TEAD inhibitors

Abstract

The present invention relates to a compound represented by formula (I), 33 The present invention relates to a compound of formula (I), or a pharma- ceutically acceptable salt thereof. The compounds of formula (I) have utility as inhibitors of TEAD. The compounds are useful as pharmaceuticals in the treatment of diseases or conditions in which inhibition of TEAD is desired, such as cancer and chronic pain.

Description

[Technical Field]

[0001] The present invention relates to therapeutically active compounds useful for inhibiting transcription enhancer associated domains (TEADs), and pharmaceutical compositions containing such compounds, which 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, abnormal organ growth, and organ regeneration. YAP and TAZ are coactivators of TEAD transcription that can shuttle between the cytoplasm and nucleus. Alterations in actin dynamics and the Hippo signaling pathway promote the 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 kinases, Sterile20-like kinase 1 / 2 (MST1 / 2), and the adaptor proteins Salvador homolog 1 (SAV1) and MOB kinase activator 1A / B (MOB1A / B). The tumor suppressor neurofibromin 2 (NF2) (also known as merlin) acts upstream of these kinases and promotes their activation, thereby inhibiting YAP and TAZ activity. The Hippo pathway is associated with many aspects of tumorigenesis, including cell proliferation, cell differentiation, cancer metastasis, and cancer therapy resistance. Therefore, dysregulation of Hippo pathway signaling has been shown to lead to carcinogenesis across various cancer types. It has also been reported that YAP and TAZ are core mechanisms underlying the pathogenesis of chronic pain, including 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 has been reported in Non-Patent Document 1.

[0005] There is a need for compounds that target diseases associated with dysregulation of Hippo pathway components, such as compounds that target the YAP-TEAD interaction. Such compounds would be useful in treating diseases or conditions in which inhibition of TEAD is desirable, such as chronic pain, including 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. Summary of the Invention

[0008] It has been discovered that compounds of formula (I) are potent inhibitors of the YAP-TEAD interaction. The compounds are therefore useful for treating conditions or diseases in which inhibition of TEAD is desirable. Such conditions or diseases include, but are not limited to, chronic pain, particularly chronic neuropathic pain and chronic musculoskeletal pain, and cancer, particularly cancers associated with deregulation of components of the Hippo pathway, including YAP-TEAD. Specific cancers include, but are not 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 compounds of formula (I) or pharmaceutically acceptable salts thereof: [ka] (In the formula, A is pyridyl, tetrahydropyranyl, or a 4- to 10-membered carbocyclic ring; L is -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O-, -OC 1-7 Alkyl- or -NH-C 1-7 alkyl-; R1 is hydrogen, 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 is alkoxy or halogen; R3 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, halogen C 1-7alkyl or cyano, or R1 and R3 together with the carbon atoms to which they are attached 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 is 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 atom to which they are attached 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] (wherein B is any of the following groups: [ka] however, When B is ring (2), L is -O- or -OC 1-7 alkyl and R1 is C 1-7 is alkoxy; When B is ring (3), L is -O-; When B is ring (4), L is -O- and R1 is C 1-7 is alkoxy; When B is ring (20), (21), (23), (25) or (26), L is -O- and R is C 1-7 alkoxy) is the basis of; L is -C 1-7 For alkyl-O-, R1 is C1-7 alkoxy, or R1 and R3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms; When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbocyclic ring, R1 is C 1-7 is 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 are independently hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, Hydroxyl, C1-7 Alkoxy or C 1-7 is alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 is 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 is alkyl; R 25 is C 1-7 is alkyl; R 30 is C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO2C 1-7 is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkyl carbonyl, 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 is alkyl or hydroxyl; In each occurrence, any substitution is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 1 to 2 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.)

[0010] According to one embodiment, the present invention provides a method for the treatment of a disease or condition in which inhibition of TEAD is desired, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. [ka] (In the formula, A is pyridyl, tetrahydropyranyl, or a 4- to 10-membered carbocyclic ring; L is -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O-, -OC 1-7 Alkyl- or -NH-C 1-7 alkyl-; R1 is hydrogen, 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 is alkoxy or halogen; R3 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, halogen C 1-7 alkyl or cyano, or R1 and R3 together with the carbon atoms to which they are attached 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 is 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 atom to which they are attached 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] (wherein B is any of the following groups: [ka] however, When B is ring (2), L is -O- or -OC 1-7 alkyl and R1 is C 1-7 is alkoxy; When B is ring (3), L is -O-; When B is ring (4), L is -O- and R1 is C 1-7 is alkoxy; When B is ring (20), (21), (23), (25) or (26), L is -O- and R is C 1-7 alkoxy) is the basis of; L is -C 1-7 For alkyl-O-, R1 is C 1-7 alkoxy, or R1 and R3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms; When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbocyclic ring, R1 is C 1-7 is 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 24or 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 are independently hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, Hydroxyl, C 1-7 Alkoxy or C 1-7 is alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 is 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 1-7is alkyl; R 25 is C 1-7 is alkyl; R 30 is C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO2C 1-7 is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkyl carbonyl, 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 is alkyl or hydroxyl; In each occurrence, any substitution is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 and 1 to 2 substituents independently selected from alkoxy and oxo.

[0011] In one embodiment, the disease or condition in which inhibition of TEAD is desired is cancer, such as mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, gastric cancer, liver cancer, lung cancer, and colon cancer.

[0012] In one embodiment, the disease or condition for which inhibition of TEAD is desired is 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. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present application provides novel compounds of formula (I) or pharmaceutically acceptable salts thereof that are useful as TEAD inhibitors.

[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 pyridyl, tetrahydropyranyl, or a 4- to 10-membered carbocyclic ring; L is -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O-, -OC 1-7 Alkyl- or -NH-C 1-7 alkyl-; R1 is hydrogen, 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 is alkoxy or halogen; R3 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, halogen C 1-7 alkyl or cyano, or R1 and R3 together with the carbon atoms to which they are attached 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 is 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 atom to which they are attached 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] (wherein B is any of the following groups: [ka] however, When B is ring (2), L is -O- or -OC 1-7 alkyl and R1 is C 1-7 is alkoxy; When B is ring (3), L is -O-; When B is ring (4), L is -O- and R1 is C 1-7 is alkoxy; When B is ring (20), (21), (23), (25) or (26), L is -O- and R is C 1-7 alkoxy) is the basis of; L is -C 1-7 For alkyl-O-, R1 is C 1-7 alkoxy, or R1 and R3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms; When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbocyclic ring, R1 is C 1-7 is 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 are independently hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, Hydroxyl, C 1-7 Alkoxy or C 1-7 is alkylcarbonyl; R 11 is hydrogen, C 1-7 Alkyl, halogen C 1-7 Alkyl or C 1-7 is 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 is alkyl; R 25 is C 1-7 is alkyl; R 30 is C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO2C 1-7 is alkyl; R 38 is hydrogen, C 1-7 Alkyl, C 1-7 Alkyl carbonyl, 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 is alkyl or hydroxyl; In each occurrence, any substitution is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 1 to 2 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 of the linker L variants is attached to ring A of formula (I) and the right bond is attached to the phenyl group. The wavy line in the group B variants indicates the position of attachment to the carboxamide group.

[0017] In one embodiment, specifically provided are compounds of formula (I) wherein A is phenyl, pyridyl, or cyclohexyl. In a subgroup of the foregoing embodiment, A is phenyl or cyclohexyl. In yet another subgroup, A is phenyl or pyridyl. In yet another subgroup, A is phenyl. In yet another subgroup, A is cyclohexyl. In yet another subgroup, A is pyridyl.

[0018] Further, according to one embodiment, specifically R 42 Compounds according to any of the above embodiments are provided wherein is hydrogen.

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

[0020] Further, according to one embodiment, specifically provided are compounds according to any of the above embodiments, wherein B is ring (1a), (3), (4), (6), (8), (9), (10), (11), (12), (13), (16), (17), or (18). In subgroups of the preceding embodiments, B is ring (1a), (4), (10), (11), (12), (13), (16), or (17). In yet another subgroup, B is ring (1a), (10), (11), or (12). In yet another subgroup, B is ring (1a) or (12). In yet another subgroup, B is ring (1a). In yet another subgroup, B is ring (12).

[0021] In a subgroup of compounds where B is (1a), R7 and R8 are hydrogen. In yet another subgroup of the above embodiment, R6 is hydrogen, C 1-7 Alkyl or C 3-7 According to another subgroup, R6 is -C(O)-Rx, where Rx is C 1-7 alkyl or an optionally substituted 4-6 membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms. Particular examples of such rings are C 1-7 Pyrrolidine and azetidine rings optionally substituted with 1 to 2 substituents independently selected from alkyl or oxo.

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

[0023] In one embodiment, L is preferably -O-, -S-, -NH-, -C 1-7 Alkyl-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O- or -OC 1-7 In a subgroup of the above embodiments, L is -O-, -C 2-7 Alkenyl-, -C 1-7 Alkyl-O- or -OC 1-7 In a subgroup of the above embodiment, L is -O-, -C 2-7 Alkenyl- or -OC 1-7 In yet another subgroup, L is -O- or -C 2-7 In another subgroup, L is -O-. 1-7 A specific example of L being alkyl is the -CH2- group. 2-7 A specific example of L being alkenyl- is the group -CH=CH-. 1-7 A specific example of L being alkyl-O- is the group -CH2-O-. 1-7 A specific example of L being alkyl- is the group -O-CH2-.

[0024] In one embodiment, specifically, R1 is hydrogen, C 1-7 In a subgroup of the above embodiments, R is C 1-7 In a subgroup of the above embodiments, R is C 1-7 Alkoxy, especially methoxy. According to one embodiment, R1 is an optionally substituted 5-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms. Particular examples of such rings include those having 1-2 C 1-7 Includes oxadiazolyl and pyrazolyl optionally substituted with alkyl or oxo substituents.

[0025] In one embodiment, R2 is preferably hydrogen, C 1-7 Compounds according to any of the above embodiments are provided wherein R2 is alkoxy or halogen. In a subgroup of the preceding embodiments, compounds are provided wherein R2 is hydrogen or halogen. In a subgroup of the preceding embodiments, compounds are provided wherein R2 is hydrogen.

[0026] In one embodiment, R3 is preferably hydrogen, halogen or C 1-7 In a subgroup, R3 is hydrogen or C 1-7 In a subgroup are compounds where R3 is hydrogen.

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

[0028] In particular, according to one embodiment, R1 and R3 together with the phenyl ring to which they are attached form the following group: [ka] (In the formula, the left wavy line indicates the position of attachment to the L group, and the right wavy line indicates the position of attachment to the carboxamide group.)

[0023] Compounds according to any of the above embodiments are provided which form an optionally substituted fused ring represented by any of C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 There may be 1 to 2 substituents independently selected from alkoxy and oxo.

[0029] In one embodiment, R4 is preferably hydrogen, halogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen C 1-7 Alkyl or halogen C 1-7 Alkoxy and R5 is hydrogen, C 1-7 Alkyl, C 1-7 Compounds according to any of the above embodiments are provided in which R4 is alkoxy, cyano, amino or halogen. 1-7 Alkyl, halogen C 1-7 Alkyl or halogen C 1-7 Alkoxy and R5 is hydrogen, C 1-7 In a subgroup, R4 is a halogen atom. 1-7 Alkyl or halogen C 1-7 In a subgroup, R4 is a halogen atom or a C 1-7 Alkyl or halogen C 1-7 In another subgroup, R4 and R5 are both C 1-7 In another subgroup, R4 and R5 are both halogen, e.g., fluoro. 1-7 Particular examples of R4 that are alkyl are -CF3 and CHF2 groups. 1-7A particular example of R4 being alkoxy is the -OCF3 group.

[0030] In one embodiment, specifically, ring A together with R4 and R5 represents the following group: [ka] (wherein X is a halogen and the wavy line indicates the point of attachment to the L group.)

[0023] There is provided a compound according to any of the above embodiments, represented by any of:

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

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

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

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

[0035] In one embodiment, Z is specifically -CH(NHR 25 )—(CH 2 ) 2 —COOH.

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

[0037] In one embodiment, there is specifically provided a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L is -O- or -CH=CH-; R2 is H or halogen; R4 is H, C 1-7 is alkyl or halogen; R5 is hydrogen, C 1-7 Alkyl or halogen C 1-7 is alkyl; B is ring (1a), (10) or (12); R1 is -OCH3 or halogen, or R1 and R3 together with the phenyl ring to which they are attached form the following group: [ka] and forming a fused ring represented by any one of the following:

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

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

[0040] The compound of formula (I) can be prepared, for example, by Scheme 1, in which A, L, Z, R1, R2, R3, R4, R5, R 23 and R 42is as defined above. In the method of Scheme 1, the aniline compound of formula [1] is coupled with a carboxylic acid derivative of formula [2] 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) in a suitable solvent such as anhydrous acetonitrile or DMF to produce a compound of formula (I). [ka]

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

[0042] The compound of formula (I) in which 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 the presence of a Mitsunobu reagent such as triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD) in a suitable solvent such as tetrahydrofuran to produce the compound of formula (I). [ka]

[0043] Intermediate compounds can be prepared according to methods disclosed in the literature or as described in this disclosure.

[0044] For example, the intermediate compound of formula [1a], wherein L is —O—, can be prepared according to Scheme 4, in which A, R1, R2, R3, R4, R5 and R 33 is as defined above. In the method of Scheme 4, a compound of formula [7] is coupled with a compound of formula [8] in the presence of a base such as pyridine and a catalyst such as copper diacetoxy in a suitable solvent such as dichloromethane to produce a compound of formula [8], which can then be reduced by hydrogenation in the presence of a suitable catalyst such as palladium on carbon to give an 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 which A, R1, R2, R3, R4, R5 and R 33 is as defined above, and X is a halogen. In the method of Scheme 5, a compound of formula [9] is coupled with a compound of formula

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

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

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used herein, the following definitions are provided to facilitate the understanding of the present invention.

[0049] As used herein, the term "subject" refers to humans and animals.

[0050] The terms "halo" or "halogen" as used herein by themselves or as part of another group mean chlorine, bromine, fluorine, or iodine. Preferred halogens are chlorine and fluorine.

[0051] As used herein, the term "C" as used by itself or as part of another group 1-7"Alkyl" means a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atoms. 1-7 Representative examples of alkyl 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 The term "C" is an alkyl group. 1-3 "Alkyl" refers to a group having 1, 2 or 3 carbon atoms. 1-7 "C" refers to an embodiment of "alkyl." 1-3 Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, and iso-propyl. 1-7 "Alkyl" is a methyl group.

[0052] As used herein, the term "C" as used by itself or as part of another group 2-7 "Alkenyl" means an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethenyl, propenyl, and hexenyl. 2-7 One preferred embodiment of "alkenyl" is C 2-4 The term "C" is an alkenyl. 2-4 "Alkenyl" refers to an alkyl group having 2, 3 or 4 carbon atoms. 2-7 Representative examples include, but are not limited to, ethenyl, propenyl, and butenyl. One preferred "C 2-7 "Alkenyl" is the group -CH=CH-.

[0053] As used herein, the term "C" as used by itself or as part of another group 3-7"Cycloalkyl" means a saturated cyclic hydrocarbon group containing 3, 4, 5, 6, or 7 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. One preferred "C 3-7 "Cycloalkyl" is a cyclopropyl group.

[0054] The term "hydroxy" as used herein by itself or as part of another group refers to an --OH group.

[0055] The term "cyano" as used herein by itself or as part of another group refers to the group --CN.

[0056] The term "carboxy" as used herein by itself or as part of another group refers to a -COOH group.

[0057] The term "carbonyl" as used herein by itself or as part of another group means a carbon atom double bonded to an oxygen atom (C=O).

[0058] The term "oxo" as used herein by itself or as part of another group refers to an oxygen atom (=O) that is attached to another atom by a double bond.

[0059] As used herein, the term "C" as used by itself or as part of another group 1-7 "Alkoxy" refers to a C alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. 1-7 It means alkyl. 1-7 Representative examples of alkoxy 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 The term "C" is an alkoxy group. 1-3"Alkoxy" refers to a group having 1, 2 or 3 carbon atoms. 1-7 C means an embodiment of "alkoxy". 1-3 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, and propoxy. 1-7 An "alkoxy" group is methoxy.

[0060] As used herein, the term "hydroxy C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 means at least one hydroxy group, as defined herein, attached through an alkyl group. 1-7 Representative examples of alkyl 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] As used herein, the term "halogen C" 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 means at least one halogen as defined herein attached through an alkyl group. 1-7 Representative examples of alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl. 1-7 "Alkyl" groups are trifluoromethyl and difluoromethyl.

[0062] As used herein, the term "halogen C" 1-7 "Alkoxy" refers to the parent molecular moiety C as defined herein. 1-7 It means at least one halogen, as defined herein, attached through an alkoxy group.

[0063] As used herein, the term "C" as used by itself or as part of another group 1-7 Alkoxy C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 at least one C as defined herein attached through an alkyl group 1-7 It means an alkoxy group.

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

[0065] The term "substituted" as used herein in connection with various residues means, unless otherwise specified, 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, HaloC 1-7 Alkyl, Hydroxy C 1-7 Alkyl or amino C 1-7 alkyl substituents. Preferred substituents are halogen, C 1-7 Alkyl, hydroxy, amino, haloC 1-7 Alkyl, C 1-7 Alkoxy and methylsulfonyl substituents. One group of preferred substituents is C 1-7 one or two substituents selected from alkyl or halogen substituents, in particular C 1-3 Alkyl or halogen substituents, particularly methyl, ethyl, chloro, fluoro, bromo substituents.

[0066] A "substituted" group can contain from 1 to 3, preferably 1 or 2, of the above substituents, unless otherwise specified.

[0067] Optically active enantiomers or diastereomers of compounds of formula (I) can be prepared, for example, by resolution of racemic final products by known methods or by using appropriate optically active starting materials. Similarly, racemic compounds of formula (I) can be prepared using racemic starting materials. Resolution of racemic compounds of formula (I) or their racemic starting materials can be achieved, for example, by converting the racemic compound to a mixture of diastereomeric salts by reaction with an optically active acid, followed by separation of the diastereomers by crystallization. Representative examples of optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography can be used to resolve racemic mixtures.

[0068] Pharmaceutically acceptable salts are well known in the field of formulation. 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 salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbic acids, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, if applicable, can be prepared by known methods using pharmaceutically acceptable acids commonly used in the pharmaceutical field, and retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphate and carbonate esters are also within the scope of the present invention.

[0069] The above definition of formula (I) includes all possible isotopes and isomers, such as stereoisomers, of the compounds, geometric isomers, e.g. Z and E isomers (cis and trans isomers), and optical isomers, e.g. 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 can have at least one chiral center. Therefore, the compounds can exist in optically active or racemic forms. Formula (I) should be understood to encompass any racemic or optically active form, or mixtures thereof. In one embodiment, the compound is the pure (R)-isomer. In yet another embodiment, the compound is the pure (S)-isomer. In another embodiment, the compound is a mixture of the (R)- and (S)-isomers. In another embodiment, the compound is a racemic mixture containing an equal mixture of the (R)- and (S)-isomers. The compound may also have two chiral centers. In such cases, according to one embodiment, the compound is a mixture of diastereomers. In another embodiment, the compounds of the present invention are mixtures of enantiomers. In yet another embodiment, the compounds are pure enantiomers. The individual isomers may be obtained using the corresponding isomers of the starting materials, or may be separated after preparation of the final compound using conventional separation methods. Separation of optical isomers, eg enantiomers or diastereomers, from a mixture thereof may be achieved using conventional resolution methods, eg fractional crystallisation.

[0071] The compounds of the present invention may exist as tautomers or as equal mixtures thereof in which the protons of the compounds shift from one atom to another. Examples of tautomers include, but are not limited to, amide-imide, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine, and cyclic tautomers of heterocycles such as pyrrole rings. Tautomeric forms are intended to be encompassed by the compounds of formula (I), even if only one tautomeric form is shown.

[0072] Examples of preferred compounds of 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-oxopyrrolidin-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)pyridin-3-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 62); N-(2-methoxy-5-((6-(trifluoromethyl)pyridin-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-pyrazol-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-oxooxazolidine-4-carboxamide (Compound 87) N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 88); N-(5-((3,4-difluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 89); N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-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-oxooxazolidine-4-carboxamide (compound 101); (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxooxazolidine-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-oxooxazolidine-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)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-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)pyridin-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)pyridin-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)pyridin-2-yl)oxy)phenyl)-3,4-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 123); (R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 124); (S)—N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 125); (R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 126); 3-ethyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 127); (R)-1-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 128); (S)-1-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 129); (S)—N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 130); 3-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 131); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 132); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-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)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 152); N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 153); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 154); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 155); (S)—N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 156); (S)—N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-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)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 159); 2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidine-4-carboxamide (compound 160); 6-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidine-3-carboxamide (compound 161); (R)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 162); (S)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 163); 3-Cyclopropyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 164); (S)-1-Cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 165); (R)-1-Cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 166); 3-ethyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 167); (S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 168); (R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 169); (R)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 170); (S)-1-Ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 171); (2R)-1-methyl-N-(2-methyl-5-((5-(trifluoromethyl)pyridin-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)pyridin-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)pyridin-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 174); (R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 175); 3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)chroman-8-yl)imidazolidine-4-carboxamide (compound 176); 1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 177); 3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidine-4-carboxamide (compound 178); 1-Cyclopropyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)pyrrolidine-2-carboxamide (compound 179); (S)-3-Methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidine-4-carboxamide (compound 180); (R)-3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidine-4-carboxamide (compound 181); 3-methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridin-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)pyridin-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)pyridin-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)imidazolidine-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)pyridin-2-yl)oxy)-1H-imidazol-7-yl)imidazolidine-4-carboxamide (compound 193); 1-methyl-N-(1-methyl-5-((5-(trifluoromethyl)pyridin-4-yl)oxy)-1H-imidazol-7-yl)-5-oxopyrrolidine-2-carboxamide (compound 194); (S)—N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 195); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 196); N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 197); (R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 198); (S)—N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 199); N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 200); N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 201); N-(5-((5-fluoropyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 202); N-(5-((5-chloropyridin-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-oxooxazolidine-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)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 211); N-(5-((5-(difluoromethyl)pyridin-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)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-carboxamide (compound 216); (R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-carboxamide (compound 217); (S)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-oxoimidazolidine-4-carboxamide (compound 218); (R)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-oxoimidazolidine-4-carboxamide (compound 219); (S)—N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 220); (R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-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)pyridin-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)pyridin-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]thiazole-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-methylpyridin-3-yl)oxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 262); (R)-N-(5-((6-fluoro-5-methylpyridin-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)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 276); N-(3-methoxy-5-((5-(trifluoromethyl)pyridin-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)pyridin-2-yl)oxy)quinolin-8-yl)pyrrolidine-2-carboxamide (compound 280); (R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-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)pyridin-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-cyclopyridin-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)pyridin-2-yl)oxy)phenyl)-2-oxopiperidine-4-carboxamide, enantiomer 1 (compound 324); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-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)pyridin-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)pyridin-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)pyridin-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)pyridin-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-dioxoimidazolidin-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)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 343); N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-3-carboxamidecarboxamide (compound 344); (S)—N-(5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 345); (S)—N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-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)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 351); N-(3-chloro-5-((5-trifluoromethyl)pyridin-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-oxopyrrolidin-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)pyridin-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (compound 358); (S)—N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 359); (S)-1,3-dimethyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidine-4-carboxamide (compound 360); (S)—N-(2,4-difluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 361); (S)—N-(3-fluoro-5-((5-(trifluoromethyl)pyridin-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)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-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)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 368); N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-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)pyridin-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-pyrazol-4-yl)pyrrolidine-2-carboxamide (compound 377); (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazol-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-dihydrooxazole-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)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 393); (S)—N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-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)pyridin-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 399); N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 400); (S)—N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 401); (R)—N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 402); (S)—N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-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)pyridin-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), and tautomers and pharmaceutically acceptable salts thereof.

[0073] The compounds of the present invention can be administered to patients in therapeutically effective amounts, typically in the range of about 0.5 to about 2000 mg per day, more typically about 1 to about 1500 mg, e.g., about 2 to about 100 mg, depending on the patient's age, sex, weight, ethnicity, condition, symptoms to be treated, route of administration, and 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 patients directly or in combination with appropriate pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. Selecting appropriate ingredients for a composition is a routine task for those skilled in the art. Suitable carriers, solvents, gel-forming ingredients, dispersion-forming ingredients, antioxidants, colorants, sweeteners, humectants, and other ingredients 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 active compound content of the composition is about 0.5 to 100% by weight of the total composition, typically about 0.5 to about 20%.

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

[0075] In the treatment of diseases or conditions where inhibition of TEAD is desired, such as various cancers and chronic pain, the combination of therapeutic agents and / or other treatments (e.g., radiation therapy) is 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 compound of the present invention can be administered in combination with other anti-cancer treatments that are useful in the treatment of cancer.For example, the compound of the present invention can be packaged with instructions that the compound is to be used in combination with other anti-cancer drugs and treatments for the treatment of cancer.Similarly, the compound of the present invention can be administered in combination with other pain relievers that are useful in the treatment of chronic pain.For example, the compound of the present invention can be packaged with instructions that the compound is to be used in combination with other anti-cancer drugs and treatments for the treatment of cancer, or in combination with other pain relievers and treatments for the treatment of chronic pain.The present invention also includes the combination of the compound of the present invention with one or more additional drugs in the form of a kit, for example, they are packaged together or sold together as a kit even if they are in separate packages, or 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 anti-cancer or pain relieving agents.

[0078] Any other anticancer agent that can be administered in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof includes, but is not limited to, - Chemotherapeutic agents (e.g., docetaxel and paclitaxel); - 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); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); CDK4 / 6 inhibitors (e.g., ribociclib); - steroid synthesis inhibitors (e.g., teronel CYP17A1 inhibitors such as abiraterone acetate and sebi); and Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and darolutamide) etc.

[0079] According to yet another embodiment, the present invention provides a method for treating atopic dermatitis comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, - Chemotherapeutic agents (e.g., docetaxel and paclitaxel); - 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); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); CDK4 / 6 inhibitors (e.g., ribociclib); - steroid synthesis inhibitors (e.g., teronel CYP17A1 inhibitors such as abiraterone acetate and sebi); and Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and darolutamide) and at least one additional active ingredient selected from the list consisting of:

[0080] Such other therapeutic agents, when used in combination with the compounds of the present invention, can be used, for example, in those amounts as described in the Physicians' Desk Reference (PDR), or as otherwise determined by one of skill in the art.

[0081] The compounds of the present invention can be prepared by various synthetic routes analogous to methods known in the literature using appropriate starting materials. The present invention is explained in more detail by the following experiments and examples. The experiments and examples are intended for illustrative purposes only and do not limit the scope of the invention as defined in the claims. [Example]

[0082] Purification method used: A) Reverse-phase HPLC (water / acetonitrile, 2-8 min 0-65%, 30 mL / min, column: SunFire 100 x 19 mm) B) Reverse-phase HPLC (water / methanol, 2-8 min 0-65%, 30 mL / min, column: SunFire 100 x 19 mm) C) Reverse-phase HPLC (water / acetonitrile / formic acid, 2-10 min 0-40%, 30 mL / min, column: SunFire 100 x 19 mm) D) Reverse-phase HPLC (water / acetonitrile / ammonia, 2-8 min 0-65%, 30 mL / min, column: SunFire 100 x 19 mm) E) Reverse-phase HPLC (water / methanol / ammonia, 2-10 min 40-50%, 30 mL / min, column: SunFire 100 x 19 mm) F) Reverse-phase HPLC (water / acetonitrile / trifluoroacetic acid, 2-10 min 0-50%, 30 mL / min, column: SunFire 100 x 19 mm) G) Reverse-phase HPLC (water / methanol / trifluoroacetic acid, 2-10 min 10-50%, 30 mL / min, column: SunFire 100 x 19 mm) H) Preparative chiral HPLC (methanol / isopropanol, 50-50, 12 mL / min, column: Chiralpak AD-H (250 x 20 mm) I) Preparative chiral HPLC (methanol / IPA / hexane, 25-25-50, 0.6 mL / min, column: Chiralpak IC (250 x 4.6 mm) I) Preparative chiral HPLC (methanol / CO2, 50-50, 2 mL / min, column: Chiralpak AD-H (250 x 4.6 mm)

[0083] Intermediate 1,5-bromo-2-fluoro-4-methoxyphenyl formate [ka] To a solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (1.000 g, 1 eq., 4.291 mmol) in CHCl (20 mL) was added 3-chlorobenzoperoxoic acid (1.851 g, 2.5 eq., 10.73 mmol) at 4 °C, followed by stirring for 30 min. 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 NaHCO (2 × 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.57 (s, 1H), 7.69 (dd, 1H), 7.29 (dd, 1H), 3.86 (d, 3H).

[0084] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 1. Where LCMS / GCMS data was not informative, the data is not shown.

[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 solution of 5-bromo-2-fluoro-4-methoxyphenyl formate (4.0 g, 1 eq., 16.06 mmol) in methanol (100 mL). The mixture was stirred at 25 °C for 12 h. The mixture was then concentrated, diluted with 50 mL of water, acidified to pH 1, and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over Na SO and concentrated. The crude product was purified twice by column chromatography using hexane-MTBE and chloroform-acetonitrile systems to give 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 indicated in the table following the procedure described for Intermediate 4. Where LCMS / GCMS data was not informative, the data is not shown.

[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 room temperature, 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 give 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 in vacuo. The residue was dissolved in ethyl acetate (5 mL), washed with brine (2×5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 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 subsequently stirred at 200 °C for 30 h. After cooling to RT, the reaction mass was poured into water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give 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 following the procedure described for intermediate 10b starting from the starting materials indicated in the table.

[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) was added chlorotriisopropylsilane (8.546 g, 9.487 mL, 1.05 eq., 44.33 mmol) at RT. The mixture was stirred for 16 h and then poured into a saturated aqueous solution of NH4Cl (40 mL) and subsequently extracted with DCM (3 x 50 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound (10.00 g, 30 mmol). 1 H 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. EtOAc (70 mL) was added, and 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 give 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 h and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL), washed with water (2 × 5 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography (hexane / MTBE) to give the title compound (0.575 g, 1.9 mmol). 1 H 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), diacetoxycopper (1 g, 1.05 eq., 6 mmol), and powdered molecular sieves 4 Å (1 g) were suspended in dichloromethane (10 mL). Air was bubbled through the resulting solution for 30 min, and the mixture was stirred at RT overnight. 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 give the title compound. LCMS: m / z 314.0 [M+H] + .

[0098] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 13. Where LCMS / GCMS data was not informative, the data is not shown.

[0099] [Table 4] TIFF0007828367000037.tif216151 TIFF0007828367000038.tif216151 TIFF0007828367000039.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-methylpropan-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 h. 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. EtOAc (100 mL) was added, and 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 give 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 bubbled through the solution at 25 °C for 1 h to remove any excess oxygen. PdCl(dppf)CHCl (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 h 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 x 50 mL). The organic layer was collected, washed with 15% brine (2 x 15 mL), and extracted with 15% Na2CO3 (2 x 25 mL). The aqueous phase was collected, and the pH was adjusted to 4-5 with 3M HCl. The aqueous phase was then extracted with ethyl acetate (2 x 50 mL). The organic layer was collected, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (810 mg, 3.6 mmol). LCMS: m / z 208.0 [M+H] +

[0102] The following intermediates were prepared following the procedure described for Intermediate 49 starting from the starting materials indicated in the table.

[0103] [Table 5]

[0104] Intermediate 51. (7-Nitrobenzo[d][1,3]dioxol-5-yl)methanol [ka] 7-Nitrobenzo[d][1,3]dioxole-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 portionwise over 10 min. The mixture was stirred at RT for 18 h 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 give 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 indicated in the table following the procedure described for Intermediate 51. Where LCMS / GCMS data was not informative, the data is not shown.

[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 37% aqueous hydrochloric acid (10 mL) and then stirred at 100° C. for 12 h. After cooling to RT, the reaction mixture was extracted with dichloromethane (2×50 mL), the organic layers were combined, washed with water (2×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude title compound (312 mg, 1.46 mmol, 30%, 100% purity), which was 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 following the procedure described for Intermediate 56 starting from the starting materials indicated in the table.

[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 min, then warmed to RT and stirred at this temperature overnight. The solution was then poured into 10% aqueous sodium bicarbonate solution (10 mL) and stirred for 10 min. 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 in vacuo to give the title compound (602 mg, 2.4 mmol, 80%, 88% purity), which was used in the next step without further purification. LCMS: m / z 219.8 [M+H] + .

[0111] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 58. Where LCMS / GCMS data was not informative, the data is not shown.

[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) was added sodium hydride (238.1 mg, 60%, 1.2 eq., 5.952 mmol) at 0 °C, and the mixture was stirred at RT for 30 min. 4-(Chloromethyl)-1-methoxy-2-nitrobenzene (1.000 g, 1 eq., 4.960 mmol) was added in one portion, and the mixture was stirred at RT for 18 h. The resulting mixture was filtered, and the filtrate was diluted with water (50 mL) and ethyl acetate (50 mL). The layers were separated, and the organic phase was washed with brine (4 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound, which was used in the next step without further purification.

[0114] The following intermediates were prepared following the procedure described for Intermediate 62 starting from the starting materials indicated in the table.

[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, and the mixture was stirred at this temperature for 30 min. 4-(Chloromethyl)-1-methoxy-2-nitrobenzene (3.41 g, 1.1 eq., 16.9 mmol) was added, and the mixture was heated at 100 °C for 16 h. The solution was cooled to RT and concentrated. The residue was taken up in ethyl acetate (60 mL). The resulting solution was washed with brine (3 × 50 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound (4.5 g, 14 mmol, 94%, 95% purity). The crude product was used in the next step without further purification.

[0117] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for intermediate 69. Where LCMS / GCMS data was not informative, the data is not shown.

[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-methylpropan-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 h. EtOAc (50 mL) was then added, and the organic phase was washed with brine (5×30 mL), dried, and evaporated under reduced pressure to give the title compound, which was used in the next step without further purification. GCMS: m / z 281 [M] +

[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 PdCl(dppf)CHCl adduct (295 mg, 0.1 eq., 361 μmol). was suspended in degassed 1,4-dioxane (12 mL) and water (2.4 mL). The mixture was heated under argon at 90° C. overnight. After cooling to RT, the solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and the residue was purified by Method A to give the title compound (205 mg, 839 μmol, 23.2%, 95.5% purity). LCMS: m / z 234.2 [M+H] + .

[0121] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 76. Where LCMS / GCMS data was not informative, the data is not shown.

[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 min, and 4-(chloromethyl)-1,2-difluorobenzene (378 mg, 1 eq., 2.33 mmol) was added. The mixture was stirred at RT for 12 h. The resulting solution was concentrated under reduced pressure. The residue was taken up in ethyl acetate (20 mL). The resulting solution was washed with brine (20 mL), water (20 mL), dried over sodium sulfate, filtered, and evaporated to give 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 indicated in the table following the procedure described for Intermediate 78. Where LCMS / GCMS data was not informative, the data is not shown.

[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 min, and 3-fluorophenol (141 mg, 114 μL, 0.9 eq., 1.25 mmol) was added. The mixture was stirred at RT for 10 h. The resulting solution was filtered and concentrated to give the title compound (0.362 g, 0.61 mmol, 44%, 50% purity), which was used in the next step without further purification. LCMS: m / z 297.2 [M+H] +

[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 then methanol (15.1 mg, 19.0 μL, 1 eq., 470 μmol) was added at 0° C. To the resulting solution was added potassium tert-butoxide (52.7 mg, 1 eq., 470 μmol) at 0° C. The mixture was stirred at 0° C. for 10 min, then the temperature was allowed to rise to RT and subsequently stirred for 12 h. The reaction mixture was quenched with water (15 mL) and subsequently stirred for 15 min. Toluene (10 mL) was added to the mixture. The layers were separated, and the aqueous layer was extracted with toluene (2×10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound, which was used in the next step without further purification. GCMS: m / 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 min, followed by the addition of 3-fluorophenol (1.612 g, 1.302 mL, 1.05 eq., 14.38 mmol). The ice bath was removed, and the mixture was stirred at RT for 17 h. The THF was evaporated, and the mixture was dissolved in MTBE (10 mL), washed with NaOH (3 mL, 10%) and water (3 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (MTBE / hexane, flow rate 30 mL / min) to give the title compound (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 indicated in the table following the procedure described for Intermediate 86. Where LCMS / GCMS data was not informative, the data is not shown.

[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 h, then concentrated and purified by flash chromatography (MTBE / hexane, flow rate 30 mL / min) to give the title compound.

[0132] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 97. Where LCMS / GCMS data was not informative, the data is not shown.

[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 h. The mixture was then poured into ice-cold saturated sodium carbonate solution (5 mL), and EtOAc (5 mL) was added. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to give 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 give 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 portionwise. The mixture was stirred at 5 °C for 30 min, 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 h, poured into ice-cold water (10 mL), and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (4 x 5 mL), dried, and concentrated to give a crude product mixture that was separated by HPLC (Method A) to give 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 h, and MeOH (5 mL) was added dropwise to the mixture at 4 °C. The mixture was concentrated under reduced pressure, and the residue was poured into a saturated 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 give 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 h. 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 give the crude title compound (6.35 g, 14.8 mmol), which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ: 8.38 (s, 1H), 7.91 (dd, 1H), 7.42 (d, 1H), 7.07 (d, 1H), 6.78 (d, 1H), 3.88 (s, 3H).

[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 for 14 h. After cooling to RT, the mixture was concentrated under reduced pressure, extracted with EtOAc (100 mL), and washed with water (20 mL), K2CO3 solution (20 mL, 15% in water), and brine (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give 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 indicated in the table following the procedure described for Intermediate 105. Where LCMS / GCMS data was not informative, the data is not shown.

[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) was added hydrazine hydride (2.266 g, 7 eq., 45.28 mmol). The mixture was heated under reflux overnight. The solvent was then evaporated under reduced pressure, and water (20 mL) was added to the residue. The resulting solid was filtered, washed with water and hexane, and dried in vacuo to give 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 following the procedure described for Intermediate 116 starting from the starting materials indicated in the table.

[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 at reflux for 14 hours. The mixture was then concentrated in vacuo to give 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 indicated in the table following the procedure described for Intermediate 119. Where LCMS / GCMS data was not informative, the data is not shown.

[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)ethan-1-one (0.300 g, 1 eq., 1.02 mmol), DMF-DMA (244 mg, 272 μL, 2 eq., 2.05 mmol), and toluene (3 mL) was stirred and heated at reflux for 16 h, then cooled to RT. The resulting solid was filtered, washed with toluene, hexane, and dried in vacuo to give 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 at reflux for 18 h. The mixture was cooled to RT, concentrated in vacuo, and purified by Method C to give the title compound (0.109 g, 329 μmol, 46.6%, 100% pure). LCMS: m / z 332.0 [M+H] + .

[0150] Intermediate 124. 7-Nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole [ka] To a stirred solution of 2-methyl-6-nitro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline (1.524 g, 1 eq., 4.865 mmol) in acetic acid (70.5 mL) was added a solution of sodium nitrite (369.2 mg, 1.1 eq., 5.352 mmol) in water (2.4 mL) and the mixture was stirred for 1 h. After completion of the reaction, acetic acid was evaporated and the resulting residue was mixed in ice water (200 mL) and extracted with MTBE (3×30 mL). The combined organic phases were washed with water (2×10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.5 g, 3.9 mmol, 80%, 84% purity). LCMS: m / z 325.0 [M+H] + .

[0151] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 124. Where LCMS / GCMS data was not informative, the data is not shown.

[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 h, cooled to RT and filtered. The filtrate was concentrated under reduced pressure and treated with EtOAc (10 mL). The precipitate was filtered and dried under reduced pressure to give the title compound (0.044 g, 0.15 mmol, 58%, 100% purity), which was used in the next step without further purification. 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)pyridin-2-yl)oxy)-1H-indazole [ka] To a solution of 7-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole (0.1 g, 1 eq., 308 μmol) in THF (4 mL) cooled to 0° C. was added sodium hydride (14.8 mg, 60 wt%, 1.2 eq., 370 μmol). After stirring at 23° C. for 1 h, 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 h. Water (1 mL) was added and the resulting mixture was concentrated under reduced pressure. The crude material was dissolved in EtOAc (10 mL), washed with water and brine, and concentrated with MgSO 4 SAfter drying at rt, the solvent was removed under reduced pressure to give the title compound (0.129 g, 310 μmol, 100%, 81.2% purity), which was used in the next step without further purification. LCMS: m / 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), CsCO (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 h. The mixture was evaporated, and the residue was purified by normal phase chromatography to give 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 at RT and 1 atmosphere overnight. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give the crude title product, which was used in the next step without further purification. LCMS: m / z 284.2 [M+H] + .

[0157] The following intermediates were prepared following the procedure described for Intermediate 129 starting from the starting materials indicated in the table.

[0158] [Table 19] TIFF0007828367000084.tif231151 TIFF0007828367000085.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 CsCO (5.68 g, 17.3 mmol) in DMF (20 mL) was heated at 100 °C for 7 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (3 × 50 mL). The organic layers were combined and evaporated to give the crude title product. 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 following the procedure described for Intermediate 158 starting from the starting materials indicated in the table.

[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 h and at RT for 16 h. 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 give the title compound. LCMS: m / z 334.2 [M+H] + .

[0163] The following intermediates were prepared following the procedure described for Intermediate 163 starting from the starting materials indicated in the table.

[0164] [Table 21] TIFF0007828367000090.tif227151 TIFF0007828367000091.tif61151

[0165] Intermediate 182. 5-((5-chloropyridin-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 and stirred under an atmosphere of hydrogen for 12 hours, then filtered and the solvent evaporated to give the title compound (175 mg, 0.66 mmol, 94%, 95% purity), which was used in the next step without further purification. LCMS: m / z 251.0 [M+H] + .

[0166] Intermediate 183. 1,1-Diphenyl-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxol-4-yl)methanimine [ka] 4-Bromo-6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]dioxole (120 g, 1 eq., 3.32 mmol), diphenylmethanimine (663 mg, 1.1 eq., 3.66 mmol), sodium 2-methylpropan-2-olate (335 mg, 1.05 eq., 3.49 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (207 mg, 0.1 eq., 332 μmol) were dissolved in toluene (20 mL). Argon was bubbled through the solution for 1 min, and then diazetoxypalladium (37.3 mg, 0.05 eq., 166 μmol) was added. The mixture was stirred at 110 °C under an argon atmosphere for 12 h. The mixture was filtered, and the solid was washed with ethyl acetate (2 × 20 mL). The ethyl acetate solution was washed with brine (2 x 50 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound, which was used in the next step without further purification. LCMS: m / z 462.0 [M+H] + .

[0167] The following intermediates were prepared following the procedure described for Intermediate 183 starting from the starting materials indicated in the table.

[0168] [Table 22]

[0169] Intermediate 189. tert-Butyl (7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)carbamate [ka] To a mixture of 5-bromo-7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxine (1.410 g, 1 eq., 3.759 mmol), tert-butyl carbamate (660.5 mg, 1.5 eq., 5.638 mmol), and cesium carbonate (3.674 g, 3 eq., 11.28 mmol) in toluene (40 mL) was added Xantphos (326.2 mg, 0.15 eq., 563.8 μmol) and tris(dibenzylideneacetone)dipalladium (172.1 mg, 0.05 eq., 187.9 μmol) under argon, and the mixture was heated at 110 °C for 18 h. After cooling to RT, the mixture was filtered and concentrated. The residue was diluted with ethyl acetate (10 mL) and washed with brine (2 × 50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from acetonitrile to give the title compound. LCMS: m / z 412.2 [M+H] + .

[0170] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 189. Where LCMS / GCMS data was not informative, the data is not shown.

[0171] [Table 23] TIFF0007828367000097.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 min, 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, and the solution was stirred at RT for 48 h. The mixture was concentrated in vacuo to give 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 following the procedure described for intermediate 202 starting from the starting materials indicated in the table.

[0174] [Table 24] TIFF0007828367000100.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)methanimine (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 at RT. The mixture was stirred at RT for 10 min and then evaporated in vacuo to give the title compound (640 mg, 1.1 mmol, 62%, 50% purity), which was used in the next step without further purification. LCMS: m / z 298.0 [M+H] + .

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

[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 h and then concentrated under reduced pressure to give the title compound (0.150 g, 0.32 mmol, 76%, 80% purity), which was used in the next step without further purification. 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) in one portion. The mixture was stirred at 27 °C for 18 h. The mixture was concentrated in vacuo, the residue was treated with water (5 mL), and the resulting suspension was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (2 × 15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 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 h. The mixture was concentrated, and the residue was concentrated three times with acetonitrile to give the title compound (77 mg, 0.43 mmol, 77%, 95% purity), which was used in the next step without further purification. 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) was added phosphorus(V) sulfide (262 mg, 0.5 eq., 1.18 mmol). 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 phase was dried and concentrated in vacuo to give the title compound (500 mg, 1.8 mmol, 76%, 77% purity), which was used in the next step without further purification. GCMS: m / z 216.1 [M] + .

[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 h. The solvent was then evaporated, and the residue was dissolved in toluene (5 mL) and concentrated to remove excess TFA, yielding 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 min. 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 h. The solvent was removed in vacuo. The crude material 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 give 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 following the procedure described for Intermediate 223 starting from the starting materials indicated in the table.

[0185] [Table 26]

[0186] Intermediate 226. tert-Butyl(3-fluorophenyl)(4-methoxy-3-(5-oxopyrrolidine-2-carboxamido)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) was added N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (243 mg, 1.5 eq., 866 μmol). The mixture was stirred at RT for 18 h and then concentrated in vacuo. 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 give 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) was added chloro(methoxy)methane (1.309 g, 1.24 mL, 95 wt%, 1.5 eq., 15.45 mmol) at 0° C., followed by stirring the mixture for 18 h at 20° C. The mixture was washed with brine (3×10 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound (2.3 g, 8.834 mmol, 85.78%, 90.75% purity), which was used in the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ: 7.29 (s, 1H), 7.13 (s, 1H), 5.23 (s, 2H), 4.63 (t, 2H), 3.87 (s, 3H), 3.49 (s, 3H), 3.20 (t, 2H).

[0188] Intermediate 227b. (4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-yl)methanol [ka] A solution of LiAlH (127 mg, 2 eq., 3.36 mmol) in THF (5 mL) was cooled to 0 °C, and a solution of methyl 4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-carboxylate (400 mg, 1 eq., 1.68 mmol) in THF (5 mL) was added dropwise. The cooling bath was removed, and the mixture was stirred at 20 °C for 18 h. The mixture was cooled to 0 °C, and water (130 μL) and a 30% solution of KCO (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 give the crude title compound (340 mg, 1.48 mmol, 88.0%, 91.31% purity) as a yellow oil, which was used in the next step without further purification. 1 H 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) was added tributylphosphane (385 mg, 0.48 mL, 2 eq., 1.90 mmol) followed by (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (480 mg, 2 eq., 1.90 mmol) under an Ar atmosphere at 0° C. 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 give the title compound (178 mg, 552 μmol, 58.1%). 1 H 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 min, 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 h. The mixture was concentrated under reduced pressure to give 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-yl trifluoromethanesulfonate [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) was added trifluoromethanesulfonic anhydride (mg, μL, eq., mmol) dropwise at 0° C., and the mixture was subsequently stirred at 20° C. for 18 h. DCM (10 mL) was added to the mixture, and the solution was washed with NaHSO solution (2 × 5 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound (mg, mmol, %, % purity) as a brown oil, which was used in the next step without further purification. 1 H 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 h and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and washed with EtOAc (2×2 mL). The aqueous mixture was acidified with NaHSO4 (5 mL, 15% in water). The resulting mixture was extracted with EtOAc (2×8 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.08 g, 0.26 mmol, 42%). LCMS: m / z 311.0 [M−H] - .

[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), diazetoxycopper (0.54 g, 1 eq., 2.96 mmol), and powdered molecular sieves 4 Å (1 g) were suspended in DCM (15 mL). Air was bubbled through the resulting solution for 30 min, and the mixture was stirred at RT overnight. The mixture was filtered, and 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 give the title compound. LCMS: m / z 314.2 [M+H] + .

[0194] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for intermediate 229. Where LCMS / GCMS data was not informative, the data is not shown.

[0195] [Table 27]

[0196] Intermediate 240. 1-Methoxy-2-nitro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzene [ka] To a mixture of 4-methoxy-3-nitrophenol (0.25 g, 1.47 mmol), 4-trifluoromethyl-1-hydroxycyclohexane (0.20 mL, 1.47 mmol), and triphenylphosphine (465 mg, 1.77 mmol) in THF (10 mL) under nitrogen, DEAD (0.28 mL, 1.77 mmol) was added dropwise at RT, and the mixture was allowed to stir for 24 h. The mixture was diluted with EtO (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 give 0.1 g of the title compound. LCMS: m / z 320.28 [M+H] +

[0197] The following intermediates were prepared following the procedure described for Intermediate 240 starting from the starting materials indicated in the table.

[0198] [Table 28] TIFF0007828367000121.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) at RT under N2. The resulting mixture was heated at 150 °C for 2 h. The mixture was cooled and purified by flash chromatography to give diethyl (3-fluorobenzyl)phosphonate. To a mixture of diethyl (3-fluorobenzyl)phosphonate (0.82 g, 3.3 mmol) in dry THF (10 mL) at 0–5 °C, NaH (0.27 mg, 11.0 mmol) was added. After 30 min, 4-methoxy-3-nitrobenzaldehyde (0.5 g, 2.8 mmol) in dry THF (10 mL) was added dropwise to the mixture, followed by stirring at RT for 3 h. The mixture was cooled, quenched with ice-water (20 mL), acidified with 2 M HCl, and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers are washed with water, dried, evaporated and then purified by flash chromatography to give the title compound: LCMS m / z 274.2 [M+H] + . 1 H 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 min. To the resulting crude product of (E)-4-methyl-N'-(3-(trifluoromethyl)benzylidene)benzenesulfonohydrazide (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 at 110 °C under a nitrogen atmosphere for 4 h and then cooled 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 give the title compound: LCMS m / z 312.3 [M+H] + . 1 H 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 starting from 4-(trifluoromethyl)benzaldehyde using the procedure described for intermediate 234. LCMS m / z 312.3 [M+H] + . 1 H 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), 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 h. The mixture was filtered through Celite. The filtrate was washed with water (2 x 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give the title compound. LCMS m / z 284.1 [M] +

[0203] The following intermediates were prepared following the procedure described for Intermediate 251 starting from the starting materials indicated in the table.

[0204] [Table 29] TIFF0007828367000127.tif218151 TIFF0007828367000128.tif223151 TIFF0007828367000129.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 pad of Celite. The Celite layer was washed with more ethanol, and the filtrate was evaporated to give 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 following the procedure for Intermediate 257, starting with 4-(4-isopropoxyphenoxy)-1-methoxy-2-nitrobenzene (0.22 g, 0.725 mmol), using 4 eq. of zinc powder and 4 eq. of NH4Cl. The crude product was purified by reversed-phase flash chromatography to give 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 CaCl (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 pad of Celite. The Celite layer was washed with EtOAc. The filtrate was washed with water (2x), dried, and evaporated to give 0.090 g of the title compound. LCMS: m / z 299.7 [M]+

[0208] The following intermediates were prepared following the procedure described for Intermediate 292 starting from the starting materials indicated in the table.

[0209] [Table 30]

[0210] Intermediate 297. 2-Amino-4-(4-(trifluoromethyl)phenoxy)benzamide [ka] This compound was prepared following the procedure for Intermediate 292, starting from 2-nitro-4-(4-(trifluoromethyl)phenoxy)benzonitrile (0.36 g, 1.168 mmol). The crude product was purified by flash chromatography to give 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 at RT until the reaction was complete. The mixture was filtered through a pad of Celite. The Celite layer was washed with EtOAc. The filtrate was washed with water (2x), dried, and evaporated. The crude product was purified by flash chromatography to give 0.15 g of the title compound. LCMS: m / z 235.4 [M] +

[0212] The following intermediates were prepared following the procedure described for Intermediate 298 starting from the starting materials indicated in the table.

[0213] [Table 31]

[0214] Intermediate 306. 5-(Bromophenoxy)-2-methoxyaniline [ka] This compound was prepared following the procedure described for intermediate 298, starting from 4-(3-bromophenoxy)-1-methoxy-2-nitrobenzene (0.46 g, 1.419 mmol) and using 7.5 eq. zinc powder and 7.5 eq. NH4Cl. Yield: 0.34 g. LCMS: m / z 294.2 [M] + .

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

[0216] [Table 32]

[0217] Intermediate 312. 5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyaniline [ka] This compound was prepared following the procedure for Intermediate 298, starting with 3-fluoro-2-(4-methoxy-3-nitrophenoxy)-5-(trifluoromethyl)pyridine (0.50 g, 1.505 mmol), using 10 eq. zinc powder and 10 eq. NH4Cl. LCMS: m / z 303.5 [M+H] + .

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

[0219] [Table 33]

[0220] Intermediate 315. 3-Amino-5-(4-(trifluoromethyl)phenoxy)benzonitrile [ka] To a mixture of 3-nitro-5-(4-(trifluoromethyl)phenoxy)benzonitrile (0.22 g, 0.714 mmol) in 1,4-dioxane (3.5 mL) was added tin(II) chloride dihydrate (0.805 g, 3.57 mmol) dissolved in 37% aqueous HCl (1.0 mL). The mixture was stirred at 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 give the title compound. Yield: 0.14 g. LCMS: m / z 279.3 [M+H] + .

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

[0222] [Table 34]

[0223] Intermediate 319. 1-Methoxy-2-nitro-4-(3-(trifluoromethoxy)phenoxy)benzene [ka] To 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) (0.182 g, 1.00 mmol), and powdered 4 Å molecular sieves (0.25 g) in dry DCM (7.5 mL) was added DIPEA (0.871 mL, 5.00 mmol). The mixture was stirred at RT until maximum conversion was achieved (48 h). The mixture was filtered through a plug of Celite, and the Celite layer was washed with EtOAc. The filtrate was washed with 5% aqueous NHOH, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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] 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) (0.363 g, 2.00 mmol), and powdered 4 Å molecular sieves (0.25 g) in dry DCM (15 mL) was added pyridine (0.809 mL, 10.0 mmol). The mixture was stirred at RT until maximum conversion was achieved (24–48 h). The mixture was filtered through a plug of Celite, and the Celite layer was washed with DCM. The filtrate was washed with 5% aqueous NH4OH, dried, and evaporated. The crude product was purified by flash chromatography to give 0.33 g of the title compound. LCMS: m / z 330.2 [M+H] + .

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

[0226] [Table 35] TIFF0007828367000146.tif53151

[0227] Intermediate 333. 4-(Cyclohexylmethoxy)-1-methoxy-2-nitrobenzene [ka] 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) was added diisopropyl azodicarboxylate (0.738 mL, 3.75 mmol). The mixture was stirred at RT overnight. 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 give 0.26 g of the title compound. LCMS: m / z 266.2 [M+H] +

[0228] The following intermediates were prepared following the procedure described for Intermediate 333 starting from the starting materials indicated in the table.

[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 EtOAc. The organic phase was washed with water, dried, and evaporated to give 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. Diethylaminosulfur trifluoride (0.521 mL, 3.95 mmol) was added in small portions and the mixture was stirred at RT for 24 h. The mixture was diluted with DCM and saturated NaHCO3 solution was added in small portions. 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 give 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] To a mixture of 3,4-difluorothiophenol (0.155 mL, 1.40 mmol), 4-methoxy-3-nitrophenylboronic acid (0.197 g, 1.00 mmol), copper(II) sulfate (8.0 mg, 0.05 mmol), and 1,10-phenanthroline (9.0 mg, 0.05 mmol) in ethanol (1.0 mL) (bubbled with oxygen before use), 40% aqueous tetrabutylammonium hydroxide (1.0 mL, 3.82 mmol) was added. The mixture was stirred at RT overnight. The mixture was then diluted with EtOAc and filtered through a pad of Celite. The Celite layer was washed with additional EtOAc. The filtrate was evaporated, and the crude product was purified by flash chromatography to give 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, followed by stirring at RT for 1 h. The formed precipitate was filtered, washed with water, and dried under reduced pressure to give 0.62 g of the title compound. LCMS: m / z 348.1 [M+H] + .

[0234] b) 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline [ka] To a mixture of 2-chloro-1-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)benzene (0.66 g, 1.898 mmol) and ammonium formate (1.197 g, 18.98 mmol) in dry methanol (35 mL) was added 10 wt% palladium on 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 plug of Celite, and the Celite layer was washed with methanol. The filtrate was evaporated, and the residue was dissolved in EtOAc. The organic phase was washed with water, dried, and evaporated to give 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 and the precipitate formed was filtered and dried to give the title compound. Yield: 1.06 g. LCMS: m / z 304.5 [M+H] + If the product did not precipitate from the water, it was extracted with EtOAc. The organic phase was washed with water, dried, and evaporated to give the title compound, which was used as is or purified by flash chromatography.

[0236] The following intermediates were prepared following the procedure described for Intermediate 339 starting from the starting materials indicated in the table.

[0237] [Table 37] TIFF0007828367000156.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 EtOAc. The organic phase was dried and evaporated. The crude product was purified by flash chromatography to give 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 EtOAc. The organic phase was dried and evaporated. The crude product was purified by flash chromatography to give 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) was added NaBH4 (0.204 g, 5.38 mmol) in small portions and stirred at RT until the reaction was complete. The solvent was evaporated and the residue was treated with water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and evaporated to give 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) was added diethylaminosulfur trifluoride (DAST) (0.25 mL, 1.892 mmol). The cooling bath was removed, and the mixture was allowed to warm to RT and stirred until the reaction was complete. The mixture was diluted with DCM (15 mL) and cooled to 0-5 °C. 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 give 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)pyridin-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 h. 2-Chloro-5-(trifluoromethyl)pyridine (0.272 g, 1.50 mmol) and K2CO3 (0.104 g, 0.75 mmol) were added, and stirring was continued at 120 °C until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc. The organic phase was washed with 1 M NaOH and water, dried, and evaporated. The crude product was purified by filtration through a short plug of silica gel eluted with EtOAc-heptane (4:1). The filtrate was evaporated, and the residue was dried under vacuum to give 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] To a mixture of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (g, mmol), (2S,4R)-1-((benzyloxy)-carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (g, mmol) in EtOAc (0.40 mL) and pyridine (0.20 mL) was added 1-propanephosphonic acid ring anhydride, 50% by weight in EtOAc (mL, mmol). The mixture was stirred at RT overnight. The reaction was quenched with 0.5% HCl solution and diluted with water and EtOAc. The phases were separated and the organic phase was washed with 0.5% HCl solution, water and brine, dried and evaporated to give the title compound. Yield: 0.111 g. LC-MS: m / z= 531.3 [M+H] + The crude product was used as is or purified by reverse phase flash chromatography to give the pure compound.

[0244] The following intermediates were prepared starting from the starting materials indicated in the table following the procedure described for Intermediate 352. Where LCMS / GCMS data was not informative, the data is not shown.

[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) was added 60 wt% NaH in oil (0.10 g, 2.50 mmol), followed by stirring at 0-5°C for 30 min. 2-Methoxyacetyl chloride (0.26 g, 2.40 mmol) dissolved in THF (2.5 mL) was added and stirring was continued at RT overnight. 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 give the title compound. Yield: 0.51 g. LCMS: m / z 258.0 [M+H] + The crude product was either used as is or purified by reverse phase flash chromatography to give the pure compound.

[0247] The following intermediates were prepared following the procedure described for Intermediate 357 starting from the starting materials indicated in the table.

[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 dry DCM (10 mL) was added 2-methoxyacetyl chloride (0.239 g, 2.20 mmol). The mixture was stirred at RT overnight. The mixture was filtered, and the filtrate was washed with saturated NH4Cl solution, saturated NaHCO3 solution, and brine, dried, and evaporated to give 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 give 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] To a mixture of tert-butyl (S)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylate (0.77 g, 2.99 mmol) in dry DCM (15 mL) was added trifluoroacetic acid (2.5 mL, 32.4 mmol, 10.8 eq.), followed by stirring at RT overnight. The mixture was stirred at RT overnight. The solvent was evaporated, and the residue was treated with toluene and evaporated again. This procedure was repeated, and the residue was dried under vacuum to give the title compound. The crude product was either (a) used directly in the next step, or (b) basified with saturated Na2CO3 solution and then extracted with DCM, followed by drying and evaporation of the organic phase. LCMS: m / z 201.9 [M+H] +

[0252] The following intermediates were prepared following the procedure described for Intermediate 364 starting from the starting materials indicated in the table.

[0253] [Table 40] TIFF0007828367000170.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), KPO (0.313 g, 2.0 mmol), and SPhos Pd G (0.040 g, 0.075 mmol) in dioxane (1 mL) and water (1 mL) was heated at 85 °C for 8 h under a nitrogen atmosphere. The mixture was extracted with ethyl acetate (2 × 4 mL). The combined organic layers were evaporated and then purified by normal phase chromatography to give the title compound (0.144 g, mp 100°C). 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 following the procedure described for Intermediate 371 starting from the starting materials indicated in the table.

[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 CHCl (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 min, DMAP (29.2 mg, 0.239 mmol, 0.1 eq.) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was further diluted with CHCl (20 mL) and washed with saturated NaHCO solution (10 mL), 0.1 M HCl solution (10 mL), and brine (10 mL), then dried (NaSO), filtered, and evaporated in vacuo to give the crude product. The crude residue was further purified using reverse-phase chromatography to give 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 5-oxo-2-pyrrolidinecarboxylic acid tert-butyl ester (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 min, 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 h. The mixture was diluted with ethyl acetate (20 mL), washed with NH 4 Cl (10 mL), brine (10 mL), then dried (Na 2 SO 4 ), filtered, and the solvent evaporated in vacuo to give the crude product. The crude residue was further purified using reverse-phase chromatography to give 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 h. The DCM and trifluoroacetic acid residues were removed in vacuo to give the crude product. The crude residue was further purified using reverse phase chromatography to give 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) was added 5-oxopyrrolidine-2-carboxylic acid (98.0 mg, 1 eq., 759 μmol) and 1-methyl-1H-imidazole (312 mg, 5 eq., 3.80 mmol). The mixture was stirred at RT for 10 min, and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (319 mg, 1.5 eq., 1.14 mmol) was added in one portion. The resulting solution was stirred at RT overnight, and the mixture was directly purified by Method A to give 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 following the procedure described for compound 1. Compound codes, structures, starting materials, purification methods and characterization data are shown in the table.

[0262] [Table 42] TIFF0007828367000178.tif228151 TIFF0007828367000179.tif230151 TIFF0007828367000180.tif196151 TIFF0007828367000181.tif240151 TIFF0007828367000182.tif248150 TIFF0007828367000183.tif200151 TIFF0007828367000184.tif242151 TIFF0007828367000185.tif184151 TIFF0007828367000186.tif241151 TIFF0007828367000187.tif225151 TIFF0007828367000188.tif181151 TIFF0007828367000189.tif227151 TIFF0007828367000190.tif232151 TIFF0007828367000191.tif229151 TIFF0007828367000192.tif224151 TIFF0007828367000193.tif175151 TIFF0007828367000194.tif235151 TIFF0007828367000195.tif222151 TIFF0007828367000196.tif212151 TIFF0007828367000197.tif221151 TIFF0007828367000198.tif243151 TIFF0007828367000199.tif184151 TIFF0007828367000200.tif226151 TIFF0007828367000201.tif224151 TIFF0007828367000202.tif241150 TIFF0007828367000203.tif223151 TIFF0007828367000204.tif225151 TIFF0007828367000205.tif175151 TIFF0007828367000206.tif241151 TIFF0007828367000207.tif221151 TIFF0007828367000208.tif228151 TIFF0007828367000209.tif213151 TIFF0007828367000210.tif189151 TIFF0007828367000211.tif248151 TIFF0007828367000212.tif197151 TIFF0007828367000213.tif209151 TIFF0007828367000214.tif225151 TIFF0007828367000215.tif223151 TIFF0007828367000216.tif189151 TIFF0007828367000217.tif250147 TIFF0007828367000218.tif190151 TIFF0007828367000219.tif227151 TIFF0007828367000220.tif232151 TIFF0007828367000221.tif226151 TIFF0007828367000222.tif180151 TIFF0007828367000223.tif239151 TIFF0007828367000224.tif196151 TIFF0007828367000225.tif232151 TIFF0007828367000226.tif234151 TIFF0007828367000227.tif234151 TIFF0007828367000228.tif174151 TIFF0007828367000229.tif232151 TIFF0007828367000230.tif222151 TIFF0007828367000231.tif223151 TIFF0007828367000232.tif220151 TIFF0007828367000233.tif224151 TIFF0007828367000234.tif221151 TIFF0007828367000235.tif216151 TIFF0007828367000236.tif224151 TIFF0007828367000237.tif235151 TIFF0007828367000238.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) was added 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). HATU (321 mg, 2 eq., 844 μmol) was then added, and the mixture was stirred overnight at RT. N-(chloro(dimethylamino)methylene)-N-methylmethanaminium 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 in vacuo, diluted with EtOAc (10 mL), washed with NaHSO (2 mL, 10%), KCO (2 mL, 10%), and water (2 mL), and dried over NaSO. EtOAc was evaporated. The residue was purified by HPLC (2–10 min, 0–55% MeCN, flow rate: 30 mL / min) to give the title compound (0.0242 g, 58.4 μmol, 13.8%, 100% pure). 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 compounds were prepared following the procedure described for compound 224. Compound codes, structures, starting materials, purification methods and characterization 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) followed by stirring for 10 min. 1-Methyl-1H-imidazole (0.1 g, 99 μL, 5 eq., 1.2 mmol) was then added followed by stirring for 10 min. N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (76 mg, 1.1 eq., 0.27 mmol) was then added in one portion followed by stirring for 10 h at 20 °C. The mixture was filtered and the filtrate was purified by HPLC (Method A) to give the title compound (0.0314 g, 74.2 μmol, 30%, 100% pure). 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 following the procedure described for compound 226. Compound codes, structures, starting materials, purification methods and characterization 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 stirred at 22 °C for 10 min. N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (198 mg, 2 eq., 706 μmol) was then added. The mixture was stirred at 22 °C for 16 h. 4-Acetoxy-1-methyl-5-oxopyrrolidine-3-carboxylic acid (92.3 mg, 1.3 eq., 459 μmol) and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (198 mg, 2 eq., 706 μmol) were added to the mixture, followed by stirring at 22° C. for 16 hours. The mixture was concentrated and a methanolic solution of ammonia (60.1 mg, 10 eq., 3.53 mmol) was added. The reaction mass was stirred at 22° C. for 16 hours. The solution was purified by reverse-phase HPLC (purification method A) to give 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) was added 5-oxopyrrolidine-2-carboxylic acid (15 mg, 1 eq., 0.12 mmol) and diisopropylethylamine (46 mg, 62 μL, 3 eq., 0.36 mmol). The mixture was stirred at RT for 15 min, and HATU (68 mg, 1.5 eq., 0.18 mmol) was added in one portion. The resulting solution was stirred at RT for 10 h. The mixture was concentrated in vacuo, diluted with ethyl acetate (10 mL), washed with NaHSO (2 mL, 10%), KCO (2 mL, 10%), and water (2 mL), and dried over NaSO. The ethyl acetate was evaporated and the residue purified by Method A to give the title compound (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 following the procedure described for compound 229. Compound codes, structures, starting materials, purification methods and characterization 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] To a mixture of 5-bromo-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxine (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) under argon, Pd(dba) (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) were added, and the mixture was heated at 110 °C for 18 h. After cooling to RT, the mixture was concentrated and the residue was purified by Method A to give the title compound (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 compounds were prepared following the procedure described for compound 233. Compound codes, structures, starting materials, purification methods and characterization data are shown in the table.

[0275] [Table 46] TIFF0007828367000248.tif233151 TIFF0007828367000249.tif172151 TIFF0007828367000250.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 min. To the resulting solution, tert-butyl (3-fluorophenyl) (4-methoxy-3-(5-oxopyrrolidine-2-carboxamido)benzyl)carbamate (300 mg, 58.89%, 1 eq., 386 μmol) was added, and the mixture was stirred at RT for 18 h. The mixture was treated with aqueous NaHCO (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (2 × 15 mL), dried over sodium sulfate, filtered, and concentrated, and the residue was purified by reverse-phase HPLC (water-acetonitrile) to give 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 min. 4,4-Difluorocyclohexan-1-ol (48.1 mg, 1.4 eq., 353 μmol) was added to the mixture at RT and stirred for 58 h. The mixture was purified by column chromatography to give 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 under argon for 12 h. The N,N-dimethylformamide was then evaporated, and the residue was diluted with EtOAc (10 mL), washed with water (2×2 mL), dried over Na SO , and concentrated in vacuo. A sample of the reaction mixture was analyzed by LCMS. The residue was purified by Method A to give the title compound (0.0035 g). 1 H 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 following the procedure described for compound 248. Compound codes, structures, starting materials, purification methods and characterization 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 at RT. The mixture was stirred at RT for 24 h. 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 phases were washed with brine (2 × 30 mL), dried over sodium sulfate, filtered, concentrated, and the residue was purified by purification method A to give the title compound (0.0079 g). 1 H 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) was added DIPEA (0.34 mL, 2.0 mmol). The mixture was stirred at RT overnight. The reaction mixture was quenched with water (10 mL) and subsequently extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, dried, evaporated, and then purified by reverse-phase chromatography to give 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 following the procedure described for compound 253. Compound codes, structures, starting materials, purification methods and characterization data are shown in the table.

[0284] [Table 48] TIFF0007828367000258.tif205151 TIFF0007828367000259.tif220151 TIFF0007828367000260.tif196151 TIFF0007828367000261.tif217151 TIFF0007828367000262.tif226151 TIFF0007828367000263.tif222151 TIFF0007828367000264.tif230151 TIFF0007828367000265.tif240151 TIFF0007828367000266.tif71151

[0285] Example 12 (R)—N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 290) [ka] To 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 added DIPEA (0.174 mL, 1.00 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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 following the procedure described for compound 290. Compound codes, structures, starting materials, purification methods and characterization data are shown in the table.

[0287] [Table 49] TIFF0007828367000269.tif172151 TIFF0007828367000270.tif217151 TIFF0007828367000271.tif216151 TIFF0007828367000272.tif208151 TIFF0007828367000273.tif216151 TIFF0007828367000274.tif219151 TIFF0007828367000275.tif229151 TIFF0007828367000276.tif246151 TIFF0007828367000277.tif128151

[0288] Example 13. N-(2-fluoro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 328) [ka] To 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 added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.081 g, 0.288 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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 compounds were prepared following the procedure described for compound 328. Compound codes, structures, starting materials, purification methods and characterization data are shown in the table.

[0290] [Table 50]

[0291] Example 14. N-(2-Methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (Compound 331) [ka] To a mixture of 2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)aniline (0.071 g, 0.25 mmol), 1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylic acid (0.053 g, 0.25 mmol) in EtOAc (0.30 mL) and pyridine (0.15 mL) was added 1-propanephosphonic acid ring anhydride, 50 wt% in EtOAc (0.25 mL, 0.424 mmol). The mixture was stirred at RT overnight. The reaction was quenched with 0.5% HCl solution and diluted with water and EtOAc. The phases were separated and the organic phase was washed with 0.5% HCl solution, water and brine, dried and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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 compounds were prepared following the procedure described for compound 331. Compound codes, structures, starting materials, purification methods and characterization data are shown in the table.

[0293] [Table 51] TIFF0007828367000282.tif229151 TIFF0007828367000283.tif230151 TIFF0007828367000284.tif233151 TIFF0007828367000285.tif217151 TIFF0007828367000286.tif216151 TIFF0007828367000287.tif222151 TIFF0007828367000288.tif232151 TIFF0007828367000289.tif232151 TIFF0007828367000290.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) was added 1-chloro-N,N,2-trimethyl-1-propenylamine (0.065 mL, 0.488 mmol), and the mixture was stirred at 0-5 °C for 1 h. 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 then added, and the mixture was stirred at RT overnight. The DCM was evaporated, and the mixture was diluted with EtOAc. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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 according to the procedure of the previous example, 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). 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)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 368) [ka] This compound was prepared using the procedure of Intermediate 306 starting from 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 KCO (0.058 g, 0.42 mmol) in dry DMF (1.0 mL). The crude product was purified by reverse-phase flash chromatography to give 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)pyridin-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 KCO (0.058 g, 0.42 mmol) in dry DMF (1.0 mL). The crude product was purified by reverse-phase flash chromatography to give 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 wt% on carbon, 0.045 g, 0.042 mmol) in methanol (15 mL) was added 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). The mixture was stirred vigorously while ammonium formate (0.132 mg, 2.09 mmol) was added. 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 EtOAc. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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 cooled (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 dry DCM (2.0 mL) was added acetyl chloride (0.018 mL, 0.248 mmol) and triethylamine (0.039 mL, 0.281 mmol) dissolved in dry DCM (0.25 mL), and the mixture was stirred at RT overnight. Further acetyl chloride (0.018 mL, 0.248 mmol) and triethylamine (0.039 mL, 0.281 mmol) were 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 give 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) was added tetrabutylammonium iodide (90 mg, 245 μmol) at RT. The solution was cooled to −50° C. Then, 1.469 mL (1469 μmol) of BCl3 1M in heptane was added dropwise. The mixture was stirred at −78° C. for 10 min and then at RT for 1 h 20 min. 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 phases were concentrated under reduced pressure. The crude product was purified by column chromatography to give 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 compounds were prepared following the procedure described for compound 372. Compound codes, structures, starting materials, purification methods and characterization 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] tert-Butyl 3-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-4-methyl-5-oxopiperazine-1-carboxylate (30.6 mg, 58.5 μmol) was dissolved in HCl (dioxane) (2.13 g, 1.43 mL, 10 wt%, 5.85 mmol) and stirred at RT overnight. The mixture was purified by HPLC (Method D) to give 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 compounds were prepared following the procedure described for compound 374. Compound codes, structures, starting materials, purification methods and characterization 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-Butyl 4-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 h and then concentrated under reduced pressure. The resulting mixture was subjected to HPLC (purification method D) to give 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-pyrazol-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-pyrazol-4-yl)-5-oxopyrrolidine-2-carboxamide (0.0341 g, 1 eq., 58.7 μmol), and the mixture was then refluxed for 16 h. The solvent was then evaporated, and the residue was purified by HPLC (Method G) to give the title compound (0.0057 g, 12 μmol, 21%, 100% purity). 1H 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 [M−H] - .

[0308] The following compounds were prepared following the procedure described for compound 377. Compound codes, structures, starting materials, purification methods and characterization 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) was added potassium carbonate (97.6 mg, 2 eq., 706 μmol), followed by hydrogen peroxide (343 mg, 309 μL, 35 wt%, 10 eq., 3.53 mmol). The mixture was stirred at 40° C. for 36 h. 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 give the title compound (13.4 mg, 28.8 μmol, 8.15%, 100% pure). 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). TBAF (89.8 mg, 343 μL, 1 mol, 1 eq., 343 μmol) was then added dropwise to the mixture at 0° C. The resulting mixture was stirred for 20 min, slowly heated to 20° C., stirred at this temperature for 10 h, and purified by HPLC (purification method A) to give 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 carbamic acid ammonium salt (183 mg, 4 eq., 2.34 mmol) in methanol (12 mL) was stirred at 22 °C for 12 h. The mixture was concentrated to provide a mixture of a light yellow sludge and an immiscible colorless liquid. The mixture was washed twice with hexane (2 × 10 mL) by decantation and dried under vacuum. The residue was triturated, stirred in ethyl acetate, filtered, and the collected solid was washed with additional ethyl acetate. The filtrate was concentrated to give a mixture of cis and trans isomers, which was purified by HPLC (purification method A) to give 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 h, 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 at RT for 3 h and filtered. The clear filtrate was purified by HPLC (purification method B) to give the title compound (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) was added NaCNBH (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). HOAc (0.01 mL) was then added, and the mixture was stirred at 25 °C for 12 h 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 h, filtered and the clear solution was purified by HPLC (purification method A) to give the title compound (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 give 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) was added a solution of sodium nitrite (12 mg, 1.2 eq., 0.18 mmol) in water (0.1 mL) at 0 ° C. The resulting mixture was stirred at the same temperature for 15 min, and then the mixture was 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 h. The mixture was concentrated under reduced pressure and purified by HPLC (purification method A) to give 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)ethan-1-one [ka] 4-Acetylphenylboronic acid (g, mmol), 4-methoxy-3-nitrophenol (0.28 g, 1.66 mmol), Cu(OAc) (0.451 mg, 2.48 mmol), and freshly activated powdered 4 Å molecular sieves were added to dry DCM (20 mL). EtN (1.15 mL, 8.28 mmol) was then added to the mixture. The mixture was stirred under air atmosphere. The reaction progress was monitored by LCMS. After 24 h, the resulting slurry was filtered through Celite and concentrated. The crude product was purified by flash chromatography (heptane: EtOAc) to give 0.3 g of the title compound. LCMS: m / z 288.21 [M+H] + .

[0318] b) 1-(4-(3-amino-4-methoxyphenoxy)phenyl)ethan-1-one [ka] A mixture of 1-(4-(4-methoxy-3-nitrophenoxy)phenyl)ethan-1-one (300 mg, 1.04 mmol), zinc (0.68 g, 10 eq., 10.44 mmol), 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 h. 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 give 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)ethan-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 at RT overnight. 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 water, dried over sodium sulfate, evaporated, and then purified by reverse-phase chromatography to give 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 min. To the crude (E)-N'-(2-methoxy-5-nitrobenzylidene)-4-methylbenzenesulfonohydrazide was added K2CO3 (0.53 g, 2.8 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.49 g, 2.6 mmol). The mixture was heated at 110 °C under a nitrogen atmosphere for 4 h. 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 give 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), 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 h. 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 give 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 at RT overnight. 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 water, dried over sodium sulfate, evaporated, and then purified by reverse-phase chromatography to give 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-dihydrooxazole-4-carboxamide (Compound 388) [ka] TMA (2 M in chlorobenzene, 397 μL, 0.794 mmol) 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-dihydrooxazole-4-carboxylate (0.064 g, 0.397 mmol) in toluene (2 mL), and the mixture was then heated at 90° C. for 3 h. The reaction mixture was quenched with ice-cold water. The aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were evaporated and then purified by reverse-phase chromatography to give 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] To a solution of 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 EtOAc, 80 μL, 0.14 mmol), and DCM (2 mL) was added DIPEA (47 μL, 0.27 mmol). After refluxing for 3 h, additional starting materials and reagents were added (1.15 eq. of 1-methyl-5-oxopyrrolidine-2-carboxylic acid, 1.5 eq. of T3P, 3.0 eq. of DIPEA), followed by stirring in a closed vessel at 80 °C for 7 h. The reaction mixture was quenched with 2 N NaOH (2 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1 × 4 mL). The combined organic layers were evaporated and then purified by reverse phase chromatography to give 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 compounds were prepared following the procedure described for compound 389. Compound codes, structures, starting materials, purification methods and characterization data are shown in the table.

[0326] [Table 55] TIFF0007828367000320.tif223151 TIFF0007828367000321.tif223151 TIFF0007828367000322.tif207151 TIFF0007828367000323.tif224151 TIFF0007828367000324.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 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) at −50° C., followed by stirring at RT for 50 min. The reaction mixture was quenched with 1 N HCl (5 mL). The organic layer was separated and evaporated. The residue was purified by reverse-phase chromatography to give 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% in 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 min. 2-(methylsulfonyl)ethanol was then added, and the mixture was heated at 50° C. for 2.5 h. Additional NaH (60% in oil, 5 eq.) and 2-(methylsulfonyl)ethanol were then added twice, and the mixture was heated at 80° C. for 4 h and at 100° C. for 5.5 h, respectively. The reaction mixture was quenched with 2 N HCl (2 mL) and extracted with EtOAc (3×3 mL). The organic layer was separated and evaporated. The residue was purified by reverse phase chromatography to give 0.012 g of the title compound. 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 EtN (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 allowed to warm gradually to RT. After completion of the reaction, the mixture was diluted with EtOAc (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 give 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 compounds were prepared following the procedure described for compound 412. Compound codes, structures, starting materials, purification methods and characterization 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-oxopyrrolidin-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 a H2 / N2 / vacuum line, the air was replaced with nitrogen, and the mixture was stirred under hydrogen for 2.5 h. The mixture was filtered through a pad of Celite® and washed with a 1:1 mixture of acetonitrile / HO. The product was frozen at -78 °C, and the solvent was removed by lyophilization to give 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 following the procedure described for intermediate 364 starting from tert-butyl (S)-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-5-oxopyrrolidine-1-carboxylate. The crude final product was treated with a saturated solution of Na2CO3 and then extracted with DCM. The organic phase was dried and evaporated to give 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)pyridin-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (Compound 416) [ka] This compound was prepared according to the procedure described for intermediate 364, starting from tert-butyl (2S)-2-((5-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)carbamoyl)-114-pyrrolidine-1-carboxylate. The crude final product was treated with a saturated solution of Na2CO3 and then extracted with DCM. The organic phase was dried and evaporated to give 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) was added sodium hydride, 60 wt% in oil (0.025 g, 0.625 mmol), followed by stirring at 0-5°C for 15 min. 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 EtOAc. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give the title compound. Yield: 0.152 g. 1H NMR (400 MHz, CDCl3), mixture of rotamers. Chemical shifts of the major rotamer: 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 - Diethyl azodicarboxylate DIPEA - N,N-Diisopropylethylamine DMA - Dimethylacetamide DMAP - 4-dimethylaminopyridine DMF - N,N-dimethylformamide DMSO - Dimethyl Sulfoxide ee - enantiomeric 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 - trimethylsilyl chloride XantPhos - 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0337] experiment Experiment 1. TEAD inhibition TEAD inhibition was analyzed using the Hippo pathway TEAD reporter—an MCF-7 cell line (BPS Biosciences, catalog number 60618) containing a firefly luciferase gene under the control of a 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 using the ONE-Glo Luciferase Assay System (Promega) and plate readings with an Enspire Multimode Plate Reader (PerkinElmer).

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

[0339] The compounds of the present invention were screened using the above assays, and the IC 50 The values ​​are listed in Table 1 below, where "A" indicates an IC of less than 50 nM. 50 "B" indicates IC values ​​in the range of 50-300 nM 50 values ​​are shown, and "C" indicates IC values ​​in the range of 301 nM to 2000 nM. 50 Indicates the value.

[0340] [Table 57]

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, A is phenyl, pyridyl, or cyclohexyl; L is —O—; 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 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 together with the carbon atoms to which they are attached 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 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 attached form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms; B is the following group: 【Chemistry 2】 (However, when B is ring (2), (4), (20), (21), (23) or (25), R 1 is C 1-7 alkoxy) either R 6 and R 9 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 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 alkylcarbonyl; R 23 , R 24 , R 27 , R 28 , R 29 , R 31 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 and R44 are independently hydrogen or C 1-7 is alkyl; R 30 is C 1-7 Alkyl, C 1-7 Alkylcarbonyl or —SO 2 C 1-7 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; At each occurrence, the optional substitution is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 1 to 2 substituents independently selected from alkoxy and oxo; However, the compound of formula (Ia) N-[4-methyl-3-[(4-methyl-2-pyridinyl)oxy]phenyl]-5-oxo-2-pyrrolidinecarboxamide; 1-ethyl-5-oxo-N-(3-phenoxyphenyl)-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. 2. The compound according to claim 1, wherein B is ring (1a), (3), (4), (6), (8), (9), (10), (11), (12), (13), (16), (17) or (18).

3. 3. The compound according to claim 2, wherein B is ring (1a), (4), (10), (11), (12), (13), (16) or (17).

4. The compound according to claim 3, wherein B is ring (1a), (10), (11) or (12).

5. The compound according to claim 4, wherein B is ring (1a) or (12).

6. R 7 and R 8 The compound according to claim 1, wherein is hydrogen.

7. R 6 But hydrogen, C 1-7 Alkyl or C 3-7 The compound of claim 1 which is cycloalkyl.

8. R 6 is —C(O)—Rx, and Rx is C 1-7 The compound of claim 1, 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.

9. R 20 is hydrogen and R 18 is C 1-7 Alkyl or C 3-7 The compound of claim 1 which is cycloalkyl.

10. R 21 is hydrogen or C 1-7 The compound of claim 1, wherein the aryl group is alkyl.

11. R 1 But hydrogen, C 1-7 2. The compound of claim 1, which is alkoxy or halogen.

12. R 1 But C 1-7 12. The compound of claim 11, which is alkoxy or halogen.

13. R 1 is C 1-7 13. The compound of claim 12, which is alkoxy.

14. R 2 But hydrogen, C 1-7 2. The compound of claim 1, which is alkoxy or halogen.

15. R 2 The compound according to claim 14, wherein is hydrogen or halogen.

16. R 2 16. The compound of claim 15, wherein is hydrogen.

17. R 3 is hydrogen, halogen or C 1-7 The compound of claim 1 which is alkoxy.

18. R 3 is hydrogen or C 1-7 18. The compound of claim 17, which is alkoxy.

19. R 3 19. The compound of claim 18, wherein is hydrogen.

20. R 1 and R 3 together with the carbon atoms 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.

21. R 1 and R 3 together with the carbon atom to which they are attached form a 5- to 6-membered ring having 1 to 2 heteroatoms independently selected from O and N as ring atoms.

22. R 1 and R 3 together with the carbon atoms to which they are attached form a 5- to 6-membered ring having 1 to 2 heteroatoms, the heteroatoms being O.

23. R 4 But hydrogen, halogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen C 1-7 Alkyl or halogen C 1-7 Alkoxy, and R 5 But hydrogen, C 1-7 Alkyl, C 1-7 2. The compound of claim 1, which is alkoxy, cyano, amino, or halogen.

24. A is phenyl or pyridyl; L is —O—; R 1 is C 1-7 is 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 of claim 1, wherein the aryl group is alkyl.

25. The compound is N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 1); 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-oxooxazolidine-4-carboxamide (Compound 87) N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-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-oxooxazolidine-4-carboxamide (compound 101); (S)—N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxooxazolidine-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)pyridin-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)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 128); (S)-1-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 129); (S)—N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 130); 3-cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 131); 1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-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)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 152); N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 153); (R)—N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 154); (S)—N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 156); (S)—N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 157); 3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 159); (R)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 162); (S)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 163); 3-cyclopropyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 164); (S)-1-Cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (Compound 165); (R)-1-cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 166); 3-ethyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 167); (S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 168); (R)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 170); (S)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 171); (R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 175); 3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)chroman-8-yl)imidazolidine-4-carboxamide (compound 176); 1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)chroman-8-yl)pyrrolidine-2-carboxamide (compound 177); 3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidine-4-carboxamide (compound 178); 1-cyclopropyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)pyrrolidine-2-carboxamide (compound 179); (S)-3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]dioxol-4-yl)imidazolidine-4-carboxamide (compound 180); 3-methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridin-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)pyridin-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)imidazolidine-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)imidazolidine-4-carboxamide (compound 192); (R)—N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-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-oxooxazolidine-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)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-carboxamide (compound 216); (R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-carboxamide (compound 217); N-(5-(3,4-dichlorophenoxy)-2-methoxyphenyl)-1-methyl-5-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-(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)pyridin-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)pyridin-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-((4,4-dimethylcyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 296); 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)pyridin-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)pyridin-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)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 351); N-(3-chloro-5-((5-trifluoromethyl)pyridin-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)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 361); (S)—N-(3-fluoro-5-((5-(trifluoromethyl)pyridin-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); (R)—N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazol-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)pyridin-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 399); N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 400); (S)—N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 401); (R)—N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 402); (S)—N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 403); 1-Glycyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, HCl (compound 414); or a tautomer or a pharmaceutically acceptable salt thereof The compound according to claim 1, wherein

26. A medicament comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. 【Transformation 3】 (In the formula, A is phenyl, pyridyl, or cyclohexyl; L is —O—; 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 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 together with the carbon atoms to which they are attached 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 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 attached form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms; B is the following group: 【Chemistry 4】 (However, when B is ring (2), (4), (20), (21), (23) or (25), R 1 is C 1-7 alkoxy) either R 6 and R 9 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 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 alkylcarbonyl; R 23 , R 24 , R 27 , R 28 , R 29 , R 31 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 and R44 are independently hydrogen or C 1-7 is alkyl; R 30 is C 1-7 Alkyl, C 1-7 Alkylcarbonyl or —SO 2 C 1-7 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; At each occurrence, the optional substitution is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 and 1 to 2 substituents independently selected from alkoxy and oxo.

27. 27. The pharmaceutical agent of claim 26 for use in treating a disease or condition in which inhibition of TEAD is desired.

28. The pharmaceutical composition according to claim 27, wherein the disease is cancer or chronic pain.

29. The pharmaceutical composition according to claim 28, wherein the cancer is mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, stomach cancer, liver cancer, lung cancer, or colon cancer.

30. The pharmaceutical composition according to claim 28, wherein the chronic pain is chronic neuropathic pain or chronic musculoskeletal pain.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 together with a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier. 【Transformation 5】 (In the formula, A is phenyl, pyridyl, or cyclohexyl; L is —O—; 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 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 together with the carbon atoms to which they are attached 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 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 attached form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms; B is the following group: 【Transformation 6】 (However, when B is ring (2), (4), (20), (21), (23) or (25), R 1 is C 1-7 alkoxy) either R 6 and R 9 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 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 alkylcarbonyl; R 23 , R 24 , R 27 , R 28 , R 29 , R 31 , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 and R44 are independently hydrogen or C 1-7 is alkyl; R 30 is C 1-7 Alkyl, C 1-7 Alkylcarbonyl or —SO 2 C 1-7 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; At each occurrence, the optional substitution is C 1-7 Alkyl, halogen, halogen C 1-7 Alkyl, C 1-7 and 1 to 2 substituents independently selected from alkoxy and oxo.

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