1H, m), 2.16 - 2.31 (3H, m), 2.64 (3H, s), 3.85 (3H, s), 4.46 (1H, m), 6.76 (1H, m), 6.92 (1H, d), 7.07 (1H, d), 7.11 (1H, m), 7.20 (1H, d), 7.80 (1H, d), 9.58 (1H, s), 10.17 (1H, s). LCMS: m / z 425.2 [M+H] +

[0329] Example 38. 1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-3-carboxamide (Compound 412) [ka] N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-3-carboxamide (74 mg, 1 eq., 1.321 mmol) and Et3N (271 μL, 10 eq., 1.945 mmol) were dissolved in DCM (5 mL) under nitrogen. Acetyl chloride was added dropwise at 0°C, and the mixture was stirred and gradually increased to RT. After the reaction was complete, the mixture was diluted with ELISA (20 mL) and washed with brine (2 × 10 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude residue was further purified by reverse-phase chromatography to obtain 36 mg of the title compound. 1 H NMR (400 MHz, mixture of CDCl3 rotamers ~1.0:1.2 ratio) δ: 8.19 (m, 1H), 7.93 (br s, 0.45H), 7.88 (br s, 0.52H), 7.57-7.50 (m, 2.1H), 7.02-6.94 (m, 2.1H), 6.90 (m, 1.1H), 6.78 (m, 1H), 3.93 (s, 1.54H), 3.92 (s, 1.72H), 3.91-3.84 (m, 0.59H), 3.81-3.65 (m, 2.7H), 3.55-3.42 (m, 1.12H), 3.16 (m, 0.5H), 3.06 (quin, 0.58H) 2.45-2.34 (m, 0.67H), 2.31-2.16 (m, 1.8H), 2.08 (s, 1.44H), 2.07 (s, 1.63H). LCMS: m / z 423.2 [M+H] +

[0330] The following compound was prepared according to the procedure described for compound 412. The compound code, structure, starting materials, purification method, and characteristic data are shown in the table.

[0331] [Table 56]

[0332] Example 39. 1-Glycyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, HCl (Compound 414) [ka] In a Buchner flask, benzyl(2-(2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-5-oxopyrrolidine-1-yl)-2-oxoethyl)carbamate (168 mg, 0.287 mmol, 1 eq.) was dissolved in EtOH (10 mL), and palladium (24.4 mg, 0.023 mmol, 0.08 eq.) and HCl (37%, 0.120 mL, 1.435 mmol, 5 eq.) were added. The flask was connected to an H2 / N2 / vacuum line, and after replacing the air with nitrogen, the mixture was stirred under hydrogen for 2.5 hours. The mixture was filtered through a Celite® pad and washed with a 1:1 mixture of acetonitrile / H2O. The product was frozen at -78°C, and the solvent was removed by lyophilization to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ: 9.91 (s, 1H), 8.17 (br.s, 1H), 7.85 (d, 1H), 7.70 (d, 2H), 7.15 (d, 1H), 7.06 (d, 2H), 6.93 (dd, 1H), 5.15 (m, 1H), 4.20 (d, 1H), 4.17 (d, 1H), 3.91 (s, 3H), 2.71-2.30 (m, 3H), 2.04 (m, 1H). LCMS: m / z 452.598 [M+H] +

[0333] Example 40. (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (Compound 415) [ka] This compound was prepared starting from tert-butyl(S)-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-5-oxopyrrolidine-1-carboxylate, following the procedure described for intermediate 364. The crude final product was treated with a saturated solution of Na2CO3 and then extracted by DCM. The organic phase was dried and evaporated to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ: 10.2 (s, 1H), 8.27 (d, 1H), 7.48-7.56 (m, 2H), 6.96-7.03 (m, 2H), 6.87 (d, 1H), 6.74 (dd, 1H), 3.91 (s, LCMS: m / z 381.7 [M+H] +

[0334] Example 41. (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (Compound 416) [ka] This compound was prepared starting from tert-butyl(2S)-2-((5-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)carbamoyl)-114-pyrrolidine-1-carboxylate, following the procedure described for intermediate 364. The crude final product was treated with a saturated solution of Na2CO3 and then extracted by DCM. The organic phase was dried and evaporated to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ: 10.2 (s, 1H), 8.37 (d, 1H), 8.14-8.19 (m, 1H), 7.64 (dd, 1H), 6.91 (d, 1H), 6.86 (dd, 1H), 3.92 (s, 3H), 3.86 (dd, 1H), 2.96-3.14 (m, 2H), 2.13 (br, 1H), 2.12-2.24 (m, 1H), 1.96-2.07 (m, 1H), 1.67-1.84 (m, 2H). LCMS: m / z 400.6 [M+H] +

[0335] Example 42. (S)-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-N,1-dimethyl-5-oxopyrrolidine-2-carboxamide (Compound 417) [ka] To a cooled (0-5°C) solution of (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.204 g, 0.50 mmol) in dry DMF (2.0 mL), 60% by weight of sodium hydride (0.025 g, 0.625 mmol) in oil was added, followed by stirring at 0-5°C for 15 minutes. Iodomethane (0.062 mL, 1.00 mmol) was added, and stirring was continued at RT until the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound. Yield: 0.152 g. 1¹H NMR (400 MHz, CDCl3), mixture of rotational isomers. Chemical shifts of the main rotational isomers: δ: 7.56-7.64 (m, 2H), 7.07-7.14 (m, 1H), 6.98-7.06 (m, 3H), 6.96 (dd, 1H), 3.93 (dd, 1H), 3.90 (s, 3H), 3.21 (s, 3H), 2.76 (s, 3H), 2.43-2.62 (m, 1H), 2.18-2.31 (m, 1H), 1.77-2.08 (m, 2H). LCMS: m / z 423.4 [M+H] + .

[0336] Abbreviation DCM - Dichloromethane DEAD - Diethylazodicarboxylate DIPEA - N,N-diisopropylethylamine DMA - Dimethylacetamide DMAP - 4-dimethylaminopyridine DMF - N,N-dimethylformamide DMSO - Dimethyl sulfoxide ee - Enantiomer excess eq. - Molar equivalent GCMS - Gas Chromatography-Mass Spectrometry HATU-2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC - High-Performance Liquid Chromatography LCMS - Liquid Chromatography-Mass Spectrometry LiHMDS - Lithium bis(trimethylsilyl)amide MTBE - Methyl tert-butyl ester Pd2(dba)3- Tris(dibenzylideneacetone)dipalladium PdCl2(dppf) - [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) RT - room temperature rt - retention time Sphos Pd G2 - Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) T3P-1-propanephosphonic acid ring anhydride TBAF - Tetra-n-butylammonium fluoride TEA - Triethylamine TFA - Trifluoroacetic acid THF - Tetrahydrofuran TMA - Trimethylaluminum TMS-Cl-trimethylsilylchloride XantPhos-4,5-bis(diphenylphosphin)-9,9-dimethylxanthene

[0337] experiment Experiment 1. TEAD Inhibition TEAD inhibition was analyzed using the MCF-7 cell line (BPS Bioscience, catalog number: 60618), which contains the firefly luciferase gene under the control of the Hippo pathway TEAD reporter-TEAD response element. In this cell line, YAP1 remains in the nucleus and induces constitutive expression of the luciferase reporter. The amount of expressed luciferase was detected by measuring a plate equipped with an Enspire Multimode Plate Reader (PerkinElmer) using the ONE-Glo luciferase assay system (Promega).

[0338] Hippo pathway TEAD reporter-MCF-7 cells were seeded at a density of 8500 cells / well in 384 plates (Corning, No. 356660) coated with white / clear poly-D-lysine. The following day, the test compound (11 concentrations of 4 reproductions) and DMSO control (0.1%) were added to the plates. After 24 hours, the cells were lysed and luciferase activity was measured. The maximum half-inhibitory inhibitory concentration (IC) of the test compound against YAP-TEAD inhibition was measured. 50 ) was decided.

[0339] The compounds of the present invention are screened by the above assay, and the compound IC 50 The values ​​are listed in Table 1 below. In the table, "A" represents ICs with a minimum impedance of 50 nM. 50 The values ​​are shown, and "B" indicates IC in the range of 50-300nM. 50 The value is shown, and "C" is the IC in the range of 301nM to 2000nM. 50 Show the value.

[0340] [Table 57]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, A is a pyridyl, tetrahydropyranyl, 4- to 10-membered carbon ring; L is -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O-,-O-C 1-7 Alkyl- or -NH-C 1-7 Alkyl- is; R 1 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 or an optionally substituted 5- to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from O, S and N as ring atoms; R 2 is hydrogen, C 1-7 Alkyl, C 1-7 It is an alkoxy or halogen; R 3 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl or cyano, or R 1 and R 3 However, together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R 4 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, cyano, or C 1-7 It is an alkylcarbonyl; R 5 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, or R 4 and R 5 Together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; Z is -CH(NHR 25 )-(CH 2 ) 2 -COOH, or formula 【Chemistry 2】 (In the formula, B is one of the following groups) 【Transformation 3】 however, If B is a ring (2), then L is -O- or -O-C 1-7 It is alkyl and R 1 is C 1-7 It is an alkoxy; If B is a ring (3), then L is -O-; If B is a ring (4), then L is -O- and R 1 is C 1-7 It is an alkoxy; If B is a ring (20), (21), (23), (25), or (26), then L is -O- and R 1 is C 1-7 (It is an alkoxy) It is the basis of; L is -C 1-7 In the case of alkyl-O-, R 1 is C 1-7 It is either an alkoxy or R 1 and R 3 However, together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; If A is a 4-membered, 5-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbon ring, R 1 is C 1-7 It is an alkoxy; R 6 and R 9 These are, independently, hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-7 Alkyl, -C(O)-Rx, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, -SO 2 C 1-7 Alkyl, -C 1-7 Alkyl-C(O)-NR 23 R 24 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; Rx is C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl-NR 36 R 37 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R 7 、R 8 、R 10 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 およびR 26 are, independently, hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, hydroxyl, C 1-7 alkoxy or C 1-7 alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 It is an alkylcarbonyl; R 23 、 R 24 、 R 27 、 R 28 、 R 29 、 R 31 、 R 32 、 R 33 、 R 34 、 R 35 、 R 36 、 R 37 、 R 40 、 R 41 、 R 42 、 R 43 、 R 44 and R 45 are, independently, hydrogen, or C 1-7 alkyl; R 25 C 1-7 It is alkyl; R 30 C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO 2 C 1-7 It is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy C 1-7 Alkylcarbonyl or -C 1-7 Alkyl-C(O)-NR 23 R 24 And; R 39 is hydrogen, C 1-7 Alkyl or hydroxyl; In each existence, any permutation is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 One or two substituents independently selected from alkoxy and oxo; However, the compound of formula (I) N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-2-pyrrolidinecarboxamide; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide; N-[3-[(4-chlorophenyl)methyl]phenyl]-5-oxo-2-pyrrolidinecarboxamide; N-[3-[(chlorohexyloxy)methyl]phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide; N-[4-methyl-3-[(4-methyl-2-pyridinyl)oxy]phenyl]-5-oxo-2-pyrrolidinecarboxamide; N-[3-(cyclopentylamino)phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide; N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-oxo-3-piperidinecarboxamide; 1-Ethyl-5-oxo-N-(3-phenoxyphenyl)-3-pyrrolidinecarboxamide; N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-2-pyrrolidinecarboxamide; 1-(1-ethylpropyl)-N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-5-oxo-3-pyrrolidinecarboxamide; N-[3-[(4-chlorophenyl)methyl]phenyl]-1,6-dihydro-6-oxo-3-pyridinecarboxamide; 1,6-dihydro-N-[4-methoxy-3-(phenylmethyl)phenyl]-6-oxo-3-pyridinecarboxamide; 1,6-dihydro-6-oxo-N-[3-[2-(2-pyridinyl)ethenyl]phenyl]-3-pyridinecarboxamide; N-[3-[(3-fluorophenoxy)methyl]phenyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxamide; 1-methyl-N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-3-pyrrolidinecarboxamide; N-[3-[(1,3-benzodioxol-5-yloxy)methyl]phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide; 1,6-dihydro-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-oxo-3-pyridinecarboxamide; N-[3-[(cyclohexyloxy)methyl]phenyl]-1-ethyl-5-oxo-3-pyrrolidinecarboxamide; 1-methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-5-oxo-3-pyrrolidinecarboxamide; 2,3-dihydro-3-methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-oxo-1H-imidazole-4-carboxamide; 2,3-dihydro-1,3-dimethyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-oxo-1H-imidazole-4-carboxamide; 1-Ethyl-N-[4-Methoxy-3-(4-pyridinylmethoxy)phenyl]-5-oxo-3-pyrrolidinecarboxamide; N-[4-methoxy-3-(4-methoxyphenoxy)phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide, or 6-oxo-N-(3-phenoxyphenyl)-2-piperazinecarboxamide isn't it.)

2. The compound according to claim 1, wherein A is phenyl, pyridyl, or cyclohexyl.

3. Z is, 【Chemistry 4】 The compound according to claim 1 or 2, which is the base of.

4. The compound according to claim 3, wherein B is a ring (1a), (3), (4), (6), (8), (9), (10), (11), (12), (13), (16), (17), or (18).

5. The compound according to claim 4, wherein B is a ring (1a), (4), (10), (11), (12), (13), (16), or (17).

6. The compound according to claim 5, wherein B is a ring (1a), (10), (11), or (12).

7. The compound according to claim 6, wherein B is a ring (1a) or (12).

8. R 7 and R 8 The compound according to any one of claims 1 to 7, wherein is hydrogen.

9. R 6 However, hydrogen, C 1-7 Alkyl or C 3-7 The compound according to any one of claims 1 to 8, which is a cycloalkyl compound.

10. R 6 However, it is -C(O)-Rx, and Rx is C 1-7 The compound according to any one of claims 1 to 9, which is an alkyl or an optionally substituted 4 to 6 membered ring having 1 to 3 heteroatoms independently selected from O, S and N as ring atoms.

11. R 20 is hydrogen and R 18 C 1-7 Alkyl or C 3-7 The compound according to any one of claims 1 to 10, which is a cycloalkyl compound.

12. R 21 However, hydrogen or C 1-7 The compound according to any one of claims 1 to 11, which is alkyl.

13. L is -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O- or -O-C 1-7 The compound according to any one of claims 1 to 12, wherein it is alkyl-.

14. L is -O-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O- or -O-C 1-7 The compound according to any one of claims 1 to 13, wherein it is alkyl-.

15. L is -O-, -C 2-7 Alkenyl- or -O-C 1-7 The compound according to any one of claims 1 to 14, wherein it is alkyl-.

16. L is -O- or -C 2-7 The compound according to any one of claims 1 to 15, wherein it is alkenyl-.

17. The compound according to any one of claims 1 to 16, wherein L is -O-.

18. R 1 However, hydrogen, C 1-7 The compound according to any one of claims 1 to 17, which is an alkoxy or halogen.

19. R 1 However, C 1-7 The compound according to any one of claims 1 to 18, which is an alkoxy or halogen.

20. R 1 C 1-7 The compound according to any one of claims 1 to 19, which is an alkoxy.

21. R 2 However, hydrogen, C 1-7 The compound according to any one of claims 1 to 20, which is an alkoxy or halogen.

22. R 2 The compound according to any one of claims 1 to 21, wherein the compound is hydrogen or a halogen.

23. R 2 The compound according to any one of claims 1 to 22, wherein is hydrogen.

24. R 3 However, hydrogen, halogen or C 1-7 The compound according to any one of claims 1 to 23, which is an alkoxy compound.

25. R 3 However, hydrogen or C 1-7 The compound according to any one of claims 1 to 24, which is an alkoxy compound.

26. R 3 The compound according to any one of claims 1 to 25, wherein is hydrogen.

27. R 1 and R 3 The compound according to any one of claims 1 to 26, wherein together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms.

28. R 1 and R 3 The compound according to any one of claims 1 to 27, wherein together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 1-2 heteroatoms independently selected from O and N as ring atoms.

29. R 1 and R 3 The compound according to any one of claims 1 to 28, wherein together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 1-2 heteroatoms, the heteroatoms being oxygen.

30. R 4 However, hydrogen, halogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen C 1-7 Alkyl or halogen C 1-7 It is an alkoxy and R 5 However, hydrogen, C 1-7 Alkyl, C 1-7 The compound according to any one of claims 1 to 29, which is an alkoxy, cyano, amino, or halogen.

31. A is phenyl or pyridyl; L is -O-; R 1 C 1-7 It is an alkoxy; R 2 , R 3 , R 5 , R 33 and R 42 is hydrogen; Z is ring (1a) or (12); and R 4 is halogen C 1-7 The compound according to any one of claims 1 to 30, which is alkyl.

32. The compound, N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 1); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 21); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 22); (E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 23); 1-Methyl-5-oxo-N-(5-(3-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidine-2-carboxamide (compound 28); 5-Oxo-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)pyrrolidine-2-carboxamide (compound 33); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 45); 1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 47); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 48); N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 59); 5-Oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 66); 1-Methyl-5-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 67); 1-Ethyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 68); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 69); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 70); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 75); N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 76); 1-Isopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 81); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 87) N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 88); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-thioxopyrrolidine-2-carboxamide (compound 91); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-thioxopyrrolidine-2-carboxamide (compound 92); (R)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 93); (R)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 97); (R)-1-methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 99); (S)-N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 100); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 101); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 102); (R)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 103); (S)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 105); (S)-1-methyl-5-oxo-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 107); 1-Cyclopropyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 109); 1-Cyclopropyl-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 110); 1-Cyclopropyl-5-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide (compound 114); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 117); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 118); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-oxopiperidine-3-carboxamide (compound 119); (R)-1-cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 128); (S)-1-cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 129); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 130); 3-Cyclopropyl-N-(2-Methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 131); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 133); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-oxopyrrolidine-2-carboxamide (compound 134); 1-(2-amino-2-oxoethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 136); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 139); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 141); (2S)-4-methoxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 143); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 149); (S)-1-methyl-5-oxo-N-(5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 150); (R)-1-methyl-5-oxo-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)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 152); N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 153); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 154); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 156); (S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 157); 3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidin-4-carboxamide (compound 159); (R)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 162); (S)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 163); 3-Cyclopropyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidin-4-carboxamide (compound 164); (S)-1-cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 165); (R)-1-cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 166); 3-ethyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidin-4-carboxamide (compound 167); (S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidin-4-carboxamide (compound 168); (R)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 170); (S)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 171); (R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 175); 3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)chroman-8-yl)imidazolidined-4-carboxamide (compound 176); 1-Methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 177); 3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 178); 1-Cyclopropyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)pyrrolidine-2-carboxamide (compound 179); (S)-3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 180); 3-methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazolidine-4-carboxamide (compound 182); 3-Methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridine-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazolidin-4-carboxamide, enantiomer 2 (compound 184); 1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidine-2-carboxamide (compound 185); 3-Methyl-2-oxo-N-(6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)imidazolidined-4-carboxamide (compound 186); 2-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperidine-4-carboxamide (compound 187); 1-(2-amino-2-oxoethyl)-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 189); 3-methyl-2-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazolidin-4-carboxamide (compound 192); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 196); N-(5-((4,4-difluorocyclohexyl)methoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 206); (R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-3-methyl-2-oxoxazolidine-4-carboxamide (compound 208); (R)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 209); (S)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 210); N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 213); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 214); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 215); (S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzofuran-7-yl)imidazolidined-4-carboxamide (compound 216); (R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridine-2-yl)oxy)benzofuran-7-yl)imidazolidin-4-carboxamide (compound 217); N-(5-(3,4-dichlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 222); N-(5-(3-chloro-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 223); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 226); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 227); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (compound 229); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-5-oxopyrrolidine-2-carbonyl)-5-oxopyrrolidine-2-carboxamide (compound 230); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(4-oxoazetidine-2-carbonyl)pyrrolidine-2-carboxamide (compound 231); 1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine-2-carboxamide, enantiomer 1 (compound 234); 1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 237); N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 239); N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 240); N-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 248); N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 253); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 255); N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 264); (R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 265); N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 276); (R)-N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 278); N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 279); (R)-N-(3-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 282); (R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 283); (R)-N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 290); N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 292); N-(5-(cyclohexylmethoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 294); N-(5-((4,4-dimethylcyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 296); N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 297); N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 298); N-(5-(3-bromophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 299); N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 300); N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 304); N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 305); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 307); (R)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 308); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 312); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 313); N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 316); N-(5-(4-cyano-3-methylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 317); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyethyl)-5-oxopyrrolidine-2-carboxamide (compound 318); (R)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 319); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-oxopiperidine-2-carboxamide (compound 320); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopiperidine-4-carboxamide (compound 322); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 335); (S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 338); (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 339); (S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 340); (S)-N-(5-((3-chloro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 345); (S)-N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 348); N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (compound 349); (S)-N-(3-chloro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 351); N-(3-chloro-5-((5-trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 352); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 355); (S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 356); (S)-N-(2,4-difluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 361); (S)-N-(3-fluoro-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 362); (S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 363); (S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 365); 4-amino-5-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)amino)-5-oxopentanoic acid (compound 375); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazole-4-yl)pyrrolidine-2-carboxamide (compound 377); N-(4-fluoro-2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 382); N-(5-(4-chloro-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 385); N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 391); N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 395); (S)-N-(5-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 398); (N-(5-((5-fluoro-6-(trifluoromethyl)pyridine-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 399); N-(5-((6-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 400); (S)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 401); (R)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridine-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 402); (S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 403); (R,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 405); (S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 406); (S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 407); ((S,E)-N-(6-(2-(4,4-difluorocyclohexyl)vinyl)benzo[d][1,3]dioxol-4-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 409); 1-Glycyl-N-(2-Methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, HCl (compound 414); or its tautomers or pharmaceutically acceptable salts The compound according to any one of claims 1 to 31.

33. A compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicine. 【Transformation 5】 (In the formula, A is a pyridyl, tetrahydropyranyl, 4- to 10-membered carbon ring; L is -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O-,-O-C 1-7 Alkyl- or -NH-C 1-7 Alkyl- is; R 1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 , or an optionally substituted 5-6 membered heterocycle having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; R 2 is hydrogen, C 1-7 Alkyl, C 1-7 It is an alkoxy or halogen; R 3 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl or cyano, or R 1 and R 3 However, together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R 4 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, cyano, or C 1-7 It is an alkylcarbonyl; R 5 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, or R 4 and R 5 Together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; Z is -CH(NHR 25 )-(CH 2 ) 2 -COOH, or formula 【Transformation 6】 (In the formula, B is one of the following groups) 【Transformation 7】 however, If B is a ring (2), then L is -O- or -O-C 1-7 It is alkyl and R 1 is C 1-7 It is an alkoxy; If B is a ring (3), then L is -O-; If B is a ring (4), then L is -O- and R 1 is C 1-7 It is an alkoxy; If B is a ring (20), (21), (23), (25), or (26), then L is -O- and R 1 is C 1-7 (It is an alkoxy) It is the basis of; L is -C 1-7 In the case of alkyl-O-, R 1 is C 1-7 It is either an alkoxy or R 1 and R 3 However, together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; If A is a 4-membered, 5-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbon ring, R 1 is C 1-7 It is an alkoxy; R 6 and R 9 These are, independently, hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-7 Alkyl, -C(O)-Rx, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, -SO 2 C 1-7 Alkyl, -C 1-7 Alkyl-C(O)-NR 23 R 24 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; Rx is C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl-NR 36 R 37 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R 7 , R 8 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 26 These are, independently, hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxyl, C 1-7 Alkoxy or C 1-7 It is an alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 It is an alkylcarbonyl; R 23 , R 24 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 and R 45 These are, independently, hydrogen, or C 1-7 It is alkyl; R 25 C 1-7 It is alkyl; R 30 C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO 2 C 1-7 It is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy C 1-7 Alkylcarbonyl or -C 1-7 Alkyl-C(O)-NR 23 R 24 And; R 39 is hydrogen, C 1-7 Alkyl or hydroxyl; In each existence, any permutation is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 (One or two substituents independently selected from alkoxy and oxo.)

34. The compound according to claim 33 for use in the treatment of a disease or condition in which inhibition of TEAD is desired.

35. The compound according to claim 34, wherein the disease is cancer or chronic pain.

36. The compound according to claim 35, wherein the cancer is mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, gastric cancer, liver cancer, lung cancer, and colon cancer.

37. The compound according to claim 36, wherein the chronic pain is chronic neuropathic pain or chronic musculoskeletal pain.

38. A method for treating a disease or condition in which inhibition of TEAD is desired, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. 【Transformation 8】 (In the formula, A is a pyridyl, tetrahydropyranyl, 4- to 10-membered carbon ring; L is -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O-,-O-C 1-7 Alkyl- or -NH-C 1-7 Alkyl- is; R 1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 , or an optionally substituted 5-6 membered heterocycle having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; R 2 is hydrogen, C 1-7 Alkyl, C 1-7 It is an alkoxy or halogen; R 3 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl or cyano, or R 1 and R 3 However, together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R 4 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, cyano, or C 1-7 It is an alkylcarbonyl; R 5 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogen C 1-7 Alkyl, halogen C 1-7 Alkoxy, or R 4 and R 5 Together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S, and N as ring atoms; Z is -CH(NHR 25 )-(CH 2 ) 2 -COOH, or formula 【Chemistry 9】 (In the formula, B is one of the following groups) 【Chemistry 10】 however, If B is a ring (2), then L is -O- or -O-C 1-7 It is alkyl and R 1 is C 1-7 It is an alkoxy; If B is a ring (3), then L is -O-; If B is a ring (4), then L is -O- and R 1 is C 1-7 It is an alkoxy; If B is a ring (20), (21), (23), (25), or (26), then L is -O- and R 1 is C 1-7 (It is an alkoxy) It is the basis of; L is -C 1-7 In the case of alkyl-O-, R 1 is C 1-7 It is either an alkoxy or R 1 and R 3 However, together with the carbon atoms to which they are bonded, they form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; If A is a 4-membered, 5-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbon ring, R 1 is C 1-7 It is an alkoxy; R 6 and R 9 These are, independently, hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-7 Alkyl, -C(O)-Rx, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, -SO 2 C 1-7 Alkyl, -C 1-7 Alkyl-C(O)-NR 23 R 24 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; Rx is C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl-NR 36 R 37 , or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms; R 7 , R 8 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 26 These are, independently, hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxyl, C 1-7 Alkoxy or C 1-7 It is an alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 It is an alkylcarbonyl; R 23 , R 24 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 and R 45 These are, independently, hydrogen, or C 1-7 It is alkyl; R 25 C 1-7 It is alkyl; R 30 C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO 2 C 1-7 It is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy C 1-7 Alkylcarbonyl or -C 1-7 Alkyl-C(O)-NR 23 R 24 And; R 39 is hydrogen, C 1-7 Alkyl or hydroxyl; In each existence, any permutation is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 (One or two substituents independently selected from alkoxy and oxo.)

39. The method according to claim 38, wherein the disease is cancer or chronic pain.

40. The method according to claim 39, wherein the cancer is mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, stomach cancer, liver cancer, lung cancer, or colon cancer.

41. The method according to claim 39, wherein the chronic pain is chronic neuropathic pain or chronic musculoskeletal pain.

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 together with a pharmaceutically acceptable carrier.

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